USP Veterinary Pharmaceutical Information Monographs

volume 26 supplement 2 october 2003

USP Veterinary Pharmaceutical Information Monographs – Antibiotics

USP VETERINARY PHARMACEUTICAL INFORMATION MONOGRAPHS – ANTIBIOTICS

CONTENTS

v Introduction

1 Aminoglycosides (Veterinary—Systemic)

33 Aminopenicillins (Veterinary—Intramammary-Local)

36 Aminopenicillins (Veterinary—Systemic)

46 Amoxicillin and Clavulanate (Veterinary—Systemic)

51 Cephalosporins (Veterinary—Systemic)

71 Cephapirin (Veterinary—Intramammary-Local)

74 Chloramphenicol (Veterinary—Systemic)

79 Erythromycin (Veterinary—Intramammary-Local)

81 Florfenicol (Veterinary—Systemic)

87 Fluoroquinolones (Veterinary—Systemic)

109 Lincosamides (Veterinary—Systemic)

119 Macrolides (Veterinary—Systemic)

144 Metronidazole (Veterinary—Systemic)

149 Penicillin G (Veterinary—Intramammary-Local)

151 Penicillin G (Veterinary—Systemic)

161 Pirlimycin (Veterinary—Intramammary-Local)

164 Potentiated Sulfonamides (Veterinary—Systemic)

185 Pyrimethamine (Veterinary—Systemic)

191 Rifampin (Veterinary—Systemic)

202 Spectinomycin (Veterinary—Systemic)

207 Sulfonamides (Veterinary—Systemic)

225 Tetracyclines (Veterinary—Systemic)

253 Indications Index

257 Dosing Index

262 Veterinary Brand and Generic Name Index

269 Human Brand and Generic Name Index

Introduction

WHAT’S DIFFERENT ABOUT A USP DRUG INFORMATION

MONOGRAPH

The Veterinary Medicine Expert Committee on Drug Information

gratefully acknowledges the financial support of its parent organiza-

tion, the United States Pharmacopeia, to publish these monographs. It

also is appreciative to the Food Animal Residue Avoidance Databank

(FARAD) for supplying slaughter and milk withdrawal information

where extra-label drug use in food animals is noted. This information is

provided in cooperation with MICROMEDEX, a Thomson Healthcare

Company.

USP history, organizational structure, and publications

In pursuit of its mission to promote public health, the United States

Pharmacopeia (USP) develops authoritative information about the

appropriate use of medicines, including those used in animals. This

non-government, not-for-profit organization draws on a long-standing

dedication to public involvement in the establishment of scientific

standards. USP achieves its goals through the contributions of

volunteers representing health care professions, as well as science,

academia, the U.S. government, the pharmaceutical industry, and

consumer organizations.

USP was established in 1820 with the primary goal of setting standards

for the identity, strength, and quality of medicinal compounds and this

remains at the core of the organization. Currently, USP provides

standards for more than 3,800 prescription and non-prescription

drugs, nutritional and dietary supplements, veterinary drugs, and

health care products. These standards are published in the United

States Pharmacopeia (USP) and the National Formulary (NF), which are

officially recognized in the Federal Food, Drug, and Cosmetic Act (21

U.S.C. § 321 et seq.). USP also produces Reference Standards, which

are an integral part of USP’s standards program.

The development of USP information on the best use of medications was

begun in 1970, growing out of the public process of developing quality

standards. USP information advisory panels were created to assure

that the information under development is evidence-based, consensus-

established, practical, and clinically relevant. This work was expanded

into a separate public health program and in 1980, the first USP DI�

was published. Today, in association with MICROMEDEX, USP

continues to provide oversight and approval of drug information

content in the USP DI� database, which covers nearly all medicines in

the U.S. and Canada.

The veterinary drug information monograph creation process

Very soon after the USP DI� was first published, an advisory panel on

veterinary medicine was created. Since 1982, veterinary pharmacol-

ogists, veterinary pharmacists, and other specialists have contributed

their time and expertise in creating and revising drug information

through USP’s unique process. This drug information is developed by

exhaustive compilation of approved product label information and also

collection and analysis of publicly available data on each drug from

research studies and clinical reports. Careful attention is paid to

differentiating species-specific information. With the agreement of

MICROMEDEX, information from the human USP DI� database is

included where it may be helpful. Each draft chapter or monograph is

then put through a review process that includes USP Veterinary

Medicine Committee members, regulatory representatives, pharma-

ceutical manufacturers, ad hoc specialists, and public review. At

present, USP monographs are the only drug information source in

veterinary medicine undergoing such extensive expert review,

a process through which the credibility of the information is

maintained.

USP drug information is a work-in-progress. The information is in

constant revision and is a continuous collection of the current

judgments of experts in the use of medications. The following chapters

have been developed over 7 years, with information added and revised,

as necessary.

Unique features

This special issue of the Journal of Veterinary Pharmacology and

Therapeutics contains a series of drug information monographs on

antimicrobials used in veterinary medicine. What makes this

information different from other sources of veterinary drug informa-

tion? A succinct listing would include:

• The incorporation of extra-label and label indications and dosages

for all domestic species. See the section below, ‘‘Finding the specific

drug information you need; Label and extra-label uses,’’ for details

on how this information is differentiated.

• The inclusion of slaughter and milk withdrawals when extra-label

drug use in food animals is considered an acceptable option for

therapy. Withdrawal times have been provided by FARAD for the

specified conditions noted.

• The inclusion of information about both U.S. and Canadian

veterinary drug products.

• The grouping of indications into three categories. The ‘‘Accepted’’

category indicates that clear evidence exists to support use of the

drug for a particular purpose. ‘‘Acceptance not established’’

(potentially useful) indicates that use of the drug for an indication

may be worthy of consideration if superior therapies do not exist,

but the evidence is either scant or subject to concern based on

experimental design. If a use is viewed as ineffective or has been

replaced by clearly superior therapies, the indication is deemed

‘‘Unaccepted.’’ These categorizations are applied to label and extra-

label uses.

• The use of tables of scientific evidence to address controversial issues

during the review process, particularly relative to extra-label drug

use.

• Review of the information by a Food and Drug Administration (FDA)

liaison to the committee. Although comments made by the FDA are

taken quite seriously, those opinions are nonbinding on the USP.

The information contained in these monographs should not be

considered an endorsement or ‘‘acceptance’’ by the FDA as to a

given use or dosage.

• The review of each monograph by the USP Veterinary Medicine

Committee. This committee consists of 10 to 15 volunteers

recognized as experts in pharmacology, internal medicine, or species

discipline(s).

Introduction v

� 2003 Thomson MICROMEDEX All rights reserved

Finding the specific drug information you need

Label and extra-label uses

The Indications section of each drug monograph is designed to provide

information about indications in drug product labeling in the U.S. and

Canada. Extra-label indications for which clinical and research data

have been evaluated are also included. Indications found in product

labeling are listed first. Brackets around an indication signify that it is

not found in any product labeling in the U.S. at the time of last major

revision. Some indications are followed by a superscript 1, meaning

they are not included in Canadian product labeling.

Examples of bracket and superscript 1 placement in the monographs:

[Pneumonia, bacterial (treatment)] An extra-label use in the U.S.

An indication is included in

Canadian product labeling.

Pneumonia, bacterial (treatment)1 An indication found in U.S.

product labeling but not in


[Pneumonia, bacterial (treatment)]1 An extra-label use in both the

U.S. and Canada.

Species and dosage forms

Within each category of the Indications section the information is arranged

in a hierarchy as follows: indication, followed by the species to which

that indication applies, and finally the dosage forms used in that species

for that indication. You will see that some species and dosage forms are

also given bracket and superscript 1 designations; these have the same

meaning for species and dosage forms as described above for indications.

To decrease clutter and confusion, only the highest level of the hierarchy

is given a bracket or superscript 1 (indication > species > dosage form).

That is, if the indication is not found on any label in the U.S. (a

bracketed, extralabel use) then the species under it will not be bracketed

because it is obvious that no species are on the label of any product in the

United States for this indication.

Dosing

In the USP veterinary drug information monographs, dosage forms are

always listed separately to provide an opportunity to list specific

information for each type of product. In the Dosage Forms section,

indications and species are bracketed or given a superscript 1 following

the same rules applied in the Indications section, except that they reflect

the labeling of the specific dosage form. Dosages listed are not always

label dosages even if the species is in the product labeling.

Label and extra-label withdrawal times

Established withdrawal times from product labeling are listed in theWithdrawal

times tables for each dosage form labeled for use in food-producing animals.

But be sure to consult the approved labeling on the product you are using for

the specific government established dose and withdrawal time.

Extra-label withdrawal times are listed in the Withdrawal times section for

each extra-label use and/or dose recommended for food-producing animals.

As always, veterinarians will use their own clinical judgment, following the

guidelines of the Animal Medicinal Drug Use Clarification Act, to determine

a safe extra-label withdrawal time.

Cory Langston, DVM, PhD, DACVCP

Chair, USP Veterinary Medicine Expert Committee on Drug

Information

ACKNOWLEDGEMENTS

The following individuals are recognized for their contributions and

support towards the production of this body of work:

USP Staff

Roger Williams, MD (CEO and Executive Vice President, USP)

Ian DeVeau, PhD (Senior Scientist, Veterinary Drugs, Information and

Standards Development, USP)

Amy S. Neal, DVM (USP consultant, writer and editor)

Jerome A. Halperin, BS, MPH, MS (former CEO and Executive Vice

President, USP)

Keith Johnson (former Director, Drug Information Division, USP)

David Nash, DVM (former Director, Veterinary Medicine, Information

and Standards Development, USP)

E. Kathryn Meyer, VMD (former Drug Information Specialist and

Coordinator, Veterinary Practitioners’ Reporting Program,

USP)

2000 to 2005 Veterinary Medicine Committee

Cory Langston, DVM, PhD, DACVCP, Chair

Michael D. Apley, DVM, PhD, BS, DACVCP

Dawn M. Boothe, BS, MS, DVM, PhD, DACVCP, DACVIM

Terrence P. Clark, DVM, PhD, DACVCP

Gigi F. Davidson, BS, RPh, DICVP

Patricia Dowling, DVM, MS, DACVIM, DACVCP

Douglas T. Kemp, PharmD, DICVP

Mark G. Papich, DVM, MS, BS, DACVCP

M. Gatz Riddell, DVM, MS

Jim E. Riviere, DVM, PhD, MS, BS

Roderick C. Tubbs, DVM, PhD

Jeff R. Wilcke, DVM, MS, DACVCP

1995 to 2000 Veterinary Medicine Advisory Panel

Cory Langston, DVM, PhD, DACVCP, Chair

Michael D. Apley, DVM, PhD, BS, DACVCP

Gordon Brumbaugh, DVM, PhD, DACVCP

Thomas Burkgren, DVM, MBA

Cynthia T. Culmo, RPh

Lloyd E. Davis, PhD, DVM

Patricia Dowling, DVM, MS, DACVIM, DACVCP

Stuart Forney, RPh, MS

Antoinette D. Jernigan, DVM, PhD, DACVCP

Mark G. Papich, DVM, MS, DACVCP

Thomas E. Powers, DVM, PhD

Jim E. Riviere, DVM, PhD

Charles R. Short, DVM, PhD, DACVCP

Hector Sumano Lopez, DVM, PhD


1990 to 1995 Veterinary Medicine Advisory Panel

Lloyd E. Davis, DVM, PhD, Chair

Arthur L. Aronson, DVM, PhD

Gordon Brumbaugh, DVM, PhD, DACVCP

Gordon L Coppoc, DVM, PhD

Sidney A. Ewing, DVM, PhD

Stuart D. Forney, RPh, MS

William G. Huber, DVM, PhD

William L. Jenkins, DVM, PhD, DACVCP

vi Introduction


Cory Langston, DVM, PhD, DACVCP

Mark G. Papich, DVM, MS, DACVCP

John W. Paul, DVM, PhD

Thomas E. Powers, DVM, PhD, DACVCP

Charles R. Short, DVM, PhD, DACVCP

Richard H. Teske, DVM, PhD


1985 to 1990 Panel on Veterinary Medicine

Lloyd E. Davis, PhD, DVM, Chair


Nicholas H. Booth, DVM, PhD




Diane K. Gerken, DVM, PhD


William L. Jenkins, DVM, PhD

Robert W. Phillips, DVM, PhD


Charles R. Short, DVM, PhD


Jeff R. Wilcke, DVM, MS

1983 to 1985 Panel on Veterinary Medicine

Lloyd E. Davis, PhD, DVM, Chair

H. Richard Adams, DVM, PhD


Nicholas H. Booth, DVM, PhD


George T. Edds, DVM, PhD


Peter A. Eyre, BVMS, PhD



Robert W. Phillips, DVM, PhD


I.A. Schipper, DVM, PhD


For more information about USP Veterinary Pharmaceutical

Information monographs you may contact:

Ian F. DeVeau, PhD

United States Pharmacopeia

12601 Twinbrook Parkway

Rockville, Maryland 20852

United States

Telephone number: 1-301-881-0666

E-mail: [email protected]

www.usp.org

Introduction vii


AMINOGLYCOSIDES Veterinary—Systemic

This monograph includes information on the following aminoglycoside

aminocyclitols: Amikacin; Dihydrostreptomycin*; Gentamicin; Kana-

mycin�; Neomycin; Streptomycin�. It also contains information on the

following aminocyclitol: Apramycin.

Some commonly used brand names are:

Note: For a listing of dosage forms and brand names by country

availability, see the Dosage Forms section(s).

CATEGORY:Antibacterial (systemic).

INDICATIONSNote: Bracketed information in the Indications section refers to uses that

either are not included in U.S. product labeling or are for products not

commercially available in the U.S.

GENERAL CONSIDERATIONSAminoglycosides are utilized primarily in the treatment of infections

caused by aerobic gram-negative organisms{R-107; 108; 116}. They are

not active against anaerobic organisms. In addition to their strength in

the treatment of gram-negative pathogens, aminoglycosides can be

effective against some gram-positive organisms, such as Staphylococcus

aureus{R-107; 108}, some mycobacteria{R-116; 124}, some mycoplasma

strains{R-116}, and some spirochetes{R-263}. They are sometimes

administered concurrently with other antibacterials for a possible

synergistic effect. However, the use of aminoglycosides in the

treatment of infection in animals has been tempered by toxicity

considerations in the animal treated{R-116}. Often, systemic use is

limited to the treatment of serious gram-negative infections resistant to

less toxic medications. Also, local environment at the therapeutic site

can affect the efficacy of these drugs, acidic or purulent conditions can

hamper their effect{R-5; 7; 20; 116; 160}, and the presence of cations

(calcium or magnesium ions, for example) can decrease antibacterial

effect{R-266}.

Streptomycin was the earliest aminoglycoside introduced{R-116}. It is

active against mycobacteria, Leptospira{R-243; 244}, Francisella tularen-

sis, and Yersinia pestis, but only some mycoplasma, gram-negative

organisms, and Staphylococcus species{R-116}. Dihydrostreptomycin is

chemically very similar to streptomycin{R-116}. The introduction of

newer aminoglycosides has eclipsed the significance of dihydrostrep-

tomycin and streptomycin in the face of increasing bacterial resis-

tance{R-122; 235; 239}, although some dosage forms of these medications

are still available.

Neomycin became available for use a few years after streptomycin.

Neomycin has been effective against many gram-negative organisms

and Staphylococcus aureus{R-116}. However, the use of neomycin is

limited by a relatively high risk of toxicity with systemic use{R-116}; it is

not available for parenteral administration.

Kanamycin was introduced as a less toxic alternative to older amino-

glycosides and was soon followed by gentamicin and later by

amikacin{R-116}. The spectrum of activity of kanamycin primarily

focuses on gram-negative organisms and a few gram-positive organ-

isms{R-93}. The prevalence of resistance of some pathogens, including

Escherichia coli and Salmonella species, to kanamycin is higher than to

gentamicin{R-108; 109–113; 144}, and this has limited the use of

kanamycin. The use of kanamycin has also been eclipsed by the

derivation of amikacin, a drug with a very similar pharmacokinetic

profile{R-178} but superior activity against pathogens such as Pseudo-

monas species and kanamycin-resistant Enterobacteriaceae{R-178}.

Gentamicin has been widely used in the treatment of gram-negative

organisms and some gram-positive organisms{R-5}. As with other

aminoglycosides, use is limited by risk of toxicity. In vitro tests have

shown gentamicin to be active against Salmonella arizonae (Arizona

hinshawii){R-7}, Enterobacter aerogenes{R-7; 125}, E. coli{R-1; 5; 7; 125},

Klebsiella species{R-1; 5; 7; 125}, Neisseria{R-1; 5; 7; 125}, most indole-

positive and some indole-negative Proteus species{R-1; 5; 7; 125}, some

Pasteurella multocida{R-122; 127}, Pseudomonas aeruginosa{R-1; 5; 7; 125},

Salmonella{R-1; 5; 7; 125}, Serratia marcescens{R-1; 5; 7; 125}, Shigella{R-1;

5; 7; 125}, Staphylococcus species{R-1; 5; 7; 109–111; 123; 125}, including

Staphylococcus intermedius{R-109–111}, and some Streptococcus species{R-1;

5; 7; 125}.

Amikacin was developed from kanamycin and has the broadest spectrum

of activity of the aminoglycosides{R-37}. It is considered effective

against strains not susceptible to other aminoglycosides because it

resists some aminoglycoside inactivating enzymes{R-91; 137; 178}. In

addition to those organisms listed above for gentamicin, in vitro tests

have shown amikacin to be effective against E. coli, Klebsiella and

Pseudomonas species resistant to gentamicin{R-143; 266}, Citrobacter

freundii, Listeria monocytogenes, and Providencia species{R-91; 92}. There

are reports in the U.S. and abroad of some in vitro resistance to

Amifuse E [Amikacin] Gen-Gard [Gentamicin]

Amiglyde-V [Amikacin] Genta-fuse [Gentamicin]

Amiglyde-V Injection [Amikacin] GentaMax 100 [Gentamicin]

Amiglyde-V Intrauterine Solution

[Amikacin]

GentaVed 50 [Gentamicin]

Amiject D [Amikacin] GentaVed 100 [Gentamicin]

Amikacin C Injection [Amikacin] Gentocin [Gentamicin]

Amikacin E Solution [Amikacin] Gentocin Solution [Gentamicin]

AmTech AmiMax C Injection [Amikacin] Gentocin Solution Injectable

[Gentamicin]

AmTech AmiMax E Solution [Amikacin] Gentozen [Gentamicin]

AmTech GentaMax 100 [Gentamicin] Kantrim [Kanamycin]

AmTech Gentamicin Sulfate Pig

Pump Oral Solution [Gentamicin]

Legacy [Gentamicin]

AmTech Gentapoult [Gentamicin] Neo-325 [Neomycin]

AmTech Neomycin Oral Solution

[Neomycin]

Neomed 325 [Neomycin]

Apralan [Apramycin] Neomix 325 [Neomycin]

Apralan Soluble [Apramycin] Neomix AG 325 [Neomycin]

Biosol Liquid [Neomycin] Neomix AG 325 Medicated

Premix [Neomycin]

CaniGlide [Amikacin] Neomix Soluble Powder [Neomycin]

Equi-Phar EquiGlide [Amikacin] Neomycin 200 [Neomycin]

Ethamycin [Dihydrostreptomycin] Neomycin 325 [Neomycin]

Garacin Pig Pump [Gentamicin] Neo-Sol 50 [Neomycin]

Garacin Piglet Injection [Gentamicin] Neosol-Oral [Neomycin]

Garacin Soluble Powder [Gentamicin] Neosol Soluble Powder [Neomycin]

Garasol Injection [Gentamicin] Neoved 200 [Neomycin]

Garasol Pig Pump Oral Solution

[Gentamicin]

Neovet 325/100 [Neomycin]

Garasol Solution Injectable [Gentamicin] Neovet Neomycin Oral Solution

[Neomycin]

*Not commercially available in the U.S. as a single entity.

�Not commercially available in Canada as a single entity.

AMINOGLYCOSIDES Veterinary—Systemic 1


gentamicin and other aminoglycosides by Salmonella species{R-113;

117–119}, but the strains tested are still susceptible to amikacin{R-118;

199; 250}.

Apramycin is an aminocyclitol antibiotic with a chemical structure very

similar to that of the aminoglycosides but different enough to leave it

unaffected by many aminoglycoside inactivating enzymes{R-245}. At

low concentrations, apramycin is more effective in inhibiting bacterial

protein synthesis than kanamycin A, streptomycin, amikacin, or

gentamicin{R-96}. Apramycin is active against Staphylococcus aureus,

many gram-negative organisms, and some mycoplasma strains{R-163}.

Apramycin has been reported to be effective in vitro against E. coli and

Salmonella species{R-96; 164} that are resistant to streptomycin and

neomycin{R-167; 173}.

Resistance to aminoglycosides is produced primarily by enzymes encoded

by genes located on bacterial plasmids{R-116; 168}. The enzymes act

inside the bacterium to modify the aminoglycoside, thereby preventing

it from binding to ribosomes{R-116; 168}. This type of plasmid-

associated resistance is transferable between bacteria. A single type

of plasmid may confer cross-resistance to multiple aminoglyco-

sides{R-116; 117; 120; 145} and also resistance to other unrelated

antimicrobials{R-7; 114; 115; 120; 145; 168}. In some cases, a single

plasmid gene encoding for one enzyme, an acetyltransferase, may

confer resistance to several aminoglycosides{R-171}. For example, the

enzyme aminoglycoside 3-N-acetyltransferase IV allows the bacterium

to be resistant to apramycin, gentamicin, netilmicin, and tobramy-

cin{R-171}. A single bacterial isolate may have any one of a variety of

combinations of resistance to different antibiotics conferred by the

particular plasmid it carries{R-168}. As an example, an E. coli strain

may be resistant to ampicillin, apramycin, chloramphenicol, gentami-

cin, kanamycin, sulfonamide, streptomycin, tetracycline, and trimeth-

oprim{R-168}. Other E. coli isolates cultured from the same geographic

region may carry resistance to a few or many of the same antibiotics in

different combinations{R-168}. The nature of resistance in organisms

such as E. coli and Salmonella species has been a focus of international

research because of concerns about potential transferance of antimi-

crobial resistance from animal to human pathogens{R-168–172}.

Bacteria may also utilize other methods of reducing the efficacy of

aminoglycosides. Some strains of bacteria are less permeable to

aminoglycosides, requiring much higher concentrations of aminogly-

cosides to kill them and, therefore, can be selected during treatment{R-116}.

Resistance developed by chromosomal resistance is minimal and

develops slowly for most of the aminoglycosides, with the exception of

streptomycin or dihydrostreptomycin; resistance to streptomycin can

occur from a single-step mutation{R-116}.

ACCEPTEDBacteremia (treatment); or

Septicemia (treatment)—Cats and dogs: Kanamycin sulfate injec-

tion1{R-93}, [amikacin injection]1{R-264}, and [gentamicin injection]1{R-7}

are indicated in the treatment of bacteremia or septicemia caused

by susceptible organisms.

Bone and joint infections (treatment)1—Cats and dogs: Kanamycin

sulfate injection{R-93}, [amikacin injection]1{R-264}, and [gentamicin

injection]{R-264} are indicated in the treatment of bone and joint

infections caused by susceptible organisms{R-93}.

Enteritis (treatment)—The primary treatment for enteritis in many

cases is aggressive fluid replacement. Treatment of enteritis with

antimicrobials should rely on a specific diagnosis and knowledge of

pathogen susceptibility.

Calves1: Neomycin sulfate for medicated feed is indicated in the

control and treatment of enteritis caused by susceptible Escherichia

coli{R-94}. Streptomycin oral solution{R-181; 182} is indicated in the

treatment of bacterial enteritis caused by susceptible organisms.

Cattle and sheep: Neomycin sulfate for medicated feed1, neomycin

sulfate powder for oral solution{R-97; 104} and neomycin sulfate oral

solution{R-98; 103} are indicated in the control and treatment of

bacterial enteritis caused by susceptible Escherichia coli. If systemic

signs develop, medications that are well absorbed systemically should

be considered for addition to or substitution for therapy with this

medication{R-98}.

Chickens: [Neomycin oral powder]{R-104}, [neomycin oral solution]{R-103},

and streptomycin1 {R-181; 182} are indicated in the control and

treatment of bacterial enteritis in chickens.

Goats1: Neomycin sulfate for medicated feed, neomycin sulfate powder

for oral solution{R-97; 104} and neomycin sulfate oral solution{R-98;

103} are indicated in the control and treatment of bacterial enteritis

caused by susceptible Escherichia coli. If systemic signs develop,

medications that are well absorbed systemically should be considered

for addition to or substitution for therapy with this medication{R-98}.

Kids1 and lambs1: Neomycin sulfate for medicated feed{R-94} is

indicated in the control and treatment of bacterial enteritis caused

by susceptible Escherichia coli.

Piglets: Apramycin sulfate powder for oral solution1{R-95}, gentamicin

injection{R-7; 9; 125}, gentamicin powder for oral solution1 {R-15},

gentamicin oral solution{R-11; 14}, neomycin sulfate for medicated

feed1{R-94}, neomycin sulfate oral solution{R-98; 103}, neomycin sulfate

powder for oral solution{R-97; 104}, [dihydrostreptomycin]{R-106}, and

streptomycin{R-181; 182} are indicated in the control and treatment of

enteritis (weanling pig scours) in piglets caused by susceptible E. coli.

If systemic signs develop, medications that are well absorbed

systemically should be considered{R-98}.

Pigs1: Neomycin sulfate for medicated feed is indicated in the control

and treatment of enteritis (weanling pig scours) in piglets caused by

susceptible E. coli{R-94}.

[Horses]: Neomycin sulfate powder for oral solution{R-97; 104} and

neomycin sulfate oral solution{R-103} are indicated in the control and

treatment of bacterial enteritis caused by susceptible Escherichia coli.

If systemic signs develop, medications that are well absorbed

systemically should be considered for addition to or substitution for

therapy with this medication.

[Turkeys]: Neomycin sulfate powder for oral solution{R-104} and

neomycin oral solution{R-103} are indicated in the control and

treatment of bacterial enteritis in turkeys.

E. coli infection (treatment)—

Chicks, 1-day-old: Gentamicin injection{R-7; 8} is indicated in the pre-

vention of early mortality in chicks caused by susceptible E. coli.

Turkeys, growing1: Neomycin sulfate powder for oral solution is

indicated in the control of mortality associated with susceptible E. coli

in growing turkeys{R-2}.

Paracolon (treatment)—Turkey poults, 1- to 3-day-old: Gentamicin

injection{R-7; 8} is indicated in the treatment of infections in turkeys

caused by susceptible Salmonella arizonae.

Pseudomonas aeruginosa infection (treatment); or

Salmonella typhimurium infection (treatment)—Chicks, 1-day-old: Genta-

micin injection{R-7; 8} is indicated in the prevention of early mortality

2 AMINOGLYCOSIDES Veterinary—Systemic


in chicks caused by suceptible Pseudomonas aeruginosa, and Salmonella

typhimurium.

Respiratory tract infections, bacterial (treatment)—Cats and dogs: Gen-

tamicin injection{R-4; 7}, kanamycin injection1{R-93}, and [amikacin

injection]1{R-264} are indicated in the treatment of susceptible respi-

ratory tract infections, including pneumonia and upper respiratory

tract infections.

Skin and soft tissue infections, bacterial (treatment)—

Cats: Gentamicin injection{R-4; 7; 123}, kanamycin injection1{R-93}, and

[amikacin injection{R-139; 140; 264}]1 are indicated in the treatment

of susceptible skin and soft tissue infections.

Dogs: Amikacin injection1{R-91}, gentamicin injection{R-4; 7}, and

kanamycin injection1{R-93} are indicated in the treatment of suscep-

tible skin and soft tissue infections. In the case of staphyloccocal

dermatitis, although the in vitro susceptibility of canine Staphylococ-

cus intermedius to gentamicin is persistently high{R-109–111}, practical

administration and toxicity considerations with long-term therapy

have limited the usefulness of aminoglycosides{R-109}.

Swine dysentery (treatment)1—Pigs: Gentamicin powder for oral solu-

tion{R-15} and gentamicin oral solution{R-11} are indicated in the

treatment of swine dysentery caused by susceptible Treponema hyody-

senteriae.

Urinary tract infections, bacterial (treatment)—

Cats: Gentamicin injection{R-4; 7}, kanamycin injection1 {R-93}, and

[amikacin injection{R-139; 140; 264}]1 are indicated in the treatment

of urinary tract infections, such as cystitis, caused by susceptible

organisms.

Dogs: Amikacin injection1{R-4; 7}, gentamicin injection{R-4; 7}, and

kanamycin injection1{R-93} are indicated in the treatment of urinary

tract infections caused by susceptible organisms.

Uterine infections, bacterial (treatment)—

Cats: Kanamycin injection1{R-93}, [amikacin injection{R-139; 140; 264}]1,

and [gentamicin injection{R-264}]1 are indicated in the treatment of

endometritis in cats{R-93}.

Dogs: Kanamycin injection1{R-93}, [gentamicin injection{R-7}], and

[amikacin injection{R-264}]1 are indicated in the treatment of uterine

infections (metritis) in dogs caused by susceptible organisms.

Horses: Amikacin uterine solution{R-92}, gentamicin uterine infusion{R-1},

and gentamicin injection{R-4; 7} are indicated in the control of

bacterial infections of the uterus caused by susceptible organisms.

ACCEPTANCE NOT ESTABLISHEDDistemper, canine (treatment)1—Dogs: U.S. product labeling includes

the use of kanamycin in the treatment of bacterial complications of

canine distemper{R-93}. This use may be appropriate for bacterial

infections that are susceptible to kanamycin; however, it is not

considered more appropriate or more generally accepted than other

antimicrobials in the treatment of bacterial infections associated

with viral infections.

Gastrointestinal infections (treatment)1;

Mastitis (treatment)1;

Otitis media (treatment)1; or

Pancreatitis (treatment)1—Cats and dogs: U.S. product labeling for

kanamycin includes use in the treatment of gastrointestinal infections,

mastitis, otitis media, and pancreatitis in cats and dogs{R-93}; however,

based on current knowledge about tissue penetration and pathogen

susceptibility, there are more appropriate antibiotics for use in the

treatment of these infections.

Infections, bacterial (treatment)—

[Calves]1 and [cattle]1: The extralabel use of aminoglycosides in cattle

has been strongly discouraged because of the long duration of drug

residues in some tissues (see the Regulatory Considerations section).

However, in the case of bacterial infections susceptible to gentamicin

in cattle that will not be used for food production, there are

pharmacokinetic data available to estimate dosing for amikacin in

calves{R-141; 144} and gentamicin in calves and cattle{R-21; 22; 25}.

Use of aminoglycosides should be restricted to susceptible bacterial

infections caused by pathogens resistant to antimicrobials that are

less likely to produce prolonged residues.

[Donkeys]1, [foals]1, [horses]1, and [ponies]1: Although the safety and

efficacy have not been established, amikacin has been recommended

in the treatment of susceptible bacterial infections in donkeys, foals,

horses (systemic administration), and ponies, based on pharmaco-

kinetic studies{R-130–132; 136; 137} and in vitro antimicrobial suscep-

tibility of common pathogens{R-159; 253}.

Although the safety and efficacy have not been established,

gentamicin has been recommended in the treatment of susceptible

bacterial infections in foals and horses, based on pharmacokinetic

studies{R-46–52; 53; 55} and in vitro antimicrobial susceptibility of

common pathogens{R-159; 253}.

[Minor species]1: Although the safety and efficacy have not been

established, amikacin has been suggested for the treatment of

susceptible bacterial infections in African gray parrots{R-150}, ball

pythons{R-155}, goats that will not be used for food production{R-151},

gopher snakes{R-154}, gopher tortoises{R-156}, guinea pigs{R-152}, and

red-tailed hawks{R-147}, based on pharmacokinetic studies.

Although the safety and efficacy have not been established,

gentamicin has been suggested for the treatment of susceptible

bacterial infections in the following species, if not used for food

production: baboons{R-76}, budgerigars{R-86}, buffalo calves{R-78},

eagles{R-88}, goats{R-40}, hawks{R-88}, llamas{R-82}, owls{R-88}, and

pythons{R-89}, based on pharmacokinetic studies.

Panleukopenia (treatment)1; or

Pneumonitis (treatment)1—Cats: U.S. product labeling includes the use of

gentamicin in the treatment of secondary bacterial infections associ-

ated with panleukopenia in cats{R-4} and the use of kanamycin in the

treatment of bacterial complications of feline pneumonitis{R-93}. These

uses may be appropriate for bacterial infections that are susceptible to

these medications; however, they are not considered more appropriate

or more generally accepted than other antimicrobials in the treatment

of bacterial infections associated with viral infections.

[Leptospirosis (treatment)]—Cattle, dogs, and pigs: Canadian product

labeling includes the use of dihydrostreptomycin in the treatment of

leptospirosis in cattle, dogs, and pigs{R-106}. Studies have shown that,

while shedding of leptospires in the urine of cattle can be halted for at

least 2 months by the administration of a single dose of dihydrostrep-

tomycin, carriers are not necessarily eliminated{R-243; 244}. Equally

effective alternative medicines exist.

UNACCEPTED[Mastitis (treatment)]—Cattle and pigs: Although some Canadian

product labeling has listed the use of dihydrostreptomycin in the

treatment of mastitis in cows and sows, there is no published

evidence that this treatment is effective. Dihydrostreptomycin is

irregularly distributed into milk when administered at the labeled

dose{R-247}. Another member of this drug family, gentamicin, has



been shown in some studies to be ineffective in the treatment of

coliform mastitis{R-259–260}.

[Pneumonia (treatment)]—Calves and cattle: Although Canadian product

labeling includes the use of dihydrostreptomycin in the treatment of

bacterial pneumonia in calves{R-106}, there is no published evidence

available pertaining to efficacy of this therapy. Such use is not

recommended by the USP Veterinary Medicine Advisory Panel{R-258}

due to the lack of efficacy data and the potential for extended tissue

withdrawal times.

[Uterine infections (treatment)]—

Cattle: Although Canadian product labeling has included the use of

gentamicin uterine solution or gentamicin injection administered by

the intrauterine route in the treatment of uterine infections in

cattle{R-7}, this use is not recommended. Intrauterine gentamicin

dosage regimens necessary to produce therapeutic concentrations in

uterine tissue other than the endometrium can lead to significant

systemic drug distribution and a risk of long-term tissue residues of

gentamicin{R-28–30}.

Dogs: Although Canadian product labeling includes the use of

gentamicin injection administered by the intrauterine route in the

treatment of uterine infections in dogs, such use is not recom-

mended{R-258}.

1Not included in Canadian product labeling or product not commercially

available in Canada.

REGULATORY CONSIDERATIONSU.S.—

Because drug residues can persist in some tissues for many months, the

extralabel use of aminoglycosides in food-producing animals should

be avoided when there are no established scientific data on residue

depletion. A voluntary resolution against the administration of

aminoglycosides to cattle has been instituted by the Academy of

Veterinary Consultants, the American Association of Bovine Prac-

titioners, the National Cattlemen’s Beef Association, and the Amer-

ican Veterinary Medical Association (AVMA){R-257}. The AMVA

resolution states that, ‘‘Until further scientific information becomes

available, aminoglycoside antibiotics should not be used in cattle,

except as specifically approved by the FDA{R-257}.’’ At issue is the

need for a clearer understanding of the complexity of aminoglycoside

residue depletion for food-producing animals{R-25; 32; 34; 36}. Drug

residues can persist in some tissues for many months.

Gentamicin is not labeled for use in horses intended for food

production. Neomycin is not labeled for use in veal calves.

Withdrawal times have been established for the use of apramycin

sulfate powder for oral solution, gentamicin sulfate oral solution, and

gentamicin sulfate powder for oral solution in pigs; gentamicin

injection in chicks, piglets, and turkey poults; neomycin sulfate for

medicated feed, neomycin sulfate oral solution or neomycin sulfate

powder for oral solution in cattle, goats, pigs, and sheep; and

streptomycin sulfate oral solution in calves, chickens, and pigs. See

the Dosage Forms section.

Canada—

Gentamicin is not labeled for use in horses intended for food

production.

Withdrawal times have been established for the use of apramycin

sulfate powder for oral solution or gentamicin sulfate oral solution

in pigs; dihydrostreptomycin injection in cattle and pigs;

gentamicin injection in chickens, cows, piglets, and turkey poults;

and neomycin sulfate oral solution and neomycin sulfate powder

for oral solution in cattle, chickens, pigs, sheep, and turkeys. See

the Dosage Forms section.

CHEMISTRYSource:

Amikacin—Semi-synthetic; derived from kanamycin{R-91}.

Apramycin—Produced by fermentation of Streptomyces tenebrarius{R-18;

96}.

Gentamicin—Created from fermentation of Micromonospora purpurea{R-1;

5; 18}.

Kanamycin—Produced through fermentation by Streptomyces kanamy-

ceticus{R-93}.

Neomycin—The sulfate of an antibacterial substance produced by

Streptomyces fradiae{R-256}.

Streptomycin—Prepared from fermentation of Streptomyces griseus, an

actinomycete organism isolated from soil{R-256}.

Chemical group:

Amikacin, dihydrostreptomycin, gentamicin, kanamycin, neomycin, and

streptomycin—Aminoglycoside antibiotics.

Apramycin—Aminocyclitol.

Note: The aminoglycosides are defined by their mechanism of action,

binding with the 30S ribosomal subunit{R-251}. The term aminocyclitol

describes the structure of both the aminoglycosides and apramycin;

however, the structure of apramycin differs just enough from other

aminoglycosides that it may be listed as an aminocyclitol rather than

specifically an aminoglycoside. It is very similar physicochemically to

other aminoglycosides{R-164}.

Chemical name:

Amikacin sulfate—d-Streptamine, O-3-amino-3-deoxy-alpha-d-glucopyr-

anosyl-(1 fi 6)-O-[6-amino-6-deoxy-alpha-d-glucopyranosyl-(1 fi 4)]-

N1-(4-amino-2-hydroxy-1-oxobutyl)-2-deoxy, (S)-, sulfate (1:2)

(salt){R-18}.

Apramycin—d-Streptamine, 4-O-[(8R)-2-amino-8-O-(4-amino-4-deoxy-

alpha-d-glucopyranosyl)-2,3,7-trideoxy-7-(methylamino)-d-glycero-

alpha-d-allo-octodialdo-1,5:8,4-dipyranos-1-yl]-2-deoxy-{R-18}.

Dihydrostreptomycin sulfate—Dihydrostreptomycin sulfate (2:3) (salt){R-

18}.

Gentamicin sulfate—A complex antibiotic substance formulated as sulfate

salts, including aminosugars{R-24}; three major components, sulfates of

gentamicin C1, gentamicin C2, and gentamicin C1A{R-18} and minor

components that are sometimes present, called A, B, B1, and X.

Kanamycin sulfate—d-Streptamine, O-3-amino-3-deoxy-alpha-d-gluco-

pyranosyl(1 fi 6)-O-[6-amino-6-deoxy-alpha-d-glucopyranosyl(1 fi 4)]-

2-deoxy-, sulfate (1:1) (salt){R-18}.

Neomycin sulfate—Neomycin sulfate{R-18}.

Streptomycin sulfate—d-Streptamine, O-2-deoxy-2-(methylamino)-alpha-

l-glucopyranosyl-(1 fi 2)-O-5-deoxy-3-C-formyl-alpha-l-lyxofurano-

syl-(1 fi 4)-N,N’-bis(aminoiminomethyl)-, sulfate (2:3) (salt){R-18}.

Molecular formula:

Amikacin sulfate—C22H43N5O13Æ2H2SO4{R-18}.

Apramycin—C21H41N5O11{R-18}.

Dihydrostreptomycin sulfate—(C21H41N7O12)2Æ3H2SO4{R-18}.

Gentamicin—

Gentamicin C1: C21H43N5O7{R-17}.

Gentamicin C2: C20H41N5O7{R-17}.

Gentamicin C1A: C19H39N5O7{R-17}.



Kanamycin sulfate—C18H36N4O11ÆH2SO4{R-18}.

Streptomycin sulfate—(C21H39N7O12)2Æ3H2SO4{R-18}.

Molecular weight:

Amikacin sulfate—781.76{R-18}.

Apramycin—539.58{R-19}.

Dihydrostreptomycin sulfate—1461.42{R-18}.

Gentamicin—

Gentamicin C1: 477.61{R-17}.

Gentamicin C2: 463.59{R-17}.

Gentamicin C1A: 449.56{R-17}.

Kanamycin sulfate—582.58{R-18}.

Streptomycin sulfate—1457.39{R-18}.

Description:

Amikacin Sulfate USP—White, crystalline powder{R-19}.

Dihydrostreptomycin Sulfate USP—White or almost white, amorphous

or crystalline powder. Amorphous form is hygroscopic{R-19}.

Gentamicin Sulfate USP—White to buff powder{R-19}.

Kanamycin Sulfate USP—White, odorless, crystalline powder{R-19}.

Neomycin Sulfate USP—White to slightly yellow powder, or cryodesic-

cated solid. Is odorless or practically so and is hygroscopic{R-19}.

Streptomycin Sulfate USP—White or practically white powder. Is

odorless or has not more than a faint odor. Is hygroscopic, but is

stable in air and on exposure to light. Its solutions are acid to

practically neutral to litmus{R-19}.

pKa:

Amikacin—8.1{R-256}.

Dihydrostreptomycin—8.8{R-254}.

Gentamicin sulfate—8.2{R-254}.

Kanamycin—7.2{R-256}.

Neomycin sulfate—8.3{R-254}.

Solubility:

Amikacin Sulfate USP—Freely soluble in water{R-19}.

Apramycin sulfate—Highly soluble in water and slightly soluble in the

lower alcohols{R-96}.

Dihydrostreptomycin Sulfate USP—Freely soluble in water; practically

insoluble in acetone, in chloroform, and in methanol{R-19}.

Gentamicin Sulfate USP—Freely soluble in water; insoluble in alcohol, in

acetone, in chloroform, and in ether{R-19}.

Kanamycin Sulfate USP—Freely soluble in water; insoluble in acetone

and in ethyl acetate{R-19}.

Neomycin Sulfate USP—Its solutions are dextrorotatary. Freely soluble in

water; very slightly soluble in alcohol; insoluble in acetone, in

chloroform, and in ether{R-19}.

Streptomycin Sulfate USP—Freely soluble in water, very slightly soluble

in alcohol; practically insoluble in chloroform{R-19}.

PHARMACOLOGY/PHARMACOKINETICSNote: See also Tables I and II for this monograph.

Mechanism of action/effect:

Aminoglycosides—Bactericidal{R-107; 116}. Aminoglycosides enter sus-

ceptible bacteria by oxygen-dependent active transport (making

anaerobes impervious to them){R-107} and by passive diffusion{R-37}.

Once the antibiotic has gained access, it binds irreversibly to a receptor

protein on the 30S ribosomal subunit{R-5; 107} and blocks the

formation of a complex that includes mRNA, formylmethionine, and

tRNA{R-107}. As a result, the tRNA is translated incorrectly, producing

a nonfunctional protein{R-107}. Aminoglycosides also disrupt protein

synthesis by disruption of polysomes and may prevent the initiation of

DNA replication{R-107}.

Aminocyclitols—Apramycin is bactericidal. It also acts against bacteria

by inhibiting protein synthesis at the ribosome level{R-96}. Like the

aminoglycosides, it inhibits the translocation step of protein synthesis

and induces translation errors{R-96}.

Absorption:

Intramammary administration—In cows with mastitis, gentamicin is

well absorbed systemically following intramammary administration.

With a single dose (1.1 mg per kg of body weight), concentrations of

antibiotic in the serum (measured in one study up to 1.09 ± 0.15 mcg

per mL) could result in prolonged tissue residues{R-26}.

Intramuscular or subcutaneous administration—Amikacin, dihydro-

streptomycin, gentamicin, and kanamycin generally are rapidly and

well absorbed from intramuscular and subcutaneous routes of

administration{R-177; 230; 247}.

Intrauterine administration—Cows: In healthy cows, 39% of a total

intrauterine dose of 2500 mg, administered once a day for 3 days, was

absorbed systemically and produced serum concentrations of up to 6.6

mcg/mL{R-28}. In cows with endometritis, absorption was similar, with

36% of an intrauterine dose of 4 mg/kg of body weight administered

once a day for 3 days absorbed systemically, producing peak serum

concentrations of 6 to 11 mcg/mL{R-29}. A smaller total intrauterine

dose of 225 to 275 mg produced plasma concentrations of 0 to 2.5

mcg/mL{R-30}, while 70% of the dose administered remained in the

lumen of the uterus{R-17; 30}.

Because of the demonstrated intrauterine absorption of aminoglyco-

sides, some clinicians have warned that intrauterine administration is

likely to result in residues above regulatory limits in food-producing

animals{R-60}.

Oral administration—In general, aminoglycosides and apramycin are

very poorly absorbed from oral administration in adult animals,

including cattle, chickens, and pigs{R-46; 96; 166; 230}. However, 11% of

an oral neomycin dose of 30 mg per kg of body weight (mg/kg) was

absorbed in 3-day-old calves and 1 to 2% of the dose was absorbed by

2-month-old calves, regardless of ruminant status{R-238}. In very

young calves, this absorption can be significant. When neomycin was

administered orally to 2- to 4-day-old calves at a dose of 33 mg/kg for

14 days, absorption was significant enough to produce relatively high

concentrations of drug in the kidneys (approximately 300 mcg per

gram of tissue){R-240}. Some absorption of apramycin has also been

shown to occur in neonatal pigs{R-296}. Damage to the gastrointestinal

mucosa can also lead to increased aminoglycoside absorption{R-166;

230}. Moderate enteritis from induction of coccidial infection in

chickens caused a significant increase in absorption of a 43 mg/kg

dose of apramycin for 5 days{R-166}. Serum concentrations were

increased from 0.04 to 0.06 mcg/mL and tissue concentrations were

also increased{R-166}.

Distribution: Aminoglycosides are distributed primarily into the

extracellular space{R-46} and over time accumulate in tissues{R-25}.

The amount of antibiotic in most tissues appears to be dependent on

the total dose administered over time rather than the size of each

individual dose{R-25; 34}. Aminoglycosides do not distribute well across

membrane barriers and, therefore, are not found at high concentra-

tions in brain tissue, cerebrospinal fluid, ocular fluid, or respiratory

secretions{R-20; 153; 230}.



Systemic administration—

Otic tissue: Aminoglycosides concentrate in the perilymph of the inner

ear. The damage to the ciliated cells can result in deafness; vestibular

nerve injury may result as well{R-263}.

Renal tissue: When aminoglycosides are administered systemically, the

predominant site of drug accumulation is the renal cortex in most

species tested, including cats, cattle, pigs, and sheep{R-20; 25; 34; 42;

67; 230}. Therapeutic concentrations are also reached in other tissues

and slow depletion from some tissues may prolong the presence of

residues{R-25; 230}. For cats, cattle, pigs, and sheep, the following

general relative gentamicin concentrations are reached over time

with repeated doses, from highest to lowest concentrations: renal

cortex; renal medulla; liver/lung/spleen; skeletal muscle{R-25; 34; 42;

67; 230}. Renal proximal tissues actively take up and accumulate

aminoglycosides by pinocytosis{R-265}. Once within the tubular cells,

the drug may cause dysfunction in lysosomes, mitochondria,

proximal tubule cell plasma membrane phospholipids and enzymes,

and glomerular filtration{R-37}.

Other tissues:

Cats: Amikacin is distributed into uterine tissue so that tissue

concentrations are about 25% of the current serum concentra-

tion{R-140}.

Horses:

Amikacin—Amikacin is distributed into peritoneal fluid and

synovial fluid in the horse with a peak of 13.7 ± 3.2 mcg/mL and

16.8 ± 8.8 mcg/mL, respectively, at the first sample, 1 hour after

an intravenous dose of 6.6 mg per kg of body weight{R-137}.

Gentamicin—Gentamicin is distributed into endometrial tissue

so that tissue concentration is higher than plasma concentrations

reached after 7 days of intramuscular therapy with a dose of 5 mg/

kg every 8 hours{R-53}.

Gentamicin is distributed into synovial fluid in normal horses to

produce a peak of 6.4 mcg/mL at 2 hours with a single 4.4 mg/kg

intravenous dose{R-58}. However, local inflammation may increase

drug concentrations in the joint and concentrations may increase

with repeated doses.

Gentamicin is distributed into jejunal and colonic tissue with a

maximum gentamicin concentration of 4.13 ± 1.8 mcg/mL

measured in the large colon at 0.5 hour after administration and

2.26 ± 1.35 mcg/mL measured in jejunum at 0.33 hour{R-59}.

Intra-articular administration—Horses: Intra-articular administration of

150 mg of gentamicin resulted in a peak synovial concentration of

1828 ± 240 mcg/mL 15 minutes after administration{R-61}.

The intra-articular administration of buffered gentamicin produced

more synovitis and higher gentamicin concentrations (2680 ±

1069 mcg/mL) than unbuffered gentamicin{R-61}; however,

synovial concentrations 12 hours later were very similar for buffered

and unbuffered gentamicin. Synovial concentrations remained

>10 mcg/mL for at least 24 hours{R-61}. A peak plasma concentra-

tion of 0.69 mcg/mL at 15 minutes after intra-articular administra-

tion was measured{R-61}; gentamicin was no longer detectable in

plasma at 6 hours.

Intrauterine administration—Horses:

Amikacin—Intrauterine administration of a total dose of 2 grams

produces a peak of greater than 40 mcg per gram of endometrial

tissue within 1 hour after infusion{R-92}. Twenty-four hours after

infusion, 2 to 4 mcg of amikacin per gram of endometrial tissue is

still present{R-92}.

Gentamicin—Intrauterine administration of 2.5 grams of gentamicin

once daily for 5 days resulted in endometrial tissue concentrations of

41.65 ± 17 mcg/gram 24 hours after the last dose{R-60}. The addition

of progesterone, administered concurrently, increased the sample to

100.33 ± 19.27 and the administration of estradiol concurrently with

gentamicin increased the sample to 74.09 ± 8.6 mcg/gram{R-60}.

At the same time, measured serum concentrations of gentamicin

peaked at 0.64 ± 0.06 for gentamicin administered alone; the

concurrent administration of progesterone or estradiol increased

gentamicin serum concentrations to a peak of 8.34 ± 1.34{R-60}.

Regional limb perfusion—Horses: Amikacin—Regional intravenous

perfusion of amikacin (125 mg diluted in 60 mL of electrolyte

solution) into the distal limb of horses produced sufficiently high

concentrations of antibiotic in local joint fluid, bone, and serum in

the limb to be effective in the treatment of most susceptible

organisms{R-267}.

Protein binding:

Amikacin—Calves: 6% at a concentration of 5 to 150 mcg per mL of

serum (mcg/mL){R-141}.

Dihydrostreptomycin—

Cows: 8%, at a concentration of 2.5 to 5 mcg/mL{R-129}.

Ewes: 12%, at a concentration of 2.5 to 5 mcg/mL{R-129}.

Gentamicin—Horses and foals: < 30%{R-1; 47}.

Kanamycin—Ewes: 0 to 4%, at a concentration of 2.5 to 5 mcg/mL{R-

129}.

Neomycin—

Cows: 45%, at a concentration of 5 to 10 mcg/mL{R-129}.

Ewes: 50%, at a concentration of 5 to 10 mcg/mL{R-129}.

Spectinomycin—Cows: 6%, at a concentration of 12.5 to 25 mcg/mL{R-

129}.

Biotransformation: In many species, aminoglycosides are eliminated

in the form of the administered drug{R-96; 143; 150; 177; 180; 238}; that

is, they are not biotransformed.

Elimination: Parenterally administered aminoglycosides are predomi-

nantly excreted unchanged in the urine{R-96; 164; 177; 180}. Only a

small amount is excreted in the bile in some species, such as cattle{R-1}.

For amikacin in dogs and gray parrots, gentamicin in calves, cows,

horses, and sheep, and kanamycin in dogs, 75 to 100% of the dose is

eliminated unchanged in the urine in the first 8 to 24 hours{R-1; 7; 20;

22; 32; 143; 150; 178; 204}.

Because the kidney is the site of predominant accumulation and

elimination of drug, the analysis of elimination seems straightforward.

However, researchers have described a dose-dependent slow elimina-

tion phase (gamma phase) many times longer than the initial

elimination phase{R-32}. It is postulated that gentamicin is bound to

tissues by one of at least two different processes so that some

gentamicin is released quickly and gentamicin bound by another

process is released more slowly{R-25; 32; 34; 36}. It is not known if these

processes are tissue-specific.

PRECAUTIONS TO CONSIDER

PREGNANCY/REPRODUCTIONAmikacin—

Dogs: Reproductive studies have not been performed in dogs{R-91}.



Horses: No evidence was found of impaired fertility in mares given an

intrauterine dose of 2 grams of amikacin 8 hours before natural

breeding{R-92}. In in vitro studies, equine sperm exposed to 0.1 mg of

benzethonium chloride per mL of solution, present in some amikacin

products, showed impaired viability{R-92}. Product labeling recom-

mends that mares not be bred for 8 hours after intrauterine

treatment with amikacin{R-92}.

Apramycin—No adverse effects have been observed in laboratory

animals pertaining to mutagenicity, teratology, or reproduction{R-96}.

Dihydrostreptomycin—Bulls: No effect was noted on spermatogenesis,

seminal pH, ejaculate volume, percentage of motile spermatozoa, rate

of spermatozoal motility, or concentration of spermatozoa from nine

beef bulls on the third or seventh days after the second dose of 22 mg

of dihydrostreptomycin per kg of body weight every 12 hours for two

doses{R-242}.

Gentamicin—

Cats and dogs: Reproductive studies have not been performed with

gentamicin in cats and dogs{R-4}.

Horses: Intrauterine treatment of mares with gentamicin is not

recommended the day of breeding{R-4}.

Rats: Ototoxicity has been shown to be a risk even before the auditory

organs have begun to function in developing rats{R-188}.

LACTATIONBecause of poor lipid solubility, aminoglycosides have relatively poor

penetration from plasma into milk{R-22; 26}. In general, parenteral

administration of gentamicin has not been shown to produce

therapeutic milk concentrations (greater than 3 to 5 mcg/mL) for

the treatment of most gram-negative mammary pathogens{R-22; 23;

25}. At any one time, approximately 10 to 15% of plasma gentamicin

levels may appear in milk{R-22; 26}. Intramammary administration of

gentamicin to cows with experimental mastitis results in significant

systemic absorption (88%), leading to long persistence of drug residues

in some tissues, such as renal tissue{R-23; 26}.

Apramycin—Cows, goats, and sheep: Apramycin has limited distribution

from parenteral administration into milk in healthy glands{R-163}. It is

distributed into bovine milk at higher concentrations during acute

clinical mastitis, but it is not known if concentrations would be high

enough to have clinical effect without significant residue and toxicity

considerations{R-163}.

Dihydrostreptomycin—Cows: When administered at an intramusuclar

dose of 11 mg/kg, dihydrostreptomycin is irregularly distributed into

the milk for at least 18 hours{R-247}.

Gentamicin—Cows: With an intramuscular dose of 5 mg/kg, a peak

concentration of 1.5 to 1.8 mcg/mL is measured 2 to 6 hours after

administration{R-22; 26}.

PEDIATRICSThe susceptibility of young animals to toxicity from aminoglycosides may

be species-specific and drug-specific. Young dogs, rabbits, and rats

have shown resistance to gentamicin nephrotoxicity in some studies{R-

219; 268}, while 2- to 3-month-old foals may be more susceptible than

adults to toxicity{R-208; 219}. The renal function of young rats, 21-days

old, was more strongly affected by the administraton of amikacin than

was the renal function of adults given the same dose{R-192}.

Young animals typically have a higher percentage of extracellular water

and, therefore, have a higher volume of distribution compared with

adults. Higher doses may be necessary in animals less than 6 weeks old

compared with adults{R-266}.

Very young animals may absorb significant amounts of orally admin-

istered apramycin or neomycin. See Absorption, above in this mono-

graph.

GERIATRICSIn a case report study of dogs, advanced age of more than 8 years

appeared to be a risk factor in susceptibility to gentamicin

nephrotoxicity{R-215}. However, it is not known if these dogs had

subclinical renal compromise, which is known to increase the

nephrotoxicity of gentamicin{R-217}, or some other dysfunction

associated with aging.

DRUG INTERACTIONS AND/OR RELATED PROBLEMSThe following drug interactions and/or related problems have been

selected on the basis of their potential clinical significance (possible

mechanism in parentheses where appropriate)—not necessarily inclu-

sive (» = major clinical significance):

Note: Combinations containing any of the following medications,

depending on the amount present, may also interact with this

medication.

Aminoglycosides, two or more concurrently{R-4; 91}

(concurrent administration may increase the risk of ototoxicity,

nephrotoxicity, or neuromuscular blockade{R-4})

Calcium

(intravenous calcium supplementation may decrease nephrotoxicity

associated with aminoglycosides; in horses, 20 mg of intravenous

calcium gluconate per kg of body weight administered every 12 hours

decreased nephrotoxicity of high dose gentamicin [20 mg/kg every

8 hours for 14 days] administered to adult ponies{R-223})

Calcium channel blocker{R-232}

(an increased risk of neuromuscular blockade may occur with

concomitant administration with an aminoglycoside{R-232})

Halothane anesthesia

(horses administered gentamicin, 4 mg/kg, while under halothane

anesthesia have significant changes in the pharmacokinetics of genta-

micin; total body clearance and volume of distribution decrease while

half-life of elimination increases; a longer gentamicin dosing interval

after anesthesia may help correct for the changes, but serious consid-

eration should be given to choice of another antimicrobial{R-204})

Iron, supplemental

(the risk of auditory and renal toxicity might be increased when

aminoglycosides are administered with iron supplements; guinea pigs

administered gentamicin at 100 mg/kg a day for 30 days showed a

more rapid and profound hearing loss within the treatment period with

concurrent administration of supplemental iron at a dose of 2 to 6 mg/

kg a day; the effect was iron dose–dependent{R-198}; a study in rats

showed increased renal tubular damage when gentamicin was

administered at a dose of 100 mg/kg a day to rats given iron

supplementation{R-202})

Ketorolac{R-224},

Phenylbutazone{R-203}, or

Nonsteroidal anti-inflammatory drugs (NSAIDs), other

(in the horse, concurrent administration of phenylbutazone with

gentamicin affects the pharmacokinetics of gentamicin by decreasing

the half-life of elimination by 23% and decreasing the volume of



distribution [area] by 26%; the pharmacokinetics of phenylbutazone

do not appear to be affected{R-203}; also, the nephrotoxic potential of

NSAIDs can increase the risk of renal toxicity, as ketorolac does

when administered to rats concurrently with gentamicin{R-224};

however, flunixin was shown to have no effect on the pharmaco-

kinetics of gentamicin when administered concurrently to adult

horses{R-265})

Loop diuretics, including{R-143}

Ethacrynic acid{R-143; 197; 229} or

Furosemide{R-4; 91; 185; 207}

(because these medications can cause ototoxicity in patients with renal

compromise, the risk of potentiating toxicity during concurrent use

with aminoglycosides should be considered{R-143}; also, there is

evidence that the combination of kanamycin and ethacrynic acid

can cause permanent auditory ototoxicity in healthy cats without

subsequent signs of renal compromise{R-197}; concurrently adminis-

tered systemic gentamicin and ethacrynic acid also causes more

profound ototoxicity in guinea pigs than either drug administered

alone{R-229})

Nephrotoxic medications, other{R-4} or

Ototoxic medications, other{R-4}

(concurrent use may increase the risk of ototoxicity or nephrotoxicity)

Neuromuscular blocking agents or drugs with neuromuscular blocking

activity{R-4; 186; 187; 199–201}, other

(concurrent use with aminoglycosides can increase the risk of

neuromuscular blockade, particularly during anesthesia{R-186} but

there may be little clinical significance; administration of gentamicin

[2 to 6 mg/kg dose] does potentiate the neuromuscular blocking

effect of atracurium in inhalant-anesthetized cats, dogs, and horses;

however, minimal to no effect on recovery from anesthesia was

noted{R-199–201}; edrophonium reversed any remaining neuromus-

cular block during recovery{R-199–201}; calcium supplementation can

also help reverse neuromuscular blockade [see Treatment of overdose])

HUMAN DRUG INTERACTIONS{R-255}

In addition to the above drug interactions reported in animals, the

following drug interactions have been reported in humans, and are

included in the human monograph, Aminoglycosides (Systemic) in USP

DI Volume I; these drug interactions are intended for informational

purposes only and may or may not be applicable to the use of

aminoglycosides in the treatment of animals:

Antimyasthenics

(concurrent use of medications with neuromuscular blocking action

may antagonize the effect of antimyasthenics on skeletal muscle;

temporary dosage adjustments of antimyasthenics may be necessary

to control symptoms of myasthenia gravis during and following use

of medications with neuromuscular blocking action)

Beta-lactam antibiotics

(aminoglycosides can be inactivated by many beta-lactam antibiotics

[cephalosporins, penicillins] in vitro and in vivo in patients with

significant renal failure; degradation depends on the concentration of

the beta-lactam agent, storage time, and temperature)

Indomethacin, intravenous

(when aminoglycosides are administered concurrently with intrave-

nous indomethacin in the premature neonate, renal clearance of

aminoglycosides may be decreased, leading to increased plasma

concentrations, increased elimination half-lives, and risk of amino-

glycoside toxicity; dosage adjustment of aminoglycosides based on

measurement of plasma concentrations and/or evidence of toxicity

may also be required)

Methoxyflurane or

Polymyxins, parenteral

(concurrent and/or sequential use of these medications with amino-

glycosides should be avoided since the potential for nephrotoxicity

and/or neuromuscular blockade may be increased; neuromuscular

blockade may result in skeletal muscle weakness and respiratory

depression or paralysis [apnea]; caution is also recommended when

methoxyflurane or polymyxins are used concurrently with amino-

glycosides during surgery or in the postoperative period)

LABORATORY VALUE ALTERATIONSThe following have been selected on the basis of their potential clinical

significance (possible effect in parentheses where appropriate)—not

necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values

Aspartamine aminotransferase (AST [SGOT]), serum and

Lactate dehydrogenase (LDH), serum

(in galahs [cockatoos] and macaws, values are reported to increase

with therapeutic gentamicin administration of 5 mg/kg every 12

hours{R-205})

HUMAN LABORATORY VALUE ALTERATIONS{R-255}

In addition to the above laboratory value alterations, the following

alterations have been reported in humans, and are included in the

human monograph Aminoglycosides (Systemic) in the USP DI Volume I;

these laboratory value alterations are intended for informational


aminoglycosides in animals:


Alanine aminotransferase (ALT [SGPT]), serum and

Alkaline phosphatase, serum and

Aspartate aminotransferase (AST [SGOT]), serum and

Bilirubin, serum and


(values may be increased)

Blood urea nitrogen (BUN) and

Creatinine, serum

(concentrations may be increased)

Calcium, serum and

Magnesium, serum and

Potassium, serum and

Sodium, serum

(concentrations may be decreased)

MEDICAL CONSIDERATIONS/CONTRAINDICATIONSThe medical considerations/contraindications included have been

selected on the basis of their potential clinical significance (reasons

given in parentheses where appropriate)—not necessarily inclusive

(» = major clinical significance).

Except under special circumstances, this medication should not be

used when the following medical problems exist:

» Dehydration, hypovolemic{R-4; 5; 91}

(hypovolemic animals can have increased susceptibility to renal

toxicity and should be rehydrated prior to treatment with amino-

glycosides{R-91}; however, clinicians may administer the first dose of



aminoglycoside to treat life-threatening infections while rehydration

is in progress{R-262})

» Hypersensitivity to aminoglycosides{R-7; 92; 93}

(a previous reaction to one aminoglycoside may contraindicate use of

the same or other aminoglycosides due to cross-sensitivity)

» Renal dysfunction{R-4; 91}

(alternative antimicrobials should be considered in animals with

severe renal compromise and/or renal azotemia{R-4; 5}; because they

lack the ability to compensate, even dogs with subclinical renal

dysfunction can develop nonreversible acute renal failure from a dose

that produces only mild polyuria in dogs with healthy kidneys{R-213;

214}; if an aminoglycosidemust be given, increasing the dosing interval

ismore effective in preventing toxicity than decreasing the dose{R-217})

Risk-benefit should be considered when the following medical

problems exist:

Cardiac dysfunction{R-5}

(gentamicin may exacerbate a decreasing heart rate or depression of

blood pressure{R-5})

Endotoxemia

(even a low serum concentration of endotoxin may increase the

toxicity of the aminoglycosides by increasing their concentration in

the kidneys{R-184}; the administration of an aminoglycoside to treat

gram-negative bacterial infections may also increase the amount of

endotoxin released{R-184}; see the Veterinary Dosing Information

section)

Hypocalcemia

(although the clinical impact is not clear, aminoglycosides, including

dihydrostreptomycin and neomycin, have been shown to decrease

the total blood calcium concentration in cattle through decreasing

the protein-bound calcium{R-187}; this effect caused signs of hypo-

calcemia in 77% of lactating cows treated with 4.5 mg of

intravenous neomycin per kg of body weight{R-187})

Potential risk factors for acute renal failure{R-185; 215}, other, including

Acidosis

Advanced age

Diabetes mellitus

Dirofilarial infection{R-91}

Electrolyte imbalances

Fever

Sepsis

Hepatic dysfunction

Hyperviscosity syndromes

Hypoalbuminemia

Hypotension

Septicemia

Trauma, severe

(level of risk of nephrotoxicity with administration of aminogly-

cosides can be difficult to assess, but caution is indicated in

animals with one or several factors associated with increased risk,

such as those affecting renal perfusion)

Pyelonephritis{R-226}

(rats with infected kidneys are more susceptible to gentamicin

toxicity than healthy rats{R-226})

PATIENT MONITORINGThe following may be especially important in patient monitoring (other

tests may be warranted in some patients, depending on condition; » =

major clinical significance):

Aminoglycoside, serum concentration

(because of the risk of nephrotoxicity and the wide variability in drug

disposition, it is recommended that, whenever possible, serum amino-

glycoside concentration should be monitored in animals receiving

repeated doses, and dosage adjustments made{R-55; 56}; when multiple

dosing is done in a24-hour period, peak and trough concentrations have

been considered the most helpful with the least number of tests{R-57}.

With once-daily dosing, serum concentrations are more typically

measured at 1 and 2 hours or 2 and 4 hours after the daily dose{R-266}.

Many sources recommend serum concentrations be allowed to drop

below1mcg/mL for gentamicin andbelow2.5 to5mcg/mL for amikacin

or kanamycin for an extended period within a dosing interval to reduce

the risk of toxicity{R-47; 51; 63; 148; 185; 209; 230}.)

Renal function tests{R-4; 91}

(serial urinalyses may be the most sensitive tests for renal toxicosis in

spite of the fact that no early urinary test has been developed that can

consistently warn clinicians when serious renal toxicity occurs; serial

urinalyses may be monitored for decreased specific gravity in the

absence of fluid therapy or appearance of casts, protein, albumin,

glucose, or blood in the absence of leukocytes and bacteria{R-4; 208};

proteinuria may be seen within 24 hours with extremely high toxic

doses{R-206}; early indication of nephrotoxicity may be possible with

the ratio of urinary gamma glutamyltranspeptidase to urinary

creatinine excretion [UGGT/UCr] ]; this enzyme concentraton ratio is

increased to three times the baseline within 2 to 3 days of a

nephrotoxic gentamicin dose of 30 mg/kg{R-206; 209; 210; 211};

however, because even a single dose of gentamicin can cause some

renal tubule changes, elevations in the UGGT/UCr ratio may occur

without subsequent severe kidney damage; therefore, some clinicians

believe that other tests may be needed to decide if gentamicin therapy

must be discontinued{R-210; 220; 221}; serum creatinine, creatinine

clearance tests, specific gravity, blood urea nitrogen and/or clinical

signs of nephrotoxicity may not be diagnostic of severe kidney damage

for at least 7 days{R-4; 206; 210; 216})

SIDE/ADVERSE EFFECTSThe following side/adverse effects have been selected on the basis of their

potential clinical significance (possible signs and, for humans, symp-

toms in parentheses where appropriate)—not necessarily inclusive:

THOSE INDICATING NEED FOR MEDICAL ATTENTIONIncidence more frequent

All species

Nephrotoxicity{R-7; 212}; ototoxicity, auditory; ototoxicity,

vestibular

Note: Evidence of physiological effects on the kidneys has been demon-

strated with a single dose of gentamicin at 15 mg per kg of body

weight (mg/kg) in 5-month-old beagles, although clinical disease is not

necessarily produced{R-209; 212}. It is assumed that renal damage

associated with aminoglycoside administration runs a range from

mild, subclinical changes to more severe nephrotoxicity, to acute renal

failure{R-4; 209; 212}. The animal’s ability to recover most likely

depends on the type of medication exposure and the amount of healthy

renal tissue remaining to compensate{R-213}. Neomycin is considered

the most nephrotoxic aminoglycoside, dihydrostreptomycin and

streptomycin the least nephrotoxic, and the other common aminogly-

cosides included in this monograph are considered somewhere

between those three drugs in their toxicity{R-254}. Aminoglycoside



administration is, as a rule, immediately withdrawn when evidence of

renal damage is found; however, many signs of toxicity may be delayed

for some time after significant damage has occurred.

Although renal toxicity is dependent on the concentration of amino-

glycoside in the renal cortex, many variables can affect how much of

the medication reaches the cortex and how serious the effects will be,

making it difficult to consistently predict which animal is likely to

develop clinical toxicity with a particular therapeutic dosage regimen.

Aminoglycosides cause nephrotoxicity by accumulating in the prox-

imal tubular cells and, once there, interfering with cellular metabolism

and transport processes{R-218; 225}. The tubular changes can progress

to proximal tubular necrosis with increasing exposure to the drug.

Fairly late in the process, glomerular filtration rate is affected and

azotemia appears{R-225}. These changes may simultaneously occur at

different rates in different parts of the renal cortex, making it possible

to have both reabsorption defects and glomerular filtration rate

reduction at the same time{R-225}.

The toxic renal changes caused by gentamicin and other aminogly-

cosides will decrease elimination of the antibiotic and increase serum

antibiotic concentrations, thereby increasing the potential toxic-

ity{R-57; 209}. Elimination half-lives of 24 to 45 hours have been

reported in the horse with renal toxicity, prolonging the toxic

exposure to the drug{R-57}. While peritoneal dialysis is useful in

lowering creatinine and blood urea nitrates, it may not be effective in

significantly speeding the elimination of the accumulating aminogly-

coside{R-57}. If there is enough healthy tissue remaining in the

kidneys, acute renal failure may be reversible by regeneration and

hypertrophy of remaining tissue{R-193; 213}. Dogs with subclinical

renal dysfunction are more sensitive to the toxicity of gentamicin;

they develop oliguria and acute renal failure that may not be

reversible from a high gentamicin dose that produces only mild

polyuria in dogs with healthy kidneys{R-213; 214}. Therefore, merely

adjusting dosage regimens to compensate for renal dysfunction may

not be sufficient to avoid toxicity. Careful selection of candidates for

aminoglycoside therapy and a dosage regimen designed to minimize

risk of nephrotoxicity is recommended.

Some aminoglycosides are more likely to cause auditory ototoxicity

and others are more likely to cause vestibular ototoxicity{R-4; 7}. This

may be due to the distribution characteristics of each drug and its

ability to concentrate in each sensory organ{R-183}. As demonstrated

in studies on guinea pigs,{R-183; 190} amikacin, kanamycin, and

dihydrostreptomycin are more toxic to the cochlea than to vestibular

organs{R-183; 190; 191; 233}. Neomycin causes severe cochlear

toxicity{R-233}. Studies in guinea pigs have shown that auditory

toxicity is often delayed{R-189}, requiring at least 4 days after admini-

stration of a toxic dose for hearing loss to be measurable{R-189}.

This period of delay may shorten with higher doses{R-189}. Vesti-

bular toxicity is more often seen than auditory toxicity with

streptomycin{R-233}.

Incidence less frequent or rare

All species

Neuromuscular blockade{R-7}

Note: Neuromuscular paralysis{R-7} is considered rare compared with the

nephrotoxic and ototoxic effects of aminoglycosides{R-232}. The

neuromuscular blocking effects of dihydrostreptomycin, gentamicin,

kanamycin, neomycin, and streptomycin at a dose of 14 to 43mg per

kg of body weight have been demonstrated during pentobarbital

anesthesia (28 to 32 mg per kg of body weight [mg/kg]) in

nonhuman primates{R-186}. However, respiratory depression and

apnea occurred only at the highest antibiotic dosages{R-186}.

Neuromuscular blockade and respiratory paralysis have been

reported in response to high doses of gentamicin (40 mg/kg) in the

cat{R-7}. The postsynaptic blocking component of this effect can be

reversed by a cholinesterase inhibitor, such as neostigmine, and the

apparent presynapic effect can be antagonized by the administration

of calcium{R-186}.

THOSE INDICATING NEED FOR MEDICAL ATTENTIONONLY IF THEY CONTINUE OR ARE BOTHERSOMEIncidence more frequent

Birds

Local tissue trauma, mild—at site of injection{R-86}

Incidence rare

Dogs

Diarrhea{R-91}—with amikacin; vomiting{R-91}—with amikacin

Incidence unknown

Calves and pigs

Diarrhea—seen in animals given oral doses of apramycin or

neomycin that are higher than the label dose{R-96; 241}.

Cats

Local tissue trauma, mild—at site of intramuscular injection with

amikacin{R-93; 139}

Dogs

Local tissue trauma, mild—at site of injection, with amikacin or

gentamicin{R-5; 91; 93}

HUMAN SIDE/ADVERSE EFFECTS{R-255}

In addition to the above side/adverse effects reported in animals, the

following side/adverse effects have been reported in humans, and are

included in the human monograph Aminoglycosides (Systemic) in USP

DI Volume I; these side/adverse effects are intended for informational


aminoglycosides in the treatment of animals:

Incidence more frequent

Nephrotoxicity; neurotoxicity; ototoxicity, auditory; ototoxic-

ity, vestibular; peripheral neuritis—only with streptomycin

Incidence less frequent

Hypersensitivity; optic neuritis—only with streptomycin

Incidence rare

Endotoxin-like reaction—gentamicin only; neuromuscular

blockade

Note: Neuromuscular blockade, respiratory paralysis, ototoxicity, and

nephrotoxicity may occur following local irrigation or topical

application of aminoglycosides during surgery.

Because of its potential toxicity, use of parenteral neomycin is not

recommended.

OVERDOSEFor more information on the management of overdose or uninten-

tional ingestion, contact the American Society for the Pre-

vention of Cruelty to Animals (ASPCA) National Animal

Poison Control Center (888–426–4435 or 900–443–0000; a fee

may be required for consultation) and/or the drug manufac-

turer.



GENERAL CONSIDERATIONSWhen systemically absorbed, the aminoglycosides have the potential to

cause nephrotoxicity, neurotoxicity, or ototoxicity{R-91}. This includes

absorption through irrigation of tissues in surgery and sometimes

from topical application{R-91}. Because of the narrow therapeutic

index, the margin between therapeutic concentrations and toxic

concentrations, for aminoglycosides used in animals, toxicity is a

potential risk in the best of circumstances. The minimum gentamicin

dose required to produce nephrotoxicity is variable between species

and between animals{R-212} and the data listed in this section cannot

clearly define the dose that will produce serious toxicity in a particular

animal.

Toxic dose—Information about toxicity of the aminoglycosides has been

drawn primarily from human therapeutic literature. It has been

reported that minimum serum concentrations within a dosing interval

of greater than 2 mcg/mL for gentamicin and greater than 2.5 to

5 mcg/mL for amikacin or kanamycin significantly increase the risk of

toxicity{R-148; 185; 209}. Persistant peak serum concentrations of

gentamicin greater than 10 to 12 mcg/mL and of amikacin or

kanamycin greater than 30 to 40 mcg/mL are also considered to

increase the risk of toxicity{R-230}.

Amikacin:

Dogs—Renal toxicity: Minimal to mild renal changes are seen with a

dose of 45 mg per kg of body weight (mg/kg) a day for 2

weeks{R-91} or 30 mg/kg a day for 90 days{R-91}.

Guinea pigs: Auditory and vestibular ototoxicity—

Marked hearing loss—150 to 225 mg/kg a day in divided doses

every 8 hours for 1 week{R-190; 191}.

Hearing loss, less pronounced—When the 150 mg/kg dose was

administered every 24 hours for 7 to 21 days, there was a

significant decrease in vestibular and auditory damage{R-190;

191}.

Apramycin:

Chickens—

No effect: With a dose of 50 mg per kg of feed, fed as the only

ration, no toxic signs are noted{R-195}.

With a dose of 150 to 250 mg per kg of feed, a reduction in serum

hemoglobin and erythrocytes may be noted, as well as

dystrophic changes in the internal organs{R-195}.

Dogs—No effect: Chronic administration yielded no toxicity with 50

parts per million (ppm) fed to dogs for 1 year{R-96}.

Pigs—

No effect: With a dose of up to 300 mg per liter of drinking water

for 15 days, no signs of toxicity were noted.

With a dose of 500 to 1000 mg per liter of drinking water (5 to 10

times the label dose) for more than 15 days, some animals

developed a drop in the percentage of neutrophils and an

increase in lymphocyte percentage in the complete blood

count{R-194}.

Rats—No effect: Chronic administration yielded no toxicity with

10,000 ppm fed to rats for 2 years{R-96}.

Gentamicin: Renal—

Cats:

No significant effect—A dose of 4.4 mg/kg every 12 hours for 12

days produced no significant effects{R-228}.

Toxic effect—Only mild nephritis was produced by 20 mg/kg a day

administered subcutaneously for 70 days{R-227}.

Dogs: Toxic effect—A parenteral dose of 30 mg/kg a day for 10 days

(or 10 mg/kg every 8 hours for 8 days) produced evidence of renal

toxicity, including elevated serum urea nitrogen concentration,

elevated serum creatinine, proteinuria, decreased urine specific

gravity, decreased exogenous creatinine clearance, decreased

glomerular filtration rate, and histological evidence of renal

toxicity{R-269; 270}.

Foals: Toxic effect—Nephrotoxicity occurred in one of twelve foals

given 17.6 mg/kg every 12 hours and one of twelve given 8.8 mg/

kg every 12 hours for 15 days{R-218}.

Hawks, red tailed: Toxic effect—An intravenous dose of 10 mg/kg

every 12 hours for 4 days caused significantly increased serum

uric acid concentrations{R-87}.

Lambs: Toxic effect—An intravenous dose of 80 mg/kg a day for up

to 20 days produced renal tubular necrosis and dilation{R-206}.

Serum creatinine concentrations of up to 132 micromoles per liter

were measured beginning 14 days, on average, after initiation of

therapy{R-206}.

Kanamycin: Dogs—Toxic effect: A single dose of 100 mg/kg

administered to three dogs caused a transient decrease in auditory

perception in one dog as measured by auditory brain stem

response{R-196}. Administration of 100 mg/kg daily for 9 weeks

caused a complete loss of hearing for high-frequency tone,

although changes did not begin until about 2 weeks after the

beginning of therapy{R-196}.

Streptomycin: Cats—

No effect: A dose of 25 mg/kg a day, administered for 9 to 28 days,

did not cause signs of toxicity{R-246}.

Toxic effect: An intramuscular dose of 50 mg/kg a day, divided into

doses administered every 8 hours for 9 to 28 days, produced

nonreversible hearing loss in most cats{R-246}. A dose of 200mg/kg

produced both permanent hearing loss and vestibular impair-

ment{R-246}.

Lethal dose—

Note: These doses have been reported as lethal but are not necessarily the

minimum lethal dose in a particular animal. No effect is listed if the

research was intended to define a lethal dose.

Amikacin: LD50—Dogs: Intramuscular or intravenous, >250 mg/kg{R-

91}.

Apramycin:

Chickens and dogs—No effect: No mortality was observed with 520

mg/kg as a single dose in chickens and dogs{R-96}.

Mice—In mice, greater than 5200 mg/kg as a single dose produced

no mortality{R-96}.

Gentamicin:

Cats—40 to 70 mg/kg a day administered subcutaneously caused

renal necrosis and death within 10 days{R-227}.

Hawks, red-tailed—An intravenous dose of 20 mg/kg every 12 hours

was lethal for all five birds in 2 to 6 days; predominant signs were

indicative of neuromuscular blockade{R-87}.

CLINICAL EFFECTS OF OVERDOSEThe following effects have been selected on the basis of their potential

clinical significance (possible signs in parentheses where appropri-

ate)—not necessarily inclusive:

Note: The following overdose effects mirror the side/adverse effects

listed in this monograph because of the small therapeutic index for



aminoglycosides. These effects may occur in some animals with

therapeutic doses so that most animals treated should be monitored for

adverse effects. These are also dose-related effects, however, with risk

increasing as the dose rises above recommended levels{R-7}.

All species

Nephrotoxicity{R-7; 212}; neuromuscular blockade; ototoxicity,

auditory; ototoxicity, vestibular

TREATMENT OF OVERDOSERecommended treatment consists of the following:

Note: Some experts suggest that administration of a beta-lactam

antibiotic that binds an aminoglycoside (ticarcillin, for example) will

decrease the toxicity after accidental overdose of aminoglycosides{R-

266}.

For neuromuscular blockade

• Administration of edrophonium, 0.5 mg/kg, will reverse neuromus-

cular blocking effects{R-200; 201}. Administration of calcium chloride

at 10 to 20 mg/kg, calcium gluconate at 30 to 60 mg/kg, or

neostigmine at a dose of 100 to 200 mcg per kg of body weight can

also reverse muscle response depression and associated dysp-

nea{R-186}.

For renal toxicity

• Aminoglycoside administration should be immediately discontin-

ued{R-208}.

• Polyionic electrolyte fluid therapy should be initiated to stimulate

diuresis{R-208}.

Note: Three or more weeks of therapy may be required for recovery in

animals with sufficient remaining renal tissue to compensate{R-215}.

Oliguria may be a poor prognostic sign{R-215}.

CLIENT CONSULTATIONThere are reports that aminoglycosides, such as neomycin or strepto-

mycin, can cause contact dermatitis in human beings{R-236}. Direct

contact with skin should be avoided by people handling these

products{R-236}.

VETERINARY DOSING INFORMATIONResistance: Reports of antimicrobial resistance support recommendations

to culture pathogens to be sure the use of an aminoglycoside is

warranted. There is also some evidence that limiting the use of

aminglycosides and, in particular, limiting administration at subther-

apeutic concentrations to a population of animals may limit the

increase in E. coli resistance that is seen with more intense antimi-

crobial use{R-234}.

FOR PARENTERAL DOSAGE FORMS ONLYSystemic aminoglycosides are generally dosed to achieve a high peak

serum concentration followed by a period of subtherapeutic serum

concentration. This strategy is built on several factors:

1) Aminoglycosides kill bacteria by a concentration-dependent mech-

anism{R-80} rather than dependence on the length of time the

organism is exposed to the antibiotic{R-160}. A spike in concentra-

tion{R-80; 232} or, in some situations, a plateau{R-155; 157} above the

minimum inhibitory concentration is neccessary for effective bacte-

rial killing.

2) A high peak of antibiotic will cause the most killing of bacteria and

will also cause the most prolonged postantibiotic effect (PAE), in

which pathogen growth is inhibited after the serum concentration

falls below minimum inhibitory concentrations{R-80}. The PAE has

been shown to occur when amikacin or gentamicin is administered

to treat gram-negative infections{R-174}. Postantibiotic effect may be

evidence that exposure to a high concentration of antimicrobial

causes cellular changes in the pathogen that will inevitably cause

death after drug concentrations have dropped below the MIC{R-158}.

The PAE may be shortened in neutropenic animals but prolonged in

animals with renal impairment{R-174}.

3) An extended period of serum drug concentrations below a minimum

amount is expected to decrease the risk of aminoglycoside toxicity.

Dosing is usually designed to produce peaks above the MIC and troughs

below a minimum concentration to prevent adverse effects, regardless

of the frequency of dosing within a 24-hour period. Many sources

recommend serum concentrations be allowed to drop below 2 mcg/mL

for gentamicin and to less than 2.5 to 5 mcg/mL for amikacin or

kanamycin for an extended period within a dosing interval to reduce

the risk of toxicity{R-47; 51; 63; 148; 185; 209; 230}. A plasma or serum

concentration of at least 8 to 10 times the MIC of the organism has been

recommended for the aminoglycoside antibiotics to be effective{R-155}.

Individualized dosing/Patient monitoring: Even within the same species,

individual animals can differ widely in the serum concentrations

produced from the same dosage regimen{R-83; 89; 213; 230}. When this

relative unpredictability is combined with the often small difference

between therapeutic and toxic serum concentrations of aminoglyco-

sides, the determination of serum concentrations in a particular

animal becomes very valuable. When it is economically possible to

measure plasma or serum concentrations during aminoglycoside

therapy, the information can be used to maximize efficacy and

minimize toxicity{R-130–132}.

Note: There can be up to a fourfold difference between avian species in

the elimination of gentamicin{R-85}. It is recommended that species-

specific pharmacokinetic data be used to develop dosing for birds, if at

all possible{R-148}.

Once daily dosing: The continuing effort to maximize therapeutic effect

and minimize toxic effect of aminoglycosides has led to ongoing

research on the efficacy of a 24-hour dosing interval{R-160; 232; 252}.

Dosing once a day is considered by some clinicians to be a rational use

of aminoglycosides in specific situations{R-232}. The supporting argu-

ments include that use of the highest safe single dose has been linked

to increased efficacy in human studies, greater bacterial killing and a

longer postantibiotic effect are expected with a higher peak concen-

tration, and once-a-day dosing allows for the longest period of low

serum concentration to minimize toxicity{R-160; 232; 252}.

Concern has been expressed that dosing once every 24 hours may be

less effective than repeated daily dosing in some situations, such as in

immunocompromised patients{R-158}. Studies with guinea pigs have

demonstrated no significant difference in bacterial killing between

gentamicin administered subcutaneously at 6 mg/kg every 24 hours

versus 2 mg/kg every 8 hours{R-80}. However, once-a-day dosing has

been less effective in treating some infections in neutropenic ani-

mals{R-158; 232}. Some researchers have demonstrated a potential for

development of resistance with dosing once a day{R-232}; but others

have described an adaptive resistance to aminoglycosides in Pseudo-

monas species that occurs with doses repeated within 16 hours in

animal models but that is reduced by longer dosing intervals in the first

3 days{R-160}. Some clinicians have expressed reservations about once-

daily dosing when intestinal damage allows continued exposure to



bacteria that may replicate during the prolonged periods of subther-

apeutic aminoglycoside concentration{R-263}.

Desired benefits include reduction of toxicity. If the total daily dose of

aminoglycoside is kept constant, less frequent dosing per day is

associated with decreasing renal toxicity{R-232}. The same is true for

gentamicin ototoxicity in guinea pigs but, while the single daily dose

has not been shown to be more toxic for amikacin or kanamycin, the

benefit in reducing ototoxicity is less clear for amikacin or kanamycin

in guinea pigs{R-190; 191; 232}.

Renal dysfunction: Treatment with gentamicin every 8 hours is not

recommended in patients with subclinical renal disease{R-72}. Because

drug clearance may be slowed with gentamicin treatment, the risk of

nephrotoxicity may be increased. Trough serum concentrations can be

reduced by increasing the dosing interval and decreasing the dose{R-

185}. Some clinicians have developed methods to calculate an

increased dosing interval based on the creatinine clearance concen-

tration; however, the most prudent course may be to avoid use of

aminoglycosides if it is necessary to significantly reduce the amino-

glycoside dose because of poor renal function{R-72}.

Endotoxemia: Producing high serum and tissue concentrations of

aminoglycoside as early as possible in animals with gram-negative

sepsis is important{R-72}. The release of endotoxin by gram-negative

organisms may be enhanced by administration of the antibiotic{R-184}.

The systemic effects of endotoxemia will also increase the risk of

concentrating aminoglycosides in the renal tissue and causing acute

renal failure{R-185}.

Diabetes mellitus: It appears that diabetic dogs may have increased

clearance of gentamicin and reduced volume of distribution (VolDss) of

gentamicin, which make them less susceptible to nephrotoxicity at

therapeutic doses of the medication{R-71}; however, the possibility of

subclinical renal disease should also be considered.

Concurrent fluid administration: In horses, the administration of thera-

peutic fluids, similar to those that are used in the treatment of colic,

does not significantly change the pharmacokinetics of concurrently

administered gentamicin{R-45}.

Gastointestinal microflora: Parenterally administered amikacin appears to

have minimal effect on gastrointestinal microflora in horses{R-136}.

Gastrointestinal surgery: When gentamicin administration (4 to 6.6mg/ kg

every 24 hours) is begun immediately after abdominal surgery for

naturally occurring colic, the pharmacokinetics of the gentamicin has

been measured to be within the reference range for normal healthy

horses{R-265}.

FOR ORAL DOSAGE FORMS ONLYChickens: Because poultry litter may contain bacteria with multiple

antibiotic resistance, treatment of litter to prevent contamination

before reutilization in soil or bedding is recommended{R-121}.

DIET/NUTRITIONDogs: Dogs with normal renal function consuming a higher protein diet

(26%) for 3 weeks before treatment have a faster gentamicin clearance

and a larger volume of distribution than dogs fed a medium (13%) or

low (9%) protein diet{R-73}.

Horses: Horses fed an alfalfa diet rather than oats alone have a smaller

degree of nephrotoxicosis from administration of gentamicin{R-222}.

Likewise, horses administered supplemental calcium gluconate,

20 mg/kg every 12 hours, have a decreased risk of acute renal failure

from gentamicin overdose compared with horses not receiving

calcium{R-223}.

Sheep: Sheep fed a low protein diet (straw and barley) have a significantly

lower total clearance and volume of distribution at steady state than

sheep fed a high protein diet (alfalfa and barley). This results in an

increased serum concentration of gentamicin in the group fed a low

protein diet{R-38}.

AMIKACIN

SUMMARY OF DIFFERENCESCategory: Aminoglycoside

Indications: General considerations—Has the broadest spectrum of

activity of the aminoglycosides and is considered effective against

strains not susceptible to other aminoglycosides.

Side/adverse effects: Intermediate renal toxicity. More toxic to the

cochlea than to vestibular organs. Diarrhea and vomiting in dogs. Mild

local tissue trauma in cats and dogs.

MUCOSAL DOSAGE FORMS

AMIKACIN SULFATE UTERINE SOLUTIONUsual dose: Uterine infections—Horses: Intrauterine, 2 grams, admin-

istered every twenty-four hours for three days{R-92; 105; 138}. The

medication should be mixed with 200 mL of 0.9% sodium chloride

injection before administration{R-92}.

Note: Product labeling recommends that mares not be bred for eight

hours after intrauterine treatment with amikacin{R-92}.

Strength(s) usually available{R-231}:

U.S.—

Veterinary-labeled product(s):

250 mg per mL (Rx) [Amifuse E; Amiglyde-V Intrauterine Solu-

tion{R-92}; Amikacin E Solution; AmTech AmiMax E Solution; Equi-

Phar EquiGlide; generic].

Note: These products contain 0.1 mg benzethonium chloride per mL as

a preservative{R-92}.

Canada—


250 mg per mL (Rx) [Amiglyde-V].

Withdrawal times: U.S. and Canada—Product is not labeled for use in

horses to be used for food production{R-92}.

Stability: A change from a colorless solution to pale yellow in color does

not indicate a decrease in potency of the antimicrobial{R-92}.

Packaging and storage: Store below 40 �C (104 �F), preferably

between 15 and 30 �C (59 and 86 �F), unless otherwise specified by

manufacturer.

USP requirements: Not in USP{R-19}.

PARENTERAL DOSAGE FORMSNote: Bracketed information in the Dosage Forms section refers to uses

that either are not included in U.S. product labeling or are for products

not commercially available in the U.S.



AMIKACIN SULFATE INJECTION USPNote: Intravenous administration—When amikacin is administered by

the intramuscular or subcutaneous route, it is rapidly and completely

absorbed. Although not always listed on product labeling, this

medication is also commonly administered intravenously. An indwell-

ing catheter is used for convenience and to minimize the discomfort of

repeated dosing{R-263}. To further decrease the risk of neuromuscular

blockade, it is recommended that the drug be diluted in saline or

administered slowly{R-263}.

Usual dose:

[Bacteremia]1;

[Bone and joint infections]1;

[Respiratory tract infections]1;

[Septicemia]1;

Skin and soft tissue infections1;

Urinary tract infections1; or

[Uterine infections]1—Dogs:

Intramuscular or subcutaneous, 10 mg per kg of body weight every

eight to twelve hours{R-91; 143}.

Once-daily dosing—Intramuscular or subcutaneous, 15 to 30 mg per

kg of body weight every twenty-four hours{R-266}.

[Bacteremia]1;


[Respiratory tract infections]1;

[Septicemia]1;

[Skin and soft tissue infections]1;

[Urinary tract infections]1; or

[Uterine infections]1—Cats:

Intramuscular or subcutaneous, 10 mg per kg of body weight every

eight hours{R-139; 140; 264}.

Once-daily dosing—Intramuscular or subcutaneous, 10 to 15 mg

per kg of body weight every twenty-four hours{R-266}.

Note: [Calves]1—Animal Medicinal Drug Use Clarification Act (AMDUCA)

regulations should be considered before the extra-label use of

aminoglycosides in food-producing animals: Although the safety and

efficacy of amikacin have not been established, a dose of 12 mg per kg

of body weight every twelve hours has been suggested for use in the

treatment of susceptible bacterial infections{R-141; 144}.

[Donkeys]1 and [ponies]1—Although the safety and efficacy of

amikacin have not been established, a dose of 6 mg per kg of body

weight every six hours, administered intravenously, has been

recommended in the treatment of bacterial infections in donkeys and

ponies{R-136}.

[Foals, less than 30 days of age]1—Although the safety and efficacy of

amikacin have not been established, a dose of 20 to 25 mg per kg of

body weight every twenty-four hours, administered by the intramus-

cular or intravenous route, has been recommended in the treatment of

susceptible bacterial infections in foals{R-6; 130–132; 134; 266; 271}.

[Goats]1—AMDUCA regulations should be considered before the extra

label use of aminoglycosides in food-producing animals—Although the

safety and efficacy of amikacin have not been established, a subcu-

taneous dose of 8 mg per kg of body weight every twelve hours has

been suggested in the treatment of susceptible bacterial infections in

goats{R-151}. In one study, this was predicted to provide peak serum

concentrations of 32.3 mcg/mL{R-151}.

[Guinea pigs]1—Although the safety and efficacy of amikacin have not

been established, an intramuscular dose of 15 mg per kg of body

weight every twelve hours has been suggested for the treatment of

susceptible bacterial infections in guinea pigs{R-152}.

[Hawks, red-tailed]1—Although the safety and efficacy of amikacin

have not been established, a dose of 15 to 20 mg per kg of body weight

every twenty-four hours or 7 to 10 mg per kg of body weight every

twelve hours, administered intramuscularly, has been suggested for

the treatment of susceptible bacterial infections in red-tailed

hawks{R-147}. This recommendation is based on pharmacokinetic

data. In this study, it was also noted that larger birds tended to develop

lower peak serum drug concentrations than smaller birds in response

to the same dose{R-147}.

[Horses]1 and [foals, more than 30 days of age]1—Although the safety

and efficacy have not been established, an intramuscular or intrave-

nous dose of 10 mg per kg of body weight every twenty-four hours has

been recommended in the treatment of susceptible bacterial infections,

based on pharmacokinetic data{R-6}. For some infections in horses,

dosing more than once a day may still be necessary and, in those cases,

an intravenous dose of 6 mg per kg of body weight every eight hours

has been recommended{R-136}.

[Parrots, African gray]1—Although the safety and efficacy of amikacin

have not been established, an intravenous or intramuscular dose of 10

to 20 mg per kg of body weight every eight to twelve hours has been

recommended in the treatment of susceptible bacterial infections, based

on pharmacokinetic data{R-150}.

[Pythons, ball]1—Although the safety and efficacy of amikacin have

not been established, an intramuscular dose of 3.48 mg per kg of body

weight as a single dose has been recommended in the treatment of

susceptible bacterial infections in ball pythons{R-155}.

[Snakes, gopher]1—Although the safety and efficacy of amikacin have

not been established, an intramuscular loading dose of 5 mg per kg

of body weight, followed by 2.5 mg per kg of body weight every

seventy-two hours has been suggested in the treatment of susceptible

bacterial infections in gopher snakes{R-154}. It has also been recom-

mended that snakes be kept at the high end of their preferred

temperature range (37 �C) to maximize distribution of drug in the

body{R-154}.

[Tortoises, gopher]1—Although the safety and efficacy of amikacin

have not been established, an intramuscular dose of 5 mg per kg of

body weight (including shell), administered every forty-eight hours,

has been suggested for the treatment of susceptible bacterial infections

in gopher tortoises{R-156}.


U.S.—


50 mg per mL (Rx) [Amiglyde-V Injection{R-91}; Amiject D; Amikacin C

Injection; AmTech AmiMax C Injection; CaniGlide; GENERIC].

Note: These products contain 0.1 mg benzethonium chloride per mL{R-

92}.

Canada—


Not commercially available.

Withdrawal times:

U.S.—This product is not labeled for use in food-producing animals and

should not be administered to such animals because of the risk of long-

term antibiotic residues{R-258}.





manufacturer.

USP requirements: Preserve in single-dose or in multiple-dose con-

tainers, preferably of Type I or Type III glass. A sterile solution of

Amikacin Sulfate in Water for Injection, or of Amikacin in Water for

Injection prepared with the aid of Sulfuric Acid. Contains an amount of

amikacin sulfate equivalent to the labeled amount of amikacin, within

–10% to +20%. Meets the requirements for Identification, Bacterial

endotoxins, pH (3.5–5.5), and Particulate matter, and for Injections{R-19}.


available in Canada

APRAMYCIN

SUMMARY OF DIFFERENCESCategory: Aminocyclitol.

Indications: General considerations—Apramycin is active against Staph-

ylococcus aureus, many gram-negative organisms, and some myco-

plasma. It has been reported to be effective in vitro against Escherichia

coli and Salmonella species{R-96; 164} that are resistant to streptomycin

and neomycin{R-167; 173}.

Side/adverse effects: This medication produces minimal side/adverse

effects and toxicity when administered by the oral route.

ORAL DOSAGE FORMS

APRAMYCIN SULFATE POWDER FOR ORAL SOLUTIONUsual dose: Enteritis, E. coli—Piglets: Oral, 12.5 mg per kg of body

weight a day for seven days (375 mg per gallon or 100 mg per liter),

administered in the only source of water{R-95; 96}.

Note: Water consumption should be monitored closely and adjusted to

avoid overdose.


U.S.—


48 grams per packet (OTC) [Apralan Soluble].

Canada—


48 grams per packet (OTC) [Apralan].

Withdrawal times:

U.S.{R-95}—

Withdrawal time

Species Meat (days)

Pigs 28

Canada{R-96}—

Withdrawal time

Species Meat (days)

Pigs 28



manufacturer. Protect from moisture and excessive heat{R-96}.

Preparation of dosage form: Prepare fresh solution daily according to

manufacturer’s labeling{R-96}.

Incompatibilities: Activity of the medication may be reduced if water

delivery system contains rust{R-96}.


DIHYDROSTREPTOMYCIN

SUMMARY OF DIFFERENCESCategory: Aminoglycoside.

Indications: General considerations—Active against mycobacteria,

Leptospira{R-243; 244}, Francisella tularensis, and Yersinia pestis, but

only some mycoplasma, gram-negative organisms, and Staphylococcus

species{R-116}. The introduction of newer aminoglycosides has eclipsed

the significance of dihydrostreptomycin in the face of increasing

bacterial resistance.

Lactation: Irregularly distributed into the milk of cows for 18 hours or

more.

Side/adverse effects: Less nephrotoxic than other aminoglycosides. Unlike

streptomycin, dihydrostreptomycin is associated with more auditory

than vestibular toxicity{R-233}.

ORAL DOSAGE FORMSNote: Bracketed information in the Dosage Forms section refers to uses



DIHYDROSTREPTOMYCIN INJECTION USPUsual dose:

Note: [Cattle], [dogs], and [pigs]—Although Canadian product labeling

includes a dose of 25 mg per kg of body weight for three to five days

in the treatment of leptospirosis in cattle, dogs, and pigs, studies have

shown that while shedding of leptospires will be halted for at least 2

months, carriers are not necessarily eliminated{R-243; 244}.

Although Canadian product labeling includes the use of dihydro-

streptomycin in the treatment of bacterial pneumonia in calves, there is

no published evidence available pertaining to efficacy of this therapy.

Such use is not recommended by the USP Veterinary Medicine

Advisory Panel{R-258} due to the lack of efficacy data and the

potential for extended tissue withdrawal times.


U.S.—



Canada—


500 mg per mL (OTC) [Ethamycin{R-106}].



Withdrawal times:

Canada—

Withdrawal time

Species Meat(days) Milk (hours)

Calves, pigs 30

Cattle 30 96



manufacturer.


tainers. Label it to indicate that it is intended for veterinary use

only. Contains an amount of Dihydrostreptomycin Sulfate equivalent

to the labeled amount of dihydrostreptomycin, within –10% to

+20%. Contains one or more suitable preservatives. Meets the

requirements for Identification, Bacterial endotoxins, Sterility, and

pH (5.0–8.0){R-19}.

GENTAMICIN


Indications: General considerations—Gentamicin has been widely used

in the treatment of gram-negative organisms and some gram-positive

organisms. As with other aminoglycosides, use is limited by risk of

toxicity.

Side/adverse effects: Intermediate nephrotoxicity. It is considered to be

equally toxic to the cochlea and to vestibular organs.

MUCOSAL DOSAGE FORMS

GENTAMICIN UTERINE INFUSION USPUsual dose:

Uterine infections, bacterial—Horses: Intrauterine, 2 to 2.5 grams as a

total dose a day for three to five days during estrus{R-1}. Before

administration, the dose should be diluted with 200 to 500 mL of

sterile physiological saline{R-1}.


U.S.—


50 mg per mL (Rx) [Gentocin Solution{R-1}].

100 mg per mL (Rx) [AmTech GentaMax 100; GentaMax 100;

GentaVed 100; Gentocin Solution; Gentozen; Legacy; GENERIC{R-3}].

Canada—



Withdrawal times:

U.S.—This product is not labeled for use in food-producing animals in the

U.S., including horses intended for food production{R-1}.

Packaging and storage: Store between 2 and 30 �C (36 and 86 �F){R-1},unless otherwise specified by manufacturer.


tainers, preferably of Type I glass. A sterile solution of Gentamicin

Sulfate in Water for Injection. Label Uterine Infusion to indicate that it

is for veterinary use only. The label states that it must be diluted with

0.9% Sodium Chloride Irrigation before aseptic uterine infusion. May

contain suitable buffers, preservatives, and sequestering agents. Con-

tains the labeled amount, within –10 to +25%. Meets the requirements

for Identification, Sterility, and pH (3.0–5.5).{R-19}

ORAL DOSAGE FORMS

GENTAMICIN ORAL SOLUTIONUsual dose:

Enteritis, E. coli—

Piglets, 1 to 3 days of age: Oral, 5 mg as a total dose, administered

once at the onset of signs{R-13; 14}.

Note: The above dose is for ‘‘pig pump’’ solutions, administered

at the strength provided in metered dose packaging{R-13; 14}; see

manufacturer’s product labeling.

Piglets, weanling1: Oral, 25 mg per gallon of water

(approximately 1.1 mg per kg of body weight), administered as

the sole source of drinking water for three consecutive days{R-11}.

Swine dysentery1—Pigs: Oral, 50 mg per gallon of water

(approximately 2.2 mg per kg of body weight), administered as the

sole source of drinking water for three consecutive days{R-11}.


U.S.—


4.35 mg per mL (OTC) [Garacin Pig Pump{R-13}].

5 mg per mL (OTC) [AmTech Gentamicin Sulfate Pig Pump Oral

Solution].

Canada—


4.35 mg per mL (OTC) [Garasol Pig Pump Oral Solution{R-14}].

Withdrawal times:

U.S.{R-13}—

Withdrawal time

Species Meat (days)

Piglets 14

Canada{R-14}—

Withdrawal time

Species Meat (days)

Piglets 11



manufacturer. Protect from freezing{R-13}.

Preparation of dosage form: This medication is dispensed in a ‘‘pig

pump.’’ Medication is administered by one plunger depression to

deliver 5 mg into each pig’s mouth{R-12}.



Stability:

Contents of ‘‘pig pump’’ medication bottle should be destroyed 90 days

after opening, if unused{R-12}.

Medicated drinking water should be prepared daily{R-11}.

Incompatibilities: To prevent inactivation of the drug, medicated

drinking water should not be stored in rusty containers{R-11}.


GENTAMICIN POWDER FOR ORAL SOLUTIONUsual dose:

Enteritis, E. coli1—Piglets: Oral, 25 mg per gallon of water (approx-

imately 1.1 mg per kg of body weight), administered as the sole

source of drinking water for three consecutive days{R-15}.

Swine dysentery1—Pigs: Oral, 50 mg per gallon of water (approxi-

mately 2.2 mg per kg of body weight), administered as the sole

source of drinking water for three consecutive days{R-15}.

Note: Under extreme hot or cold weather conditions, product labeling

recommends that the concentration of medication be adjusted, based

on expected changes in water consumption{R-15}.


U.S.—


66.7 mg of gentamicin per gram of powder (OTC) [Garacin Soluble

Powder].

333.3 mg of gentamicin per gram of powder (OTC) [Gen-Gard].

Canada—


Withdrawal times:

U.S.{R-15}—

Withdrawal time

Species Meat (days)

Pigs, piglets 10



manufacturer. To avoid degradation of medication, this product should

not be stored in rusty containers{R-15}.

Preparation of dosage form: Prepare daily according to manufac-

turer’s recommendation{R-15}.


1Not included on Canadian product labeling or product not commercially



that either are not included in U.S. product labeling or are not


GENTAMICIN INJECTION USPNote: Intravenous administration—When gentamicin is administered by

the intramuscular or subcutaneous route, it is rapidly and completely

absorbed. Although not always listed on product labeling, this

medication is also commonly administered intravenously. An indwell-

ing catheter is used for convenience and to minimize the discomfort of

repeated dosing{R-263}. To further decrease the risk of neuromuscular

blockade, it is recommended that the drug be diluted in saline or

administered slowly{R-263}.

Usual dose:

[Bacteremia];


Respiratory tract infections;

[Septicemia];

Skin and soft tissue infections;

Urinary tract infections; or

[Uterine infections]1—

Cats:

Intramuscular, intravenous, or subcutaneous, 3 mg per kg of body

weight every eight hours{R-63; 64}.

Once-daily dosing—Intramuscular, intravenous, or subcutaneous,

5 to 8 mg per kg of body weight every twenty-four hours{R-266}.

Dogs:

Intramuscular or subcutaneous, 4.4 mg per kg of body weight

every eight hours{R-4; 7}.

Once-daily dosing—Intramuscular or subcutaneous, 10 to 15 mg


Note: Authors of a study of obese cats considered to be approximately

45% overweight (4.6 to 6.6 kg body weight) recommended an

intramuscular, intravenous, or subcutaneous dose of 2.5 mg per kg

of body weight every eight hours to compensate for pharmacokinetic

differences from normal-weight cats{R-68}.

Treatment of urinary tract infections with aminoglycosides should be

reserved for those cases in which resistance exists to safer alternative

antimicrobials. Despite label directions to limit treatment duration to

7 days{R-4}, most urinary tract infections will require extended

therapy. This is possible with the aminoglycosides, provided careful

monitoring is performed (see Patient monitoring).

According to product labeling, treatment with gentamicin injection

should not exceed 7 days{R-4}.

Enteritis, Escherichia coli—Piglets, 1- to 3-day-old: Intramuscular, 5 mg

as a single total dose{R-7; 9}.

E. coli infection;

Pseudomonas aeruginosa infection; or

Salmonella typhimurium infection—Chicks, 1-day-old: Subcutaneous,

0.2 mg as a total single dose{R-7; 8}.

Paracolon—Turkey poults, 1- to 3-day-old: Subcutaneous, 1 mg as a

total single dose{R-7; 8}.

Uterine infections, bacterial—Horses: Intrauterine, 2 to 2.5 grams a

day for three to five days during estrus{R-4; 7}. Before administration,

the dose should be diluted with 200 to 500 mL of sterile

physiological saline{R-4; 7}.

Note: The following recommendations have been suggested based on

pharmacokinetic studies:

[Baboons]1—Although the safety and efficacy of gentamicin have not

been established, an intramuscular dose of 3 mg per kg of body

weight every six to eight hours has been suggested in the treatment

of Pseudomonas aeruginosa infections in baboons{R-76}.

[Buffalo calves]1—Animal Medicinal Drug Use Clarification Act

(AMDUCA) regulations should be considered before the extra label



use of aminoglycosides in food-producing animals: Although the

safety and efficacy of gentamicin have not been established, an

intramuscular dose of 3.25 mg per kg of body weight as an initial

dose, followed by 2 to 3 mg per kg of body weight every twelve hours

has been recommended in the treatment of susceptible bacterial

infections in buffalo calves{R-77; 78}.

[Budgerigars]1—Although the safety and efficacy of gentamicin have

not been established, an intramuscular dose of 5 mg per kg of body

weight every eight hours for three days has been suggested in the

treatment of susceptible bacterial infections in budgerigars{R-86}.

[Calves, less than 2 weeks of age]1—AMDUCA regulations should be

considered before the extra label use of aminoglycosides in food-

producing animals: Although the safety and efficacy have not been

established, an intravenous dose of 12 to 15 mg per kg of body

weight every twenty-four hours has been recommended in the

treatment of susceptible bacterial infections, based on pharmacokinetic

data{R-21; 266}.

[Cattle]1—AMDUCA regulations should be considered before the extra

label use of aminoglycosides in food-producing animals: Although the

safety and efficacy have not been established, an intramuscular dose

of 5 to 6 mg per kg of body weight every twenty-four hours has been

recommended in the treatment of susceptible bacterial infections, based

on pharmacokinetic data{R-22; 25; 261; 266}.

[Eagles]1, [hawks]1, or [owls]1—Although the safety and efficacy of

gentamicin have not been established, an intramuscular or intrave-

nous dose of 2.5 mg per kg of body weight every eight hours has

been recommended in the treatment of susceptible bacterial infections

in eagles, hawks, and owls{R-88}. Caution is advised in extrapolating

dosage recommendations from one avian species to another, as

pharmacokinetics can vary widely.

[Goats]1—AMDUCA regulations should be considered before the

extra label use of aminoglycosides in food-producing animals:

Although the safety and efficacy of gentamicin have not been

established, an intravenous dose of 4 mg per kg of body weight every

eight hours has been recommended for use in the treatment of

susceptible bacterial infections in goats{R-40}.

[Horse foals]1 and [pony foals]1, less than 30 days of

age—Although the safety and efficacy have not been established,

some researchers suggest that dosing of gentamicin for horse and

pony foals less than 30 days of age should be an intramuscular or

intravenous dose of 10 to 14 mg per kg of body weight every

twenty-four hours{R-6; 266}.

[Horses]1 and [foals, more than 30 days of age]1—Although the

safety and efficacy of gentamicin have not been established, an

intramuscular or intravenous dose of 4 to 6.8 mg per kg of body

weight every twenty-four hours has been suggested for the treatment

of susceptible bacterial infections in horses and foals more than 30

days of age{R-6; 46; 50; 52; 53; 55; 252; 265; 266}.

[Llamas]1—AMDUCA regulations should be considered before the

extra label use of aminoglycosides in food-producing animals:

Although the safety and efficacy of gentamicin have not been

established, a dose of 2.5 mg per kg of body weight every eight hours

for six days has been suggested in the treatment of bacterial infections

in llamas{R-82}.

[Pythons]1—Although the safety and efficacy of gentamicin have not

been established, an intramuscular dose of 2.5 mg per kg of body

weight as an initial dose, followed by 1.5 mg per kg of body weight at

ninety-six–hour intervals has been suggested in the treatment of

susceptible bacterial infections in pythons{R-89}.


U.S.—

Veterinary-labeled products:

5 mg per mL (Rx) [Garacin Piglet Injection{R-9}].

50 mg per mL (Rx) [GentaVed 50; Gentocin{R-4}].

100 mg per mL (OTC) [AmTech Gentapoult; Garasol Injection{R-8};

Genta-fuse; generic].

Canada—


5 mg per mL (Rx) [Garasol Solution Injectable{R-10}].

50 mg per mL (Rx) [Gentocin Solution Injectable{R-7}].

100 mg per mL (Rx [Gentocin Solution Injectable].

Withdrawal times:

U.S.—This product is not labeled for use in horses to be used in food

production{R-4}.

Withdrawal time

Species Meat (days)

Chicks 35

Piglets 40

Turkey poults 63

Canada—This product is not labeled for use in horses to be used in food

production{R-7}.

Withdrawal time

Species Meat (days)

Chicks 35

Piglets 42

Turkey poults 63

Note: The administration of gentamicin to cattle in the treatment of

uterine infections is included in Canadian product labeling. However,

gentamicin is not labeled for use in food-producing animals in the U.S.

and the USP Veterinary Medicine Advisory Panel does not recommend

use in the treatment of uterine infections in cattle. Therefore, the

labeled intrauterine dose and withdrawal time for cattle are not listed

in this monograph.

Packaging and storage: Store between 15 and 30 �C (59 and 86 �F){R-4},unless otherwise specified by manufacturer. Keep from freezing{R-4}.


tainers, preferably of Type I glass. May contain suitable buffers, pre-

servatives, and sequestering agents, unless it is intended for intrathecal

use, in which case it contains only suitable tonicity agents. Contains

an amount of gentamicin sulfate equivalent to the labeled amount of

gentamicin, within –10% to +25%. Meets the requirements for Iden-

tification, Bacterial endotoxins, pH (3.0–5.5), and Particulate matter,

and for Injections{R-19}.





KANAMYCIN


Indications: General considerations—Spectrum of activity focuses primar-

ily on gram-negative organisms and a few gram-positive organisms.

Side/adverse effects: Intermediate nephrotoxicity. More toxic to the

cochlea than to vestibular organs.

PARENTERAL DOSAGE FORMS

KANAMYCIN INJECTION USPUsual dose:

Bacteremia or septicemia1;

Bone and joint infections1;

Otitis media1;

Pancreatitis1;

Respiratory tract infections1;


Urinary tract infections1; or

Uterine infections1—Cats and dogs: Subcutaneous, 5.5 mg per kg of

body weight every twelve hours{R-93}. According to product labeling,

this medication may also be given by intramuscular injection, if

necessary{R-93}.

Note: Another source recommends a dose of 10 mg per kg of

body weight every six hours in the dog, based on pharmacokinetic

data{R-177}.


U.S.—


200 mg per mL (Rx) [Kantrim].

Canada—





manufacturer.

Stability: Unopened vials may darken in color during storage, but

potency is unaffected{R-93}.


tainers, preferably of Type I or Type III glass. Contains suitable buffers

and preservatives. Contains an amount of Kanamycin Sulfate equi-

valent to the labeled amount of kanamycin, within –10% to +15%.

Meets the requirements for Identification, Bacterial endotoxins, Ste-

rility, pH (3.5–5.0), and Particulate matter and for Injections{R-19}.



NEOMYCIN


Indications: General considerations—Effective against many gram-

negative organisms and Staphylococcus aureus.

Side/adverse effects: High risk of nephrotoxicity and severe cochlear

toxicity when parenterally administered.


that either are not included in U.S. product labeling or are not


NEOMYCIN SULFATE FOR MEDICATED FEEDUsual dose: Enteritis, Escherichia coli (treatment)1—Cattle, goats, pigs,

and sheep: Oral, 22 mg per kg of body weight a day for up to a maxi-

mum of fourteen days{R-16; 94}.

Note: This product is labeled for use in the preparation of Type B or

Type C medicated feeds; Type C medicated feeds may be either

medicated solid feeds or milk replacers. To administer the recom-

mended dosage, adjustments must be made in the concentration of

neomycin in feed or milk replacer, based on factors altering

consumption, such as age and weight of the animal, disease signs,

and environmental factors{R-94}.


U.S.—


715 grams per kg (OTC) [Neomix AG 325 Medicated Premix].

Canada—


Not commerically available.

Withdrawal times:

U.S.—

Withdrawal time

Species Meat (days)

Cattle and ruminating calves 1

Goats and kids, pigs and piglets 3

Sheep and lambs 2

Note: Products are not labeled for use in preruminating calves to be

processed for veal or for lactating dairy cattle or goats producing milk

for human consumption.

Packaging and storage: Store below 40 �C (104 �F), preferably be-

tween 15 and 30 �C (59 and 86 �F), in a tightly closed container,

unless otherwise specified by manufacturer.

Store in a dry place, securely closing packaging to prevent caking of

contents{R-231}.

Preparation of dosage form: Prepare solutions daily according to

manufacturer’s instructions.


NEOMYCIN SULFATE ORAL SOLUTION USPUsual dose: Enteritis, E. coli—Cattle, goats1, [horses], pigs, and sheep:

Oral, 22 mg per kg of body weight a day, administered in the only

source of drinking water for fourteen days{R-98–100}.

Note: For many of these products, individual animal treatment is also

possible by dividing the daily dose and administering as a drench with

milk or water or by mixing in an individual animal’s only water

supply{R-98–100}. Consult the manufacturer’s product labeling.



Canadian product labeling lists the dose of neomycin in terms of mL

per liter of drinking water and an incrementally increasing dose from

2 weeks to adult, or 2 weeks to 26 weeks of age, for chickens and

turkeys, respectively{R-103}. See product labeling for specific dosing

directions.


U.S.—


200 mg per mL (OTC) [AmTech Neomycin Oral Solution; Biosol

Liquid{R-98}; Neomycin 200{R-100}; Neosol-Oral; Neoved 200; Neovet

Neomycin Oral Solution; generic{R-99}].

Canada—


200 mg per mL (OTC) [Biosol Liquid{R-103}].

Withdrawal times:

U.S.—

Withdrawal time

Species Meat (days)

Cattle 1

Goats, pigs 3

Sheep 2




Withdrawal time

Species Meat (days)

Cattle, goats 30

Pigs, sheep 20




Canada—

Withdrawal time

Species Meat (days)

Cattle 30

Chickens, broiler 7

Chickens, laying, pigs, sheep, turkeys 14

Note: This product is not labeled for use in lactating dairy cattle or horses

to be slaughtered for human consumption.



manufacturer.


manufacturer’s instructions. When administered in the drinking

water, adjustments must be made in concentration, based on factors

altering water consumption, such as age, disease signs, and environ-

mental factors{R-98}.

USP requirements: Preserve in tight, light-resistant containers, pref-

erably at controlled room temperature. Contains an amount of neo-

mycin sulfate equivalent to the labeled amount of neomycin, within –

10 to +25%. Meets the requirements for Identification and pH

(5.0–7.5){R-19}.

NEOMYCIN SULFATE POWDER FOR ORAL SOLUTIONUsual dose:

E. coli infection1—Turkeys, growing: Oral, 22 mg per kg of body weight

a day, administered in the only source of drinking water for five

days{R-2; 97}.

Enteritis, E. coli—Cattle, goats1, [horses], pigs, and sheep: Oral, 22 mg

per kg of body weight a day for fourteen days, administered in the

only source of drinking water{R-97; 104}.

Note: For many of these products, individual animal treatment is also

possible by dividing the daily dose and administering as a drench with

milk or water or by mixing in an individual animal’s only water

supply{R-97}. Consult manufacturer’s product labeling for specific

dosing directions.

Canadian product labeling lists the dose of neomycin in terms of mL

per liter of drinking water and an incrementally increasing dose from 2

weeks to adult, or 2 weeks to 26 weeks of age, for chickens and turkeys,

respectively{R-104}. Consult manufacturer’s product labeling for spe-

cific dosing directions.


U.S.—


715 mg per gram of powder (OTC) [Neo-325; Neomix 325{R-97};

Neomix AG 325; Neomycin 325{R-101}; Neo-Sol 50; Neosol Soluble

Powder; Neovet 325/100].

Canada—


715 mg per gram of powder (OTC) [Neomix Soluble Powder{R-104}].

813 mg per gram of powder (OTC) [Neomed 325; Neomycin 325].

Withdrawal times:

U.S.—

Withdrawal time

Species Meat (days)

Cattle 1

Goats, pigs 3

Sheep 2

Turkeys, growing 0



for human consumption.{R-97; 101}

Withdrawal time

Species Meat (days)

Cattle, goats 30

Pigs, sheep 20



for human consumption{R-97}.



Canada—

Withdrawal time

Species Meat (days)

Cattle 30

Chickens, broiler 7

Chickens, laying, pigs, sheep, turkeys 14



manufacturer.


manufacturer’s instructions. When administered in the drinking wa-

ter, adjustments must be made in concentration, based on factors

altering water consumption, such as age, disease signs, and environ-

mental factors{R-98}.




STREPTOMYCIN


Indications: General considerations—First aminoglycoside introduced.

Active against mycobacteria, Leptospira{R-243; 244}, Francisella tularen-

sis, and Yersinia pestis, but only some mycoplasma, gram-negative

organisms, and Staphylococcus species{R-116}. The introduction of

newer aminoglycosides has eclipsed the significance of streptomycin

in the face of increasing bacterial resistance.

Side/adverse effects: Less nephrotoxic than other aminoglycosides.

Vestibular toxicity is more often seen than auditory toxicity.

ORAL DOSAGE FORMS

STREPTOMYCIN SULFATE ORAL SOLUTIONUsual dose: Enteritis, bacterial1—Calves, chickens, and pigs: Oral, 22 to

33 mg per kg of body weight, administered in the only source of

drinking water{R-181; 182}.

Note: Strength of administered solution may be adjusted to

compensate for variations in age or weight, the severity of disease

signs, and environmental factors that may affect water consump-

tion{R-182}.


U.S.—


250 mg per mL (OTC) [GENERIC].

Canada—



Withdrawal times:

U.S.—

Withdrawal time

Species Meat (days)

Calves 2

Chickens 4

Pigs 0

Note: Product labeling listing the above withdrawal times states that they

are not labeled for use in chickens producing eggs for human

consumption.

Packaging and storage: Store below 40 �C (104� F), preferably be-

tween 15 and 30� C (59 and 86� F), unless otherwise specified by

manufacturer.

Preparation of dosage form: Prepare according to manufacturer’s

instruction.




Developed: 05/1/00

Revised: 09/30/02

Interim revision: 04/04/03



Table 1. Pharmacology/pharmacokinetics—intravenous administration.

Species

Dose

(mg/kg)

Number

of doses

VolDarea

(L/kg)

VolDsteady state

(L/kg)

Clearance

(mL/min/kg)

Elimination

half-life, initial

phase (hour)

Elimination

half-life, gamma

phase* (hour)

AMIKACIN

Birds

Chickens{R-146} 10 Single 0.229 ± 0.08 0.193 ± 0.06 1.82 ± 0.28

Emus{R-149} 7.2 Single 0.18 ± 0.03 0.17 ± 0.07 0.5 ± 0.16 0.87 6.06

Parrots, African grey{R-150} 5 Single 0.289 0.233 3.1 1.06

10 Single 0.184 0.122 2.4 0.9

20 Single 0.444 0.308 3.8 1.34

Calves{R-142} 7.5 Single 0.35 ± 0.01 1.5 ± 0.2 2.51 ± 0.58{R-141} 10 Single 0.4 ± 0.03 0.27 ± 0.02 1.5 ± 0.03 3.09 ± 0.27

Cats{R-139} 5 Single 0.17 ± 0.02 1.46 ±0.26 1.31 ± 0.32{R-140} 5 Single 0.134 ± 0.008 1.83 ± 0.26 0.8 to 1.3

10 Single 0.141 ± 0.08 2.02 ± 0.38 0.8 to 1.3

20 Single 0.184 ± 0.22 2.3 ± 0.04 0.8 to 1.3

Dogs{R-143} 5 Single 0.258 2.82 1.07

10 Single 0.227 2.66 0.98

20 Single 0.361 3.57 1.03

Donkeys{R-136} 6 Single 0.157 0.15 0.97 1.9

Foals,

3 days of age�{R-130} 7 Single 0.473 ± 0.067 0.422 ± 0.051 1.92 ± 0.37 2.69

5 days of age�{R-130} 7 Single 2.22 ± 0.35

Premature, hypoxic{R-131} 7 Every 8 hours

for 2 days

0.60 ± 0.09 1.9 ± 1.13 5.39 ± 3.46

Neonatal, critically ill{R-131; 132} 7 Every 8 hours

for 2 d/6 days

0.56 ± 0.11 2.44 ± 0.73 2.86 ± 0.89

Neonatal, critically ill, azotemic,

and hypoxemic{R-132}7 Every 8 hours

for 6 days

0.43 ± 0.05 1.3 ± 0.3 4 ± 1.11

Horses{R-137} 4.4 Single 0.198 ± 0.052 1.49 ± 0.39 1.44{R-136} 6 Single 0.215 0.207 0.75 2.8{R-137} 6.6 Single 0.174 ± 0.028 1.28 ± 0.19 1.57{R-137} 11 Single 0.138 ± 0.018 1.41 ± 0.22 1.14

Ponies{R-136} 6 Single 0.173 0.15 1.5 1.3

Pythons, ball{R-155}

25 �C 3.48; IC Single 0.46 ± 0.17 0.04 ± 0.01 126

37 �C 3.48; IC Single 0.41 ± 0.11 0.04 ± 0.01 110

Sheep{R-142} 7.5 Single 0.2 ± 0.03 0.7 ± 0.06 1.93 ± 0.27

APRAMYCIN

Birds

Chicks, 18-day-old{R-62} 10 Single 0.245 ± 0.01 3.63 ± 0.23 0.8 ± 0.01

Chickens{R-162} 10 Single 0.182 ± 0.021 1.3 ± 0.17 1.68 ± 0.07

Chickens{R-165} 75 Single 5.62 ± 0.14 4.82 ± 0.08 31.3 ± 0.83 2.1 ± 0.01

Pigeons{R-162} 10 Single 0.077 ± 0.001 3.5 ± 0.03 0.25 ± 0

Quail, Japanese{R-167} 10 Single 0.133 ± 0.007 3.1 ± 0.01 0.5 ± 0.02

Calves, 3- to 5-week old{R-164} 20 Single 0.708 ± 0.012 3.22 ± 0.44 4.4 ± 1.21

Cows, lactating{R-163} 20 Single 1.26 ± 0.18 12.16 ± 1.69 2.10 ± 0.24

Goats, lactating{R-163} 20 Single 1.36 ± 0.11 11.69 ± 2.31 0.47 ± 0.16

Rabbits{R-162} 10 Single 0.284 ± 0.035 4.3 ± 0.68 0.80 ± 0.14

Sheep{R-162} 10 Single 0.167 ± 0.08 1.3 ± 0.07 1.51 ± 0.14

Ewes, lactating{R-163} 20 Single 1.45 ± 0.10 14.14 ± 1.75 1.84 ± 0.19

GENTAMICIN

Birds

Eagles{R-88} 10 Single 0.21 ± 0.01 1.01 ± 0.09 2.46 ± 0.32

Hawks, red-tailed{R-88} 10 Single 0.24 ± 0.03 2.09 ± 0.16 1.35 ± 0.18

Owls{R-88} 10 Single 0.23 ± 0.02 1.41 ± 0.1 1.93 ± 0.24

Roosters{R-84} 5 Single 0.23 ± 0.02 0.21 ± 0.01 0.78 ± 0.13 3.38 ± 0.62

Buffalo calves, 3 to 4 months

of age (Murrah){R-77}5 Single 0.43 ± 0.03 0.91 ± 0.12 5.69 ± 0.54

Camels{R-79} 2 Single 0.32 ± 0.02 1.35 ± 0.11 2.93 ± 0.24

Cats,{R-65}

with induced endotoxemia 3 Single 0.19 ± 0.02 2.6 ± 0.7 1.1 ± 0.2

without endotoxemia 3 Single 0.2 ± 0.03 2 ± 0. 2 1.28 ± 0.21



Table 1. (Contd.)

Species

Dose

(mg/kg)

Number

of doses

VolDarea

(L/kg)

VolDsteady state

(L/kg)

Clearance

(mL/min/kg)

Elimination

half-life, initial

phase (hour)

Elimination

half-life, gamma

phase* (hour)

Cats, obese{R-68} 3 Single 0.12 ± 0.02 1.07 ± 0.25 1.37 ± 0.24

Cats{R-64} 3 Every 8 hours

for 5 days

1.79 ± 0.21

{R-63} 5 Single 0.14 ± 0.02 1.38 ± 0.35 1.25 ± 0.3

Calves,{R-21}

1 day of age 4 Single 0.4 ± 0.04 0.37 ± 0.04 1.92 ± 0.43 2.5 ± 0.6

5 days of age 4 Single 0.4 ± 0.05 0.38 ± 0.04 2.44 ± 0.34 2 ± 0.3

10 days of age 4 Single 0.34 ± 0.02 0.32 ± 0.02 2.02 ± 0.27 2 ± 0.2

15 days of age 4 Single 0.33 ± 0.04 0.31 ± 0.03 2.10 ± 0.32 1.9 ± 0.1

Calves,{R-20} 4 to 5 weeks of age 3 Single 1.95 ± 1.24 0.75 ± 0.2 4.9 ± 1.9 3.9 ± 1.7

Calves,{R-180} 6 weeks of age 5 Single 0.3 ± 0.08 1.68 ± 0.4 2.16 ± 0.25

Cows, adult{R-21} 4 Single 0.14 ± 0.02 0.13 ± 0.02 1.29 ± 0.26 1.3 ± 0.2{R-26} 4.4 Single 0.25 1.12 1.9

Cows, lactating{R-22} 5 Single 0.19 ± 0.04 0.16 ± 0.03 1.32 ± 0.17 1.83 ± 0.18

Puppies, 5 months of age

(beagles){R-70}10 Single 0.35 ± 0.04 4.08 ± 0.62

Dogs (mixed breed){R-69} 3 Single 0.17 ± 0.03 2.29 ± 0.48 0.91 ± 0.26

Dogs,{R-71}

with diabetes mellitus 4.4 Single 0.32 ± 0.13 0.2 ± 0.05 2.84 ± 0.95 1.1

without diabetes 4.4 Single 0.23 ± 0.08 0.18 ± 0.03 2.27 ± 0.41 1.08

Donkeys{R-43} 2.2 Single 0.2 ± 0.06 1.67 ± 0.48 1.87

Goats{R-39} 5 Single 0.26 ± 0.04 3.10 ± 0.27 0.96 ± 0.09{R-40} 5 Single 0.24 0.2 1.7 1.73

Horse foals,{R-47}

1 day of age 4 Single 0.32 ± 0.03 0.3 ± 0.03 1.75 ± 0.47 2.12 ± 0.39





Horses{R-47} 4 Single 0.17 ± 0.03 0.16 ± 0.22 1.69 ± 0.65 1.09 ± 0.92{R-61} 2.2 Single 0.3 ± 0.05 2.18 ± 0.5 1.52 ± 0.32{R-45} 2.2 Single 0.18 ± 0.02 0.15 ± 0.01 1.04 ± 0.13 1.96{R-50} 2.2 Every 8 hours

for 24 hours

0.46 ± 0.05 0.83

2.2 Every 8 hours

for 10 days

0.18 ± 0.02 1.06

Horses,{R-54}

with induced endotoxemia 3 Single 0.15 ± 0.04 0.14 ± 0.04 1.17 ± 0.35 1.54 ± 0.15

without endotoxemia 3 Single 0.2 ± 0.03 0.17 ± 0.01 1.41 ± 0.19 1.66 ± 0.06

Horses{R-46} 3.3 Single 0.12 ± 0.02 1.4 ± 0.2 1.2 ± 0.3

3.3 Every 12 hours

for 2.5 days

0.18 ± 0.01 1.4 ± 0.2 1.2 ± 0.2

Horses,{R-204}

without halothane 4 Single 0.26 ± 0.02 1.54 ± 0.27 2.01 ± 0.35

with halothane anesthesia 4 Single 0.26 ± 0.03 0.81 ± 0.32 4.03 ± 1.69

Horses{R-44} 5 Single 0.25 ± 0.03 0.24 ± 0.03 1.15 ± 0.12 2.54 ± 0.33{R-252} 6.6 Single 0.14 ± 0.06 3.44 ± 0.44 3 ± 2.8{R-50} 6.6 Every 8 hours for

24 hours

0.12 ± 0.04 0.78

6.6 Every 8 hours for

10 days

0.21 ± 0.01 1.08

Llamas{R-82} 2.5 Single 0.22 ± 0.06 0.97 ± 0.13 2.75 ± 0.67

5 Single 0.25 ± 0.03 1.1 ± 0.14 2.77 ± 0.34{R-81} 4 Single 0.12 0.51 3.03

Piglets,{R-41}

newborn 5 Single 0.59 ± 0.11 0.79 ± 0.04 2 ± 0.17 5.19 ± 0.3


Pigs{R-42} 2 Every 8 hours

for 7 days

0.32 ± 0.32 0.24 ± 0.03 1.66 ± 0.12 1. 9 20.2

Rabbits{R-75} 3 Single 0.14 ± 0.01 1.69 ± 0.07 0.94 ± 0.04

Rabbits,{R-76}

with induced endotoxemia 3 Single 0.77 ± 0.08

without endotoxemia 3 Single 1.5 ± 0.029

Rabbits{R-74} 3.5 Single 0.11 ± 0.02 2.82 ± 0.97 0.74 ± 0.25



Table 1. (Contd.)

Species

Dose

(mg/kg)

Number

of doses

VolDarea

(L/kg)

VolDsteady state

(L/kg)

Clearance

(mL/min/kg)

Elimination

half-life, initial

phase (hour)

Elimination

half-life, gamma

phase* (hour)

Sheep{R-31} 2.2 Single 0.19 ± 0.06 1.56 ± 0.40 1.4 ± 0.08{R-35} 3 Single 0.16 ± 0.01 0.15 ± 0.01 1.15 ± 0.08 1.68 ± 0.28{R-36; 37} 3 Single 0.41 ± 0.2 0.66 ±0.26 41.9 ± 18.5{R-36} 3 Every 8 hours

for 7 days

57.5 ± 26.2

{R-33} 4 Single 0.16 1.03 1.75{R-32} 10 Single 0.24 ± 0.03 1.03 ± 0.15 2.4 ± 0.5 30.4 ± 18.9{R-36; 37} 10 Single 0.38 ± 0.2 0.81 ± 0.32 88.9 ± 19.8{R-36; 37} 20 Single 0.71 ± 0.75 0.88 ± 0.34 167.2 ± 42.7

KANAMYCIN

Birds

Chicks, 18-day-old{R-162} 10 Single 0.671 ± 0.045 4.78 ± 0.26 1.6

Chickens{R-162} 10 Single 0.294 ± 0.004 1.4 ± 0.1 2.4

Pigeons{R-162} 10 Single 0.292 ± 0.034 3.55 ± 0.08 0.9

Dogs{R-177} 10 Single 0.255 ± 0.030 3.21 ± .72 0.97 ± 0.31

10 Every 8 hours

for 7 doses

0.252 ± 0.018 3.04 ± 0.55 0.98 ± 0.18

Goats{R-162} 10 Single 0.263 ± 0.022 1.5 ± 0.18 1.9

Horses{R-176} 10 Single 0.228 ± 0.025 1.48 ± 0.19 1.8 ± 0.17

Rabbits{R-162} 10 Single 0.254 ± 0.017 2.95 ± 0.20 1

Sheep{R-162} 10 Single 0.262 ± 0.027 1.67 ± 0.15 1.8

NEOMYCIN

Calves,{R-180}

2 days of age 10 Single 0.356 ± 0.042 2.26 ± 0.61 2.12 ± 0.39

1 week of age 10 Single 0.472 ± 0.085 3.62 ± 0.58 1.5 ± 0.03

2 weeks of age 10 Single 0.322 ± 0.056 2.31 ± 0.31 1.59 ± 0.08

4 weeks of age 10 Single 0.462 ± 0.065 2.63 ± 0.24 1.9 ± 0.01

>8 months of age 10 Single 0.355 ± 0.075 2.03 ± 0.54 2.04 ± 0.19

Calves, 3 months of age{R-237} 12 Single 1.17 ± 0.23 4.16 ± 0.67 1.4 ± 0.47 7.48 ± 2.02

Horses{R-176} 10 Single 0.232 ± 0.06 1.38 ± 0.39 2.1 ± 0.97

Sheep{R-248} 10 Single 0.304 ± 0.08 1.52 ± 0.33 1.98 ± 0.5

STREPTOMYCIN

Horses{R-176} 10 Single 0.231 ± 0.04 0.79 ± 0.13 3.40 ± 0.42

*Researchers have described a dose-dependent slow elimination phase (gamma) many times longer than the initial elimination phase{R-32}. It is postulated that gentamicin is

bound to tissues by one of at least two different processes so that some gentamicin is released quickly and gentamicin bound to tissue by another process is more gradually

eliminated{R-25; 32; 34; 36}.

�Clearance was the only pharmacokinetic value that differed with statistical significance for amikacin between 3 and 5 days of age{R-130}. Another study showed no

pharmacokinetic differences for amikacin between foals of 1 and 7 days of age{R-133}.

IC = Intracardiac

Table 2. Pharmacology/pharmacokinetics—other systemic data.

Species

Dose

(mg/kg);

Route

Number of

doses

Absorption

half-life

(hour)

Peak serum

concentration

(mcg/mL)

Time to peak

concentration

(hour)

Bioavailability

(%)

Terminal

half-life,

initial phase

(hours)

Terminal half-life,

gamma phase*

(hours)

AMIKACIN

Birds

Chickens{R-157} 10; IM Single 19.9 0.25 2.3

20; IM Single 30.8 0.25 2.9{R-146} 20; IM Single 0.48 ± 0.158 50.79 ± 4.05 0.5 ± 0.258 91 1.43 ± 0.34

20; IM Every 8 hours

for 10 doses

38.58 ± 6.96 0.79 ± 0.37 1.86 ± 0.42

Cockatiels {R-148} 15; IM Every 12 hours

for 3 days

27.3 ± 6.89 1 1.29

Hawks, red tailed{R-147} 20; IM Single 0.16 ± 0.05 56 ± 8.8 0.64 ± 0.16 2.02 ± 0.63

Parrots, African gray{R-150} 5; IM Single 10.8 ± 0.63 1 98 1.08

10; IM Single 21.1 ± 1.77 0.75 61 1.04

20; IM Single 32.7 ± 1.23 0.75 106 0.97



Table 2. (Contd.)

Species

Dose

(mg/kg);

Route

Number of

doses

Absorption

half-life

(hour)

Peak serum

concentration

(mcg/mL)

Time to peak

concentration

(hour)

Bioavailability

(%)

Terminal

half-life,

initial phase

(hours)

Terminal half-life,

gamma phase*

(hours)

Calves{R-142} 7.5; IM Single 23.5 ± 2.4 0.83 ± 0.14 99 1.94 ± 0.34{R-144} 10; IM Single 30 ± 3.7 0.05 2.2

25; IM Single 57.7 ± 3.6 0.05

Cats{R-139} 5; IM Single 16.41 ± 1.98 0.75 ± 0.2 95

5; SC Single 22.61 ± 4.29 0.67 ± 0.12 123{R-140} 5; IM Single 18.45 0.5 94

5; SC Single 23.17 0.75 100

10; IM Single 38.51 0.5 94

10; SC Single 39.55 0.75 100

20; IM Single 65.57 0.5 94

20; SC Single 67.88 0.75 100

Dogs{R-143} 10; IM Single 1 1

10; SC Single 14 (from graph) 1 1.5

Goats{R-151} 10; IM Single 0.24 27.63 ± 1.61 0.75 102

10; SC Single 0.21 38.93 ± 3.06 0.5 107

Guinea pigs{R-152} 3.75; IM Single 0.03 ± 0 12.2 ± 0.4 0.14 ±0.03 0.98 ± 0.07

7.5; IM Single 0.11 ± 0.06 20.5 ± 1.1 0.3 ± 0.09 1.25 ± 0.07

15; IM Single 0.14 ± 0.05 41.6 ± 1.5 0.4 ± 0.07 1.17 ± 0.75

Horse foals, 3- to 5-day

old{R-130}�7; IO Single 34.17 ± 3.54 0.05 98

Horses{R-137} 4.4; IM Single 13.3 ± 1.6 1

6.6; IM Single 23 ± 0.6 1

11; IM Single 29.8 ± 3.2 1

Pony foals, 2- to 11-day

old{R-135}7; IM Single 14.7 ± 1.14 0.5 3 ± 0.29

Pythons, ball{R-155}

25 �C 3.48; IM Single 1.31 11.94 ± 1.67 1.47 ± 0.72 109

37 �C 3.48; IM Single 2.27 13.87 ± 2.61 1.27 ± 0.6 109

Sheep{R-139} 7.5; IM Single 34.4 ± 6.5 1.26 ± 0.34 87 1.96 ± 0.38

Snakes, gopher{R-154}

25 �C� 5; IM Single 5.58 ± 2.77 71.9 ± 10

37 �C� 5; IM Single 5.69 ± 1.11 75.4 ± 30.1

Tortoises, gopher{R-156} 5; IM Single 25 (from graph) 0.5

APRAMYCIN

Calves, 3- to 5-week

old{R-164}10; IM Single 18.6 0.5

20; IM Single 40.8 1



Cows, lactating{R-163} 20; IM Single 42.52 ± 4.79 0.5 ± 0 60 4.42 ± 0.63

Birds

Chickens{R-165} 75; IM Single 0.19 ± 0 11.06 ± 0.31 0.76 ± 0.03 58 2.31 ± 0.02

75; PO Single 0.1 ± 0 0.79 ± 0.02 0.2 ± 0.01 2 1.22 ± 0.01

Quail, Japanese{R-167} 50; PO Single 0.84 ± 0.24 0.53 ± 0.09 56 2.31 ± 0.38

Ewes, lactating{R-163} 10; IM Single 31.04 ± 3.67 0.5 ± 0 70 2.42 ± 0.29

DIHYDROSTREPTOMYCIN

Cattle{R-247} 11; IM Single 44.7 ± 25.6 1

16.5; IM Single 65{R-249} 25; IM Single 78 1.5

Pigs{R-249} 25; IM Single 87 2.5

GENTAMICIN

Baboons{R-76} 3; IM Single 1.58

Birds

Budgerigars{R-86} 5; IM Single 17.3 0.25 0.53

10; IM Single 37 0.25 0.53

Cockatiels{R-148} 5; IM Every 12 hours

for 3 days

4.66 ± 1.45 1 1.29

Cranes{R-85} 5 to 20;

IM

Single 2.75 ± 0.62

Galahs{R-205} (cockatoos) 5; IM Single 20.55 ± 1.3 0.5 1.23



Table 2. (Contd.)

Species

Dose

(mg/kg);

Route

Number of

doses

Absorption

half-life

(hour)

Peak serum

concentration

(mcg/mL)

Time to peak

concentration

(hour)

Bioavailability

(%)

Terminal

half-life,

initial phase

(hours)

Terminal half-life,

gamma phase*

(hours)

Eagles{R-88} 10; IM Single 70

Hawks{R-88} 10; IM Single 95

Macaws{R-205} 5; IM Single 20.62 ± 2.45 0.5 1.17


for 7 days

14.15 ± 1.75 0.5

Owls{R-88} 10; IM Single 95

Quail{R-85} 5 to 20;

IM

Single 0.7 ± 0.2

Pheasants{R-85} 5 to 20;

IM

Single 1.25 ± 0.25

Buffalo calves, 3 to 4 months

of age{R-78}10; IM Single 0.43 ± 0.08 39.4 ± 9.6 0.75 3.79 ± 0.23

Camels,{R-79}

normal hydration 2; IM Single 5.4 ± 0.4 1.09 ± 0.21 135

dehydrated 2; IM Single 3 ± 0.36 1.83 ± 0.48 54

Cats{R-62} 2.5; IM Single 9.1 ± 0.8 0.5

5; IM Single 23.1 ± 2.1 0.5

Cats,{R-65}

with endotoxemia 3; IM Single 12.53 ± 3.57 0.54 ± 0.16 1.0 ± 0.23

3; SC Single 12.43 ± 2.05 0.42 ± 0.12 1.08 ± 0.23

without endotoxemia 3; IM Single 13.79 ± 3.15 0.43 ± 0.11 1.0 ± 0.17

3; SC Single 15.25 ± 1.49 0.54 ± 0.17 1.24 ± 0.1

Cats{R-68} 3; SC Single 0.11 ± 0.16 17 ± 2 0.58 ± 0.13 84 1.24 ± 0.22{R-63} 5; IM Single 21.6 ± 1.96 0.67 ± 0.12 68 1.27 ± 0.27

5; SC Single 23.5 ± 3.57 0.25 76 1.14 ± 0.11

Cows{R-29} 5; IM Single 0.28 ± 0.02 40.46 ± 1.05 0.98 ± 0.05 2.52 ± 0.1{R-29} 5; IM Every 8 hours

for 3 days

0.23 ± 0.01 32.56 ± 2.39 0.98 ± 0.09 70 2.65 ± 0.27

Cows, lactating{R-22} 5; IM Single 0.63 ± 0.28 15.39 ± 6.19 0.75 92

Cows, lactating{R-22} 5; IM Every 8 hours

For 10 days

44.91 ± 9.38

Cows, with endometritis{R-29} 5; IM Single 0.21 ± 0.02 19.36 ± 1.56 0.84 ± 0.06 2.71 ± 0.35

Dogs, (mixed-breed){R-69} 3; IM Single 0.16 10.7 0.52 96

3; SC Single 0.26 10.2 0.69 94

Goats{R-39} 5; IM Single 33.9 ± 4.37 0.67 ± 0 96 2.37 ± 0.47{R-39} 5; SC Single 28 ± 3.84 0.66 ± 0 77 3.56 ± 0.39

Horse foals{R-48}

1 month of age 2; IM Single 0.19 ± 0.08 18.2 ± 5.3 0.5 4.28 ± 2.23

1 month of age 4; IM Single 0.22 ± 0.09 52 0.5 3.07 ± 0.68

3 months of age 2; IM Single 0.21 ± 0.11 18.2 ± 5.3 0.5 3.68 ± 0.71

3 months of age 4; IM Single 0.15 ± 0.03 66 0.5 2.87 ± 0.82

Horses{R-46} 3.3; IM Single 11.7 ± 1.7 0.8 ± 0.3 2.5 ± 0.9

3.3; IM Every 12 hours

for 2.5 days

12.2 ± 2.8 0.8 ± 0.1 3.5 ± 0.6

{R-57} 4.4; IM Single 16.8 0.5{R-252} 6.6; IM Single 22 ± 4.9 1.3 ± 0.5 100

Pony foals{R-49} 2; IM Single 6.85 0.25 2.81 ± 0.28

Ponies{R-53} 5; IM Every 8 hours

for 7 days

0.25 ± 0.06 12.74 ± 1.94 1 2.13 ± 0.48

Pythons, blood{R-89} 2.5; IM Single 5.76 50.9

Rabbits{R-74} 3.5; IM Single 14.5 ± 1.7 0.48 ± 0.25 132 0.83 ± 0.14

3.5; SC Single 11.5 0.57 ± 0.16 113 0.78 ± 0.15

Sheep{R-32} 4; IM Single 99 1.82{R-33} 3; IM Every 8 hours

for 7 days

13.7 82.1 ± 17.8

KANAMYCIN

Calves{R-144; 179} 10; IM Single 31 ± 3.1 0.5 2.2

25; IM Single 57.3 ± 4.9 0.5 2.2

Cattle{R-179} 10; IM Single 30.7 ± 6.54 1

Chickens{R-179} 10; IM Single 19.28 ± 3.7 0.5

25; IM Single 58.98 ± 4.58 0.5

Dogs{R-178} 7.5; IM Single 0.4 25.8 0.49 1.03{R-177} 10; IM Single 0.15 ± 0.02 27.6 ± 7.5 0.53 ± 0.37 89 0.77 ± 0.094



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Table 2. (Contd.)

Species

Dose

(mg/kg);

Route

Number of

doses

Absorption

half-life

(hour)

Peak serum

concentration

(mcg/mL)

Time to peak

concentration

(hour)

Bioavailability

(%)

Terminal

half-life,

initial phase

(hours)

Terminal half-life,

gamma phase*

(hours)

Dogs{R-179} 15; IM Single 37.75 ± 1.32 0.5{R-178} 25; IM Single 0.5 55.6 0.68 0.93{R-179} 39; IM Single 84.56 ± 24.81 0.5

Horses{R-175} 5; IM Single 12.55 ± 1.89 1{R-176} 10; IM Single 0.32 ± 0.04 35.8 ± 5.7 1 100 2.66 ± 0.51


for 7 doses

0.38 ± 0.13 36.8 ± 12.5 1 96 2.34 ± 0.45

Pigs{R-179} 10; IM Single 32.2 ± 9.01 0.5

20; IM Single 55.62 ± 8.12 1

Sheep{R-179} 15; IM Single 36.9 ± 8.97 1

20; IM Single 54.74 ± 18.53 0.5

30; IM Single 58.5 ± 27.11 0.5

NEOMYCIN

Calves, 3 months of age{R-237} 24; IM Single 31.7 ± 11.8 1.38 ± 0.95 127 11.5 ± 3.8

96; PO Every 12 hours

for 15.5 days

0.26 ± 0.37 2.6 ± 2.9 0.45

Horses{R-176} 10; IM Single 0.16 ± 0.05 2.43 ± 9.9 74 2.58 ± 0.69


for 7 doses

0.21 ± 0.08 25.6 ± 8.8 66 2.67 ± 0.69

Sheep{R-248} 10; IM Single 0.31 ± 0.13 17.63 ± 2.27 1.33 ± 0.41 75 2.68 ± 0.29

10; SC Single 0.35 ± 0.14 18.66 ± 3.05 1 ± 0.32 85 2.82 ± 0.51

STREPTOMYCIN

Horses{R-176} 10; IM Single 0.34 ± 0.15 43.4 ± 21.4 1 83 3.83 ± 0.3


for 7 doses

0.32 ± 0.14 44.5 ± 2.7 1 98 3.84 ± 1.18

*Researchers have described a slow elimination phase (gamma) many times longer than the initial elimination phase{R-32}. It is postulated that gentamicin is bound to tissues

by one of at least two different processes so that some gentamicin is released quickly and gentamicin bound to tissue by another process is more gradually eliminated{R-25; 32;

34; 36}.

� The major pharmacokinetic values for intraosseus administration of amikacin did not significantly differ from those measured for intravenous administration{R-130}.

� Although the half-lives of absorption and elimination were similar at different temperatures, the estimated volume of distribution and clearance were significantly higher at

the warmer temperature{R-154}.

IM = intramuscular, IO = intraosseous, SC = subcutaneous



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administration. Zentralbl Veterinarmed [A] 1990 Apr; 37(3): 163–9.

249. Stalheim OHV. Absorption and excretion of tritiated dihydrostreptomycin in

cattle and swine. Am J Vet Res 1970 Mar; 31(3): 497–500.

250. National Antimicrobial susceptibility Monitoring Program-Veterinary

Isolates. FDA/USDA/CDC. Center for Veterinary Medicine. April 1998.

p. 1–27.

251. Dorland’s illustrated medical dictionary. 28th ed. Philadelphia: W.B.

Saunders Company; 1994. p. 58.

252. Magdesian KG, Hogan PM, Cohen ND, et al. Pharmacokinetics of a high dose

of gentamicin administered intravenously or intramuscularly to horses. J Am

Vet Med Assoc 1998 Oct 1; 213(7): 1007–11.

253. Snyder JR, Pascoe JR, Hirsh DC. Antimicrobial susceptibility of microorgan-

isms isolated from equine orthopedic patients. Vet Surg 1987 May-Jun;

16(3): 197–201.

254. Riviere JE, Craigmill AL, Sundlof SF. Handbook of comparative pharmaco-

kinetics and residues of veterinary antimicrobials. Boca Raton, FL: CRC Press,

Inc; 1991. p. 263–75.

255. Klasco RK, editor. USP DI Drug information for the healthcare professional.

Volume I. Greenwood Village, CO: MICROMEDEX, Inc.; 2003.

256. Gennaro AR, editor. Remington: the science and practice of pharmacy. 19th

ed. Easton, PA: Mack Publishing Company; 1995. p. 1299–303.

257. Resolutions submitted for HOD actions. J Am Vet Med Assoc 1998 Jun 15;

212(12): 1852–3.

258. Panel comment, Rec 6/99.

259. Erskine RJ, Davis BS, Spears HJ. Intramammary administration of gentamicin

as treatment for experimentally induced Escherichia coli mastitis in cows.

Am J Vet Res 1992 Mar; 53(3): 375–81.

260. Jones GF, Ward GE. Evaluation of systemic administration of gentamicin for

treatment of coliform mastitis in cows. J Am Vet Med Assoc 1990 Sep 15;

197(6): 731–5.

261. Panel comment, Rec 6/1/99.



264. Panel consensus, 9/10/99.

265. Tudor RA, Papich MG, Redding WR. Drug disposition and dosage determi-

nation of once daily administration of gentamicin sulfate in horses after

abdominal surgery. J Am Vet Med Assoc 1999 Aug 15; 215(4): 503–6.


267. Murphey ED, Santschi EM, Papich MG. Regional intravenous perfusion of the

distal limb of horses with amikacin sulfate. J Vet Pharmacol Ther 1999; 22:

68–71.

268. Cowan RH, Jukkola AF, Avant BS. Pathophysiologic evidence of gentamicin

nephrotoxicity in neonatal puppies. Pediatr Res 1980; 14: 1204–11.

269. Cronin RE, Bulger RE, Southern P, et al. Natural history of aminoglycoside

nephrotoxicity in the dog. J Lab Clin Med 1980; 95(3): 463–74.

270. Davies C, Forrester SD, Troy GC, et al. Effects of a prostaglandin E1 analogue,

misoprostol, on renal function in dogs receiving nephrotoxic doses of

gentamicin. Am J Vet Res 1998; 59(8): 1048–54.

271. McFarlane D, Papich M, Breuhaus B, et al. Pharmacokinetics of amikacin

sulfate in sick and healthy foals. International Veterinary Emergency

and Critical Care Society. Proceedings of the 5th Conference. San Antonio,

Texas.



AMINOPENICILLINS Veterinary—Intramammary-Local�

This monograph includes information on the following: Amoxicillin;

Hetacillin.

Some commonly used brand names for veterinary-labeled products are:

Amoxi-Mast and Hetacin-K Intramammary Infusion.



�Not commercially available in Canada.

CATEGORY:Antibacterial (intramammary-local).

INDICATIONS

GENERAL CONSIDERATIONSAminopenicillins have activity against penicillin-sensitive gram-positive

bacteria as well as some gram-negative bacteria. Aminopenicillins are

susceptible to destruction by beta-lactamases and therefore are not

effective against bacteria that produce these enzymes.{R-1-3} Most

strains of Klebsiella, Proteus, Pseudomonas, and Staphylococcus{R-17}

are resistant.{R-1; 4}

ACCEPTEDMastitis (treatment)1—Cows, lactating: Amoxicillin and hetacillin are

indicated in the treatment of mastitis caused by susceptible organisms

such as Streptococcus agalactiae.{R-5; 6} Intramammary therapy alone is

indicated only in the treatment of subacute or subclinical mastitis

manifested by mild changes in the milk or udder. Acute or peracute

mastitis, in which gross inflammatory changes in the milk or udder or

systemic signs appear, requires administration of other medications also,

which may include systemic antibiotics and/or supportive therapy.{R-7}




Withdrawal times have been established. See the Dosage Forms section.

CHEMISTRYSource:

Amoxicillin—Semisynthetic derivative of ampicillin.{R-8}

Hetacillin—Derived from the penicillin nucleus, 6-aminopenicillanic acid

and chemically related to ampicillin.{R-6}

Chemical group: Beta-lactam antibiotics.

Chemical name:

Amoxicillin—4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6-

[[amino(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-, trihy-

drate [2S-[2alpha,5alpha,6beta(S*)]]-.{R-9}

Hetacillin potassium—4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic

acid, 6-(2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl)-3,3-dimethyl-

7-oxo-, monopotassium salt, [2S-[2alpha,5alpha,6beta(S*)]]-.{R-9}

Molecular formula:

Amoxicillin—C16H19N3O5SÆ3H2O.{R-9}

Hetacillin potassium—C19H22KN3O4S.{R-9}

Molecular weight:

Amoxicillin—419.45.{R-9}

Hetacillin potassium—427.56.{R-9}

Description:

Amoxicillin USP—White, practically odorless, crystalline powder.{R-10}

Hetacillin potassium—White to light buff, crystalline powder.

Solubility:

Amoxicillin USP—Slightly soluble in water and in methanol; insoluble in

carbon tetrachloride and in chloroform.{R-10}

Hetacillin potassium—Freely soluble in water; soluble in alcohol.

PHARMACOLOGY/PHARMACOKINETICS

Mechanism of action/effect: Like other penicillins, the aminopenicil-

lins produce their bactericidal effect by inhibiting bacterial cell wall

synthesis.{R-11} These antibiotics must penetrate the cell wall to attach

to specific proteins on the inner surface of the bacterial cell membrane.

In actively growing cells, the binding of ampicillin or amoxicillin

within the cell wall leads to interference with production of cell wall

peptidoglycans and subsequent lysis of the cell in an isoosmotic envi-

ronment.{R-11–13}

Distribution: Medications infused into a teat are considered to be fairly

evenly distributed in that quarter of the healthy mammary gland;

however, in an udder affected by moderate to severe mastitis, the

presence of edema, blockage of milk ducts, and reduced blood circu-

lation causes uneven distribution.{R-14}





Bacteriologic pathogens in milk

(milk samples should be tested 3 weeks after treatment is discontinued;

mastitis is not considered bacteriologically cured until samples show

an absence of the mastitis-causing organisms)

Clinical signs of mastitis

(although a resolution of clinical signs of mastitis is not an indication

that a bacteriologic cure has been achieved{R-15}, monitoring of the

clinical condition of the mammary gland, teat, and milk produced can

aid in diagnosis of a recurrence of mastitis or initial diagnosis of

mastitis in another cow in the herd)

Somatic cell count

(somatic cell counts performed on milk to monitor the dairy herd are

used primarily to maintain milk quality, but they are also used to

assess the approximate overall effectiveness of mastitis control

programs, which may include antibiotic treatment of cows).{R-7}


potential clinical significance (possible signs in parentheses where

appropriate)—not necessarily inclusive:

AMINOPENICILLINS Veterinary—Intramammary-Local 33


THOSE INDICATING NEED FOR MEDICAL ATTENTIONIncidence unknown

Cows

Allergic reactions{R-6}—local or systemic

OVERDOSEFor information in cases of overdose or unintentional ingestion, contact

the American Society for the Prevention of Cruelty to Animals

(ASPCA) National Animal Poison Control Center (888-426-4435

or 900-443-0000; a fee may be required for consultation) and/or the

drug manufacturer.

CLIENT CONSULTATIONTreatment of mastitis in dairy cattle is best achieved by a comprehen-

sive mastitis control program in which herd management is the

primary focus. The program should include good maintenance of

milking equipment and constant evaluation of milking procedures

and teat health as well as strategic treatment of clinical cases of

mastitis.

VETERINARY DOSING INFORMATIONThe choice of antibiotic for the treatment of mastitis should be based on

knowledge of culture and sensitivity of pathogens causing mastitis in

the cow and the dairy herd.

The available intramammary aminopenicillin products are formulated

for use in the lactating cow only.{R-15; 16}

Before administration of intramammary amoxicillin or hetacillin, the

following steps should be performed:{R-5; 6}

• The udder should be milked out completely and the teats and udder

washed with warm water and a disinfectant. Care should be taken to

avoid washing excess dirt down from the udder onto the teat ends.

The area should be dried thoroughly and each teat wiped with a

separate cotton ball soaked with an antiseptic such as 70% isopropyl

alcohol.

• Persons performing the treatment should wash and dry their hands

before each treatment.

• The tip of the syringe should be inserted into the teat end as little as

possible and the contents of the syringe should be injected into each

streak canal while the teat is held firmly. The medication should

then be gently massaged up the teat canal into the udder.

A teat dip is recommended on all teats following treatment.

AMOXICILLIN

INTRAMAMMARY DOSAGE FORMS

AMOXICILLIN INTRAMAMMARY INFUSION USPUsual dose: Mastitis1—Cows, lactating: Intramammary, 62.5 mg into

each affected quarter of the udder every twelve hours for a maximum

of three doses.{R-5}

Strength(s) usually available:

U.S.—{R-5}


62.5 mg per 10 mL (Rx) [Amoxi-Mast].

Canada—



Withdrawal times:

U.S.—{R-5}

Withdrawal time

Species Meat (days) Milk (hours)

Cows, lactating 12 60

Packaging and storage: Store below 24 �C (75 �F){R-5}, unless

otherwise specified by manufacturer.

USP requirements: Preserve in well-closed disposable syringes. A sus-

pension of Amoxicillin in a suitable vegetable oil vehicle. Label it to

indicate that it is intended for veterinary use only. Contains the labeled

amount, within )10% to +20%. Contains a suitable dispersing agent

and preservative. Meets the requirements for Identification and Water

(not more than 1.0%).{R-10}


available.

HETACILLIN

SUMMARY OF DIFFERENCESPharmacology/pharmacokinetics: Hetacillin must undergo a rapid and

spontaneous local hydrolysis to ampicillin to be therapeutically active.

Hydrolysis is believed to occur in aqueous solution with high

efficiency; however, hydrolysis is slower in strongly acidic environ-

ments.{R-17–19}


HETACILLIN POTASSIUM INTRAMAMMARYINFUSIONNote: The dosing and strength of the dosage form available are expressed

in terms of ampicillin activity.{R-6}

Usual dose: Mastitis1—Cows, lactating: Intramammary, 62.5 mg

(ampicillin activity) into each affected quarter of the udder every

twenty-four hours for a maximum of three doses.{R-6}


U.S.—


62.5 mg (ampicillin activity) per 10 mL (Rx) [Hetacin-K Intramam-

mary Infusion].

Canada—



Withdrawal times:

U.S.—

Withdrawal time



34 AMINOPENICILLINS Veterinary—Intramammary-Local



tween 15 and 30 �C (59 and 86 �F), unless otherwise specified by

manufacturer.

USP requirements: Not in USP.{R-10}



Developed: 06/05/95

Interim revision: 04/24/96; 05/14/97; 5/26/98; 10/12/99; 09/30/02;

02/28/03

REFERENCES1. Ampicillin package insert (Amp-equine, SmithKline Beecham—US), Rev

5/1991, Rec 10/18/94.

2. Amoxicillin package insert (Moxilean, M.T.C. Pharmaceuticals—Canada), Rec

9/27/94.

3. Ampicillin package insert (Polyflex, Fort Dodge Laboratories, Inc.—US), Rev

1/94, Rec 10/24/94.

4. Sarasola P, McKellar QA. Pharmacokinetics and applications of ampicillin

sodium as an intravenous infusion in the horse. J Vet Pharmacol Ther 1993;

16: 63–9.

5. Amoxicillin intramammary infusion package insert (Amoxi-Mast, Pfizer

Animal Health—US), Rev 9/97. Downloaded from www.pfizer.com/ah on

8/26/02.

6. Hetacillin intramammary infusion package insert (Hetacin-K, Fort Dodge

Laboratories, Inc.—US), Rec 10/24/94.

7. Heath SE. Bovine mastitis. In: Howard JL. Current veterinary therapy 3: food

animal practice. Philadelphia: W. B. Saunders; 1993. p. 762–9.

8. Amoxicillin package insert (Amoxi-Tabs, SmithKline Beecham—US), Rev

7/93, Rec 10/18/94.


MD: The United States Pharmacopeial Convention, Inc. 2002.

10. The United States pharmacopeia. The national formulary. USP 26th revision

(January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United

States Pharmacopeial Convention, Inc. 2002. p. 141, 2548.

11. Donowitz GR, Mandell GL. Beta-lactam antibiotics. N Engl J Med 1988; 318:

419–26.

12. Papich MG. The beta-lactam antibiotics: clinical pharmacology and recent

developments. Compend Contin Educ Pract Vet 1987; 9(1): 68–74.

13. Wright AJ, Wilkowski CJ. The penicillins. Mayo Clin Proc 1983; 58: 21–32.

14. Jarp J, Bugge JP, Larsen S. Clinical trial of three therapeutic regimens for

bovine mastitis. 1989; 124: 630–4.

15. Craven N. Efficacy and financial value of antibiotic treatment of bovine clinical

mastitis during lactation—a review. Br Vet J 1987; 143: 410–22.

16. Hady PJ, Lloyd JW, Kaneene JB. Antibacterial use in lactating dairy cattle. J Am

Vet Med Assoc 1993 Jul; 203(2): 210–20.

17. Panel comment, 2/20/95.

18. Manufacturer comment, 2/28/95.

19. Sutherland R, Robinson OP. Laboratory and pharmacological studies in man

with hetacillin and ampicillin. Br Med J 1967 Jun 24; 2(555): 804–8.

AMINOPENICILLINS Veterinary—Intramammary-Local 35


AMINOPENICILLINS Veterinary—Systemic

This monograph includes information on the following: Amoxicillin;

Ampicillin.


For veterinary-labeled products—

Amoxi-Drop [Amoxicillin] Biomox Tablets [Amoxicillin]

Amoxi-Inject [Amoxicillin] Moxilean-50 Suspension [Amoxicillin]

Amoxil Tablets [Amoxicillin] Polyflex [Ampicillin]

Amoxi-Tabs [Amoxicillin] Robamox-V Oral Suspension [Amoxicillin]

Biomox Oral Suspension Robamox-V Tablets

[Amoxicillin] [Amoxicillin]

For human-labeled products—

Ampicin [Ampicillin] Penbritin [Ampicillin]

Apo-Ampi [Ampicillin] Polycillin-N [Ampicillin]

Novo-Ampicillin [Ampicillin] Principen [Ampicillin]

Nu-Ampi [Ampicillin] Totacillin [Ampicillin]

Omnipen [Ampicillin] Totacillin-N [Ampicillin]

Omnipen-N [Ampicillin]





GENERAL CONSIDERATIONSThe aminopenicillins have activity against penicillin-sensitive gram-

positive bacteria as well as some gram-negative bacteria. Ampicillin is

effective against alpha- and beta-hemolytic streptococci, including

Streptococcus equi{R-1}, non–penicillinase-producing Staphylococcus spe-

cies, some Bacillus anthracis, and most strains of Clostridia.{R-3}

Ampicillin is also effective against gram-negative bacteria, including

many strains of Escherichia coli (E. coli), Salmonella, and Pasteurella

multocida.{R-3} Amoxicillin has the same spectrum of activity as

ampicillin, but has slightly better activity against some gram-negative

bacteria, including E. coli, and Salmonella species.{R-4} Most anaerobic

bacteria, except beta-lactamase–producing strains of Bacteroides, are

sensitive to amoxicillin{R-78}. The aminopenicillins are subject to

destruction by beta-lactamases and therefore are not effective against

some bacteria that produce these enzymes.{R-1; 3} Most strains of

Klebsiella, Proteus, and Pseudomonas are resistant.{R-1; 23}

ACCEPTEDDermatitis, bacterial (treatment)—Dogs: Amoxicillin is indicated in the

treatment of bacterial dermatitis caused by susceptible organisms;

however, amoxicillin is not the treatment of choice because bacteria that

cause dermatitis are often resistant to this medication{R-7; 14; 68–70}.

Gastroenteritis, bacterial (treatment)—Cats and dogs: Amoxicillin and

parenteral ampicillin are indicated in the treatment of bacterial gas-

trointestinal tract infections caused by susceptible organisms.{R-3; 6}

Genitourinary tract infections, bacterial (treatment)—Cats and dogs:

Amoxicillin and parenteral ampicillin are indicated and [oral]

ampicillin is used in the treatment of genitourinary tract infections,

including cystitis and urethritis, caused by susceptible organisms.{R-3;

5; 6; 15; 24}

Pneumonia, bacterial (treatment)—

Calves, nonruminating1: Parenteral ampicillin is indicated for the

treatment of respiratory tract infections caused by susceptible

organisms, including some bacterial pneumonias associated with

shipping fever complex.{R-3}

Catsand dogs:Parenteral ampicillin and [amoxicillin] are indicated in the

treatment of pneumonia caused by susceptible organisms.{R-12}

Cattle: Parenteral amoxicillin and parenteral ampicillin are indicated

for the treatment of respiratory tract infections caused by susceptible

organisms, including some bacterial pneumonias associated with

shipping fever complex.{R-3; 5; 11}

[Horses]1: Parenteral ampicillin is used for the treatment of pneumo-

nia caused by susceptible organisms.{R-1}

Pododermatitis, necrotic, acute (treatment)1—Cattle: Parenteral amoxi-

cillin is indicated in the treatment of acute necrotic pododermatitis

caused by susceptible Fusobacterium necrophorum{R-11}; if administered

early in the course of the disease, amoxicillin may reduce the severity

of lesions.{R-62}

Skin and soft tissue infections (treatment)—

Cats and dogs: Amoxicillin and parenteral ampicillin are indicated in

the treatment of soft tissue infections and wounds caused by

susceptible organisms.{R-3; 5; 6; 13}

[Horses]1: Parenteral ampicillin is used in the treatment of skin and soft

tissue infections, including abscesses and wounds, caused by

susceptible organisms.{R-1}

[Strangles (treatment)]1—Horses: Parenteral ampicillin may be used in the

treatment of strangles caused by susceptible Streptococcus equi.{R-1}

Tonsillitis, bacterial (treatment); or

Tracheobronchitis, bacterial (treatment); or

Upper respiratory tract infections (treatment)—Cats and dogs: Amoxicil-

lin and parenteral ampicillin are indicated in the treatment of

tonsillitis, tracheobronchitis, and upper respiratory tract infections

caused by susceptible organisms{R-3; 5; 6}.

ACCEPTANCE NOT ESTABLISHED[Bacterial infections (treatment)]1—Calves, nonruminating: Until re-

cently, amoxicillin tablets were labeled in the United States for use in

the treatment of infections in calves caused by susceptible E. coli{R-8}.

Although the labeled product is no longer available, oral amoxicillin

may be used in the treatment of susceptible infections in calves.

[Leptospirosis (treatment)]1—Dogs: Although the efficacy has not been

established, amoxicillin is used in therapy of leptospirosis in dogs.

Penicillin and penicillin derivatives (including amoxicillin) are consid-

ered to be effective for eliminating leptospiremia, but it is not known if

they are effective in terminating the carrier state{R-30; 31; 91}.




Ampicillin is not labeled for use in horses to be used for food

production.{R-1}

Withdrawal times have been established for amoxicillin and ampicillin.

See the Dosage Forms section.{R-3; 8}

36 AMINOPENICILLINS Veterinary—Systemic


Canada—

Withdrawal times have been established for ampicillin. See the Dosage

Forms section.{R-5}

CHEMISTRYSource:

Amoxicillin—Semisynthetic derivative of ampicillin{R-14}.

Ampicillin—Semisynthetic penicillin{R-1}.

Chemical name:

Amoxicillin—4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid,

6-[[amino(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-, trihy-

drate[2S-[2 alpha,5 alpha,6 beta(S*)]]-{R-16}.

Ampicillin—4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid,

6-[(aminophenylacetyl)amino]-3,3-dimethyl-7-oxo-, [2S-[2 alpha,5

alpha,6 beta(S*)]]-{R-16}.

Ampicillin sodium—4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic

acid, 6-[(aminophenylacetyl)amino]-3,3-dimethyl-7-oxo-, mono-

sodium salt, [2S-[2 alpha,5 alpha,6 beta(S*)]]-{R-16}.

Molecular formula:

Amoxicillin—C16H19N3O5SÆ3H2O{R-16}.

Ampicillin—C16H19N3O4S{R-16}.

Ampicillin sodium—C16H18N3NaO4S{R-16}.

Molecular weight:

Amoxicillin—419.45{R-16}.

Ampicillin—349.41{R-16}.

Ampicillin sodium—371.39{R-16}.

Description:

Amoxicillin USP—White, practically odorless, crystalline powder{R-17}.

Ampicillin USP—White, practically odorless, crystalline powder{R-17}.

Ampicillin Sodium USP—White to off-white, odorless or practically

odorless, crystalline powder. Is hygroscopic.{R-17}

pKa:{R-22}

Amoxicillin—2.8 and 7.2.

Ampicillin—2.7 and 7.3.

Solubility:


carbon tetrachloride and in chloroform{R-17}.

Ampicillin USP—Slightly soluble in water and in methanol; insoluble in

carbon tetrachloride and in chloroform{R-17}.

Ampicillin Sodium USP—Very soluble in water and in isotonic sodium

chloride and dextrose solutions{R-17}.

PHARMACOLOGY/PHARMACOKINETICSNote: Unless otherwise noted, pharmacokinetic data in this section are

based on intravenous administration of ampicillin or amoxicillin.

There is evidence that administering ampicillin concurrently with

either gentamicin or kanamycin does not alter the pharmacokinetics of

either of the medications in horses{R-84; 89}.

Mechanism of action/effect: Like other penicillins, the aminopeni-

cillins produce their bactericidal effect by inhibiting bacterial cell wall

synthesis.{R-18} These antibiotics must penetrate the cell wall to attach

to specific proteins within the bacterial cell membrane. In actively

growing cells, the binding of ampicillin or amoxicillin within the cell

wall leads to interference with production of cell wall peptidoglycans

and subsequent lysis of the cell in an iso-osmotic environment{R-18–20}.

The aminopenicillins penetrate gram-negative bacterial cell walls more

rapidly than do the natural penicillins such as penicillin G and therefore

are more efficient in destroying those organisms. Amoxicillin enters the

gram-negative cell more easily than does ampicillin; this is considered

to be the basis for the greater activity of amoxicillin against some gram-

negative bacteria.{R-19}

Absorption:

The aminopenicillins are stable in gastric fluid.{R-8} One of the primary

differences between ampicillin and amoxicillin is the difference in

absorption after oral administration. A higher percentage of amoxi-

cillin than of ampicillin is absorbed after oral administration to cats,

dogs, pigs, and preruminant calves.{R-25–28; 46} In people, the more

complete oral absorption of amoxicillin leaves less drug remaining in

the intestinal tract than does ampicillin; therefore amoxicillin is

associated with a lower incidence of diarrhea as a side effect; however,

amoxicillin is also less effective than ampicillin in the treatment of

some intestinal bacterial infections in people.{R-20}

In horses, ampicillin sodium is well absorbed following intramuscular or

subcutaneous administration; however, oral dosage forms are poorly

absorbed by adult horses{R-84}. Oral absorption of amoxicillin has been

reported to be between 5.3 and 10.4%{R-42; 86}. Ampicillin trihydrate

administered intramuscularly produces lower ampicillin blood con-

centrations that extend over a longer period of time than does

ampicillin sodium{R-27; 49}.

Note: There is evidence that giving amoxicillin and clavulanate

concurrently has little effect on the pharmacokinetics of either

medication{R-82}; therefore, the following information based on

dosing with amoxicillin and clavulanate combination may be useful

in predicting the absorption of amoxicillin alone.

Calves—{R-82}

Preruminant calves (2 weeks old): Absorption of amoxicillin

when administered orally in combination with clavulanate at

doses of 10 to 20 mg per kg of body weight (mg/kg) is 34 to 36%.

Early ruminant calves (6 weeks old): Absorption of amoxicillin

and clavulanate combination is much poorer than in preruminant

calves given the same oral dose; therapeutic serum amoxicillin

concentrations are not achieved in early ruminant calves.

Distribution: The aminopenicillins are rapidly and widely distributed

into most body fluids{R-6; 8; 23; 39} with the exception of fluids of the

eye and the prostate gland{R-69}; also, distribution into cerebrospinal

fluid is low unless the meninges are inflamed{R-8}. Penetration into

synovial fluid is high{R-87; 89}.

Volume of distribution—

Amoxicillin: Horses—

Adult:

Area—325 mL per kg of body weight (mL/kg){R-42}.

Steady state—192 mL/kg{R-86}.

Foal (6 to 7 days of age):

Area—369 mL/kg{R-41}.

Steady state—265 mL/kg{R-41}.

Ampicillin:

Cats—Area: 116 mL/kg{R-40}.

Horses—Steady state: 180 mL/kg{R-23; 86}; 263 mL/kg{R-85}.

Protein binding:

Amoxicillin—Horses: Moderate (37 to 38%){R-45}.

AMINOPENICILLINS Veterinary—Systemic 37


Ampicillin—

Cattle: Low (18%).{R-43; 44}

Horses: Very low (6.8 to 8%).{R-48}

Rabbits: Low (17.5%).{R-44}

Sheep: Low (13.8%).{R-43; 44}

Half-life:

Distribution—Ampicillin:

Cats—13 minutes.{R-40}

Pigs—5 to 7 minutes.{R-39}

Elimination—

Amoxicillin:

Goats—67 minutes.{R-47}

Horses—

Adult: 39 minutes{R-42}; 85 minutes{R-45; 86}.

Foal (6 to 7 days of age): 44 minutes.{R-41}

Sheep—46 minutes.{R-47}

Ampicillin:

Cats—73 minutes.{R-40}

Dogs—20 minutes.{R-44}

Horses—37 minutes{R-23}; 42 minutes{R-85}; 93 minutes{R-48}; 103

minutes{R-86}.

Pigs—30 to 35 minutes.{R-39}

Rabbits—24 minutes.{R-44}

Peak serum concentration: Ampicillin—Horses:

6.2 to 9.7 mcg/mL at 16 minutes (intramuscular dose of 10 mg of

ampicillin sodium per kg of body weight){R-84}.

21.6 mcg/mL in nonpregnant mares (intramuscular dose of 22 mg of


8.9 mcg/mL in pregnant mares (intramuscular dose of 22 mg of


Elimination: Amoxicillin{R-6} and ampicillin{R-23} are primarily ex-

creted unchanged in the urine. Ten to twenty-five percent of the

administered dose of amoxicillin is excreted in the form of penicilloic

acid.

Total clearance—

Amoxicillin:

Goats—11.4 mL per minute per kg of body weight (mL/min/kg).{R-47}

Horses and foals, 6 to 7 days of age—5.7 mL/min/kg.{R-41; 42}

Sheep—10.1 mL/min/kg.{R-47}

Ampicillin: Horses—3.5 mL/min/kg{R-89}.


CROSS-SENSITIVITY AND/OR RELATED PROBLEMSAnimals allergic to one penicillin may be allergic to other penicillins

also.{R-49}

SPECIES SENSITIVITYCalves—In neonatal calves, ampicillin administered orally at 12 mg per kg

of body weight (mg/kg) every eight hours has been shown to cause

diarrhea and malabsorption. Aminopenicillins are not recommended

for treatment of enteritis in calves unless secondary complications, such

as septicemia or bacterial arthritis, are present.{R-9; 10}

Guinea pigs, hamsters, and rabbits—Oral ampicillin often disturbs the

normal microflora; the severity of this side effect makes the use of

aminopenicillins in these species contraindicated.{R-58; 73}

Horses—Large oral doses of the aminopenicillins can disturb the normal

cecal microflora and are generally contraindicated.{R-49; 58}

Ruminants—Oral ampicillin administration disrupts the rumen flora.

PREGNANCY/REPRODUCTIONThe safety of amoxicillin and ampicillin in the treatment of infections

during pregnancy has not been established.{R-33} Penicillins have been

shown to cross the placenta; however, laboratory animal reproduction

studies have shown no evidence of adverse effects in the fetus.{R-28; 33; 36}

LACTATIONIn humans, penicillins are distributed into milk{R-33; 37}. Ampicillin has

been shown to be distributed into the milk of cows and ewes.{R-50}







medication.

Antibacterials, bacteriostatic, such as:

Tetracycline{R-46}

(because the aminopenicillins act only on cells that are actively

reproducing, bacteriostatic antibiotics may decrease the efficacy of

amoxicillin and ampicillin by depressing the activity of target

cells{R-53}; however, the clinical significance of this interference is

not well documented)

Probenecid

(probenecid is a competitive inhibitor of renal tubular secretion

and slows the body clearance of aminopenicillins in horses, calves,

pigs, and possibly other species, resulting in increased serum

concentrations and longer elimination half-life){R-51; 52; 55}

LABORATORY VALUE ALTERATIONSThe following have been selected on the basis of their potential clinical-



Note: Laboratory value alterations relating specifically to use of amino-

penicillins in animals appear to be rarely described. Human labora-

tory value alterations have been reported and are included in this

section.


The following laboratory value alterations have been reported in

humans, and are included in the human monograph Penicillins

(Systemic) in USP DI Volume I; these laboratory value alterations are

intended for informational purposes only and may or may not be

applicable to the use of amoxicillin or ampicillin in the treatment of

animals:



With diagnostic test results

Glucose, urine

(high urinary concentrations of a penicillin may produce false

positive or falsely elevated test results with copper sulfate tests

[Benedict’s, Clinitest, or Fehling’s]; glucose enzymatic tests [Clinis-

tix or Testape] are not affected)

Direct antiglobulin (Coombs’) tests

(false-positive result may occur during therapy with any penicillin)


Alanine aminotransferase (ALT [SGPT]) and

Alkaline phosphatase and

Aspartate aminotransferase (AST [SGOT]) and

Lactate dehydrogenase (LDH)

(serum values may be increased)

Estradiol or

Estriol, total conjugated, or

Estriol-glucuronide or

Estrone, conjugated

(concentrations may be transiently decreased in pregnant women

following administration of ampicillin)

White blood cell count

(leukopenia or neutropenia is associated with the use of all

penicillins; the effect is more likely to occur with prolonged

therapy and severe hepatic function impairment)






problems exist:

Congestive heart failure or

Renal function impairment or

Electrolyte imbalance due to other causes

(the sodium content of ampicillin sodium administered at high doses

may contribute to electrolyte imbalances associated with congestive

heart failure, renal function impairment, or other causes; also,

because the aminopenicillins are excreted primarily by the kidneys,

the dosage regimen should be adjusted to avoid unneccessary

accumulation of medication in the plasma and tissues of animals

with renal function impairment{R-54})

Patient monitoring

The following may be especially important in patient monitoring

(other tests may be warranted in some patients, depending on

condition; » = major clinical significance):

Culture and pathogen susceptibility, in vitro, and

Minimum inhibitory concentration (MIC)

(in vitro cultures and MIC tests should be done on samples collected

prior to aminopenicillin administration to determine pathogen

susceptibility)

SIDE/ADVERSE EFFECTSThe following side/adverse effects have been selected on the basis of

their potential clinical significance (possible signs and, for humans,

symptoms in parentheses where appropriate)—not necessarily inclu-

sive:


Calves

Diarrhea and malabsorption{R-9}

Note: In healthy neonatal calves, oral administration of 12 mg of

ampicillin per kg of body weight (mg/kg) every eight hours has been

shown to cause diarrhea and malabsorption.{R-9}

Incidence unknown

All species {R-1; 6; 8; 11; 49}

Hypersensitivity reactions, specifically acute anaphylaxis;

hypersensitivity (urticaria, fever)

Horses

Diarrhea—primarily with oral dosage forms{R-49}


Horses

Injection site reaction (mild to moderate heat, pain, or swell-

ing)—with ampicillin trihydrate{R-1; 57}

Incidence less frequent{R-63}

Cats and dogs

Anorexia{R-28}; diarrhea{R-28}; vomiting{R-28}




included in the human monograph Penicillins (Systemic) in USP DI

Volume I; these side/adverse effects are intended for informational

purposes only and may or may not be applicable to the use of amox-

icillin or ampicillin in the treatment of animals:


Gastrointestinal reactions; headache; oral candidiasis; vaginal

candidiasis


Allergic reactions, specifically anaphylaxis; exfoliative derma-

titis; serum sickness–like reactions; skin rash, hives, or itching

Incidence rare

Clostridium difficile colitis; interstitial nephritis; leukopenia or

neutropenia; painat site of injection; thrombocytopenia; seizures

Note: Clostridium difficile colitis may occur up to several weeks after

discontinuation of these medications.

Interstitial nephritis is seen primarily with methicillin, and to a lesser

degree with nafcillin and oxacillin, but may occur with any penicillin.

Seizures are more likely to occur in patients receiving high doses of a

penicillin and/or patients with severe renal function impairment.





drug manufacturer.

VETERINARY DOSING INFORMATIONAll species: Beta-lactam antibiotics are believed to produce time-

dependent bacterial killing; that is, efficacy is related to the time the



serum concentrations are maintained above the minimum inhibitory

concentration (MIC) of the pathogen. As such, in critical cases frequent

dosings (short dosage intervals) may be preferred.

FOR ORAL DOSAGE FORMS ONLYCalves—Both amoxicillin and ampicillin are more bioavailable in calves

when administered in a glucose-glycine-electrolyte solution than when

administered with water or milk; however, unlike ampicillin, the

bioavailability of amoxicillin is not significantly altered by adminis-

tration with milk as compared with water.{R-60}

Dogs—There is some decrease in systemic availability when oral amox-

icillin or ampicillin is administered after a standard meal instead of on

an empty stomach.{R-25} However, because amoxicillin has twice the

oral bioavailability of ampicillin in dogs, the therapeutic efficacy of

amoxicillin may be less affected than that of ampicillin by adminis-

tration with food.{R-25}

Horses—Oral ampicillin is not recommended in adult horses because of

poor oral bioavailability (5%) and the risk of disturbing gastrointestinal

bacterial balance, thus causing diarrhea.{R-49} Amoxicillin trihydrate

is also poorly absorbed following oral administration, with a fractional

absorption of 10%; oral amoxicillin trihydrate should be used to treat

only highly susceptible pathogens.{R-42}

Sheep—In adult sheep, oral administration of ampicillin does not

provide therapeutically significant ampicillin plasma concentra-

tions.{R-61}

FOR TREATMENT OF ADVERSE EFFECTSTreatment includes the following:

For anaphylaxis:

• Administration of parenteral epinephrine.{R-6}

• Oxygen administration and respiratory support.

• Parenteral fluid administration as needed.

AMOXICILLIN

SUMMARY OF DIFFERENCESPharmacology/pharmacokinetics: Absorption—Cats, dogs, pigs, and pre-

ruminant calves: A higher percentage of amoxicillin than of ampicillin is

absorbed after oral administration.{R-25–28; 46} In dogs, orally admin-

istered amoxicillin is about 70% absorbed.{R-46}




AMOXICILLIN FOR ORAL SUSPENSION USPUsual dose: Antibacterial—Cats and dogs: Oral, 10 to 22 mg per kg of

body weight every eight, twelve, or twenty-four hours.{R-14; 26; 69}

Note: Although the efficacy has not been established, amoxicillin is

used in the treatment of [leptospirosis]1 in dogs at an intravenous

or oral dose of 22 mg per kg of body weight every six to eight

hours{R-91; 92}. It is not known if this therapy will eliminate the

carrier state.

Note: As beta-lactams appear to have time-dependent bacterial killing

properties, shorter dosing intervals, whenever possible, are

recommended to improve efficacy. Once daily dosing should be used

only when organisms with very low MICs are suspected.{R-80}

Strength(s) usually available: When reconstituted according to

manufacturer’s instructions—

U.S.:{R-6; 13; 21; 38}

Veterinary-labeled product(s)—

50 mg per mL (Rx) [Amoxi-Drop; Biomox Oral Suspension; Robamox-V

Oral Suspension].

Canada:{R-38}


50 mg per mL (Rx) [Moxilean-50 Suspension].


between 15 and 30 �C (59 and 86 �F). Store in a tight container.

Preparation of dosage form: To reconstitute, add the amount of water

recommended by the manufacturer and shake vigorously. Before each

use, shake well to resuspend.{R-6; 21}

Stability: After reconstitution, the suspension retains potency for 14

days. Some products require refrigeration.{R-6; 21}

USP requirements: Preserve in tight containers, at controlled room

temperature. Contains the labeled amount, within –10% to +20%.

Contains one or more suitable buffers, colors, flavors, preservatives,

stabilizers, sweeteners, and suspending agents. Meets the requirements

for Identification, Uniformity of dosage units (single-unit containers),

Deliverable volume (multiple-unit containers), pH (5.0–7.5 in the

suspension constituted as directed in the labeling), and Water (not

more than 3.0%).{R-17}

AMOXICILLIN TABLETS USPUsual dose: Antibacterial—Cats and dogs: See Amoxicillin For Oral

Suspension USP.

Note: [Calves, nonruminating]1—An oral dose of 10 to 22 mg per kg of

body weight every eight, twelve, or twenty-four hours has been used in

the treatment of suceptible bacterial infections.{R-69}

As beta-lactams appear to have time-dependent bacterial killing

properties, shorter dosing intervals, whenever possible, are recom-

mended to improve efficacy. Once daily dosing should be used only

when organisms with very low MICs are suspected.{R-80}


U.S.—{R-7; 8; 13; 14; 38}


50 mg (Rx) [Amoxi-Tabs; Biomox Tablets; Robamox-V Tablets].


150 mg (Rx) [Amoxi-Tabs].



Canada—{R-29; 38}


50 mg (Rx) [Amoxil Tablets].

100 mg (Rx) [Amoxil Tablets; GENERIC].





Withdrawal times: There are no established withdrawal times for food-

producing animals in the United States or Canada because products

labeled for this use are not available. Based on previously available U.S.

product labeling, if oral amoxicillin is administered to nonruminating

calves at a dose of 8.8 mg per kg of body weight every twelve hours for

five days or less, a meat withdrawal time of 20 days should be suffi-

cient to avoid residues{R-8}.




temperature. Label chewable Tablets to indicate that they are to be

chewed before swallowing. Tablets intended solely for veterinary use

are so labeled. Contain the labeled amount, within )10% to +20%.

Meet the requirements for Thin-layer chromatographic identification

test and Dissolution (80% in 90 minutes in water in Apparatus 2 at 75

rpm; and for products labeled as Chewable Tablets: 70% in 90 minutes

in water in Apparatus 2 at 75 rpm).{R-17}






AMOXICILLIN FOR INJECTABLE SUSPENSION USPUsual dose: Antibacterial1—

Cats and dogs: Intramuscular or subcutaneous, 11 to 22 mg per kg of

body weight every eight, twelve, or twenty-four hours.{R-64; 69}

Note: Although the efficacy has not been established, amoxicillin is

used in the treatment of [leptospirosis]1 in dogs at an intravenous or

oral dose of 22 mg per kg of body weight every six to eight

hours{R-91; 92}. It is not known if this therapy will eliminate the

carrier state.

Cattle: Intramuscular or subcutaneous, 6.6 to 22 mg per kg of body

weight every eight, twelve, or twenty-four hours.{R-69}

Note: Maximum volume per injection site should not exceed thirty

mL.{R-11}







U.S.:{R-11; 38; 64}


100 mg per mL (Rx) [Amoxi-Inject (3-gram vial labeled for cats and

dogs)].

250 mg per mL (Rx) [Amoxi-Inject (3-gram vial labeled for cats and

dogs or 25-gram vial labeled for cattle)].

Canada:


Not commercially available.{R-38}

Withdrawal times:{R-11}

U.S.—

Note: Product labeling listing the above withdrawal times states that

the recommended withdrawal times are based on a dose of 6.6 mg per

kg of body weight every twenty-four hours and a course of therapy not

exceeding five days.{R-11}



manufacturer.

Preparation of dosage form: Dosage form is reconstituted by adding

the amount of sterile water for injection recommended by the manu-

facturer.{R-11}

Stability: After reconstitution, the suspension retains potency for twelve

months when refrigerated or for three months when stored at room

temperature (72 �F).{R-11}

USP requirements: Preserve in Containers for Sterile Solids. A sterile

mixture of Amoxicillin and one or more suitable buffers, preservatives,

stabilizers, and suspending agents. Label it to indicate that it is for

veterinary use only. Contains the labeled amount, within )10% to

+20%. Meets the requirements for Identification, Bacterial endotoxins,

Sterility, pH (5.0–7.0, in the suspension constituted as directed in the

labeling), and Water (11.0–14.0%).{R-17}



AMPICILLIN

SUMMARY OF DIFFERENCESPharmacology/pharmacokinetics: Absorption—Calves, nonruminating,

cats, dogs, and pigs: With oral administration, ampicillin is more poorly

absorbed than is amoxicillin; the dosage is adjusted to compen-

sate.{R-25; 26} In dogs, orally administered ampicillin trihydrate is only

about 35% absorbed{R-46}; in cats, oral anhydrous ampicillin is about

20 to 40% absorbed.{R-40}

ADDITIONAL DOSING INFORMATIONSee also Veterinary Dosing Information.

Pharmacology/pharmacokinetics: Horses—There is evidence that admin-

istering ampicillin concurrently with either gentamicin or kanamycin

does not alter the pharmacokinetics of either of the medications{R-84;

89}.

Parenteral dosage forms—Ampicillin sodium produces higher plasma

concentrations than does ampicillin trihydrate; ampicillin trihydrate

produces relatively low plasma concentrations but maintains measur-

able concentrations for a longer period of time.{R-49}

Withdrawal time


Cattle 25 96






AMPICILLIN CAPSULES USPUsual dose: [Antibacterial]

1

—

Cats: Oral, 10 to 20 mg per kg of body weight every eight to twenty-

four hours.{R-40; 69}

Dogs: Oral, 20 to 40 mg per kg of body weight every eight to twelve

hours.{R-32; 69}






U.S.—{R-33; 34; 35}



Human-labeled product(s):

250 mg (Rx) [Omnipen; Principen; Totacillin; GENERIC].

500 mg (Rx) [Omnipen; Principen; Totacillin; GENERIC].

Canada—{R-36; 37}




250 mg (Rx) [Apo-Ampi; Novo-Ampicillin; Nu-Ampi; Penbritin].

500 mg (Rx) [Apo-Ampi; Novo-Ampicillin; Nu-Ampi; Penbritin].



manufacturer. Store in a tight container.

USP requirements: Preserve in tight containers. Label Capsules to

indicate whether the ampicillin therein is in the anhydrous form or is

the trihydrate. Contain an amount of ampicillin (anhydrous or as the

trihydrate) equivalent to the labeled amount of ampicillin, within

)10% to +20%. Meet the requirements for Identification, Dissolution

(75% in 45 minutes in water in Apparatus 1 at 100 rpm), Uniformity

of dosage units, and Loss on drying (not more than 4.0% for the

anhydrous and 10.0–15.0% for the trihydrate).{R-17}






The dosing and strengths of the dosage forms available are expressed

in terms of ampicillin free acid (not the sodium salt).

AMPICILLIN FOR INJECTABLE SUSPENSION USPUsual dose: Antibacterial—

Cats: Intramuscular or subcutaneous, 10 to 20 mg per kg of body

weight every twelve to twenty-four hours.{R-40}

Dogs: Intramuscular or subcutaneous, 10 to 50 mg per kg of body

weight every twelve hours.{R-32}

Cattle and calves1, including nonruminating calves1: Intramuscular, 4.4

to 11 mg per kg of body weight every twenty-four hours.{R-3}


properties, shorter dosing intervals, whenever possible, are

recommended to improve efficacy. Once daily dosing should be used

only when organisms with very low MICs are suspected.{R-80}

Size(s) usually available:

U.S.—{R-3; 38}


10 grams (Rx) [Polyflex].


Canada—{R-5; 38}





U.S.—{R-3}


treatment should not exceed seven days for withdrawal times to

apply.{R-3}

Canada—{R-5}

Note: Product labeling listing the above withdrawal times states that the

recommended withdrawal times are based on a dose of 6 mg per kg of

body weight every twenty-four hours and a course of therapy not

exceeding seven days.{R-5}



manufacturer.

Preparation of dosage form:

The sizes may be reconstituted according to manufacturer’s directions to

one of the following strengths: 100, 200, 250, 300, or 400 mg per mL.

Before each use, shake well to resuspend.{R-5}

Stability: After reconstitution, the solution retains potency for twelve

months when refrigerated and for three months when stored at

25 �C.{R-3}

USP requirements: Preserve in Containers for Sterile Solids. A dry

mixture of ampicillin trihydrate and one or more suitable buffers,

Withdrawal time


Cattle 6 48

Withdrawal time


Cattle 6 48

Pigs 4



preservatives, stabilizers, and suspending agents. Contains the equiv-

alent of the labeled amount of ampicillin, within -10% to +20%. Meets

the requirements for Identification, Bacterial endotoxins, Sterility, pH

(5.0–7.0, in the suspension constituted as directed in the labeling), and

Water (11.4–14.0%), and for Uniformity of dosage units, and Labeling

under Injections.{R-17}

AMPICILLIN FOR INJECTION USPUsual dose: [Antibacterial]1—

Cats and dogs: Intramuscular or intravenous, 10 to 20 mg (free acid)

per kg of body weight every six to eight hours.{R-32; 40}

Horses: Intramuscular or intravenous, 10 to 20 mg (free acid) per kg of

body weight every six to eight hours.{R-78; 79}

Note: The dose of 10 to 20 mg per kg of body weight every six to

eight hours is sufficient for most sensitive bacteria; however, for

infections due to moderately resistant organisms or infections

associated with natural tissue barriers, such as those of the central

nervous system, doses of up to 25 to 40 mg per kg of body weight

every six to eight hours have been used.{R-83}

A possible increased risk of gastrointestinal side effects with

increasing dose should be considered.


U.S.—{R-1; 38; 76}




125 mg (free acid) (Rx) [Omnipen-N; Polycillin-N; GENERIC].

250 mg (free acid) (Rx) [Omnipen-N; Polycillin-N; Totacillin-N; GENERIC].

500 mg (free acid) (Rx) [Omnipen-N; Polycillin-N; Totacillin-N; GENERIC].

1 gram (free acid) (Rx) [Omnipen-N; Polycillin-N; Totacillin-N; GENERIC].

2 grams (free acid) (Rx) [Omnipen-N; Polycillin-N; Totacillin-N;

GENERIC].

10 grams (free acid) (Rx) [Omnipen-N; Polycillin-N; GENERIC].

Canada—{R-77}




125 mg (free acid) (Rx) [Ampicin; Penbritin].



1 gram (free acid) (Rx) [Ampicin; Penbritin].

2 grams (free acid) (Rx) [Ampicin; Penbritin].

Packaging and storage: Prior to reconstitution, store below 40 �C

(104 �F), preferably between 15 and 30 �C (59 and 86 �F), unless

otherwise specified by manufacturer. Protect the reconstituted solution

from freezing.

Preparation of dosage form: Dosage form should be reconstituted

according to manufacturer’s directions.{R-1}

Stability:

After reconstitution, the solution retains potency for 1 hour at room

temperature (70 to 75 �C).{R-1}

After reconstitution for intravenous infusion, solutions with concentra-

tions of up to 30 mg per mL retain at least 90% of their potency for 2 to

8 hours at room temperature or up to 72 hours if refrigerated in

suitable diluents (see manufacturer’s package insert).{R-75}

Concentrated solutions (100 mg per mL) prepared from pharmacy bulk

vials retain their potency for 2 hours at room temperature or 4 hours if

refrigerated.{R-75}

Diluted solutions (20 mg per mL or less) in 5% dextrose injection retain

their potency for 2 hours at room temperature or 3 hours if

refrigerated.{R-75}

Incompatibilities: Extemporaneous admixtures of beta-lactam anti-

bacterials (penicillins and cephalosporins) and aminoglycosides may

result in substantial mutual inactivation. These types of antibacterial

agents should not be mixed in the same intravenous bag, bottle, or

tubing.

Additional information: This product contains approximately 3 mil-

liequivalents (mEq; millimoles [mmol]) of sodium per gram of ampi-

cillin and could result in electrolyte overload in some animals.{R-54}

USP requirements: Preserve in Containers for Sterile Solids. Protect the

constituted solution from freezing. Contains an amount of Ampicillin

Sodium equivalent to the labeled amount of ampicillin within )10% to

+15%. Meets the requirements for Constituted solution, Bacterial

endotoxins, Particulate matter, Uniformity of dosage units, and for

Identification tests, Crystallinity, pH, and Water under Ampicillin

Sodium, and for Sterility tests, and Labeling under Injections{R-17}.



Developed: 07/25/95

Revised: 06/30/02

Interim revision: 07/18/96; 06/02/97; 05/27/98; 10/12/99; 04/04/03

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44. Powers TE, Garg RC. Pharmacotherapeutics of newer penicillins and cepha-

losporins. J Am Vet Med Assoc 1980 May; 10(2): 1054–60.

45. Montesissa C, et al. Pharmacokinetics of sodium amoxicillin in horses. Res Vet

Sci 1988; 44: 233–6.

46. Yeoman GH. Microbiology and bioavailability of amoxicillin. Vet Med Small

Anim Clin 1977; 4(suppl): 720–38.

47. Craigmill AL, Pass MA, Wetzslich S. Comparative pharmacokinetics of

amoxicillin administered intravenously to sheep and goats. J Vet Pharmacol

Ther 1992; 15: 72–7.

48. Durr A. Comparison of the pharmacokinetics of penicillin G and ampicillin in

the horse. Res Vet Sci 1976; 20: 24–9.

49. Sarasola P, McKellar QA. Ampicillin and its congener prodrugs in the horse. Br

Vet J 1994; 150(2): 173–87.

50. Ziv G, Shani J, Sulman FG. Pharmacokinetic evaluation of penicillin and

cephalosporin derivatives in serum and milk of lactating cows and ewes. Am J

Vet Res 1973 Dec; 34(12): 1561–5.

51. Ziv G, Horsey J. Elevation and prolongation of serum ampicillin and

amoxycillin concentrations in calves by the concomitant administration of

probenecid. J Vet Pharmacol Ther 1979; 2: 187–94.

52. Sarasola P, McKellar QA. Effect of probenecid on disposition kinetics of

ampicillin in horses. Vet Rec 1992; 131: 173–5.

53. Huber WG. Penicillins. In: Booth NH, McDonald LE. Veterinary pharmacol-

ogy and therapeutics, 5th ed. Ames, IA: Iowa State University Press; 1988.

p. 796–812.

54. Riviere JE, Coppoc GL. Dosage of antimicrobial drugs in patients with renal

insufficiency. J Am Vet Med Assoc 1981 Jan; 178(1): 70–2.

55. Galtier P, Alvinerie M. Enhancement of ampicillin bioavailability in pigs. J Vet


56. Mason MJ, Mason KV. A pemphigus foliaceus-like eruption associated with the

use of ampicillin in a cat. Aust Vet J 1987 Jul; 64(7): 223–4.

57. Traver DS, Riviere JE. Penicillin and ampicillin therapy in horses. J Am Vet

Med Assoc 1981 Jun; 178(11): 1186–9.

58. Prescott JF, Baggot JD. Antimicrobial therapy in veterinary medicine, 2nd ed.

Ames, IA: Iowa State University Press; 1993. p. 90–5.

59. Leib MS. Acute vomiting: a diagnostic approach and symptomatic manage-

ment. In: Kirk RW, Bonagura JD, editors. Current veterinary therapy XI. Small

animal practice. Philadelphia: W.B. Saunders Company; 1992. p. 583–7.

60. Palmer GH, Bywater RJ, Stanton A. Absorption in calves of amoxicillin,

ampicillin, and oxytetracycline given in milk replacer, water or an oral

rehydration formulation. Am J Vet Res 1983 Jan; 44(1): 68–71.

61. Oukessou M, Toutain PL. Effect of water deprivation on absorption (oral,

intramuscular) and disposition of ampicillin in sheep. J Vet Pharmacol Ther

1992; 15: 421–32.

62. Braun RK, et al. Efficacy of amoxicillin trihydrate for the treatment of

experimentally induced foot rot in cattle. Am J Vet Res 1987 Dec; 48(12):

1751–4.

63. Francis ME, Marshall AB, Turner WT. Amoxycillin: clinical trials in dogs and

cats. Vet Rec 1978 Apr; 102: 377–80.

64. Amoxicillin package insert (Amoxi-Inject [Cats and Dogs], SmithKline

Beecham—US), Rev 3/91, Rec 10/18/94.

65. Hjerpe CA. The bovine respiratory disease complex. In: Howard JL. Current

veterinary therapy 3. Food animal practice. Philadelphia: W.B. Saunders

Company; 1993. p. 653–64.

66. Robinson NE, editor. Current therapy in equine medicine 3. Philadelphia: W.B.

Saunders Company; 1992. p. 815.

67. Brown MP, et al. Ampicillin trihydrate in foals: serum concentrations and

clearance after a single oral dose. Equine Vet J 1984; 16(4): 371–3.









76. PDR Physicians’ desk reference, 48th ed. 1994. Montvale, NJ: Medical

Economics Data Production Company; 1994. p. 2571.

77. Krogh, CME, editor. CPS Compendium of pharmaceuticals and specialities,

29th ed. Ottawa: Canadian Pharmaceutical Association; 1994. p. 63–4, 995.




81. Bywater RJ, Palmer GH, Buswell JF, Stanton A. Clavulanate and amoxycillin:

activity in vitro and bioavailability in the dog. Vet Rec 1985; 116: 33–6.

82. Soback S, Bor A, Kurtz B, et al. Clavulanate-potentiated amoxycillin: in vitro

antibacterial activity and oral bioavailability in calves. J Vet Pharmacol Ther

1987; 10: 105–13.


84. Firth EC, Klein WR, Nouws JFM, et al. Effect of induced synovial inflammation

on pharmacokinetics and synovial concentration of sodium ampicillin and

kanamycin sulfate after systemic administration in ponies. J Vet Pharmacol

Ther 1988; 11: 56–62.



85. Sarasola P, McKellar QA. Pharmacokinetics of bacampicillin in equids. Am J

Vet Res 1995 Nov; 56(11): 1486–92.

86. Ensink JM, Klein WR, Mevius DJ, et al. Bioavailability of oral penicillins in the

horse: a comparison of pivampicillin and amoxicillin. J Vet Pharmacol Ther

1992; 15: 221–30.


88. Traver DS, Riviere JE. Ampicillin in mares: a comparison of intramuscular

sodium ampicillin or sodium ampicillin-ampicillin trihydrate injection. Am J

Vet Res 1982 Mar; 43(3): 402–4.

89. Bowman KF, Dix LP, Riond JL, Riviere JE. Prediction of pharmacokinetic

profiles of ampicillin sodium, gentamicin sulfate, and combination ampicillin

sodium-gentamicin sulfate in serum and synovia of healthy horses. Am J Vet

Res 1986; 47(7): 1590–6.

90. Beech J, Leitch M, Kohn CW, et al. Serum and synovial fluid levels of sodium

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350–4.

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cases (1990-1998). J Am Vet Med Assoc 2000 Feb 1; 216(3): 371–5.

92. Committee comment, 1/22/02.



AMOXICILLIN AND CLAVULANATE Veterinary—Systemic

A commonly used brand name for a veterinary-labeled product is

Clavamox.


availability, see the Dosage Forms sections(s).




commercially available in Canada.

GENERAL CONSIDERATIONSAmoxicillin has activity against penicillin-sensitive gram-positive bac-

teria as well as some gram-negative bacteria. The gram-positive

spectrum of activity includes alpha- and beta-hemolytic streptococci,

some Staphylococci species, Clostridia species, and some Bacillus

anthracis{R-2}. Amoxicillin is also effective against gram-negative

bacteria, including Escherichia coli (E. coli), many strains of Salmonella,

and Pasteurella multocida.{R-2} Amoxicillin is sensitive to destruction by

beta-lactamases and therefore when administered by itself is not

effective against bacteria, such as Klebsiella and Proteus, that produce

these enzymes.{R-2}

Clavulanate is a naturally occurring noncompetitive inhibitor of beta-

lactamase produced by gram-positive, and also many gram-negative,

bacteria.{R-3; 4} Although it has a beta-lactam chemical structure,

clavulanic acid has little antibacterial activity of its own. However,

when clavulanic acid is administered concurrently with amoxicillin, it

extends the activity of amoxicillin by preventing its destruction by

bacterial enzymes. Beta-lactamase inhibitors will only assist in the

destruction of bacteria that produce beta-lactamase enzymes; other

forms of resistance, such as alteration of penicillin-binding protein, are

not affected. Also, the beta-lactam structure of amoxicillin and

clavulanate may stimulate some bacteria to produce more beta-

lactamase; it is easier for clavulanate to protect amoxicillin against a

small amount of enzyme than against a large amount.

Clavulanate extends the spectrum of activity of amoxicillin to include

beta-lactamase producing E. coli, Klebsiella, Proteus, and Staphylo-

coccus species.{R-4; 6} Most anaerobes, including Bacterioides fragilis,

are susceptible to the combination of clavulanic acid and

amoxicillin.{R-5} However, some beta-lactamase enzymes, including

those produced by Enterobacter and Pseudomonas, are unaffected by

clavulanate.{R-6}

ACCEPTEDPeriodontal infections (treatment)—Dogs: Amoxicillin and clavulanate

combination is indicated in the treatment of periodontal

infections caused by susceptible strains of aerobic and anaerobic

bacteria{R-1; 31}.

Skin and soft tissue infections (treatment)—Cats and dogs:{R-7; 8}

Amoxicillin and clavulanate combination is indicated in the treatment

of skin and soft tissue infections caused by susceptible Staphylococcus

species, E. coli, Pasteurella species, and Streptococcus species.

Urinary tract infections, bacterial (treatment)—Cats{R-7} and [dogs]:{R-9–

11} Amoxicillin and clavulanate combination is indicated in the

treatment of urinary tract infections, including those caused by

susceptible E. coli.

ACCEPTANCE NOT ESTABLISHED[Osteomyelitis (treatment)]1—Cats and dogs: There are insufficient data

to show that amoxicillin and clavulanate combination is effective in

the treatment of osteomyelitis in cats and dogs; however, in vitro

studies show that the bacteria causing this type of infection are often

susceptible.{R-32–34; 37}



CHEMISTRYSource:

Amoxicillin—Semisynthetic derivative of ampicillin.{R-12}

Clavulanate—A fermentation product of the actinomycete Streptomyces

clavuligerus.{R-7; 8}

Chemical name:

Amoxicillin—4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6-

[[amino(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-, trihy-

drate[2S-[2alpha,5alpha,6beta(S*)]]-.{R-13}

Clavulanate potassium—4-Oxa-1-azabicyclo[3.2.0]heptane-2-carboxylic

acid, 3-(2-hydroxyethylidene)-7-oxo-, monopotassium salt, [2R-

(2alpha,3Z,5alpha)]-.{R-13}

Molecular formula:

Amoxicillin—C16H19N3O5SÆ3H2O.{R-13}

Clavulanate potassium—C8H8KNO5.{R-13}

Molecular weight:

Amoxicillin—419.45.{R-13}

Clavulanate potassium—237.25.{R-13}

Description:

Amoxicillin USP—White, practically odorless, crystalline powder.{R-14}

Clavulanate Potassium USP—White to off-white powder. Is moisture-

sensitive.{R-14}

pKa:

Amoxicillin—2.8 and 7.2.{R-16}

Clavulanate—2.7.{R-17}

Solubility:


carbon tetrachloride, and in chloroform.{R-14}

Clavulanate Potassium USP—Freely soluble in water, but stability in

aqueous solution is not good; optimum stability at a pH of 6.0 to 6.3;

soluble in methanol, with decomposition.{R-14}

PHARMACOLOGY/PHARMACOKINETICSNote: There is evidence that giving amoxicillin with clavulanate has little

effect on the pharmacokinetics of either medication.{R-17; 24}


Amoxicillin—Bactericidal. Amoxicillin must reach and bind to the

penicillin-binding proteins on the inner membrane of the bacterial

46 AMOXICILLIN AND CLAVULANATE Veterinary—Systemic


cell wall. In actively growing cells, the binding of amoxicillin within

the cell wall leads to interference with production of cell wall

peptidoglycans and subsequent lysis of the cell in an iso-osmotic

environment.{R-18–20}

Clavulanate—Binds irreversibly to susceptible beta-lactamase enzymes,

preventing hydrolysis of the amoxicillin beta-lactam ring. When

clavulanate binds with the enzyme, a chemical complex is formed,

which destroys the clavulanate and inactivates the beta-lactama-

se.{R-3; 4; 6}

Absorption:

Cats and dogs—Both amoxicillin and clavulanate are stable in

gastric fluid and, therefore, are well absorbed after oral admini-

stration.{R-6; 7; 21–23}

Calves—

Preruminant calves (2 weeks old): Absorption of amoxicillin when

administered in combination with clavulanate at doses of 10 to 20

mg per kg of body weight (mg/kg) is 34 to 36%.

Early ruminant calves (6 weeks old): Absorption of amoxicillin and

clavulanate combination is much poorer than in preruminant calves

given the same dose; early ruminant calves do not develop

therapeutic serum amoxicillin concentrations.{R-26}

Horses—Orally administered amoxicillin is only 10% absorbed in adult

horses.{R-36}

Peak serum concentration: Amoxicillin—

Calves, preruminant:

Oral, 10 mg/kg dose—2 mcg per mL (mcg/mL) at 78 minutes.{R-26}

Oral, 20 mg/kg dose—3.3 mcg/mL at 64 minutes.{R-26}

Dogs: Oral, 12.5 mg/kg dose—5 to 6 mcg/mL at 60 minutes.{R-38}

Distribution: Cats and dogs—Amoxicillin and clavulanate diffuse

into most body tissues and fluids; however, distribution of amoxi-

cillin into cerebrospinal fluid is low unless the meninges are in-

flamed.{R-7; 8}

Elimination: Amoxicillin—Primarily excreted unchanged in the urine.

10 to 25% is excreted in the form of penicilloic acid.{R-25}


CROSS-SENSITIVITY AND/OR RELATED PROBLEMSAnimals allergic to one penicillin or cephalosporin may also be allergic to

amoxicillin or clavulanate.{R-9}

SPECIES SENSITIVITYHorses and rabbits—This medication is generally contraindicated in these

species because of the potential for disturbance of the normal

gastrointestinal microflora.{R-6}

PREGNANCY/REPRODUCTIONThe safety of administration of amoxicillin and clavulanate to

pregnant or breeding animals is unknown.{R-8; 9} Penicillins have

been shown to cross the placenta; however, laboratory animal

reproduction studies have shown no evidence of adverse effects on

the fetus.{R-17}

LACTATIONIn humans, penicillins are distributed into milk, and the same is true for

many animals.{R-27; 28}



mechanism in parentheses where appropriate)—not necessarily

inclusive (» = major clinical significance):



medication.

Probenecid

(probenecid decreases tubular secretion and slows the body clearance

of amoxicillin, resulting in increased serum concentrations and

longer elimination half-lives in many species{R-24; 29}; however,

clavulanic acid is unlikely to be affected because it is cleared

primarily by glomerular filtration{R-17})




Note: Laboratory value alterations relating specifically to use of

amoxicillin and clavulanate in animals appear to be rare. Human

laboratory value alterations have been reported and are included in

this section.



humans, and are included in the human monograph Penicillins and

Beta-lactamase Inhibitors (Systemic) in USP DI Volume I; these

laboratory value alterations are intended for informational purposes

only and may or may not be applicable to the use of amoxicillin and

clavulanate combination in the treatment of animals:


Glucose, urine

(high urinary concentrations of a penicillin may produce false-

positive or falsely elevated test results with copper-reduction tests

[Benedict’s, Clinitest, or Fehling’s]; glucose enzymatic tests

[Clinistix or Testape] are not affected)

Direct antiglobulin (Coombs’) tests

(false-positive result may occur during therapy with any penicillin)







Bilirubin, serum


Estradiol or

Estriol-glucuronide or

Estriol, total conjugated, or

Estrone, conjugated

(concentrations may be transiently decreased in pregnant women

following administration of amoxicillin)

AMOXICILLIN AND CLAVULANATE Veterinary—Systemic 47


White blood count

(leukopenia or neutropenia is associated with the use of all

penicillins; the effect is more likely to occur with prolonged

therapy and severe hepatic function impairment)




Culture and susceptibility, in vitro, and


(in vitro cultures and MIC test should be done on samples collected

prior to amoxicillin and clavulanate administration to determine

pathogen susceptibility{R-7; 8})


potential clinical significance (possible signs and, for humans,

symptoms in parentheses where appropriate)—not necessarily

inclusive:


All species{R-7; 8; 25}

Hypersensitivity reactions, specifically acute anaphylaxis, fever,

or urticaria

THOSE INDICATING NEED FOR MEDICAL ATTENTIONONLY IF THEY CONTINUE OR ARE BOTHERSOMEIncidence less frequent

Cats and dogs{R-6; 17}

Anorexia; diarrhea; vomiting




included in the human monograph Penicillins and Beta-lactamase

Inhibitors (Systemic) in USP DI Volume I; these side/adverse effects are


applicable to the use of amoxicillin and clavulanate in the treatment of

animals:


Gastrointestinal reactions; headache


Allergic reactions, specifically anaphylaxis; oral candidiasis;

serum sickness–like reactions; skin rash, hives, or itching;

vaginal candidiasis

Incidence rare

Chest pain; chills; Clostridium difficile colitis; dysuria or

urinary retention; edema; epistaxis; erythema multiforma or

Stevens-Johnson syndrome; fatigue; glossitis; hepatic dysfunc-

tion, including cholestatic hepatitis; leukopenia or neutrope-

nia; malaise; platelet dysfunction; proteinuria or pyuria;

seizures; toxic epidermal necrolysis









drug manufacturer.

VETERINARY DOSING INFORMATIONIn cats and dogs, the therapeutic efficacy of amoxicillin{R-21} and

clavulanate is not significantly affected by administration with food.

FOR TREATMENT OF ADVERSE EFFECTSFor anaphylaxis

• Parenteral epinephrine.{R-25}

• Oxygen administration and breathing support.

ORAL DOSAGE FORMSNote: The dosing and strengths of the dosage forms available are

expressed in terms of clavulanic acid (not the potassium salt).

AMOXICILLIN AND CLAVULANATE POTASSIUM FORORAL SUSPENSION USPUsual dose: Antibacterial—Cats and dogs: Oral, 11 to 20 mg of amox-

icillin and 2.75 to 5 mg of clavulanic acid per kg of body weight every

eight to twelve hours.{R-32–34}

Note: Urinary tract infections should be treated for fourteen days or

longer. Deep pyoderma may require treatment for twenty-one

days. Treatment for any indication should not exceed thirty

days.{R-8}

Strength(s) usually available{R-30}: When reconstituted according to


U.S.:


50 mg of amoxicillin and 12.5 mg clavulanic acid per mL (Rx)

[Clavamox].

Canada:


50 mg of amoxicillin and 12.5 mg of clavulanic acid per mL (Rx)

[Clavamox].



Stability: After reconstitution, suspensions retain their potency for ten

days if refrigerated.{R-8}

Auxiliary labeling:

• Refrigerate.

• Shake well.


temperature. Contains the labeled amount of amoxicillin, within –10%

to +20%, and an amount of clavulanate potassium equivalent to the



labeled amount of clavulanic acid, within )10% to +25%. Contains

one or more suitable buffers, colors, flavors, preservatives, stabilizers,

sweeteners, and suspending agents. Meets the requirements for Iden-

tification, pH (3.8–6.6, in the suspension constituted as directed in the

labeling, the test being performed immediately after constitution), and

Water (not more than 7.5%, where the label indicates that after

constitution as directed, the suspension contains 25 mg of amoxicillin

per mL; not more than 8.5%, where the label indicates that after

constitution as directed, the suspension contains 50 mg of amoxicillin

per mL).{R-14}

AMOXICILLIN AND CLAVULANATE POTASSIUMTABLETS USPUsual dose: See Amoxicillin and Clavulanate Potassium for Oral Suspension

USP.


U.S.—


50 mg of amoxicillin and 12.5 mg of clavulanic acid (Rx) [Clavamox].

100 mg of amoxicillin and 25 mg of clavulanic acid (Rx) [Clavamox].



Canada—


50 mg of amoxicillin and 12.5 mg of clavulanic acid (Rx) [Clavamox].




Packaging and storage: Store below 25 �C (77 �F), unless otherwise

specified by manufacturer. Store in a tight container.

Auxiliary labeling:

• Do not remove from foil strip until ready to use.

USP requirements: Preserve in tight containers. Label chewable Ta-

blets to include the word ‘‘chewable’’ in juxtaposition to the official

name. The labeling indicates that chewable Tablets may be chewed

before being swallowed or may be swallowed whole. Tablets intended

for veterinary use only are so labeled. Contain the labeled amount of

amoxicillin, within )10% to +20%, and an amount of clavulanate

potassium equivalent to the labeled amount of clavulanic acid, within

)10% to +20%. Meet the requirements for Identification, Disintegra-

tion (for Tablets labeled for veterinary use only, 30 minutes, in

simulated gastric fluid TS), Dissolution (85% of amoxicillin and 80% of

clavulanic acid in 30 minutes [or 45 minutes where the Tablets are

labeled as chewable] in water in Apparatus 2 at 75 rpm [Note: Tablets

labeled for veterinary use only are exempt from this requirement]),

Uniformity of dosage units, and Water (not more than 6.0% where the

Tablets are labeled as being chewable; not more than 7.5% where the

labeled amount of amoxicillin in each Tablet is 250 mg or less; not

more than 10.5% where the labeled amount of amoxicillin in each

Tablet is greater than 250 mg).{R-14}

Developed: 06/30/95


04/04/03

REFERENCES1. Clavamax Drops Freedom of Information Summary. NADA 055-101. 12/23/

97. Sponsor: Pfizer Inc.

2. Ampicillin package insert (Polyflex, Fort Dodge—US), Rec 9/27/94.

3. Barragry TB. Veterinary drug therapy. Philadelphia: Lea & Febiger; 1994.

p. 221–4.

4. Kilgore WR, Simmons RD, Jackson JW. Beta-lactamase inhibition: a new

approach in overcoming bacterial resistance. Compend Contin Educ Pract Vet

1986; 8: 325.

5. Indiveri MC, Hirsh DC. Clavulanic acid-potentiated activity of amoxicillin

against Bacteroides fragilis. Am J Vet Res 1985; 46(10): 2207–9.

6. Prescott JF, Baggot JD, editors. Antimicrobial therapy in veterinary medicine.

2nd ed. Ames, IA: Iowa State University Press 1993: 119–26.

7. Amoxicillin and clavulanic acid package insert (Clavamox Tablets, SmithKline


8. Amoxicillin and clavulanic acid package insert (Clavamox Drops, SmithKline


9. Clavamox drops. In: Bennett K, editor. Compendium of veterinary products.

3rd ed. Hensall, ON: North American Compendiums Inc., 1993; 173–4.

10. Clavamox tablets. In: Bennett K, editor. Compendium of veterinary products.

3rd ed. Hensall, ON: North American Compendiums Inc., 1993: 173.

11. Senior, et al. Amoxycillin and clavulanic acid combination in the treatment

of experimentally induced bacterial cystitis in cats. Res Vet Sci 1985; 39(1):

41–6.

12. Amoxicillin package insert (Amoxitabs, SmithKline Beecham—US), Rev 7/93,

Rec 10/18/94.

13. USP dictionary of USAN and international drug names, 2002. Rockville, MD:

The United States Pharmacopeial Convention, Inc.; 2002.



States Pharmacopeial Convention, Inc.; 2002. p. 143, 144, 2548, 2555.



16. Riviere JE, Craigmill AL, Sundlof SF. Handbook of comparative pharmacoki-


Inc. 1991.


Publishing 1991: 467–9, 480–6.

18. Donowitz DR, Mandell GL. Beta-lactam antibiotic. N Engl J Med 1988; 318:

419–26.

19. Wright AJ, Wilkowski CJ. The penicillins. Mayo Clin Proc 1983; 58: 21–32.

20. Papich MG. The beta-lactam antibiotics: Clinical pharmacology and recent


21. Watson ADJ, et al. Effect of ingesta on systemic availability of penicillins

administered orally in dogs. J Vet Pharmacol Ther 1986: 9: 140–9.

22. Papich MG. Therapy of gram-positive bacterial infections. Vet Clin North Am

Small Anim Pract 1988; 18(6): 1267–85.

23. Spurlock SL, Wilcke JR. Penicillins and cephalosporins. In: Proceedings of the

thirty-second annual convention of the American Association of Equine

Practitioners; 1987. p. 175–82.

24. Soback S, et al. Clavulanate-potentiated amoxycillin: in vitro antibacterial

activity and oral bioavailability in calves. J Vet Pharmacol Ther 1987; 10:

105–13.

25. Amoxicillin package insert (Amoxi-drops, SmithKline Beecham—US), Rev

9/90, Rec 10/18/94.

26. Soback S, Bor A, Kurtz B, et al. Clavulanate-potentiated amoxycillin: in vitro

antibacterial activity and oral bioavailability in calves. J Vet Pharmacol Ther

1987; 10: 105–13.


28. Ampicillin (Apo-Ampi, Apotex). In: Krogh CME, editor. CPS Compendium of


Association, 1994; 83: 995.

29. Ziv G, Horsey J. Elevation and prolongation of serum ampicillin and

amoxycillin concentrations in calves by the concomitant administration of

probenecid. J Vet Pharmacol Ther 1979; 2: 187–94.



31. Clavamox Tabs Freedom of Information Summary. NADA 055-099. 12/23/

97. Sponsor: Pfizer Inc.


33. Budsberg SC, Kemp DT. Antimicrobial distribution and therapeutics in bone.

Compend Contin Ed Small Animal Pract 1990; 12(12): 1758–62.

34. Fossum TW, Hulse DA. Osteomyelitis. Semin Vet Med Surg (Small Anim) 1992

Feb; 7(1): 85–97.

AMOXICILLIN AND CLAVULANATE Veterinary—Systemic 49


35. Sarkiala E, Harvey C. Systemic antimicrobials in the treatment of periodontitis

in dogs. Semin Vet Med Surg (Small Anim) 1993 Aug; 8(3): 197–203.

36. Wilson WD, Spensley MS, Baggot JD, et al. Pharmacokinetics and estimated

bioavailability of amoxicillin in mares after intravenous, intramuscular, and

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37. Johnson KA. Osteomyelitis in dogs and cats. J Am Vet Med Assoc 1994 June;

205(12): 1882–7.

38. Bywater RJ, Palmer GH, Buswell JF, et al. Clavulanate and amoxycillin:

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39. Todd PA, Benfield P. Amoxicillin/Clavulanic acid. Drugs 1990; 39: 264–307.



CEPHALOSPORINS Veterinary—Systemic

This monograph includes information on the following: Cefaclor;

Cefadroxil; Cefazolin; Cefixime; Cefotaxime; Cefotetan; Cefoxitin; Cef-

tiofur; Cephalexin; Cephalothin; Cephapirin�; Cephradine.



Cefa-Drops [Cefadroxil] Excenel RTU [Ceftiofur]

Cefa-Tabs [Cefadroxil] Naxcel [Ceftiofur]

Excenel [Ceftiofur]

For selected human-labeled products—

Ancef [Cefazolin] Keflin [Cephalothin]

Apo-Cefaclor [Cefaclor] Keftab [Cephalexin]

Apo-Cephalex [Cephalexin] Kefzol [Cefazolin]

Ceclor [Cefaclor] Mefoxin [Cefoxitin]

Cefadyl [Cephapirin] Novo-Lexin [Cephalexin]

Cefotan [Cefotetan] Nu-Cephalex [Cephalexin]

Ceporacin [Cephalothin] PMS-Cephalexin [Cephalexin]

Claforan [Cefotaxime] Suprax [Cefixime]

Keflex [Cephalexin] Velosef [Cephradine]








GENERAL CONSIDERATIONSCephalosporins are wide-spectrum antibiotics used to treat a variety of

infections in animals. They have been grouped into three ‘‘genera-

tions’’ based primarily on their spectrum of antibacterial activity{R-1; 2}.

Some of the more recently developed cephalosporins may not easily fit

into one of the generations, but are usually included in the generation

their antibacterial properties most closely resemble.

First-generation cephalosporins include cefadroxil, cefazolin, cephalexin,

cephalothin, cephapirin, and cephradine.

First-generation cephalosporins have the highest activity of the ceph-

alosporins against gram-positive bacteria, including most Corynebac-

teria, Streptococci, and Staphylococci, particularly Staphylococcus

aureus{R-3} and Staphylococcus intermedius{R-32}. Cephalothin and

cephapirin generally have the greatest activity against staphylo-

cocci{R-2}; Staphylococcus epidermidis is only variably susceptible to

cephalexin and cefadroxil.{R-1} Rhodococcus equi, methicillin-resistant

S. aureus, and Enterococcus species are usually resistant.{R-1} The first-

generation cephalosporins have activity against gram-negative bac-

teria, including some Escherichia coli{R-3}, Klebsiella pneumoniae,

Haemophilus influenzae, Proteus mirabilis{R-3}, Actinobacillus, Pasteurel-

la, and Salmonella; however, Actinobacter, Citrobacter, Enterobacter,

indole-positive Proteus, and Pseudomonas are resistant.{R-1; 4; 53}

Many anaerobic bacteria are susceptible to these antibacterials, with

the exception of beta-lactamase–producing Bacteroides{R-1; 4} and

Clostridium difficile{R-98}.

Second-generation cephalosporins include cefaclor, cefamandole, cef-

metazole, cefonicid, cefotetan, cefoxitin, cefprozil, and cefuroxime.

Second-generation cephalosporins have the same efficacy as or perhaps

slightly less efficacy than first-generation cephalosporins against

gram-positive pathogens; however, this lack of efficacy is primarily

against S. aureus and S. intermedius. Second-generation are more

effective than first-generation cephalosporins in the treatment of

infections caused by gram-negative bacteria such as E. coli, Klebsiella,

Enterobacter, and Proteus.{R-1; 4; 7} Many anaerobic bacteria are

susceptible to second-generation cephalosporins; cefoxitin{R-7–9} and

cefotetan{R-80} can also be effective against Bacteroides fragilis.

However, Enterococcus and Pseudomonas species are resistant to

second-generation cephalosporins{R-80}. Use of these antimicrobials is

generally reserved for infections that are resistant to first-generation

cephalosporins.

Third-generation cephalosporins include cefixime, cefoperazone, cefotax-

ime, cefpodoxime, ceftazidime, ceftizoxime, and ceftriaxone.

Third-generation cephalosporins are the most effective of the cephalo-

sporins against antibiotic-resistant gram-negative bacteria{R-1; 2; 7}.

Ceftazidime and cefoperazone are active against Pseudomonas, but the

majority of the third-generation cephalosporins commonly used in

veterinary practice are not{R-4; 80}. Third-generation cephalosporins,

in general, are no more and perhaps are less effective than other

cephaosporins against gram-positive bacteria{R-1; 4; 7}. Cefotaxime,

ceftazidine, ceftizoxine, and ceftriaxone are the only cephalosporins

that consistently reach effective antibacterial concentrations in the

central nervous system in people with inflamed meninges.

Ceftiofur is a cephalosporin that does not clearly fit into the third-

generation category and has been called a ‘‘new-generation’’

cephalosporin{R-91}. It has broader gram-positive activity, including

good activity against Streptococci, and less activity against Pseudomo-

nas than other third-generation cephalosporins{R-68}. It is active

against beta-lactamase–producing strains as well as anaerobes, such

as Fusobacterium necrophorum and Bacteroides melaninogenicus{R-81}.

Ceftiofur is rapidly metabolized to desfuroylceftiofur in vivo and

S. aureus is four- to eightfold{R-100} less sensitive to desfuroylceftiofur

than to the parent ceftiofur{R-63}. Proteus mirabilis has a widely

variable susceptibility to some metabolites of ceftiofur{R-72}.

ACCEPTEDEscherichia coli infections (treatment)—Chicks1 and turkey poults, day-old:

Ceftiofur sodium for injection is indicated in the treatment of infections

(colibacillosis) caused by susceptible E. coli{R-11; 12}.

Metritis (treatment)1—Cattle: Ceftiofur hydrochloride injection is indi-

cated in the treatment of acute metritis (up to 14 days postpartum),

caused by susceptible organisms{R-81}.

Pododermatitis, acute (treatment)—Cattle: Ceftiofur sodium for injection

and ceftiofur hydrochloride injection are indicated in the treatment of

bovine interdigital necrobacillosis associated with F. necrophorum and

B. melaninogenicus{R-11; 12; 81; 99}.

Respiratory tract infections (treatment)—

Cattle: Ceftiofur sodium for injection and ceftiofur hydrochloride

injection are indicated in the treatment of respiratory tract infections,

CEPHALOSPORINS Veterinary—Systemic 51


including bovine respiratory disease complex (shipping fever),

caused by susceptible organisms, including Mannheimia (Pasteurella)

haemolytica, Pasteurella multocida, and Haemophilus somnus{R-11; 12;

81; 99}.

Goats1: Ceftiofur sodium for injection is indicated in the treatment of

caprine respiratory disease caused by susceptible organisms, includ-

ing M. haemolytica and P. multocida{R-11}.

Horses: Ceftiofur sodium for injection is indicated in the treatment of

respiratory tract infections caused by susceptible organisms, includ-

ing Streptococcus zooepidemicus{R-11; 12}.

Pigs: Ceftiofur hydrochloride injection and ceftiofur sodium for

injection are indicated in the treatment of respiratory tract infections

caused by susceptible organisms, including Actinobacillus pleuropneu-

moniae, P. multocida, Salmonella choleraesuis, and Streptococcus suis

type 2.{R-11; 81; 96; 99}

Sheep: Ceftiofur sodium for injection is indicated in the treatment of

respiratory tract infections caused by susceptible M. haemolytica and

P. multocida{R-11; 12; 97}.

Skin and soft tissue infections (treatment)—Cats and dogs: Cefadroxil and

[cephalexin]1{R-32} are indicated in the treatment of skin and soft tissue

infections caused by susceptible organisms, including P. multocida,

S. aureus, some S. epidermidis, S. intermedius{R-32}, and Streptococcus

species.{R-3; 79}

Urinary tract infections (treatment)—Dogs:Cefadroxil and ceftiofur sodium

for injection are indicated in the treatment of urinary tract infections

caused by susceptible organisms, including E. coli, P. mirabilis, and

S. aureus{R-3; 11; 12}.

[Perioperative infections (prophylaxis)]1—Dogs: Cefazolin is used in the

prevention of infections associated with surgery, including bone

surgery, and caused by susceptible organisms when the risk of

infection is high or potentially severely damaging.{R-1; 2; 6; 82; 83}

ACCEPTANCE NOT ESTABLISHEDInfections, bacterial (treatment)—

[Birds]1: There are insufficient data to establish the efficacy and safety

of cephalexin and cephalothin in the treatment of bacterial infections

in birds, such as cranes, ducks, emu, pigeons, and quail; however,

based on pharmacokinetic studies and the apparent wide margin of

safety, they have been used in the treatment of susceptible bacterial

infections{R-34}.

Cats: There are insufficient data to establish the efficacy and safety of

[cefotaxime] 1{R-42} and [cephalexin]1{R-49; 50} in the treatment of

bacterial infections in cats; however, based on pharmacokinetics,

pathogen sensitivities, and the apparent wide margin of safety, these

medications are used to treat a variety of susceptible infections,

including certain bone, respiratory, skin, soft tissue, and urinary tract

infections.

Dogs: There are insufficient data to establish the efficacy and safety of

[cefaclor]1, [cefazolin]1, [cefotaxime]1, ceftiofur (for non–urinary

tract infections), [cephalexin]1, [cephalothin]1, [cephapirin]1, and

[cephradrine]1 for the treatment of bacterial infections in dogs;

however, based on pharmacokinetic data{R-43; 49; 50; 72; 82; 83},

knowledge about in vitro efficacy, and the apparent wide margin of

safety, these medications are used to treat a variety of susceptible

infections, including certain bone, respiratory, skin, soft tissue, and

urinary tract infections. Also, there are insufficient data to establish

the clinical efficacy and safety of [cefixime]1 in the treatment

of bacterial infections in dogs; however, pharmacokinetics and

determination of minimum inhibitory concentrations against com-

mon pathogens show that cefixime is likely to be effective in the

treatment of bone, bladder, skin, and soft tissue infections{R-77}. There

are insufficient data to establish the clinical efficacy and safety of

[cefotetan]1 and [cefoxitin]1 in the treatment of gram-negative or

polymicrobial infections (such as Enterobacteriaceae species and an

obligate anaerobe) in dogs; however, pharmacokinetics and a

determination of minimum inhibitory concentrations against com-

mon pathogens show that cefotetan and cefoxitin are likely to be

effective in the treatment of these types of infections{R-84}.

[Foals]1 : There are insufficient data to establish the efficacy and safety

of ceftiofur{R-48} and cephradine{R-85} in foals for the treatment of

bacterial infections; however, based on the pharmacokinetics known,

pathogen sensitivities, and the apparent wide margin of safety, these

medications are used to treat a variety of susceptible infections,

including certain bone, joint, respiratory, skin, soft tissue, and urinary

tract infections. There are also insufficient data to establish the

efficacy and safety of cefotaxime and other third-generation ceph-

alosporins in the treatment of neonatal sepsis and secondary bacterial

meningitis in foals; however, based on known human central nervous

system distribution and clinical response in foals, cefotaxime is used

to treat these infections when they are not responsive to other

antimicrobials{R-62; 67}.

Horses: There are insufficient data to establish the efficacy and safety of

[cefoxitin]1{R-29} and [cephalothin]1 {R-9; 19} in horses for the

treatment of bacterial infections; however, based on the pharmaco-

kinetics known, pathogen sensitivities, and the apparent wide

margin of safety, these medications are used to treat a variety of

susceptible infections, including certain bone, joint, respiratory, skin,

soft tissue, and urinary tract infections.1



REGULATORY CONSIDERATIONSU.S. and Canada—{R-11; 12}

Withdrawal times have been established for ceftiofur (see the Dosage

Forms section). Ceftiofur is not for use in horses intended for human

consumption.

CHEMISTRYSource: Most cephalosporins are semisynthetic derivatives of the met-

abolic products of the fungus Cephalosporium acremonium.{R-1–3}

Chemical group: Beta-lactam antibiotics.{R-2; 7}

Molecular formula:{R-13}

Cefaclor—C15H14ClN3O4S Æ H2O.

Cefadroxil—C16H17N3O5S Æ H2O.

Cefazolin sodium—C14H13N8NaO4S3.

Cefixime—C16H15N5O7S2 Æ H2O.

Cefotaxime sodium—C16H16N5NaO7S2.

Cefotetan disodium—C17H15N7Na2O8S4.

Cefoxitin sodium—C16H16N3NaO7S2.

Ceftiofur hydrochloride—C19H17N5O7S3 Æ HCl.Ceftiofur sodium—C19H16N5NaO7S3.

Cephalexin—C16H17N3O4S Æ H2O.

Cephalexin hydrochloride—C16H17N3O4S Æ HCl Æ H2O.

Cephalothin sodium—C16H15N2NaO6S2.

52 CEPHALOSPORINS Veterinary—Systemic


Cephapirin sodium—C17H16N3NaO6S2.

Cephradine—C16H19N3O4S.

Molecular weight:{R-13}

Cefaclor—385.82.

Cefadroxil—381.40; 372.39 (hemihydrate); 363.4 (anhydrous){R-14}.

Cefazolin sodium—476.49.

Cefixime—507.50.

Cefotaxime sodium—477.45.

Cefotetan disodium—619.59.

Cefoxitin sodium—449.44.

Ceftiofur hydrochloride—560.03.

Ceftiofur sodium—545.55.

Cephalexin—365.41.

Cephalexin hydrochloride—401.87.

Cephalothin sodium—418.42.

Cephapirin sodium—445.45.

Cephradine—349.41.

Description:{R-14}

Cefaclor USP—White to off-white, crystalline powder.

Cefadroxil USP—White to off-white, crystalline powder.

Cefazolin Sodium USP—White to off-white, practically odorless, crystal-

line powder, or white to off-white solid.

Cefixime USP—White to light yellow, crystalline powder.

Cefotaxime Sodium USP—Off-white to pale yellow crystalline powder.

Cefotaxime sodium injection—Solutions of cefotaxime sodium range

from very pale yellow to light amber depending on the concentration

and the diluent used.

Cefotetan disodium—White to pale yellow powder.

Cefotetan disodium injection—Solution varies from colorless to yellow,

depending on the concentration.

Cefoxitin Sodium USP—White to off-white, granules or powder, having a

slight characteristic odor. Is somewhat hydroscopic.

Cephalexin USP—White to off-white, crystalline powder.

Cephalexin Hydrochloride USP—White to off-white crystalline powder.

Cephalothin Sodium USP—White to off-white, practically odorless,

crystalline powder.

Cephapirin Sodium USP—White to off-white crystalline powder, odorless

or having a slight odor.

Cephradine USP—White to off-white, crystalline powder.

pKa:

Cefotaxime—3.35.{R-15}

Cefoxitin—2.2.{R-16; 17}

Cephalexin—5.3 and 7.3.{R-16; 17}

Cephalothin—5.0.{R-17}

Cephapirin—2.15 and 5.44.{R-16}

Cephradine—2.6 and 7.3.{R-17}

Solubility:{R-14}

Cefaclor USP—Slightly soluble in water; practically insoluble in meth-

anol and in chloroform.

Cefadroxil USP—Slightly soluble in water; practically insoluble in

alcohol, in chloroform, and in ether.

Cefazolin Sodium USP—Freely soluble in water, in saline TS, and in

dextrose solutions; very slightly soluble in alcohol; practically insoluble

in chloroform; and in ether.

Cefixime USP—Freely soluble in methanol; soluble in propylene glycol;

slightly soluble in alcohol, in acetone, and in glycerin; very slightly

soluble in 70% sorbitol and in octanol; practically insoluble in ether, in

ethyl acetate, in hexane, and in water.

Cefotaxime Sodium USP—Freely soluble in water; practically insoluble in

organic solvents.

Cefotetan disodium—Very soluble in water.

Cefoxitin Sodium USP—Very soluble in water; soluble in methanol;

sparingly soluble in dimethylformamide; slightly soluble in acetone;

insoluble in ether and in chloroform.

Ceftiofur sodium—Solubility is pH dependent (greater than 400 mg per

mL at pH > 5.5){R-68}.

Cephalexin USP—Slightly soluble in water; practically insoluble in

alcohol, in chloroform, and in ether.

Cephalexin Hydrochloride USP—Soluble to the extent of 10 mg per mL in

water, in acetone, in acetonitrile, in alcohol, in dimethylformamide,

and in methanol; practically insoluble in chloroform, in ether, in ethyl

acetate, and in isopropyl alcohol.

Cephalothin Sodium USP—Freely soluble in water, in saline TS, and in

dextrose solutions; insoluble in most organic solvents.

Cephapirin Sodium USP—Very soluble in water; insoluble in most

organic solvents.

Cephradine USP—Sparingly soluble in water; very slightly soluble in

alcohol and in chloroform; practically insoluble in ether.

PHARMACOLOGY/PHARMACOKINETICSNote: See also Table 1. Pharmacology/Pharmacokinetics at the end of this

monograph.

Mechanism of action/effect: Cephalosporins are beta-lactam antibi-

otics that produce their bactericidal effect by inhibition of cell wall

synthesis. The site of action for beta-lactam antibiotics is the penicillin-

binding proteins (PBPs) on the inner surface of the bacterial cell

membrane that are involved in synthesis of the cell wall.{R-2} In ac-

tively growing cells, the cephalosporins bind to the PBPs within the

cell wall and lead to interference in production of cell wall peptido-

glycans and subsequent lysis of the cell in an iso-osmotic environ-

ment.{R-7; 9} Differences in affinity for the types of PBPs by different

beta-lactam antibiotics and the bacterial defense mechanisms explain

the variations in bactericidal activity among cephalosporins.{R-9}

Distribution: Cephalosporins distribute into most body tissues and

fluids.{R-18} They penetrate into pleural fluid, synovial fluid, pericardial

fluid, and urine. Cephalosporins can be found in bile fluid if no biliary

obstruction is present.{R-1} The cephalosporins penetrate aqueous

humor and prostatic fluid less than other body fluids. Most of the

cephalosporins have poor penetration of the blood-brain barrier.{R-2}

Cefuroxime is the only second-generation cephalosporin known to

adequately penetrate into cerebrospinal fluid in people; also, the third-

generation antibiotics cefotaxime and cefoxitin{R-1} have been shown

to penetrate inflamed meninges in people. Ceftriaxone has been shown

to penetrate normal meninges in horses{R-103}.

The high level of protein binding by ceftiofur in adult animals causes its

distribution to differ from that of other cephalosporins{R-91}. Also, the

primary metabolite of ceftiofur, desfuroylceftiofur, has a reactive

sulfhydryl group that forms reversible covalent bonds with plasma and

tissue proteins{R-63}. Free concentrations of ceftiofur and its active

metabolites tend to be lower than expected when dosages shown to be

effective in the treatment of a disease are administered, possibly because

of their unique protein binding abilities{R-63}. Concentrations of ceftiofur

and activemetabolites in Pasteurella-infected tissue chambers implanted

into cattle tend to be higher than concentrations in uninfected



chambers{R-73}. Studies of distribution of ceftiofur into other tissues have

also shown it to be unique, although the way in which this affects

efficacy in the extra-label treatment of infections is not known.

Biotransformation: Cefotaxime{R-20},cephalothin{R-19},andcephapirin

undergo biotransformation in the liver to desacetyl derivatives.{R-1; 2}

Ceftiofur is rapidly converted in vivo to desfuroylceftiofur, which is

structurally similar to and, in most instances, equally active micro-

biologically to, ceftiofur.{R-30} The significant exceptions are that

Staphylococcus aureus is four- to eightfold{R-100} less sensitive to des-

furoylceftiofur than to ceftiofur{R-63}, and that Proteus mirabilis has a

widely variable susceptibility to some ceftiofur metabolites{R-72}. The

metabolites of other cephalosporins may retain some antibacterial

activity.

Elimination: For most cephalosporins, elimination is by renal tubular

secretion and/or glomerular filtration.


SPECIES SENSITIVITYRabbits and small rodents{R-80}—Cephalosporins may disturb the normal

intestinal microflora, particularly when administered orally at high

doses.{R-21}

CROSS-SENSITIVITYThe incidence of cross-sensitivity in animals is unknown. Caution should

be used when cephalosporins are administered to patients with a

history of an anaphylactic reaction to other beta-lactam antibiotics

because cross-reaction may occur{R-1}; however, a history of a delayed

allergic reaction to penicillin does not contraindicate use of a

cephalosporin.{R-2}

PREGNANCY/REPRODUCTIONPregnancy—Cephalosporins have been shown to cross the placenta in

animals. Studies in laboratory animals have not shown the cephalo-

sporins to cause adverse effects in the fetus.{R-22–24} Studies with

cefoxitin have not shown that the medication is teratogenic or

fetotoxic in mice and rats, but a slight decrease in fetal weight{R-21}

has occurred.

LACTATIONCephalosporins are distributed into milk{R-25}; however, when adminis-

tered systemically at accepted doses, therapeutic concentrations are not

reached in milk.{R-67; 69}When ceftiofur is administered systemically at

recommended dosages, distribution is too low to produce residues

greater than established regulatory tolerances.{R-68; 69}







medication.

Although cephalothin has been associated with an increased human

risk of nephrotoxicity when administered with an aminoglycoside, this

interaction may not apply to other cephalosporins{R-98}. In fact, there

is some evidence that certain cephalosporins such as cefamandole,

cefazolin, and cephalothin provide a protective effect against amino-

glycoside-induced nephrotoxicity in rats{R-101} while others, such as

cephalexin, have no effect{R-102}.

Probenecid

(probenecid administered concurrently with a cephalosporin will

inhibit renal tubular secretion and in some cases increase the serum

concentrations and prolong the serum half-life of the cephalosporin{R-2},

including cefadroxil{R-3}, cefoxitin{R-26}, cephalothin{R-30}, and ceph-

apirin{R-27}; probenecid has not been shown to alter the renal tubular

secretion of ceftiofur{R-70})




included in the human monograph Cephalosporins (Systemic) in USP DI

Volume I; these drug interactions are intended for informational


cephalosporins in the treatment of animals:

Antacids

(the extent of absorption of cefaclor is decreased with concurrent use

of aluminum hydroxide- or magnesium-containing antacids; cefaclor

should not be taken within 1 hour of taking these antacids)

Anticoagulants, coumarin- or indandione-derivative, or

Heparin or

Thrombolytic agents

(concurrent use of these medications with cefotetan may increase

the risk of bleeding because of the N-methylthiotetrazole [NMTT]

side chain on these medications; however, critical illness, poor

nutritional status, and the presence of liver disease may be more

important risk factors for hypoprothrombinemia and bleeding;

because all cephalosporins can inhibit vitamin K synthesis by

suppressing gut flora, prophylactic vitamin K therapy is recom-

mended when any of these medications is used for prolonged

periods in malnourished or seriously ill patients; dosage adjust-

ments of anticoagulants may be necessary during and after

therapy with cefotetan; concurrent use with thrombolytic agents

may increase the risk of severe hemorrhage and is not recom-

mended)

(an increased anticoagulant effect has been reported with concur-

rent use of cefaclor and oral anticoagulants)

Nephrotoxic medications

(cephalothin has been associated with an increased incidence of

nephrotoxicity when used concurrently with aminoglycosides; this

effect has rarely been seen with other commercially available

cephalosporins used at appropriate doses; the potential for increased

nephrotoxicity exists when cephalosporins are used with other

nephrotoxic medications, such as loop diuretics, especially in patients

with pre-existing renal function impairment; renal function should

be monitored carefully in patients receiving cephalosporins and

aminoglycosides concurrently)

Platelet aggregation inhibitors, other

(hypoprothrombinemia induced by large doses of salicylates and/or

cephalosporins, and the gastrointestinal ulcerative or hemorrhagic



potential of nonsteroidal anti-inflammatory drugs [NSAIDs], salicy-

lates, or sulfinpyrazone may increase the risk of hemorrhage)





Coombs’ test

(positive reactions for the Coombs’ test may be seen in animals

receiving cephalosporins; this may be due to changes in the red blood

cells, but hemolytic anemia usually is not occurring{R-2})


Ketones, urine

(values may be increased){R-68}



humans, and are included in the human monograph Cephalosporins



applicable to the use of cephalosporins in the treatment of animals:


Coombs’ (antiglobulin) tests

(a positive Coombs’ reaction frequently appears in patients who

receive large doses of a cephalosporin; hemolysis rarely occurs, but

has been reported; test may be positive in neonates whose mothers

received cephalosporins before delivery)

Creatinine, serum and urine

(cefotetan, cefoxitin, or cephalothin may falsely elevate test values

when the Jaffe’s reaction method is used; serum samples should

not be obtained within 2 hours after administration)

Glucose, urine

(some cephalosporins [cefaclor, cefazolin, cefixime, cefotetan,

cefoxitin, cephalexin, cephalothin, cephapirin, cephradine] may

produce false-positive or falsely elevated test results with copper

sulfate tests [Benedict’s, Fehling’s, or Clinitest]; glucose enzymatic

tests, such as Clinistix and Tes-Tape, are not affected)

Protein, urine

(cefamandole may produce false-positive tests for proteinuria with

acid and denaturization-precipitation tests)

Prothrombin time (PT)

(may be prolonged; cephalosporins may inhibit vitamin K synthe-

sis by suppressing gut flora; also, cephalosporins with the NMTT

side chain [cefamandole, cefoperazone, cefotetan] have been

associated with an increased incidence of hypoprothrombinemia;

patients who are critically ill, malnourished, or have liver function

impairment may be at the highest risk of bleeding)


Alanine aminotransferase (ALT [SGPT]), serum, or

Alkaline phosphatase, serum, or

Aspartate aminotransferase (AST [SGOT]), serum, or



Bilirubin, serum, or

Blood urea nitrogen (BUN) or

Creatinine, serum


Complete blood count (CBC) or

Platelet count

(transient leukopenia, neutropenia, agranulocytosis, thrombocy-

topenia, eosinophilia, lymphocytosis, and thrombocytosis have

been reported on rare occasions)






problems exist:

Bleeding disorders, history of

(some of the second- and third-generation cephalosporins have been

associated with an increased risk of bleeding in people{R-65} due to a

decrease in prothrombin activity, and bleeding is considered a

potential human risk with all the cephalosporins; there is evidence of

a significant increase in bleeding time after cephalothin administra-

tion to beagles{R-28} but not outside normal reference ranges; clinical

problems have not been reported in animals and the clinical

significance is unknown)

Hepatic dysfunction, severe

(because cefotaxime, cephalothin, and cephapirin are hepatically

metabolized before renal elimination, severe liver dysfunction can

inhibit metabolism{R-2})

Renal insufficiency

(nephrotoxicity may occur in patients with renal insufficiency who

are receiving the full dosage of cephalosporin; dosage should be

adjusted){R-1}



symptoms in parentheses where appropriate)—not necessarily inclu-

sive:


All species

Hypersensitivity reactions (acute anaphylaxis or angioedema,

allergic agranulocytosis{R-31}, fever{R-31}, serum sickness, urticaria{R-

2})

Dogs

Anemia; thrombocytopenia{R-11}

Note: Anemia and thrombocytopenia have been seen in dogs given

ceftiofur at high doses (three to five times the labeled dose) or for long

periods of time (5 to 6 weeks). These side effects appear to be

reversible when treatment is discontinued.

Horses

Diarrhea{R-11}—with ceftiofur



THOSE INDICATING NEED FOR MEDICALATTENTION ONLY IF THEY CONTINUE OR AREBOTHERSOMEAll species

Anorexia{R-10; 32}; diarrhea and vomiting{R-3}—possibly due to

local irritation from the oral dosage forms{R-1}; diarrhea caused

by altered gut flora{R-2; 10}; local reactions{R-1; 11} (mild to

moderate pain, heat, swelling)—with parenteral dosage forms,

especially cephalothin and cephapirin; phlebitis{R-2}—with intrave-

nous administration

Note: Diarrhea and vomiting can occur with any dosage but are more

common with high doses.{R-33} Administration of the antibiotic

with food may decrease the incidence of gastrointestinal

effects.{R-33}




included in the human monograph Cephalosporins (Systemic) in USP DI

Volume I; these side/adverse effects are intended for information


cephalosporins in the treatment of animals:



candidiasis


Hypoprothrombinemia—more frequent for cefotetan; pseudo-

membranous colitis

Incidence rare

Allergic reactions, specifically anaphylaxis, erythema multi-

forme, or Stevens-Johnson syndrome (blistering, peeling, or

loosening of skin and mucous membranes, which may involve the

eyes or other organ systems); hearing loss—has occurred rarely in

pediatric patients being treated for meningitis, but more frequently

with cefuroxime; hemolytic anemia, immune, drug-induced—

has occurred with many cephalosporins, but reported more com-

monly with cefotetan; hypersensitivity reactions—has occurred

with many cephalosporins, but reported more commonly with

cefazolin; renal dysfunction; serum sickness–like reac-

tions—may be more frequent with cefaclor; seizures—especially

with high doses and in patients with renal function impairment;

thrombophlebitis





drug manufacturer.

VETERINARY DOSING INFORMATIONExcept for specific veterinary labeled medications, most doses listed have

been derived from phamacokinetic data, rather than from clinical

studies.{R-74}

FOR ORAL DOSAGE FORMS ONLYAdministration of oral cephalosporins, such as cefadroxil, with food

appears to decrease nausea in those animals prone to the side

effect{R-33}; however, administration of cefixime with food can

decrease by one half the bioavailability of the antibiotic{R-77}.

FOR PARENTERAL DOSAGE FORMS ONLYMany cephalosporins can be reconstituted with 1% lidocaine to decrease

injection pain. See the manufacturer’s package insert{R-80}.


Recommended treatment consists of the following:

• Parenteral epinephrine.



CEFACLOR

SUMMARY OF DIFFERENCESIndications: General considerations—Second-generation cephalosporin.




CEFACLOR CAPSULES USPUsual dose:

Note: [Dogs]1—Although the efficacy and safety of cefaclor in dogs

have not been established, an oral dose of 4 to 20 mg per kg of body

weight every eight hours has been used in the treatment of

susceptible bacterial infections in dogs.{R-2} There is very

little canine-specific information about cefaclor; therefore, dose

recommendations are based primarily on human pharmacokinetics


U.S.—{R-24}




250 mg (Rx) [Ceclor].

500 mg (Rx) [Ceclor].

Canada—{R-36}




250 mg (Rx) [Apo-Cefaclor; Ceclor].

500 mg (Rx) [Apo-Cefaclor; Ceclor].




USP requirements: Preserve in tight containers. Contain the equiva-

lent of the labeled amount of anhydrous cefaclor, within )10% to



+20%. Meet the requirements for Identification, Dissolution (80% in

30 minutes in water in Apparatus 2 at 50 rpm), Uniformity of dosage

units, and Water (not more than 8.0%).{R-14}

CEFACLOR FOR ORAL SUSPENSION USPUsual dose: See Cefaclor Capsules USP.



U.S.:{R-24}



Human-labeled product(s)—

25 mg per mL (Rx) [Ceclor; GENERIC].

37.4 mg per mL (Rx) [Ceclor; GENERIC].



Canada:{R-36}




25 mg per mL (Rx) [Apo-Cefaclor; Ceclor].



Packaging and storage: Prior to reconstitution, store below 40 �C(104 �F), preferably between 15 and 30 �C (59 and 86 �F), unlessotherwise specified by manufacturer. Store in a tight container.

Stability: After reconstitution, suspensions retain their potency for 14

days if refrigerated.

Auxiliary labeling:

• Refrigerate.

• Shake well.

USP requirements: Preserve in tight containers. A dry mixture of

Cefaclor and one or more suitable buffers, colors, diluents, and flavors.

Contains the equivalent of the labeled amount of anhydrous cefaclor,

within –10% to +20%. Meets the requirements for Identification,

Uniformity of dosage units (solid packaged in single-unit containers),

Deliverable volume (solid packaged in multiple-unit containers), pH


Water (not more than 2.0%).{R-14}



CEFADROXIL

SUMMARY OF DIFFERENCESIndications:

General considerations—First-generation cephalosporin.

Indicated for treatment of susceptible genitourinary tract infections in

dogs and skin and soft tissue infections in cats and dogs.

Drug interactions and/or related problems: Concurrent administration of

probenecid may prolong the serum half-life of cefadroxil.{R-3}

ORAL DOSAGE FORMS

CEFADROXIL FOR ORAL SUSPENSION USPUsual dose:

Skin and soft tissue infections—

Cats: Oral, 22 mg per kg of body weight every twenty-four

hours{R-37; 38}.

Dogs: Oral, 22 mg per kg of body weight every twelve hours{R-37; 38}.

Urinary tract infections—Dogs: Oral, 22 mg per kg of body weight

every twelve hours{R-37; 38}.



U.S.:


50 mg per mL (Rx) [Cefa-Drops].

Canada:


50 mg per mL (Rx) [Cefa-Drops].




Stability: When reconstituted according to manufacturer’s directions

and refrigerated, suspensions retain their potency for 14 days.{R-37}


Cefadroxil and one or more suitable buffers, colors, diluents, and fla-

vors. Contains the equivalent of the labeled amount of anhydrous

cefadroxil, within –10% to +20%. Meets the requirements for Identi-

fication, Uniformity of dosage units (solid packaged in single-unit

containers), Deliverable volume (solid packaged in multiple-unit con-

tainers), pH (4.5–6.0, in the suspension constituted as directed in the

labeling), and Water (not more than 2.0%).{R-14}

CEFADROXIL TABLETS USPUsual dose: See Cefadroxil for Oral Suspension USP.


U.S.—


50 mg (Rx) [Cefa-Tabs].



1 gram (Rx) [Cefa-Tabs].

Canada—










USP requirements: Preserve in tight containers. The Tablets prepared

using the hemihydrate form of Cefadroxil are so labeled. Contain the

labeled amount of anhydrous cefadroxil, within –10% to +20%. Meet

the requirements for Identification, Dissolution (75% in 30 minutes in

water in Apparatus 2 at 50 rpm), Uniformity of dosage units, and


CEFAZOLIN

SUMMARY OF DIFFERENCESIndications: General considerations—First-generation cephalosporin.





in terms of cefazolin base (not the sodium salt).

CEFAZOLIN INJECTION USPUsual dose: Although Cefazolin Injection USP is the same antimicrobial

as Cefazolin For Injection USP, it is only available frozen in premixed

dilute concentrations, making it less practical for veterinary use. For

dosing information, see Cefazolin For Injection USP.


U.S.—




500 mg (base) in 50 mL (Rx) [Ancef].

1 gram (base) in 50 mL (Rx) [Ancef].

Canada—


Packaging and storage: Store at –10 �C (14 �F) or below, unless

otherwise specified by the manufacturer.

Preparation of dosage form: Cefazolin sodium injection should be

thawed at room temperature, and all ice crystals should have melted,

before administration. Thawing should not be forced by immersion in

water baths or by microwave irradiation.

Stability: See manufacturer’s product labeling for stability information.

Incompatibilities:

The admixture of cefazolin sodium injection with other medications is not

recommended.

The admixture of beta-lactam antibacterials (penicillins and cephalospo-

rins) and aminoglycosides may result in substantial mutual inactiva-

tion; they should not be mixed in the same intravenous bag or bottle.

USP requirements: Preserve in Containers for Injections. Maintain in

the frozen state. A sterile solution of Cefazolin and Sodium Bicarbonate

in a diluent containing one or more suitable tonicity-adjusting agents.

It meets the requirements for Labeling under Injections. The label

states that it is to be thawed just prior to use, describes conditions for

proper storage of the resultant solution, and directs that the solution is

not to be refrozen. Contains the labeled amount, within –10% to

+15%. Meets the requirements for Identification, Bacterial endotoxins,

Sterility, pH (4.5–7.0), and Particulate matter.{R-14}

CEFAZOLIN FOR INJECTION USPUsual dose: [Perioperative infections (prophylaxis)]1—Dogs: Intrave-

nous, 22 mg (base) per kg of body weight every two hours, or 8 mg

(base) per kg of body weight every hour, starting at the beginning of

surgery and continuing until the end of surgery{R-82}.

Note: The above dose is based on pharmacokinetic studies, including

studies performed during surgical procedures.

Also for [dogs]1, based on pharmacokinetics studies, an intramuscu-

lar or intravenous dose of 20 to 35 mg (base) per kg of body weight

every four to eight hours has been used for the treatment of

susceptible bacterial infections{R-2; 38; 86}.


U.S.—{R-39}




500 mg (base) (Rx) [Ancef; Kefzol; GENERIC].

1 gram (base) (Rx) [Ancef; Kefzol; GENERIC].

5 grams (base) (Rx) [Ancef].

10 grams (base) (Rx) [Ancef; Kefzol; GENERIC].

Canada—{R-40}




50 mg (base) (Rx) [Kefzol].

500 mg (base) (Rx) [Ancef; Kefzol; GENERIC].

1 gram (base) (Rx) [Ancef; Kefzol; GENERIC].

10 grams (base) (Rx) [Ancef; Kefzol; GENERIC].

Packaging and storage: Prior to reconstitution, store below 40 �C(104 �F), preferably between 15 and 30 �C (59 and 86 �F), unlessotherwise specified by manufacturer.

Preparation of dosage form: To prepare the 100mg of cefazolin (base)

permL dilution commonly used in veterinary practice for intramuscular

or intravenous administration, 9.6 mL of sterile water for injection

should be added to each 1-gram vial{R-39; 95}. See manufacturer’s

package insert for other preparation instructions.


Incompatibilities: The admixture of beta-lactam antibacterials (peni-

cillins and cephalosporins) and aminoglycosides may result in sub-

stantial mutual inactivation; they should not be mixed in the same

intravenous bag or bottle.

USP requirements: Preserve in containers for Sterile Solids. Contains

an amount of Cefazolin Sodium equivalent to the labeled amount of



cefazolin, within –10% to +15%. Meets the requirements for Consti-

tuted solution, Identification, Specific rotation (–10� to –24�), Bacterialendotoxins, Sterility, pH (4.0–6.0, in a solution containing 100 mg of

cefazolin per mL), Uniformity of dosage units, Water (not more than

6.0%), and Particulate matter, and for Labeling under Injections {R-14}.



CEFIXIME

SUMMARY OF DIFFERENCESIndications: General considerations—Third-generation cephalosporin.

Veterinary Dosing Information: Administration with food decreases the

bioavailability by one half.




CEFIXIME FOR ORAL SUSPENSION USPUsual dose:

Note: [Dogs]1—Although the efficacy and safety of cefixime have not

been established, an oral dose of 5 mg per kg of body weight every

twelve to twenty-four hours has been used in the treatment of cystitis

in dogs, based on pharmacokinetic data.{R-77}

There are also some pharmacokinetic data to suggest that the same

dose, administered for two to four weeks, is likely to be effective for

treatment of bone, skin, and soft tissue infections in dogs{R-77}.


manufacturer’s directions—

U.S.—




20 mg per mL (Rx) [Suprax].

Canada—




20 mg per mL (Rx) [Suprax].


Stability: After reconstitution, suspension retains its potency for 14

days at room temperature or if refrigerated.

Auxiliary labeling:

• Shake well.


Cefixime and one or more suitable diluents, flavors, preservatives, and

suspending agents. Label it to indicate that the cefixime contained

therein is in the trihydrate form. Contains the labeled amount of

anhydrous cefixime, within –10% to +20%, per mL when constituted

as directed in the labeling. Meets the requirements for Identification,

Uniformity of dosage units (solid packaged in single-unit containers),

Deliverable volume (solid packaged in multiple-unit containers), pH



CEFIXIME TABLETS USPUsual dose: See Cefixime for Oral Suspension USP.


U.S.—




200 mg (Rx) [Suprax].


Canada—








manufacturer.

USP requirements: Preserve in tight containers. Label Tablets to

indicate that the cefixime contained therein is in the trihydrate form.

Contain the labeled amount of anhydrous cefixime, within ±10%.

Meet the requirements for Identification, Dissolution (75% in 45

minutes in 0.05 M potassium phosphate buffer [pH 7.2] in Apparatus

1 at 100 rpm), Uniformity of dosage units, and Water (not more than

10.0%).{R-14}



CEFOTAXIME

SUMMARY OF DIFFERENCESIndications: General considerations—Third-generation cephalosporin.

Pharmacology/pharmacokinetics:

Biotransformation—Significant metabolism occurs with the major

pathway yielding a desacetyl derivative. Desacetylcefotaxime is less

active against staphylococci but acts synergistically with the parent

compound against sensitive gram-negative bacteria.{R-1}

Distribution—In people, when administered at high doses, cefotaxime

enters the cerebrospinal fluid in therapeutic concentrations when

meninges are inflamed.{R-1}

Medical considerations/contraindications: Severe hepatic dysfunction

can inhibit metabolism.{R-2}







in terms of cefotaxime free acid (not the sodium salt).

CEFOTAXIME INJECTION USPUsual dose:

Note: [Cats]1—Although the efficacy and safety have not been

established, an intramuscular or intravenous dose of 20 to 80 mg

(free acid) per kg of body weight every six hours has been used in the

treatment of susceptible bacterial infections in cats, based on

pharmacokinetic data{R-42}.

[Dogs]1—Although the efficacy and safety have not been established,

a subcutaneous dose of 50 mg (free acid) per kg of body weight every

twelve hours has been used in the treatment of susceptible bacterial

infections in dogs, based on pharmacokinetic data. When adminis-

tered intramuscularly, the dose should be repeated every eight

hours{R-43}.

[Foals]1—Although the efficacy and safety have not been established,

an intravenous dose of 40 mg (free acid) per kg of body weight every

six hours has been used in the treatment of neonatal sepsis or

susceptible bacterial meningitis in foals{R-62}.


U.S.—{R-44}




20 mg (free acid) per mL (Rx) [Claforan].

40 mg (free acid) per mL (Rx) [Claforan].

Canada—


Packaging and storage: Store at –20 �C (–4 �F) or below, unless

otherwise specified by manufacturer.{R-44}

Preparation of dosage form: {R-44} Cefotaxime sodium injection should

be thawed at room temperature, and all ice crystals should have

melted, before administration.


USP requirements: Preserve in single-dose containers. Maintain in the

frozen state. A sterile solution of Cefotaxime Sodium in Water for

Injection. Contains one or more suitable buffers. It meets the

requirements for Labeling under Injections. The label states that it is to

be thawed just prior to use, describes conditions for proper storage of

the resultant solution, and directs that the solution is not to be

refrozen. Contains an amount of cefotaxime sodium equivalent to the

labeled amount of cefotaxime, within ±10%. Meets the requirements

for Identification, Bacterial endotoxins, Sterility, pH (5.0–7.5), Partic-

ulate matter, and Chromatographic purity.{R-14}

CEFOTAXIME FOR INJECTION USPUsual dose: See Cefotaxime Sodium Injection USP.


U.S.—{R-44}




500 mg (free acid) (Rx) [Claforan].

1 gram (free acid) (Rx) [Claforan].

2 grams (free acid) (Rx) [Claforan].


Canada—




500 mg (free acid) (Rx) [Claforan].

1 gram (free acid) (Rx) [Claforan].


Packaging and storage: Prior to reconstitution, store below 30 �C (86

�F), preferably between 15 and 30 �C (59 and 86 �F), unless otherwise

specified by manufacturer.

Preparation of dosage form: Dilutions should be prepared according

to manufacturer’s instructions.


Additional information: A solution containing 1 gram of cefotaxime

sodium in 14 mL of sterile water for injection is isotonic{R-44}.

USP requirements: Preserve in Containers for Sterile Solids. Contains

an amount of Cefotaxime Sodium equivalent to the labeled amount of

cefotaxime, within –10% to +15%. Meets the requirements for Con-

stituted solution, Identification, Bacterial endotoxins, Sterility, Unifor-

mity of dosage units, Particulate matter, and Chromatographic purity,

for pH and Loss on drying under Cefotaxime Sodium, and for Labeling

under Injections.{R-14}



CEFOTETAN

SUMMARY OF DIFFERENCESIndications: General considerations—Second-generation cephalosporin.





in terms of cefotetan base (not the disodium salt).

CEFOTETAN FOR INJECTION USPUsual dose:

Note: [Dogs]1—Although the efficacy and safety have not been

established, an intravenous dose of 30 mg (base) per kg of body

weight every eight hours or the same dose administered subcutane-

ously every twelve hours has been used in the treatment of

susceptible bacterial infections in dogs, based on pharmacokinetic

data{R-80; 84}.




U.S.—




1 gram (base) (Rx) [Cefotan].

2 grams (base) (Rx) [Cefotan].


Canada—




1 gram (base) (Rx) [Cefotan].


Packaging and storage: Prior to reconstitution, do not store above

22 �C (72 �F), unless otherwise specified by manufacturer. Protect

from light.




Incompatibilities: The admixture of beta-lactam antibacterials and

aminoglycosides may result in substantial mutual inactivation. They

should not be mixed in the same intravenous bag or bottle.

USP requirements: Preserve in containers for Sterile Solids. Contains

an amount of Cefotetan Disodium equivalent to the labeled amount

of cefotetan, within –10 to +20%. Meets the requirements for

Constituted solution, Bacterial endotoxins, Sterility, and Particulate

matter, for Identification, pH, and Water under Cefotetan Disodi-

um, for Uniformity of dosage units, and for Labeling under Injec-

tions.{R-14}



CEFOXITIN

SUMMARY OF DIFFERENCESIndications: General considerations—Second-generation cephalosporin;

good activity against anaerobic organisms, but only active against

some Bacteroides fragilis.{R-1}

Pharmacology/pharmacokinetics: Distribution—In people, when admin-

istered at high doses, cefoxitin enters the cerebrospinal fluid in

therapeutic concentrations when meninges are inflamed.{R-1}

Drug interactions and/or related problems: Concurrent administration

with probenecid may prolong the serum half-life of cefoxitin.{R-26}





in terms of cefoxitin base (not the sodium salt).

CEFOXITIN INJECTION USPUsual dose:



weight every six hours or the same dose administered subcutaneously

every eight hours has been used in the treatment of susceptible

bacterial infections in dogs, based on pharmacokinetic data{R-38; 84}.

[Horses]1—Although the efficacy and safety have not been


weight every four to six hours has been used in the treatment of

susceptible bacterial infections in horses, based on pharmacokinetic

data{R-29}.

Strength(s) usually available:{R-45}

U.S.—




20 mg (base) per mL (Rx) [Mefoxin].

40 mg (base) per mL (Rx) [Mefoxin].

Canada—


Packaging and storage: {R-45} Store at –20 �C (–4 �F) or below, unless


Preparation of dosage form: See manufacturer’s product labeling.

USP requirements: Preserve in Containers for Injections. Maintain in

the frozen state. A sterile solution of Cefoxitin Sodium and one or more

suitable buffer substances in Water for Injection. Contains Dextrose or

Sodium Chloride as a tonicity-adjusting agent. It meets the require-

ments for Labeling under Injections. The label states that it is to be

thawed just prior to use, describes conditions for proper storage of the

resultant solution, and directs that the solution is not to be refrozen.

Contains an amount of cefoxitin sodium equivalent to the labeled

amount of cefoxitin, within –10% to +20%. Meets the requirements for

Identification, Bacterial endotoxins, Sterility, pH (4.5–8.0), and Par-

ticulate matter.{R-14}

CEFOXITIN FOR INJECTION USPUsual dose: See Cefoxitin Injection USP.


U.S.—{R-21}




1 gram (base) (Rx) [Mefoxin].

2 grams (base) (Rx) [Mefoxin].


Canada—




1 gram (base) (Rx) [Mefoxin; GENERIC].

2 grams (base) (Rx) [Mefoxin; GENERIC].








USP requirements: Preserve in Containers for Sterile Solids. Con-

tains Cefoxitin Sodium equivalent to the labeled amount of cefoxitin,

within –10% to +20%. Meets the requirements for Constituted solu-

tion, Bacterial endotoxins, Sterility, and Particulate matter, for Iden-

tification tests, pH, and Water under Cefoxitin Sodium, for Uniformity

of dosage units, and for Labeling under Injections.{R-14}



CEFTIOFUR

SUMMARY OF DIFFERENCESIndications:

General considerations—‘‘New-generation’’ cephalosporin{R-11}.

Indicated in the treatment of susceptible Escherichia coli infections in

chicks and turkey poults; metritis and pododermatitis in cattle,

respiratory tract infections in cattle, goats, horses, pigs, and sheep,

and urinary tract infections in dogs.

Pharmacology/pharmacokinetics: Biotransformation—Biotransforma-

tion to an active antibacterial metabolite, desfuroylceftiofur, oc-

curs.{R-66}

Drug interactions and/or related problems: Probenecid has not been

shown to alter the excretion of ceftiofur.{R-70}

Side/adverse effects: Often-reversible anemia and thrombocytopenia can

occur in animals given three to five times the recommended dose of

ceftiofur.{R-66}





in terms of ceftiofur free acid (not the sodium salt).

CEFTIOFUR HYDROCHLORIDE INJECTIONUsual dose:

Metritis1—Cattle: Intramuscular or subcutaneous, 2.2 mg per kg of

body weight every twenty-four hours for five days{R-81}.

Pododermatitis—Cattle: Intramuscular or subcutaneous, 1.1 to 2.2 mg


Respiratory tract infections—

Cattle: Intramuscular or subcutaneous, 1.1 to 2.2 mg per kg of

body weight every twenty-four hours{R-81}. Alternatively, the

clinician may choose, based on the severity of disease, patho-

gen susceptibility, and the clinical response, to administer

intramuscularly or subcutaneously, 2.2 mg per kg of body weight

every forty-eight hours for two doses{R-81}.

Pigs: Intramuscular, 3 to 5 mg per kg of body weight every twenty-

four hours for three days{R-81; 96}.

Strength(s) usually available{R-81; 96; 99}:

U.S.—


50 mg per mL (Rx) [Excenel RTU].

Note: Be aware that this product differs from Excenel available in

Canada.

Canada—


50 mg per mL (Rx) [Excenel RTU].

Withdrawal times{R-81; 96; 99}:

U.S.—

Withdrawal time


Cattle 2 None

Pigs 0 –

Note: At labeled doses, discarding of milk during treatment is not

required.

Product labeling listing the above withdrawal times states that

treatment should not exceed five days for cattle or three days for pigs

for these withdrawal times to apply.

This product is not labeled for use in preruminating calves. Trim-out of

edible tissue at slaughter may occur within 11 days of injection because

of areas of discoloration associated with the injection site{R-81}.

Canada—

Withdrawal time


Cattle 3 None

Pigs 2 –

Note: Product labeling listing the above withdawal times states that it

applies to a dose for pigs of 3 mg per kg of body weight every twenty-

four hours for three days and a dose for cattle of 1 mg per kg of body

weight every twenty-four hours for up to five days{R-99}.

In pigs, trim-out of edible tissue at slaughter may occur within 11 days

of intramuscular injection.

In cattle, trim-out of edible tissue at slaughter may occur within 11

days of the last subcutaneous injection or within 28 days of the last

intramuscular injection into the neck{R-99}.



manufacturer. Protect from freezing.

Auxiliary labeling:

• Shake well before using{R-35}.

• Keep out of reach of children{R-81}.


CEFTIOFUR SODIUM FOR INJECTIONUsual dose:

Escherichia coli infections—

Chicks1, day-old: Subcutaneous, 0.08 to 0.2 mg (free acid) per chick

as a single dose{R-11}.



Turkey poults, day-old: Subcutaneous, 0.17 to 0.5 mg (free acid) per

poult as a single dose{R-11}.

Pododermatitis—Cattle: Intramuscular, 1.1 to 2.2 mg (free acid) per kg

of body weight every twenty-four hours{R-11}.

Respiratory tract infections—

Cattle: Intramuscular, 1.1 to 2.2 mg (free acid) per kg of body weight

every twenty-four hours{R-11}.

Goats1: Intramuscular, 1.1 to 2.2 mg (free acid) per kg of body

weight every twenty-four hours{R-11}.

Horses: Intramuscular, 2.2 to 4.4 mg (free acid) per kg of body

weight every twenty-four hours{R-11; 12}.

Note: For treatment of susceptible infections in foals, a dose of 2.2 to

6.6 mg (free acid) per kg of body weight every twelve to twenty-

four hours has been used, based on pharmacokinetic data{R-48}.

Pigs: Intramuscular, 3 to 5 mg (free acid) per kg of body weight every

twenty-four hours{R-11}.

Sheep: Intramuscular, 1.1 to 2.2 mg (free acid) per kg of body weight

every twenty-four hours for three days{R-11; 97}. If a satisfactory

response is not seen, the dose may be repeated on the fourth and

fifth days{R-11; 97}.

Urinary tract infections—Dogs: Subcutaneous, 2.2 mg (free acid) per


Note: Also for dogs, for treatment of [bacterial infections other than

urinary tract infections]1 a dose of 2.2 to 4.4 mg (free acid) per kg of

body weight every twenty-four hours has been used, based on

pharmacokinetic data{R-74; 76}.



U.S.:{R-11}


50 mg per mL (Rx) [Naxcel].

Canada:{R-12}


50 mg per mL (Rx) [Excenel].

Withdrawal times:

U.S.—{R-11}

Withdrawal time


Cattle 0 None

Goats, pigs, sheep 0 –


required.{R-68}


treatment should not exceed five days for cattle, goats, or sheep; or

three days for pigs, for these withdrawal times to apply.

Canada—{R-12}

Withdrawal time


Cattle 0 None

Pigs, sheep 1 —


required.


treatment should not exceed five days for cattle or three days for

lambs or pigs for these withdrawal times to apply.

Packaging and storage:

Store unreconstituted product at controlled room temperature, 20

to 25 �C (68 to 77 �F){R-11}, unless otherwise specified by manu-

facturer.

Store reconstituted product either in a refrigerator at 2 to 8 �C (36 to 46 �F)for up to sevendays or at controlled roomtemperature, 20 to25 �C (68 to77 �F), for up to twelve hours{R-11}, unless otherwise specified by

manufacturer.

Protect from light.

Preparation of dosage form: To prepare dilution for intramuscular

use, 20 or 80 mL of sterile water for injection should be added to the

1-gram or 4-gram vial, respectively{R-11}.

Stability:{R-11}

After reconstitution, solutions retain their potency for 7 days when

refrigerated at 2 to 8 �C (36 to 46 �F) or 12 hours at room

temperature, 15 to 30 �C (59 to 86 �F).After reconstitution, solutions may be frozen for up to eight weeks.

Frozen ceftiofur sodium may be thawed at room temperature or under

warm to hot running water. Solutions should not be refrozen.

Variations in color do not affect potency.




CEPHALEXIN





CEPHALEXIN CAPSULES USPUsual dose:

Note: [Birds]1—Although the efficacy and safety have not been

established, an oral dose of 35 to 50 mg per kg of body weight

every two to six hours has been used in the treatment of susceptible

bacterial infections in birds, based on pharmacokinetic studies{R-34}.

In general, larger birds maintain measurable serum concentrations of

cephalexin longer than do smaller birds; adequate concentrationsmay

be achieved in larger birds with a six-hour dosing interval{R-34}.


an oral dose of 10 to 30 mg per kg of body weight every six to twelve

hours has been used in the treatment of susceptible bacterial infections

in dogs, based on pharmacokinetic data{R-49; 50}.



For pyoderma in dogs, a dose of 25 mg per kg of body weight

every twelve hours for three weeks has been used, based on

clinical efficacy studies{R-32}. Recurrent pyodermas may require at

least five weeks of therapy and deep pyodermas, nine weeks{R-32}.


U.S.—{R-23}




250 mg (Rx) [Keflex; GENERIC].

500 mg (Rx) [Keflex; GENERIC].

Canada—




250 mg (Rx) [Novo-Lexin].

500 mg (Rx) [Novo-Lexin].




USP requirements: Preserve in tight containers. Contain the equiva-

lent of the labeled amount of anhydrous cephalexin, within –10% to

+20%. Meet the requirements for Identification, Dissolution (80% in

30 minutes in water in Apparatus 1 at 100 rpm), Uniformity of dosage

units, and Water (not more than 10.0%).{R-14}

CEPHALEXIN FOR ORAL SUSPENSION USPUsual dose: See Cephalexin Capsules USP.



U.S.:{R-23}




25 mg per mL (Rx) [Keflex; GENERIC].

50 mg per mL (Rx) [Keflex; GENERIC].

Canada:




25 mg per mL (Rx) [Keflex; Novo-Lexin; PMS-Cephalexin].

50 mg per mL (Rx) [Keflex; Novo-Lexin; PMS-Cephalexin].

Packaging and storage: Prior to reconstitution, store below 40 �C(104 �F), preferably between 15 and 30 �C (59 and 86 �F), unlessotherwise specified by manufacturer. Store in a tight container.

Stability: {R-23} After reconstitution, suspensions retain their potency for

14 days if refrigerated.

Auxiliary labeling:

• Refrigerate.

• Shake well.


Cephalexin and one or more suitable buffers, colors, diluents, and

flavors. Contains the equivalent of the labeled amount of anhydrous

cephalexin per mL when constituted as directed in the labeling, within

–10% to +20%. Meets the requirements for Identification, Uniformity

of dosage units (solid packaged in single-unit containers), Deliverable

volume (solid packaged in multiple-unit containers), pH (3.0–6.0, in

the suspension constituted as directed in the labeling), and Water (not


CEPHALEXIN TABLETS USPUsual dose: See Cephalexin Capsules USP.


U.S.—




250 mg (Rx) [GENERIC].


Canada—




250 mg (Rx) [Apo-Cephalex; Keflex; Novo-Lexin; Nu-Cephalex; PMS-

Cephalexin].

500 mg (Rx) [Apo-Cephalex; Keflex; Novo-Lexin; Nu-Cephalex; PMS-

Cephalexin].




USP requirements: Preserve in tight containers. They are prepared

from Cephalexin or Cephalexin Hydrochloride. The label states whe-

ther the Tablets contain Cephalexin or Cephalexin Hydrochloride.

Contain the equivalent of the labeled amount of anhydrous cephalexin,

within –10% to +20%. Meet the requirements for Identification, Dis-

solution (80% in 30 minutes in water in Apparatus 1 [use 40-mesh

cloth] at 100 rpm for cephalexin and 75% in 45 minutes in water in

Apparatus 1 [use 10-mesh cloth] at 150 rpm for cephalexin hydro-

chloride), Uniformity of dosage units, and Water (not more than 9.0%

where Tablets contain cephalexin; not more than 8.0% where Tablets

contain cephalexin hydrochloride).{R-14}

CEPHALEXIN HYDROCHLORIDE TABLETS USPUsual dose: See Cephalexin Capsules USP.


U.S.—{R-51}




500 mg (Rx) [Keftab].

Canada—


Packaging and storage: Store between 15 and 30 �C (59 and 86 �F),unless otherwise specified by manufacturer. Store in a tight container.



USP requirements: Preserve in tight containers. They are prepared

from Cephalexin or Cephalexin Hydrochloride. The label states whe-

ther the Tablets contain Cephalexin or Cephalexin Hydrochloride.

Contain the equivalent of the labeled amount of anhydrous cephalexin,

within –10% to +20%. Meet the requirements for Identification, Dis-

solution (80% in 30 minutes in water in Apparatus 1 [use 40-mesh

cloth] at 100 rpm for cephalexin and 75% in 45 minutes in water in

Apparatus 1 [use 10-mesh cloth] at 150 rpm for cephalexin hydro-

chloride), Uniformity of dosage units, and Water (not more than 9.0%

where Tablets contain cephalexin; not more than 8.0% where Tablets

contain cephalexin hydrochloride).{R-14}



CEPHALOTHIN



with probenecid may prolong the serum half-life of cephalothin.{R-30}

Medical considerations/contraindications: Severe hepatic dysfunction

may inhibit metabolism.{R-2}

Side/adverse effects: Local irritation may occur.{R-1}





in terms of cephalothin base (not the sodium salt).

CEPHALOTHIN FOR INJECTION USPUsual dose:

Note: [Birds]1—Although the efficacy and safety have not been

established, an intramuscular dose of 100 mg (base) per kg of body

weight every two to six hours has been used in the treatment of

susceptible bacterial infections in birds, based on pharmacokinetic

studies{R-34}.

In general, larger birds maintain measurable serum concentrations

of cephalothin longer than do smaller birds; adequate concentrations

may be achieved in larger birds with a six-hour dosing interval{R-34}.


an intramuscular or intravenous dose of 10 to 30 mg (base) per kg of

body weight every four to eight hours has been used in the treatment

of susceptible bacterial infections in dogs, based on pharmacokinetic

data{R-38}.

[Horses]1—Although the efficacy and safety have not been estab-

lished, an intramuscular or intravenous dose of 10 to 25 mg (base)

per kg of body weight every four hours has been used in the

treatment of susceptible bacterial infections in horses, based on

pharmacokinetic data{R-9; 19}.


U.S.—{R-22; 53}





Canada—{R-54}




1 gram (base) (Rx) [Ceporacin; Keflin].


Preparation of dosage form: {R-22; 53} Dilutions should be prepared

according to manufacturer’s instructions.

Stability:{R-22}

After reconstitution, solutions retain their potency for 96 hours if

refrigerated. Solutions for intramuscular use retain their potency for

12 hours at room temperature.

A precipitate may form in the solution. Upon being warmed to room

temperature and shaken, the precipitate will dissolve.

Concentrated solutions will darken in color, especially at room temper-

ature. However, slight discoloration does not affect potency.

If frozen immediately after reconstitution with sterile water for injection,

5% dextrose injection, or 0.9% sodium chloride injection, solutions

retain their potency in the original container up to 12 weeks at –20 �C(–4 �F). Once thawed, solutions should not be refrozen.

Incompatibilities:

The admixture of other medications with cephalothin sodium injection is

not recommended.

The admixture of beta-lactam antibiotics (penicillins and cephalosporins)

and aminoglycosides may result in substantial mutual inactivation;

they should not be mixed in the same intravenous bag or bottle.


an amount of Cephalothin Sodium equivalent to the labeled amount of

cephalothin, within –10% to +15%. May contain Sodium Bicarbonate.

Meets the requirements for Constituted solution, Specific rotation

(+124� to +134�, calculated on the dried and sodium bicarbonate-free

basis), Content of sodium bicarbonate (if present), Bacterial endotox-

ins, Sterility, pH (6.0–8.5, in the solution constituted as directed in the

labeling), Uniformity of dosage units, and Particulate matter, for

Identification test A and Loss on drying under Cephalothin Sodium,

and for Labeling under Injections.{R-14}



CEPHAPIRIN


Pharmacology/pharmacokinetics: Human biotransformation—Hepatic

metabolism to the desacetyl form occurs.{R-2}


with probenicid may prolong the serum half-life of cephapirin.{R-30}



Medical considerations/contraindications: In people, severe hepatic

dysfunction can inhibit metabolism.{R-2}

Side/adverse effects: Local reactions may occur.{R-1}





in terms of cephapirin base (not the sodium salt).

CEPHAPIRIN FOR INJECTION USPUsual dose:


established, an intramuscular or intravenous dose of 10 to 30 mg

(base) per kg of body weight every four to eight hours has been used

in the treatment of susceptible bacterial infections in dogs, based on

pharmacokinetic data{R-2; 38; 86}.

[Horses]1—Although the efficacy and safety have not been estab-

lished, an intramuscular or intravenous dose of 20 to 30 mg per kg

of body weight every four to eight hours has been used in the

treatment of susceptible bacterial infections in horses, based on

pharmacokinetic data{R-18; 29; 35; 86}.


U.S.—{R-55}




500 mg (base) (Rx) [Cefadyl].

1 gram (base) (Rx) [Cefadyl].

2 grams (base) (Rx) [Cefadyl].



Canada—






Incompatibilities: The admixture of beta-lactam antibiotics (penicillins

and cephalosporins) and aminoglycosides may result in substantial

mutual inactivation; they should not be mixed in the same intrave-

nous bag or bottle.


an amount of Cephapirin Sodium equivalent to the labeled amount of

cephapirin, within –10% to +15%. Meets the requirements for Con-

stituted solution, Bacterial endotoxins, Sterility, and Particulate mat-

ter, for Identification, Crystallinity, pH, and Water under Cephapirin

Sodium, and for Uniformity of dosage units and Labeling under

Injections.{R-14}



CEPHRADINE





CEPHRADINE CAPSULES USPUsual dose:

Note: [Dogs]1—Although the efficacy and safety have not been estab-

lished, an oral dose of 10 to 25 mg per kg of body weight every six to


infections in dogs, based on pharmacokinetic data{R-2; 38}.


anoral dose of 25mgper kg of bodyweight every six to eight hourshas

been used in the treatment of susceptible bacterial infections in foals,

based on pharmacokinetic data{R-85}.


U.S.—




250 mg (Rx) [Velosef; GENERIC].

500 mg (Rx) [Velosef; GENERIC].

Canada—


Packaging and storage: Store below 30 �C (86 �F), preferably between

15 and 30 �C (59 and 86 �F), unless otherwise specified by manu-

facturer. Store in a tight container.

USP requirements: Preserve in tight containers. The quantity of

cephradine stated in the labeling is in terms of anhydrous cephradine.

Contain the labeled amount of cephradine, within –10% to +20%,

calculated as the sum of cephradine and cephalexin. Meet the

requirements for Identification, Dissolution (75% in 45 minutes in

0.12 N hydrochloric acid in Apparatus 1 at 100 rpm), Uniformity of

dosage units, and Loss on drying (not more than 7.0%).{R-14}

CEPHRADINE FOR ORAL SUSPENSION USPUsual dose: See Cephradine Capsules USP.



U.S.:






25 mg per mL (Rx) [Velosef; GENERIC].

50 mg per mL (Rx) [Velosef; GENERIC].

Canada:


Packaging and storage: Prior to reconstitution, store below 40� C

(104� F), preferably between 15 and 30� C (59 and 86� F), unless

otherwise specified by manufacturer. Store in a tight container.

Stability:

After reconstitution, suspensions retain their potency for 7 days at room

temperature or for 14 days if refrigerated.

Auxiliary labeling:

• Refrigerate.

• Shake well.


Cephradine and one or more suitable buffers, colors, diluents, and

flavors. Contains the labeled amount of cephradine, within –10% to

+25%, calculated as the sum of cephradine and cephalexin. Meets the

requirements for Identification, Uniformity of dosage units (solid

packaged in single-unit containers), Deliverable volume (solid pack-

aged in multiple-unit containers), pH (3.5–6.0, in the suspension

constituted as directed in the labeling), and Water (not more than

1.5%).{R-14}



Developed: 08/02/95

Interim revision: 07/08/98; 11/5/99; 09/30/02; 04/04/03

Table 1. Pharmacology/Pharmacokinetics*.

Drug

Protein

binding

(%)

Half-life of

elimination

(hr)

VolDSteady state

(L/kg)

Clearance

(mL/min/kg)

Route; Dose

(mg/kg)

Tmax

(min)

Cmax

(mcg/mL)

Bioavailability

(%)

First-Generation

Cefadroxil

Cats {R-3} Low (20) Oral; 22 60–120 17.4

Dogs {R-3} Low (20) Oral; 22 60–120 18.6

Horses

Adult{R-78} 0.8 0.46 7 IV; 25

Foal{R-56} 1.4 Oral; �100 90 23.4 37–100

Cefazolin

Dogs{R-5} 0.8–1.2 IV; 15

Horses{R-57} Low (8) 0.6–0.8 0.19 5.51 IV; 11

Pigs{R-5} 0.27 IV; 15

Cephalexin

Birds{R-34} Oral; 25–50 30–60 20

Cats{R-50} Oral; 15 120 11–29

Oral; 25 60–120 15{R-49} SQ; 20 66 54

IM; 20 42 61.8

Dogs{R-2; 49} 1.3

Oral; 10–15 108 18.6

SQ; 10 72 24.9

IM; 10 54 31.9

Pigs{R-5} 1 IV; 15

Cephalothin

Birds{R-34} IM; 100 30 18

Dogs{R-5} 0.7 IV; 15

Horses{R-19} Low (18) 0.25 0.15 13.6 IV; 11

IM; 11 47 11.3 65

Cephapirin

Calves{R-58}

(3–16 wks) IM; 10 20 6.3

Cows{R-25} IM; 10 10 13.3

Dogs{R-2} 0.4

Foals{R-59} IM; 20 10 21.2

(4–6 days)

Horses{R-18} 0.9 0.17 10 IV; 20

IM; 20 25 14.8 95

Cephradine

Dogs{R-2} 1.4

Foals{R-85} 1.6 0.4 6.7 IV; 25

Oral; 25 90 13.2

Second-Generation

Cefaclor

Dogs{R-5} 2 IV; 3.75



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Table 1 (Contd.)

Drug

Protein

Binding

(%)

Half-life of

Elimination

(hr)

VolDSteady state

(L/kg)

Clearance

(mL/min/kg)

Route; Dose

(mg/kg)

Tmax

(min)

Cmax

(mcg/mL)

Bioavailability

(%)

Cefotetan

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SC; 30 30-60 84

Cefoxitin

Calves{R-26} Moderate 1.1 0.32 4.9 IV; 20

(42–55) IM; 20 74

Dogs{2; 84) 0.7; 1.3

Horses{R-29} 0.8 0.12 4.32 IV; 20

IM; 20 77

Third-Generation

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SQ; 50 36–60 30 100

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IM; 50 30 47 85

SQ; 50 48 30 100

Goats{R-15} 0.4 IV

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New Generation

Ceftioflur�Calves{R-61} IM; 2.2 120 8.8

IM; 4.4 120 17.3

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IM; 2 60 4.6 100

Dogs{R-72} 5 to 7 SQ; 0.22 45 1.7

SQ; 2.2 60 8.9

SQ; 4.4 90 26.7

Foals{R-48} IM; 2.2 45 3.6

Horses{R-93} 3–5{R-75} IM; 2.2 60 4.4

Pigs{R-75} 12-13 IM; 3 35 19.2

Sheep{R-97} 5-6 IV; 1.1–2.2

IM; 1.1–2.2 30 4.1–6.2

*Abbrevations: IM = Intramuscular, IV = Intravenous, SQ = Subcutaneous, VolD = Volume of distribution, Tmax = Time to peak concentration, Cmax = Peak serum

concentration.

�Assays for serum concentrations of ceftiofur listed include ceftiofur and its active desfuroylceftiofur metabolite.



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treatment of sheep respiratory disease. Public Master File Number 5544.

NRSP-7 Minor Use Animal Drug Program.


99. Ceftiofur package insert (Excenel RTU, Pharmacia Animal Health—Canada).

In: Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port


100. Manufacturer comment, Rec 2/24/97.

101. Barza M, Pinn V, Tanguay P, et al. Nephrotoxicity of newer cephalosporins

and aminoglycosides alone and in combination in a rat model. J Antimicrob

Chemother 1978; 4(Suppl A): 59–68.

102. Diaz JAO, Sumano LH, Ocampo CL. Evaluacion de la nefrotoxicidad de

cejelexiuagentamicin eu perros. Vet Mex 1995; 26: 247–9.

103. Ringer NC, Pearson EG, Gronwall R, et al. Pharmacokinetics of ceftriaxone in

healthy horses. Equine Vet J 1996; 28(6): 476–9.



CEPHAPIRIN Veterinary—Intramammary-Local


Cefa-Dri; Cefa-Lak; ToDay; and ToMorrow.




INDICATIONS

GENERAL CONSIDERATIONSCephapirin is a first-generation cephalosporin that has a wide spectrum

of activity against gram-positive and gram-negative organisms.{R-5}

Cephapirin is more resistant to beta-lactamases than are the

penicillins{R-6} and so is effective against staphylococci, with the

exception of methicillin-resistant staphylococci.{R-5}

ACCEPTEDMastitis (treatment)—Cattle: Cephapirin is indicated in the treatment of

mastitis caused by susceptible bacteria, such as Staphylococcus

aureus{R-1-4; 7} and Streptococcus agalactiae.{R-1–4} Cephalosporins are

the primary treatment of choice for acute staphylococcal mastitis{R-9};

however, cows with acute or peracute mastitis are often given other

medications, such as systemic antibiotics and/or supportive therapy,

concurrently with intramammary therapy.{R-10}

REGULATORY CONSIDERATIONSU.S. and Canada—

Withdrawal times have been established for cephapirin benzathine and

cephapirin sodium intramammary infusion (see the Dosage Forms

section).{R-1–4; 17; 18}

CHEMISTRYSource: Cephalosporins are semi-synthetic derivatives of metabolic

products of the fungus Cephalosporium acremonium.{R-6; 11}

Chemical group: Beta-lactam antibiotics.{R-5}

Chemical name:

Cephapirin benzathine—5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxy-

lic acid, 3-[(acetyloxy)methyl]-8-oxo-7-[[(4-pyridinylthio)acetyl]amino]-,

(6R-trans)-, cmpd. with N,N¢-bis(phenylmethyl)-1,2-ethanediamine

(2:1){R-12}.

Cephapirin sodium—5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic

acid, 3-[(acetyloxy)methyl]-8-oxo-7-[[(4-pyridinylthio)acetyl]amino]-,

monosodium salt, [6R-trans]-.{R-12}

Molecular formula:

Cephapirin benzathine—(C17H17N3O6S2)2 Æ C16H20N2{R-12}.

Cephapirin sodium—C17H16N3NaO6S2.{R-12}

Molecular weight:

Cephapirin benzathine—1087.27{R-12}.

Cephapirin sodium—445.45.{R-12}

Description:

Cephapirin Benzathine USP—White, crystalline powder{R-21}.

Cephapirin Sodium USP—White to off-white crystalline powder, odorless

or having a slight odor{R-21}.

pKa: Cephapirin sodium—2.15 and 7.3.{R-13}

Solubility:

Cephapirin Benzathine USP—Practically insoluble in water, in ether, and

in toluene; freely soluble in alcohol; soluble in 0.1 N hydrochloric

acid{R-21}.

Cephapirin Sodium USP—Very soluble in water; insoluble in most

organic solvents{R-21}.

PHARMACOLOGY/PHARMACOKINETICSMechanism of action/effect: Cephapirin produces its bactericidal

effect by inhibiting cell wall synthesis. Its action is only effective in

actively growing cells.


evenly distributed in the treated quarter of the healthy mammary

gland; however, in an udder affected by moderate to severe mastitis,

the presence of edema, blockage of milk ducts, and reduced blood

circulation can cause uneven distribution of medication.{R-14}





Bacterial pathogens in milk

(milk samples should be tested 3 weeks after treatment is

discontinued; mastitis is not considered bacteriologically cured until

samples show an absence of the mastitis-causing organisms)

Clinical signs

(although resolution of clinical signs of mastitis is not an indication


clinical condition of the mammary gland, teat, and milk produced

can aid in diagnosis of a recurrence of mastitis or initial diagnosis of


Somatic cell count


used primarily to maintain milk quality but are also used to assess

the approximate overall effectiveness of mastitis control programs,

which may include antibiotic treatment of cows){R-10}





Cows

Allergic reactions{R-1; 2}—local or systemic; drug fever{R-19}



CEPHAPIRIN Veterinary—Intramammary-Local 71




drug manufacturer.

CLIENT CONSULTATIONTreatment of mastitis in dairy cattle is best achieved by a comprehensive

mastitis control program in which herd management is the primary

focus. The program should include routine milk testing, good

maintenance of milking equipment, and constant evaluation of

milking procedures and teat health as well as strategic treatment of

clinical cases of mastitis.{R-16}

VETERINARY DOSING INFORMATIONAntibiotic therapy in the dry cow is more effective than treatment during

lactation for mastitis caused by Staphylococcus aureus.{R-15; 16; 20}

Choice of antibiotic for treatment of mastitis should be based on

knowledge of identity and sensitivity of pathogens causing mastitis in

the cow and the dairy herd.

Before intramammary administration of cephapirin, the following actions

should be taken:{R-1–4}

• The udder should be milked out completely and the teats washed

with warm water and a disinfectant. Care should be taken to avoid

washing excess dirt down from the udder onto the teat ends. The

area should be dried thoroughly. An effective germicidal teat dip

should be applied for one minute and then each teat wiped with a

separate cotton ball soaked with an antiseptic such as 70% alcohol.







Following treatment, an effective teat dip is recommended on all teats.


CEPHAPIRIN BENZATHINE INTRAMAMMARYINFUSION USPUsual dose: Mastitis—Cows, nonlactating: Intramammary, 300 mg

administered into each quarter of the udder at the time of drying-

off.{R-1; 2}


U.S.—{R-1; 2; 22}


300 mg per 10 mL (OTC) [Cefa-Dri; ToMorrow].

Canada—{R-17; 22}


300 mg per 10 mL (Rx) [Cefa-Dri].

Withdrawal times:

U.S.—{R-1; 2; 22}

Withdrawal time


Cows, nonlactating 42 72

Note: Cephapirin benzathine intramammary infusion should not be used

any later than thirty days prior to calving.

Canada—{R-17; 22}

Withdrawal time


Cows, nonlactating 42 84

Note: Cephapirin benzathine intramammary infusion should not be used

any later than thirty days prior to calving.

Packaging and storage: Store between 15 and 30 �C (59 and 86 �F),unless otherwise specified by manufacturer. Protect from freezing.

USP requirements: Preserve inwell-closed unit-dose disposable syringes

at controlled room temperature. A suspension of Cephapirin Benzathine

in a suitable vegetable oil vehicle. Contains a suitable dispersing agent.

Label Intramammary Infusion to indicate that it is for veterinary use

only. Contains an amount of cephapirin benzathine equivalent to the

labeled amount of cephapirin, within -10% to +20%. Meets the

requirements for Identification and Water (not more than 1.0%){R-21}.

CEPHAPIRIN SODIUM INTRAMAMMARY INFUSIONUSP

Usual dose: Mastitis—Cows, lactating: Intramammary, 200 mg into

each affected quarter of the udder every twelve hours for two treat-

ments.{R-3; 4}


U.S.—{R-3; 4; 22}


200 mg per 10 mL (OTC) [Cefa-Lak; ToDay].

Canada—{R-18; 22}


200 mg per 10 mL (Rx) [Cefa-Lak].

Withdrawal times:

U.S. and Canada—{R-3; 4; 18; 22}

Withdrawal time



Packaging and storage: Store between 15 and 30 �C (59 and 86 �F),unless otherwise specified by manufacturer. Protect from freezing.

USP requirements: Preserve in well-closed unit-dose disposable syr-

inges at controlled room temperature. A suspension of Cephapirin

Sodium in a suitable vegetable oil vehicle. Contains a suitable disper-

sing agent. Label Intramammary Infusion to indicate that it is for

veterinary use only. Contains an amount of cephapirin sodium

equivalent to the labeled amount of cephapirin, within )10% to +20%.

Meets the requirements for Identification and Water (not more than

1.0%){R-21}.

72 CEPHAPIRIN Veterinary—Intramammary-Local


Developed: 06/30/95


02/28/03

REFERENCES1. Cefa-Dri package insert (Fort Dodge—US). Downloaded 2/16/03 from

www.wyeth.com.

2. ToMorrow package insert (Fort Dodge—US). Downloaded 8/6/03 from

www.wyeth.com.

3. Cefa-Lak package insert (Fort Dodge—US), Rev 3/00. Downloaded 8/6/03

from www.wyeth.com.

4. ToDay package insert (Fort Dodge—US). Downloaded 8/6/03 from www.

wyeth.com.


419–26.

6. Caprile KA. The cephalosporin antimicrobial agents: a comprehensive review.


7. Owens WE, et al. Efficacy of a cephapirin dry cow product for treatment of

experimentally induced Staphylococcus aureus mastitis in heifers. J Dairy Sci

1991; 74(10): 3376–82.

8. Watson ADJ. Penicillin G and the alternatives. Vet Annu 1985; 25: 277-83.

9. Barragry TB. Veterinary drug therapy. Philadelphia: Lea & Febiger, 1994.

p. 665.

10. Heath SE. Bovine mastitis. In: Howard JL. Current veterinary therapy 3 food

animal practice. Philadelphia: W.B. Saunders, 1993. p. 762–9.

11. Papich MG. Clinical pharmacology of cephalosporin antibiotics. J Am Vet Med

Assoc 1984; 184(3): 344–7.


MD: The United States Pharmacopeial Convention, Inc., 2002.

13. Gennaro AR, editor. Remington’s pharmaceutical sciences. 18th ed. Easton,

PA: Mack Publishing Company, 1990. p. 1199.

14. Jarp J, Bugge HP, Larsen S. Clinical trial of three therapeutic regimens for





Vet Med Assoc 1993 Jul; 203(2): 210–20.

17. Cephapirin (Cefa-Dri, Wyeth Ayerst—Canada). In: Bennett K, editor.

Compendium of veterinary products. 3rd ed. Hensall, ON: North American

Compendiums Inc., 1993. p. 163.

18. Cephapirin (Cefa-Lak, Wyeth Ayerst—Canada). In: Bennett K, editor.

Compendium of veterinary products. 3rd ed. Hensall, ON: North American

Compendiums Inc., 1993. p. 164.





States Pharmacopeial Convention, Inc., 2002. p. 398, 400, 2554.

22. Arrioja-Dechert A, editor. Compendium of Veterinary Products, CD edition.


CEPHAPIRIN Veterinary—Intramammary-Local 73


CHLORAMPHENICOL Veterinary—Systemic


For veterinary-labeled products—Amphicol Film-Coated Tablets; Azra-

mycine S125; Azramycine S250; Chlor 100; Chlor 250; Chlor 500;

Chlor 1000; Chlor Palm 125; Chlor Palm 250; Duricol; Karomycin

Palmitate 125; Karomycin Palmitate 250; and Viceton.

For human-labeled products—Chloromycetin and Novochlorocap.







ACCEPTEDChloramphenicol is a broad-spectrum antibiotic shown to have specific

activity against a wide variety of organisms that are the causative

agents of several disease conditions in domestic animals. Such

organisms include Staphylococcus aureus, Streptococcus pyogenes, Bru-

cella bronchoseptica, Escherichia coli, Proteus vulgaris, Aerobacter aerog-

enes, Corynebacterium renale, Salmonella species, Pseudomonas species,

Shigella species, Neisseria catarrhalis, anaerobic bacteria, and many

rickettsiae. The species treated with chloramphenicol include dogs,

[cats]1, and [horses]1.




Food and Drug Administration regulations ban chlorampheni-

col from use in animals that are used for food production.

There are no safe residue levels, and no withdrawal times have been

established.

Chloramphenicol Tablets USP are labeled for veterinary use only.

Canada—

Chloramphenicol is prohibited from use in food-producing

animals by the Canadian Health Protection Branch.

Chloramphenicol Tablets USP are labeled for veterinary use only.

CHEMISTRYSource:

Originally derived from Streptomyces venezuelae.{R-8}

Chemical name:

Chloramphenicol—Acetamide, 2,2-dichloro-N-[2-hydroxy-1-(hydroxy-

methyl)-2-(4-nitrophenyl)ethyl]-, [R-(R*,R*)]-.{R-9}

Chloramphenicol palmitate—Hexadecanoic acid, 2-[(2,2-dichloroacetyl)-

amino]-3-hydroxy-3-(4-nitrophenyl) propyl ester, [R-(R*,R*)]-.{R-9}

Chloramphenicol sodium succinate—Butanedioic acid, mono[2-[(2,2-

dichloroacetyl)amino]-3-hydroxy-3-(4-nitrophenyl)propyl]ester,mono-

sodium salt, [R-(R*,R*)]-{R-9}.

Molecular formula:

Chloramphenicol—C11H12Cl2N2O5.{R-9}

Chloramphenicol palmitate—C27H42Cl2N2O6.{R-9}

Chloramphenicol sodium succinate—C15H15Cl2N2NaO8.{R-9}

Molecular weight:

Chloramphenicol—323.13.{R-9}

Chloramphenicol palmitate—561.54.{R-9}

Chloramphenicol sodium succinate—445.18.{R-9}

Description:{R-10}

Chloramphenicol USP—Fine, white to grayish white or yellowish white,

needle-like crystals or elongated plates. Its solutions are practically

neutral to litmus. Is reasonably stable in neutral or moderately acid

solutions. Its alcohol solution is dextrorotatory and its ethyl acetate

solution is levorotatory.

Chloramphenicol Palmitate USP—Fine, white, unctuous, crystalline

powder, having a faint odor.

Chloramphenicol Sodium Succinate USP—Light yellow powder.

Solubility:{R-10}

Chloramphenicol USP—Slightly soluble in water; freely soluble in

alcohol, in propylene glycol, in acetone, and in ethyl acetate.

Chloramphenicol Palmitate USP—Insoluble in water; freely soluble in

acetone and in chloroform; soluble in ether; sparingly soluble in

alcohol; very slightly soluble in solvent hexane.

Chloramphenicol Sodium Succinate USP—Freely soluble in water and in

alcohol.

PHARMACOLOGY/PHARMACOKINETICSNote: See also Table 1. Pharmacokinetic Parameters at the end of this

monograph.


Chloramphenicol is bacteriostatic. However, it may be bactericidal in high

concentrations or when used against highly susceptible organisms.

Chloramphenicol, which is lipid soluble, diffuses through the bacterial cell

membrane and reversibly binds to the 50 S subunit of the bacterial

ribosomes where transfer of amino acids to growing peptide chains is

prevented (perhaps by suppression of peptidyl transferase activity), thus

inhibiting peptide bond formation and subsequent protein synthesis.

Absorption:

Chloramphenicol is rapidly absorbed from the gastrointestinal tract after

oral administration in many simple-stomach animals.

Cats—Chloramphenicol palmitate is not absorbed well after oral admin-

istration to fasted cats.{R-1; 2}

Distribution:

Chloramphenicol diffuses readily into all body tissues, but at different

concentrations. Highest concentrations are found in the liver and

kidneys of dogs.

The lungs, spleen, heart, and skeletal muscles contain concentrations

similar to that in the blood. Chloramphenicol reaches significant

concentrations in the aqueous and vitreous humors of the eye. Within

3 to 4 hours after administration, the concentration in the cerebrospinal

fluid reaches, on the average, 50% of the concentration in the serum.

The percentage increases if there is inflammation of the meninges.

74 CHLORAMPHENICOL Veterinary—Systemic


Chloramphenicol diffuses readily into milk and pleural and ascitic fluids

and crosses the placenta, attaining concentrations of about 75% of

that in maternal blood.

Biotransformation: Chloramphenicol is rather rapidly metabolized,

mainly in the liver, by conjugation with glucuronic acid.

Elimination: Approximately 55% of a single daily dose can be recov-

ered from the urine of a treated dog. A small fraction of this is in the

form of unchanged chloramphenicol. The unchanged chloramphenicol

is excreted by glomerular filtration (5 to 10%), whereas 80% is

excreted via tubular secretion as inactive metabolite.


SPECIES SENSITIVITYCats—Chloramphenicol should not be used in the cat for more than 14

days{R-2} because it can cause dose-related blood dyscrasias. The

reported increased susceptibility of cats to development of blood

dyscrasias relative to dogs or horses may be attributable to chloram-

phenicol’s significantly longer elimination half-life in the cat.{R-6}

PEDIATRICSAll species

In the fetus and neonate, the immature liver cannot conjugate

chloramphenicol, and toxic concentrations of active drug accumulate.

Dogs and cats

Sudden death has been reported in puppies and kittens receiving

intravenous chloramphenicol.





Note: Combinations containing any of the following medications, depend-

ing on the amount present, may also interact with this medication.

Digitalis glycosides

(chloramphenicol decreases the rate of elimination of digitalis

glycosides, which may lead to their accumulation to toxic concen-

trations{R-3})

Erythromycin

(erythromycin and chloramphenicol compete for the same ribosome;

therefore, the 2 medications may antagonize each other if used

concurrently)

Medications metabolized by mixed function oxidase system, especially:

Phenobarbital or

Primidone

(chloramphenicol irreversibly inhibits the hepatic microsomal

enzymes of the cytochrome P450 complex, which may potentiate

the effects of other medications that are metabolized by this

complex)

Pentobarbital

(pentobarbital-induced anesthesia in dogs can be significantly

prolonged by concurrent administration of chloramphenicol{R-4})




» Complete blood counts (CBCs)

(CBCs may be required during therapy with chloramphenicol,

particularly during prolonged administration, to detect aplastic

anemia or bone marrow depression)




prior to chloramphenicol administration to determine pathogen

susceptibility)

SIDE/ADVERSE EFFECTSNote: Although aplastic anemia has occurred in human patients as a

result of chloramphenicol administration, it has not been documented

in animals.{R-6; 7} A dose-related reversible bone marrow suppression

may occur, sometimes manifesting as pancytopenia or agranulocyto-

sis.

The following side/adverse effects have been selected on the basis of



inclusive:

THOSE INDICATING NEED FOR MEDICAL ATTENTIONAll species

Anorexia; bone marrow suppression{R-7}; depression; diarrhea

and vomiting{R-6}

Note: Intermediate metabolites are thought to be responsible for the

reversible bone marrow suppression seen in domestic animals.

The effect is dose-dependent, often occurring with long-term therapy.




included in the human monograph Chloramphenicol (Systemic) in USP



chloramphenicol in the treatment of animals:

Note: The hematologic toxicity of chloramphenicol can manifest

itself in 1 of 2 ways—either as a reversible bone marrow

depression or an idiosyncratic aplastic anemia. Bone marrow

depression is dose-related and most commonly seen when serum

concentrations of chloramphenicol exceed 25 mcg/mL. Bone

marrow changes are usually reversible when chloramphenicol is

discontinued. Aplastic anemia is an idiosyncratic reaction that

occurs in 1 of every 25,000 to 40,000 courses of treatment. It is

not related to dose or duration of therapy. Most cases have been

associated with oral chloramphenicol, and the onset of aplasia

may not occur until weeks or months after treatment with

chloramphenicol has been discontinued.


Blood dyscrasias; gastrointestinal reaction

Incidence rare

Gray syndrome—in neonates only; hypersensitivity reactions;

neurotoxic reactions; optic neuritis; peripheral neuritis

CHLORAMPHENICOL Veterinary—Systemic 75


Note: Gray syndrome (or ‘‘gray baby syndrome’’) almost always

occurs in newborn infants treated with inappropriately high doses

of chloramphenicol. Typically, the infant has been started on

chloramphenicol within the first 48 hours of life; symptoms first

appear after 3 to 4 days of continued treatment with high doses of

chloramphenicol; and serum concentrations are high, often

between 40 and 200 mcg/mL. If detected early and chloramphe-

nicol is discontinued, the infant may have a complete recovery. On

rare occasion, older patients, including adults with severe liver

disease, have also had a gray syndrome–type reaction.

Symptoms of possible fatal, irreversible bone marrow depression

Pale skin; sore throat and fever; unusual bleeding or bruising;

unusual tiredness or weakness

Note: Pale skin, sore throat and fever, unusual bleeding or bruising,

unusual tiredness or weakness may be symptoms of irreversible bone

marrow depression leading to aplastic anemia, and the need for

immediate medical attention if they occur weeks or months after

medication is discontinued.





drug manufacturer.

CLIENT CONSULTATIONBecause of the risk of idiosyncratic aplastic anemia that occurs in

people after exposure to chloramphenicol, extreme care during

administration to animals should be exercised. Animals do not

appear prone to develop the idiosyncratic aplastic anemia that can

occur in people weeks or months after cessation of drug therapy.{R-5}

In humans, the reported incidence of idiosyncratic aplastic anemia

following chloramphenicol exposure ranges from 1/25,000 to 1/

40,000. Aplastic anemia in humans may occur following oral,

intramuscular, intravenous, ophthalmic, and/or topical administra-

tion. Due to these risks, chloramphenicol is banned in food-

producing animals in the United States and people should avoid

other types of exposure as well.

When administering chloramphenicol to animals, people should avoid

direct contact with the medication (for example, avoid opening the

capsules).

VETERINARY DOSING INFORMATIONMost susceptible infectious disease organisms will respond to chloram-

phenicol therapy in 3 to 5 days when the recommended dosage

regimen is followed.

If no response to chloramphenicol therapy is obtained in 3 to 5 days, use

should be discontinued and the diagnosis reviewed.

Cats—Chloramphenicol should not be used in the cat for more than 14

days{R-2} because it can cause dose-related blood dyscrasias.

Chloramphenicol palmitate is not absorbed well after oral administration

to fasted cats.{R-1; 2}





in terms of chloramphenicol base.

CHLORAMPHENICOL CAPSULES USPUsual dose: Antibacterial1—

Dogs: Oral, 45 to 60 mg per kg of body weight every eight hours.

[Cats]: Oral, 13 to 20 mg per kg of body weight every twelve hours.

Note: The oral dose for cats is based on the best information

available, which may, however, underestimate the dose needed in

some cases. Doses of 25 to 50 mg per kg of body weight every

twelve hours have been recommended, and may be necessary for

some infections, but could increase the risk of side effects.

[Horses]: Oral, 45 to 60 mg per kg of body weight every eight hours.


U.S.{R-11; 12}—


50 mg (Rx) [Duricol].






Canada—




250 mg (Rx) [Novochlorocap].




USP requirements: Preserve in tight containers. Contain the labeled

amount, within –10 to +20%. Meet the requirements for Identifi-

cation, Dissolution (85% in 30 minutes in 0.01 N hydrochloric acid

in Apparatus 1 at 100 rpm), and Uniformity of dosage units{R-10}.

CHLORAMPHENICOL PALMITATE ORAL SUSPENSIONUSPUsual dose: [Antibacterial]—


Cats1: Oral, 13 to 20 mg per kg of body weight every twelve hours.



some cases. Doses of 25 to 50 mg every twelve hours have been

recommended, and may be necessary for some infections, but

could increase the risk of side effects.


U.S.—



Canada{R-11}—


25 mg (base) per mL (Rx) [Azramycine S125; Chlor Palm 125;

Karomycin Palmitate 125].



50 mg (base) per mL (Rx) [Azramycine S250; Chlor Palm 250;

Karomycin Palmitate 250].



manufacturer. Store in a tight, light-resistant container. Protect from

freezing.

USP requirements: Preserve in tight, light-resistant containers. Con-

tains an amount of chloramphenicol palmitate equivalent to the

labeled amount of chloramphenicol, within )10 to +20%. Contains

one or more suitable buffers, colors, flavors, preservatives, and sus-

pending agents. Meets the requirements for Identification, Uniformity

of dosage units (suspension packaged in single-unit containers),

Deliverable volume (suspension packaged in multiple-unit containers),

pH (4.5–7.0), and Limit of polymorph A{R-10}.

CHLORAMPHENICOL TABLETS USPUsual dose: Antibacterial—


[Cats]1: Oral, 13 to 20 mg per kg of body weight every twelve hours.



some cases. Doses of 25 to 50 mg per kg of body weight every

twelve hours have been recommended, and may be necessary for

some infections, but could increase the risk of side effects.

[Horses]1: Oral, 45 to 60 mg per kg of body weight every eight

hours.


U.S.—


100 mg (Rx) [Viceton].

250 mg (Rx) [Amphicol Film-Coated Tablets; Viceton].



Canada—


100 mg (Rx) [Chlor 100].

250 mg (Rx) [Chlor 250].

500 mg (Rx) [Chlor 500].

1000 mg (Rx) [Chlor 1000].





indicate that they are for veterinary use only and are not to be used in

animals raised for food production. Contain the labeled amount, within

–10 to +20%. Meet the requirements for Identification, Disintegration

(60 minutes), and Uniformity of dosage units.







in terms of chloramphenicol base.

CHLORAMPHENICOL SODIUM SUCCINATE FORINJECTION USPUsual dose: [Antibacterial]1—

Cats: Intramuscular, intravenous, or subcutaneous, 12 to 30 mg

(base) per kg of body weight every twelve hours.

Dogs and horses: Intramuscular, intravenous, or subcutaneous, 45 to

60 mg (base) per kg of body weight every six to eight hours.

Strength(s) usually available{R-8; 12}:

U.S.—




1 gram (base) per vial (Rx) [Chloromycetin; GENERIC].

Canada—




1 gram (base) (Rx) [Chloromycetin].




Preparation of dosage form: To prepare a 10% (100-mg-per-mL)

solution, add 10 mL of an aqueous diluent such as sterile water for

injection or 5% dextrose injection to each 1-gram vial{R-8}.


an amount of chloramphenicol sodium succinate equivalent to the

labeled amount of chloramphenicol, within –10 to +15%. Meets the

requirements for Bacterial endotoxins, Sterility, Particulate matter,

and Limit of free chloramphenicol (not more than 2.0%), and for

Identification, Specific rotation, pH, and Water under Chloramphenicol

Sodium Succinate{R-10}.



Revised: 07/28/94


09/30/02; 04/04/03

Table 1. Pharmacokinetic Parameters

Species

Elimination

half-life (hours)

First order

elimination

rate constant

(min)1) VolD (L/kg)

Total body

clearance

(mL/min/kg)

Cats 5.1 0.0023 2.36 5.55

Dogs 1.20 ± 0.10 0.0098 ± 0.001 0.85 ± 0.06 8.57 ± 0.83

Horses 0.63 ± 0.04 0.0188 ± 0.001 1.41 ± 0.08 26.14 ± 1.28

CHLORAMPHENICOL Veterinary—Systemic 77


REFERENCES1. Watson ADJ. Effect of ingesta on systemic availability of chloramphenicol from

2 oral preparations in cats. J Vet Pharm Ther 1979; 2: 117–21.


3. Davis LE. Emergency drugs. In: Zaslow IM, editor. Veterinary trauma and

critical care. Philadelphia: Lea and Febiger 1984. p. 287–338.

4. Teske RH, Carter GG. Effect of chloramphenicol on pentobarbital-

induced anesthesia in dogs. J Am Vet Med Assoc 1971 Sep; 159(6):

777–80.

5. Booth NH, McDonald LE. Veterinary pharmacology and therapeutics, 6th ed.

Ames: Iowa State University Press 1988. p. 837–8.

6. Plumb DC. Veterinary drug handbook. St. Paul: PharmaVet Publishing 1991.

p. 530–4.

7. Weiss DJ. Aplastic anemia. In: Kirk RW, Bonagura JD, editors. Current

veterinary therapy XI small animal practice. Philadelphia: W.B. Saunders

1992. p. 479–84.

8. Chloromycetin Sodium Succinate Product Information (King Pharmaceuti-

cals—US), Rev 5/99. Downloaded 2/16/03 from www.kingpharm.com.





States Pharmacopeial Convention, Inc., 2002. p. 407, 413, 414, 2554.







ERYTHROMYCIN Veterinary—Intramammary-Local


Erythro-36; Erythro-Dry Cow; Gallimycin-36; and Gallimycin-Dry Cow.




INDICATIONS

GENERAL CONSIDERATIONSErythromycin is an antibiotic that is active primarily against gram-

positive bacteria, such as Staphylococcus and Streptococcus species,

including many that are, by means of beta-lactamase production,

resistant to penicillins. Resistant strains of streptococci have been

reported{R-1}, particularly in populations recently treated with eryth-

romycin.{R-2} Cross-resistance to the other macrolide antibiotics can

also occur.{R-2}

ACCEPTEDMastitis (treatment)—Cattle: Erythromycin is indicated in the treatment

of mastitis caused by susceptible Staphylococcus aureus{R-4}, Streptococ-

cus agalactiae, Streptococcus dysgalactiae, and Streptococcus uberis{R-3; 14}. It

may be most effective against Streptococcus agalactiae{R-5; 17} and

Streptococcus dysgalactiae{R-4}. Intramammary therapy alone is indi-

cated only in the treatment of subacute or subclinical mastitis

manifested by mild changes in the milk or udder. Cows with acute

or peracute mastitis, which has been defined as the presence of gross

changes in the milk or udder or systemic signs, should be administered

other medications also, which may include systemic antibiotics and/or

supportive therapy.{R-6}

REGULATORY CONSIDERATIONSU.S. and Canada—{R-3}

Withdrawal times have been established. See the Dosage Forms section.

CHEMISTRYSource: Produced from a strain of Streptomyces erythraeus.

Chemical group: Macrolide group of antibiotics.{R-2}

Chemical name: Erythromycin.{R-7}

Molecular formula: C37H67NO13.{R-7}

Molecular weight: 733.93.{R-7}

Description: Erythromycin USP—White or slightly yellow, crystalline

powder. Is odorless or practically odorless.{R-8}

pKa: Erythromycin base—8.8.{R-9; 10}

Solubility: Erythromycin USP—Slightly soluble in water; soluble in

alcohol, in chloroform, and in ether.{R-8}

PHARMACOLOGY/PHARMACOKINETICSMechanism of action/effect: Bacteriostatic; however, high concentra-

tions may be bactericidal.{R-2; 11} Erythromycin is thought to enter the

cell and reversibly bind to the 50S ribosomal subunit, inhibiting

translocation of peptides and therefore inhibiting protein

synthesis.{R-11} Erythromycin is effective only against rapidly dividing

bacteria. Bacterial resistance occurs by alteration of the ribosome

receptor site and/or by not allowing erythromycin to enter the cell.

Distribution: Medications infused into a teat are thought to be fairly




lation can cause uneven distribution.{R-12}


PREGNANCY/REPRODUCTIONPregnancy—Erythromycin crosses the placenta; however, there was no

evidence of teratogenicity or other adverse effects when pregnant rats

were fed erythromycin base{R-13}.





(milk samples should be tested 3 weeks after treatment is discon-

tinued; mastitis is not considered bacteriologically cured until

samples show an absence of the mastitis-causing organisms)

Clinical signs of mastitis

(although a resolution of clinical signs of mastitis is not an

indication that a bacteriologic cure has been achieved, monitoring

of the clinical condition of the mammary gland, teat, and milk

produced can aid in diagnosis of a recurrence of mastitis or initial

diagnosis of mastitis in another cow in the herd)

Somatic cell count

(somatic cell counts performed on milk to monitor the dairy herd

are used primarily to maintain milk quality, but they are also

used to assess the approximate overall effectiveness of mastitis

control programs, which may include antibiotic treatment of

cows)





Cows

Allergic reaction—local or systemic





drug manufacturer.

ERYTHROMYCIN Veterinary—Intramammary-Local 79




focus. The program should include good maintenance of milking

equipment and constant evaluation of milking procedures and teat

health as well as strategic treatment of clinical cases of mastitis.{R-15}


knowledge of the identity and sensitivity of the pathogens causing

mastitis in the cow and the dairy herd.

Before administration of intramammary erythromycin, the following

actions should be taken:

• The udder should be milked out completely and the teats and udder

washed with warm water and a disinfectant. Care should be taken to

avoid washing excess dirt down from the udder onto the teat ends.

The area should be dried thoroughly and each teat wiped with a


alcohol.







A teat dip is recommended on all teats following treatment.


ERYTHROMYCIN INTRAMAMMARY INFUSION USPUsual dose: Mastitis—

Cows, lactating: Intramammary, 300 mg administered into each

affected quarter every twelve hours for three treatments.{R-14; 17}

Cows, nonlactating: Intramammary, 600 mg administered into each

quarter at the time of drying-off.{R-3; 17}


U.S.—{R-3; 14; 16}


50 mg per mL (OTC) [Gallimycin-36 (lactating cows); Gallimycin-Dry

Cow (dry cows only)].

Canada—{R-16; 17}


50 mg per mL (OTC) [Erythro-36 (dry or lactating cows); Erythro-Dry

Cow (dry cows only); Gallimycin-36 (dry or lactating cows)].

Withdrawal times:

U.S.—{R-3; 14; 16}

Withdrawal time

Species Meat (day) Milk (hours)

Cows 14 36

Note: Also, for nonlactating cows, treated animals should not be

slaughtered for food within 96 hours post-calving. Calves born to

treated cows should not be slaughtered for food until they are 10 days

of age.{R-3}

Canada—{R-16; 17}

Withdrawal time

Species Milk (hours)

Cows, lactating 36

Packaging and storage: Store at 15 to 30 �C (59 to 86 �F). Protect

from freezing.

USP requirements: Preserve in single-dose disposable syringes that are

well-closed containers. A solution of Erythromycin in a suitable veg-

etable oil vehicle. Contains one or more suitable preservatives. Label it

to state that it is for veterinary use only. Contains the labeled amount,

within )10% to +20%. Meets the requirements for Identification,

Minimum fill, and Water (not more than 1.0%).{R-8}

Developed: 07/25/95


03/28/03

REFERENCES1. Mondel GL, Douglas RG, Bennett JE, editors. Principles and practice of

infectious diseases. 3rd ed. New York: Churchill Livingstone, 1990. p. 308–12,

800, 1594, 1818, 1940.

2. Barragry TB. Veterinary drug therapy. Philadelphia: Lea & Febiger, 1994.

p. 224–6, 256.

3. Gallimycin-Dry Cow package insert (Bimeda—US), Rec 2/17/03.



5. Edmonson PW. An economic justification of ‘‘blitz’’ therapy to eradicate

Streptococcus agalactiae from a dairy herd. Vet Rec 1989; 125: 591–3.




MD: The United States Pharmacopeial Convention Inc. 2002.


(January 1, 2003). NF 21st ed. (January 1, 2003). Rockville, MD: The United

States Pharmacopeial Convention Inc. 2002. p. 729, 2560.

9. Ewing PJ, Burrows G, MacAllister C, et al. Comparison of oral erythromycin

formulations in the horse using pharmacokinetic profiles. J Vet Pharmacol

Ther 1994; 17: 17–23.

10. Clarke CR, Barron SJ, Ayalew S, et al. Response of Pasteurella haemolytica to

erythromycin and dexamethasone in calves with established infection. Am J

Vet Res 1992; 53(5): 684–7.


2nd ed. Ames, Iowa: State University Press, 1993. p. 119–26.



13. Erythromycin base (Novo-rythro Encap, Novopharm). In: Krogh CME. CPS

Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian

Pharmaceutical Association, 1993.

14. Gallimycin-36 package insert (Bimeda—US), Rec 2/17/03.

15. Hady PJ, Lloyd JW, Kaneene JB. Antibacterial use in lactating dairy cattle.

J Am Vet Med Assoc 1993; 203(2): 19–20.



17. Gallimycin-36 package insert (A.P.A. of Sanofi—Canada), Rec 2/13/95.

80 ERYTHROMYCIN Veterinary—Intramammary-Local


FLORFENICOL Veterinary—Systemic


Aquaflor and Nuflor.







GENERAL CONSIDERATIONSFlorfenicol is a broad-spectrum, primarily bacteriostatic, antibiotic with a

range of activity similar to that of chloramphenicol, including many

gram-negative and gram-positive organisms{R-1}; however, florfenicol

does not carry the risk of inducing human aplastic anemia that is

associated with chloramphenicol{R-13}. Florfenicol has been demon-

strated to be active in vitro and in vivo againstMannheimia (Pasteurella)

haemolytica, Pasteurella multocida, and Haemophilus somnus{R-1; 2}.

In vitro studies have demonstrated florfenicol activity against Enterob-

acter cloacae, Escherichia coli, Klebsiella pneumoniae, Salmonella typhi, and

Shigella dysenteriae{R-2; 15; 16} but with at least a 2- to 10-fold higher

minimum inhibitory concentration than that for the Mannheimia,

Pasteurella and Haemophilus species listed above{R-15; 16}. It also has

activity against some chloramphenicol-resistant strains of bacte-

ria{R-17}, possibly because it is less affected by the major enzyme

produced in plasmid-mediated bacterial resistance against chloram-

phenicol and thiamphenicol{R-2; 26}. Although the activity of florfeni-

col against obligate anaerobes is not addressed in the literature, it is

likely to be quite effective{R-28}.

ACCEPTEDPneumonia, bacterial (treatment and control1)—Cattle: Florfenicol

injection is indicated in the treatment of bacterial pneumonia and

associated respiratory infections (bovine respiratory disease) in cattle

caused by susceptibleM. haemolytica, P. multocida, and H. somnus{R-1; 3}.

Florfenicol injection is also indicated in the control of bacterial

pneumonia and associated respiratory disease in cattle at high risk of

developing bovine respiratory disease associated with susceptible

M. haemolytica, P. multocida, and H. somnus{R-1; 3; 32}.

Pododermatitis (treatment)—Cattle: Florfenicol injection is indicated in

the treatment of infectious pododermatitis (interdigital phlegmon)

associated with susceptible Fusobacterium necrophorum and Bacteroides

melaninogenicus{R-1; 3; 30}.

[Furunculosis (treatment)]—Salmon: Florfenicol premix is indicated in

the treatment of furunculosis caused by susceptible strains of Aeromo-

nas salmonicida in salmon{R-11}.

[Keratoconjunctivitis (treatment)]—Cattle: Florfenicol injection is indi-

cated in Canadian product labeling in the treatment of infectious

bovine keratoconjunctivitis caused by Moraxella bovis{R-3; 33; 34}.


Withdrawal times have been established for florfenicol in cattle;

however, it is not labeled for use in lactating dairy cattle or in veal

calves{R-1} (see the Dosage Forms section).

Canada—

Withdrawal times have been established for florfenicol in cattle and

salmon; however, it is not labeled for use in lactating dairy cattle{R-1}

(see the Dosage Forms section).

CHEMISTRYSource: A fluorinated derivative of thiamphenicol{R-12}.

Chemical name: Acetamide, 2,2-dichloro-N-[1-(flouromethyl)-2-hy-

droxy-2-[4-(methylsulfonyl)phenyl]ethyl]-[R-(R*,S*)]-{R-4}.

Molecular formula: C12H14Cl2FNO4S{R-14}.

Molecular weight: 358.21{R-4}.

Description: Melting point 153 to 154 �C{R-12}.Solubility: Soluble in water{R-12; 13}. Lipid soluble{R-13}.


Mechanism of action/effect: Florfenicol is a bacteriostatic antibiotic

that inhibits protein synthesis by binding to ribosomal subunits

of susceptible bacteria, leading to the inhibition of peptidyl trans-

ferase{R-1; 13; 26} and thereby preventing the transfer of amino acids to

growing peptide chains and subsequent protein formation. The bac-

terial receptor that is the site of action for florfenicol is considered to be

the same as that for chloramphenicol and thiamphenicol{R-13; 26}. In

the treatment of bovine respiratory disease, florfenicol may be con-

sidered bactericidal against some Mannheimia (Pasteurella) hemolytica

and Pasteurella multocida when it is administered to achieve minimum

inhibitory concentrations (MICs){R-14}; the minimum bactericidal

concentrations (MBCs) are very close to the MICs.

Florfenicol has a fluorine atom instead of the hydroxyl group located

at C-3 in the structure of chloramphenicol and thiamphenicol{R-13}.

This may allow florfenicol to be less susceptible to deactivation by

bacteria with plasmid-transmissible resistance that involves acetyla-

tion of the C-3 hydroxyl group in chloramphenicol and thiamphe-

nicol, and prevents their interaction with bacterial ribosomes{R-13; 26}.

Other actions/effects: Florfenicol, like thiamphenicol, lacks the nitro

group located on the chloramphenicol aromatic ring that has been

associated with chloramphenicol-induced, non–dose-related, irrevers-

ible aplastic anemia in people{R-13; 24; 25}. However, chloramphenicol

and thiamphenicol also cause a dose-dependent, reversible bone

marrow suppression in some animals and people{R-13} due to mito-

chondrial injury{R-24}. It is theoretically possible that florfenicol could

cause some dose-dependent, reversible bone marrow suppression, but

it has not been clinically reported{R-13}.

Absorption: Bioavailability—

Intramuscular administration:

Calves, 3 to 6 months of age—78.5% (range 59.3 to 106%), with a

dose of 20 mg per kg of body weight (mg/kg){R-1; 2; 8}.

Cattle, lactating—38 ± 14%, with a dose of 20 mg/kg{R-9}.



FLORFENICOL Veterinary—Systemic 81


Horses—81%, with a dose of 22 mg/kg{R-19}.

Oral administration:

Calves, 2 to 5 weeks of age—89%, at a dose of either 11 or 22 mg/kg;

however, the absorption was widely variable{R-6; 7}. Oral absorp-

tion may decrease when florfenicol is administered with milk

replacers{R-6; 7}; one study reported bioavailability that ranged from

44 to 86% among calves when florfenicol was administered 5

minutes after feeding{R-7}.

Horses—83.3%, with a dose of 22 mg/kg{R-19}.

Salmon, Atlantic—96.5%, with a dose of 10 mg/kg when water

temperature is 10.8 ± 1.5 �C{R-22}.Note: After intramammary administration of a 20 mg/kg dose to lactating

dairy cows, the systemic bioavailability was found to be 54 ± 18%{R-9}.

Distribution:

Cattle, 2 to 5 weeks of age—After multiple oral dosing (11 mg/kg every

twelve hours for seven doses), florfenicol was well distributed into

many tissues, reaching concentrations of 4 to 8 mcg per gram (mcg/

gram) in lungs, heart, pancreas, skeletal muscle, spleen, and

synovia{R-6}. These concentrations were at least as high as serum

concentrations{R-6}. Relatively high concentrations were found in

bile, kidney, small intestine, and urine{R-6}. Concentrations in the

brain (1 to 2 mcg/gram), cerebrospinal fluid (2 to 3 mcg/mL), and

aqueous humor (2 to 3 mcg/mL) have been found to be one quarter

to one half the serum concentration in healthy calves{R-6}.

Salmon, Atlantic—Florfenicol is distributed to all organs and tissues

with a dose of 10 mg/kg when the water temperature is 8.5 to

11.5 �C{R-23}. Concentrations in muscle and blood are similar to

serum concentrations, while fat and the central nervous system

(CNS) have lower concentrations. Only 25% of serum drug and

metabolite concentrations are found in the brain{R-23}.

Volume of distribution (VolD) —Intravenous administration:

Calves, 2 weeks to 6 months of age—

Area: 0.88 liter per kg (L/kg){R-2}; 0.91 L/kg{R-6}.

Steady state: 0.77 L/kg{R-1; 2; 8}; 0.87 L/kg{R-6}.

Cattle—

Lactating: Steady state—0.35 L/kg{R-9}.

Nonlactating:

Area—0.67 L/kg (range, 0.62 to 0.76 L/kg){R-5}.

Steady state—0.62 L/kg (range, 0.57 to 0.68 L/kg){R-5}.

Note: Although the data above imply that lactation causes a decrease

in the volume of distribution of florfenicol, other data from these

studies, including half-life of elimination and clearance, correlate

well between the two trials, one conducted in lactating and one in

nonlacting cattle. The apparent difference here between lactating

and nonlactating cattle may be due to calculation methods or

dosing{R-27}.

Goats, lactating—Steady state: 0.98 ± 0.09 L/kg{R-18}.

Horses—Steady state: 0.72 ± 0.17 L/kg{R-19}.

Salmon, Atlantic—Steady state: 1.12 L/kg at a water temperature of

10.8 ± 1.5 �C{R-22}.

Protein binding:

Calves, 3 to 6 months of age—

Low (12.7%), with serum concentration of 0.5 mcg/mL{R-2}.

Low (13.2%), with serum concentration of 3 mcg/mL{R-1; 2}.

Low (18.3%), with serum concentration of 16 mcg/mL{R-1; 2}.

Cattle—Considered independent of drug concentration:

Low (17.5%), with serum concentration of 5 mcg/mL{R-5}.

Low (18.6%), with serum concentration of 50 mcg/mL{R-5}.

Biotransformation:

Cattle—Approximately 64% of a 20 mg/kg dose of intramuscular

florfenicol administered two times, 48 hours apart, is excreted as

parent drug in the urine{R-13}. Urinary metabolites include florfenicol

amine, florfenicol alcohol, florfenicol oxamic acid, and mono-

chloroflorfenicol{R-13}. Florfenicol and its metabolites, such as

monochloroflorfenicol and florfenicol oxamic acid, also are eliminated

in the feces{R-13}. Florfenicol amine is the longest-lived major

metabolite in the liver, and, therefore, it was used as the marker

residue for withdrawal calculations{R-13}.

Salmon,Atlantic—Florfenicol is rapidlymetabolized at water temperatures

of 8.5 to 11.5 �C and the major metabolite is florfenicol amine{R-23}.

Half-life:

Distribution—Intravenous administration: Calves, less than 8 weeks of

age—0.13 hour (range, 0.075 to 0.27 hour){R-6}; 0.098 hour (range,

0.081 to 0.17 hour){R-7}.

Elimination—

Intravenous administration:

Calves, less than 8 weeks of age—2.86 hours (range, 2.3 to 3.39

hours){R-7}; 3.71 hours (range, 3.5 to 4.11 hours){R-6}.

Calves, 3 to 6 months of age—2.6 hours (range, 2.4 to 3 hours){R-2; 8}.

Cows—

Lactating: 2.9 hours{R-9}.

Nonlactating: 3.2 hours{R-5}.

Goats, lactating—2.3 ± 0.2 hours{R-18}.

Horses—1.8 ± 0.9 hours{R-19}.

Salmon, Atlantic—12.2 hours at a water temperature of 10.8 ±

1.5 �C{R-22}.Intramuscular administration (terminal half-life): Calves, 3 to 6

months of age—18.3 hours (range, 8.3 to 44 hours){R-1; 2}.

Concentrations:

Peak serum concentration—


Calves, 3 to 6 months of age—3 mcg per mL (range, 1.43 to 5.6 mcg/

mL), with a dose of 20 mg/kg{R-1; 2; 8}.

Cows, lactating—2.3 mcg/mL, with a dose of 20 mg/kg{R-9}.

Horses—4 ± 1.2 mcg/mL, with a dose of 22 mg/kg{R-19}.


Calves, less than 8 weeks of age—11.32 ± 4.04 mcg/mL, with a dose

of 22 mg/kg{R-7}.

Horses—13.8 ± 4.8 mcg/mL, with a dose of 22 mg/kg{R-19}.

Salmon, Atlantic—4 mcg/mL, with a dose of 10 mg/kg when water

temperature is 10.8 ± 1.5 �C{R-22}.Note: After intramammary administration of 20 mg/kg to lactating

dairy cows, the peak serum concentration was 6.9 mcg/mL at

6 hours{R-9}.

Time to peak serum concentration—


Calves, 3 to 6 months of age—3.33 hours (range, 0.75 to 8 hours),

with a dose of 20 mg/kg{R-1; 2; 8}.

Cows, lactating—3 hours, with a dose of 20 mg/kg{R-9}.

Horses—1.3 ± 0.5 hours, with a dose of 22 mg/kg{R-19}.

82 FLORFENICOL Veterinary—Systemic



Calves, less than 8 weeks of age—2.5 ± 0.72 hours, with a dose of 22

mg/kg{R-7}.


Salmon, Atlantic—10.3 hours, with a dose of 10 mg/kg when water

temperature is 10.8 ± 1.5 �C{R-22}.Other peak concentrations—In milk:

Intramuscular administration—

Cows, lactating: 1.6 mcg/mL at 10 hours, with a 20 mg/kg dose{R-9}.

Intravenous administration:

Cows, lactating: 5.4 mcg/mL at 3 hours, with a 20 mg/kg dose{R-9}.

Goats, lactating: 13.2 ± 1.9 mcg/mL at 1 hour, with a 25 mg/kg

dose{R-18}.

Duration of action:

Calves, 3 to 6 months of age—The serum concentration of florfenicol was

maintained above 1 mcg per mL for 22.3 ± 5.9 hours after

intramuscular administration and 11.5 ± 1.1 hours after intravenous

administration of 20 mg/kg{R-2}.

Salmon, Atlantic—Plasma concentrations were maintained above the

minimum inhibitory concentration of 0.8 mcg/mL reported for

Aeromonas salmonicida, Vibrio anguillarum, and V. salmonicida for 36

to 40 hours after a single oral florfenicol dose of 10 mg/kg in water

temperatures of 10.8 ± 1.5 �C{R-22}.

Elimination:

Calves, less than 8 weeks of age—Approximately 50% of a 22 mg/

kg intravenous dose is eliminated unchanged in the urine within 30

hours{R-7}.

Cattle—Approximately 64% of a 20 mg/kg intramuscular dose

administered two times, 48 hours apart, is excreted as parent drug

in the urine{R-13}.

Horses—Approximately 13% of a 22 mg/kg intravenous dose, 7% of

the same dose given intramuscularly, and 6% when given orally, is

excreted unchanged in the urine in the first 30 hours{R-19}.

Rats—Approximately 60 to 70% of a 20 mg/kg oral dose administered

once a day for 7 days is eliminated in the urine{R-13}. Approximately

20 to 30% is eliminated in the feces in the first 24 hours after a 20

mg/kg oral dose{R-13}.

Total clearance—Intravenous administration:

Calves—

Less than 8 weeks of age: 2.9 mL per minute per kg (range, 2.44 to 4

mL/min/kg){R-6; 7}.

3 to 6 months of age: 3.75 mL/min/kg (range, 3.17 to 4.31 mL/

min/kg){R-1; 2; 8}.

Cows—

Lactating: 2.7 ± 0.6 mL/min/kg{R-9}.

Nonlactating: 2.45 mL/min/kg (range, 2.25 to 2.67 mL/min/kg){R-5}.

Goats, lactating—8.1 ± 2.6 mL/min/kg{R-18}.

Horses—6.7 ± 1.7 mL/min/kg{R-19}.

Salmon, Atlantic—1.4 mL/min/kg when water temperature is 10.8 ±

1.5 �C{R-22}.


PREGNANCY/REPRODUCTIONThe effects of florfenicol on reproductive performance and pregnancy

have not been determined{R-1}. Administration to breeding cattle is not

recommended by product labeling{R-3}.

LACTATIONThe effect of florfenicol on lactation has not been determined{R-1}.

Goats: Florfenicol concentrations in milk equal serum concentrations

when serum concentrations are nearly constant{R-18}.



given in parentheses where appropriate)—not necessarily inclusive (»

= major clinical significance).


used when the following medical problem exists:

» Previous allergy or toxic reaction to florfenicol




THOSE INDICATING NEED FOR MEDICAL ATTENTIONNote: There is no documentation of dose-dependent, reversible bone-

marrow suppression caused by florfenicol use in animals; however, the

protection against human aplastic anemia, due to the difference in

structure of florfenicol from chloramphenicol, does not necessarily

protect against suppression of mitochondrial protein synthesis in bone

marrow and subsequent reversible anemia{R-13}. This phenomenon is

not considered a side/adverse effect with normal clinical use, but an

awareness of this possibility may be useful if long-term therapy with

this medication is considered.

Incidence unknown

Horses, ponies

Diarrhea, mild—in one study, occurred in all three horses and three

ponies administered a single dose of 22 mg per kg of body weight by

either the oral or parenteral route{R-19}.

THOSE INDICATING NEED FOR MEDICAL ATTENTIONONLY IF THEY CONTINUE OR ARE BOTHERSOMEIncidence unknown

Cattle

Decreased food consumption{R-1}—usually transient; decreased

water consumption{R-1}—usually transient; diarrhea{R-1}—usually

transient; local tissue reactions—more severe if administered at

injection sites other than the neck{R-10}.

Note: In a controlled study over 43 days, florfenicol administration had

no long-term effect on body weight, rate of weight gain, or feed

consumption, although a transient decrease in food and water

consumption occurred at the start of therapy{R-1; 10}.

OVERDOSEFor more information in cases of overdose or unintentional ingestion,

contact the American Society for the Prevention of Cruelty to

Animals (ASPCA) National Animal Poison Control Center (888-

426-4435 or 900-443-0000; a fee may be required for consultation)

and/or the drug manufacturer.






Acute—

Calves, with intramuscular administration of 200 mg per kg of body

weight (mg/kg) repeated in forty-eight hours (10 times the label

dose){R-1}

Anorexia, marked{R-1}; decreased body weight{R-1}; decreased

rumen activity{R-10}; decreased water consumption{R-1; 10}; keto-

sis, slight{R-10}—secondary to anorexia; serumenzymes, including

alanine aminotransferase [SGPT], aminoacyltransferase [GGT],

aspartate aminotransferase [SGOT], and lactase dehydrogenase

[LDH], mildy increased{R-1; 10}; soft feces{R-10}

Chronic—

Dogs, 4- to 6-months old, with oral administration of 12 mg/kg a day

for thirteen weeks{R-10}

Hepatotoxicity

Note: Oral dosing of 100 mg/kg for thirteen weeks resulted in CNS

vacuolation, hematopoietic toxicity, renal tubule dilation, and

testicular atrophy{R-10}.

TREATMENT OF OVERDOSEThere is no specific treatment for florfenicol overdose. Therapy should be

supportive.

VETERINARY DOSING INFORMATIONMinimum inhibitory concentrations (MICs) of florfenicol were determined

for pathogens involved in natural bovine respiratory complex in the

U.S., Canada, and Europe between 1990 and 1993{R-1; 3}:

Note: MIC can vary according to pathogen strain; therefore, cattle in

different geographic locations may harbor organisms with different

MICs{R-10}.

Safety considerations—Precautions for personnel administering florfeni-

col injection include the recommendation to avoid direct contact with

eyes, skin, and clothing{R-1}. In case of accidental eye exposure, flush

with water for 15 minutes; for skin exposure, wash with soap and

water{R-1}. Remove exposed clothing and consult a physician if

irritation persists. Accidental injection may cause local irritation and a

physician should be consulted immediately{R-1}.

FOR TREATMENT OF ADVERSE EFFECTSRecommended treatment consists of the following:

For anaphylaxis

• Parenteral epinephrine and cardiovascular support.





FLORFENICOL FOR MEDICATED FEEDUsual dose: [Furunculosis]—Salmon: Oral, 10 mg per kg of body weight

a day, administered in the only ration, according to manufacturer

labeling{R-11}.


U.S.—



Canada—


500 grams per kg of premix (Rx) [Aquaflor{R-11}].

Withdrawal times:

Canada—

Note: Not labeled for use in fish maintained at water temperatures less

than 5 �C.

Packaging and storage: Store between 2 and 30 �C (36 and 86 �F),unless otherwise specified by the manufacturer. Keep separate from

other feeds{R-11}. Store in a dry place{R-29}.

Stability: Premix should be used within 12 months of opening

pouch{R-11}. Medicated feed should be used within 6 months of the

manufacture date{R-11}.

Caution: Product labeling recommends that handlers avoid inhalation

of dust and contact with skin and eyes{R-11}. Protective clothing

should be worn when handling the medication and hands should be

washed after administration{R-11}.





FLORFENICOL INJECTIONUsual dose:

Pneumonia (bovine respiratory disease) (treatment); or

Pododermatitis—Cattle:

Intramuscular, 20 mg per kg of body weight to be repeated in forty-

eight hours{R-1; 3}.

Subcutaneous, 40 mg per kg of body weight as a single dose{R-1}.

Organism

Number of

Isolates MIC50 (mcg/mL) MIC90 (mcg/mL)

Mannheimia (Pasteurella)

haemolytica

398 0.5 1

Pasteurella multocida 350 0.5 0.5

Haemophilus somnus 66 0.25 0.5

Withdrawal time

Species Meat (days)

Salmon 12



Note: Canadian product labeling lists the same dose as above, a single

subcutaneous dose of 40 mg per kg of body weight or two

intramuscular doses of 20 mg per kg of body weight, administered

forty-eight hours apart, in the treatment of [keratoconjunctivitis] in

cattle{R-3}.

Pneumonia (bovine respiratory disease) (control)1—Cattle: Subcuta-

neous, 40 mg per kg of body weight as a single dose{R-1; 32}

Note: No more than 10 mL should be injected at each site{R-1}.

Injections should be given in the neck to avoid local reaction and

trim loss of edible tissues at slaughter{R-1}. According to the

product labeling, if clinical improvement is not noted within

twenty-four hours, the diagnosis should be reevaluated{R-1}.


U.S.—


300 mg per mL (Rx) [Nuflor{R-1}].

Canada—


300 mg per mL (Rx) [Nuflor{R-3}].

Withdrawal times:

U.S.{R-1}—

Note: This product is not labeled for use in dairy cattle 20 months of age

or older, veal calves, calves under 1 month of age, or calves being fed

an all-milk diet{R-1} as withdrawal times have not been studied.

If florfenicol is injected at sites other than the neck, local reaction may

result in trim loss of edible tissue at slaughter{R-1}.

Canada{R-3}—

Note: This product is not labeled for use in lactating dairy cattle{R-3}.



the manufacturer. Protect from freezing.

Caution: Florfenicol injection can be irritating to eyes and skin; there-

fore, avoid direct contact with skin, eyes, and clothes{R-1}. Accidental

injection may cause local irritation{R-1}.

Additional information: The light yellow to straw color of the solution

does not affect potency{R-1}.




Developed: 07/08/98

Revised: 6/30/02

Interim revision: 10/15/99; 04/04/03

REFERENCES1. Nuflor product information (Schering-Plough—US). Downloaded 1/16/03

from www.spah.com.

2. Lobell RD, Varma KJ, Johnson JC, et al. Pharmacokinetics of florfenicol

following intravenous and intramuscular doses to cattle. J Vet Pharmacol Ther

1994; 17: 253–8.

3. Nuflorproduct information(Schering-Plough—Canada).Downloaded fromScher-

ing-Plough Animal Health Product Label Retrieval Service on 2/21/03.



5. Bretzlaff KM, Neff-Davis CA, Ott RS, et al. Florfenicol in nonlactating dairy

cows: pharmacokinetics, binding to plasma proteins, and effects on phagocy-

tosis by blood neutrophils. J Vet Pharmacol Ther 1987; 10: 233–40.

6. Adams PE, Varma KJ, Powers TE, et al. Tissue concentrations and pharma-

cokinetics of florfenicol in male veal calves given repeated doses. Am J Vet Res

1987 Dec; 48(12): 1725–32.

7. Varma KJ, Adams PE, Powers TE, et al. Pharmacokinetics of florfenicol in veal

calves. J Vet Pharmacol Ther 1986; 9: 412–25.

8. Varma KJ, Sams RA, Lobell RD, et al. Pharmacokinetics and efficacy of a new

broad spectrum antibiotic, florfenicol in cattle. Acta Vet Scand Suppl 1991; 87:

102–4.

9. Soback S, Paape MJ, Filep R, et al. Florfenicol pharmacokinetics in lactating

cows after intravenous, intramuscular and intramammary administration.


10. Freedom of Information Summary. Nuflor Injectable Solution for the treatment

of bovine respiratory disease. NADA 141-063. Sponsor: Schering-Plough. June

1996.

11. Aquaflor product labeling (Schering-Plough—Canada). Downloaded

from Schering-Plough Animal Health Product Label Retrieval Service on

2/21/03.

12. Budavari S, editor. The Merck Index. An encyclopedia of chemicals, drugs, and

biologicals. 12th ed. Whitehouse Station, NJ: Merck Research Laboratories;

1996. p. 4146.

13. Sams RA. Florfenicol: chemistry and metabolism of a novel broad-spectrum

antibiotic. In: Proceedings of the XVIII World Buiatrics Congress. Bologna,

Italy; 1994. p. 13–7.

14. Varma KJ. Microbiology, pharmacokinetic disposition and safety of florfenicol

in cattle. In: Proceedings of the XVIII World Buiatrics Congress. Bologna, Italy;

1994. p. 18–24.

15. Syriopoulou VP, Harding AL, Goldmann DA, et al. In vitro antibacterial

activity of flourinated analogs of chloramphenicol and thiamphenicol. Anti-

microb Agents Chemother 1981 Feb; 19(2): 294–7.

16. Marshall SA, Jones RN, Wanger A, et al. Proposed MIC quality control

guidelines for national committee for clinical laboratory standards suscepti-

bility tests using seven veterinary antimicrobial agents: ceftiofur, enrofloxacin,

florfenicol, penicillin G-novobiocin, pirlimycin, premafloxacin, and spectino-

mycin. J Clin Microbiol 1996 Aug; 34(8): 2027–9.

17. Martel J. In vitro activity of florfenicol on the primary pathogenic bacteria of

the respiratory tract in european cattle. In: Proceedings of the XVIII World

Buiatrics Congress. Bologna, Italy; 1994. p. 25–30.

18. Lavy E, Ziv G, Soback S, et al. Clinical pharmacology of florfenicol in lactating

goats. Acta Vet Scand 1991; 87 Suppl: 133–6.

19. McKeller QA, Varma KJ. Pharmacokinetics and tolerance of florfenicol in

Equidae. Equine Vet J 1996; 28(3): 209–13.

20. Wilson DJ, Sears PM, Gonzalez RN, et al. Efficacy of florfenicol for treatment

of clinical and subclinical bovine mastitis. Am J Vet Res 1996 Apr; 57(4): 526–8.

21. Paape MJ, Miller RH. Effects of florfenicol, chloramphenicol, and thiamphenicol

on phagocytosis, chemiluminescence, and morphology of bovine polymorpho-

nuclear neutrophil leukocytes. J Dairy Sci 1990; 73: 1734–44.

22. Martinsen B, Horsberg TE, Varma KJ, et al. Single dose pharmacokinetic study

of florfenicol in Atlantic salmon (Salmo salar) in seawater at 11 �C.Aquaculture 1993; 112: 1–11.

23. Horsberg TE, Martinsen B, Varma KJ. The disposition of 14C-florfenicol in

Atlantic salmon (Salmo salar). Aquaculture 1994; 122: 97–106.

24. Yunis AA. Chloramphenicol: relation of structure to activity and toxicity.

Annu Rev Pharmacol Toxicol 1988; 28: 83–100.

25. Skolimowski IM, Knight RC, Edwards DI. Molecular basis of chloramphenicol

and thiamphenicol toxicity to DNA in vitro. J Antimicrob Chemother 1983;

12: 535–42.

Withdrawal time

Species Meat (days)

Cattle

Intramuscular injection 36

Subcutaneous injection 55

Withdrawal time

Species Meat (days)

Cattle

Intramuscular injection 28




26. Cannon M, Harford S, Davies J. A comparative study on the inhibitory

actions of chloramphenicol, thiamphenicol and some fluorinated derivatives.

J Antimicrob Chemother 1990; 26: 307–17.




30. Freedom of information summary. Nuflor Injectable Solution for the treatment

of bovine interdigital phlegmon. NADA 141-063 Sponsor: Schering-Plough

Animal Health. Rev 1/99, Rec 5/5/99.



States Pharmacopeial Convention, Inc., 2002.

32. Freedom of Information Summary. Nuflor injectable solution for the control of

respiratory disease in cattle at high risk. NADA 141-063. Sponsor: Schering-

Plough Animal Health. December 17, 1998.

33. Dueger EL, Angelos JA, Cosgrove S, et al. Efficacy of florfenicol in the treatment

of experimentally induced infectious bovine keratoconjunctivitis. Am J of Vet

Res 1999; 60(8), 960–964.

34. Angelos JA, Dueger EL, George LW, et al. Efficacy of florfenicol for treatment of

naturally occurring infectious bovine keratoconjunctivitis. J Am Vet Med

Assoc 2000 January 1; 216(1): 62–4.





FLUOROQUINOLONES Veterinary—Systemic

This monograph includes information on the following: Ciprofloxacin,

Difloxacin, Enrofloxacin, Marbofloxacin, and Orbifloxacin.


Baytril 3.23% Concentrate

Solution [Enrofloxacin]

Baytril Taste Tabs

[Enrofloxacin]

Baytril Injectable Solution

[Enrofloxacin]

Dicural Tablets [Difloxacin]

Baytril Injectable Solution

2.27% [Enrofloxacin]

Orbax Tablets [Orbifloxacin]

Baytril 100 Injectable Solution

[Enrofloxacin]

Zeniquin Tablets

[Marbofloxacin]

Baytril Tablets [Enrofloxacin]

Some commonly used brand names for human-labeled products are: Cipro

[Ciprofloxacin] and Cipro I.V. [Ciprofloxacin].

Note: For a listing of dosage forms and brand names by country and






GENERAL CONSIDERATIONSThe fluoroquinolone antimicrobials are rapidly bactericidal against a

variety of clinically important organisms, are well tolerated by

animals, and can be administered by a variety of routes{R-95}. The

members of this group that are currently labeled for use in animals

have the same quinolone structure, each with modifications that

account for pharmacokinetic variations in the medications but do not

significantly change the antibacterial spectrum of activity.{R-1; 95–98;

100; 102; 112}.

Fluoroquinolones exhibit good activity against most gram-negative

bacteria, including Escherichia coli, Enterobacter species, Klebsiella

species, Pasteurella species, Proteus species, and Salmonella species.

Pseudomonas aeruginosa is variably susceptible, usually having a higher

minimum inhibitory concentration (MIC) than other susceptible

organisms.{R-1; 95–98; 100; 102; 112}.

Some gram-positive bacteria are susceptible to fluoroquinolones.

Staphylococcus aureus and Staphylococcus intermedius usually are

susceptible{R-1; 96–98; 112}. However, the MIC values for staphylococci

typically are higher than for gram-negative bacteria and staphylococ-

cal resistance to fluoroquinolones has been a problem in human

patients{R-95}.

Chlamydia, mycobacteria, mycoplasma, and ureaplasma can also be

moderately to very susceptible to fluoroquinolones{R-9}.

Local factors that affect activity are cations at the site of infection and low

pH; however, fluoroquinolones are active in abscesses in spite of often

unfavorable environmental conditions {R-95}.

Bacterial resistance to fluoroquinolones most commonly occurs by

alteration of the target, DNA-gyrase (topoisomerase II), via mutation

(gyr-A). Less commonly, but perhaps more importantly for gram-

positive bacteria, mutation occurs at the topoisomerase-IV target

(parC){R-9; 21; 86}. Other mechanisms of resistance occur when

bacteria decrease the ability of the drug to enter the cell or increase

active transport out of the cell{R-9; 21}. Resistance is usually chromo-

somally developed and, therefore, remains after antimicrobial therapy

ends{R-90; 95}. While there is evidence for plasmid-mediated resistance,

its clinical significance in veterinary medicine has not been

shown{R-90}. Cross-resistance of enrofloxacin with other fluoroquinol-

ones can occur{R-9; 10; 50}. Changes in levels of resistance to

fluoroquinolones over time by Campylobacter and Salmonella species

are being monitored because of their possible impact on human

health{R-55; 56; 91}.

ACCEPTEDColibacillosis (treatment)1—Chickens and turkeys: Enrofloxacin oral

solution is indicated in the control of mortality associated with

Escherichia coli infection in chickens and turkeys{R-3; 49}.

Fowl cholera (treatment)1—Turkeys: Enrofloxacin oral solution is indi-

cated in the control of mortality associated with Pasteurella multocida

infection in turkeys{R-3}.

Infections, bacterial (treatment), including

Cystitis, urinary, bacterial (treatment);

Respiratory infections, bacterial (treatment); or


Cats: Enrofloxacin [injection]1 and tablets{R-1; 104}, marbofloxacin

tablets1{R-97; 101}, and orbifloxacin tablets{R-98; 100} are indicated in

the treatment of susceptible bacterial infections in cats. Clinical

efficacy has been established specifically in the treatment of skin and

soft tissue infections{R-1; 97; 98; 100; 102}.

Dogs: Difloxacin tablets{R-96; 99}, enrofloxacin injection and tablets{R-1;

104}, marbofloxacin tablets{R-97; 101}, and orbifloxacin tablets{R-98;

100} are indicated in the treatment of susceptible bacterial infections

in dogs. Clinical efficacy has been established specifically in the

treatment of skin and soft tissue infections and urinary tract

infections, as noted on product labeling{R-96–101}. Clinical

efficacy has also been established for enrofloxacin injection and

tablets in the treatment of respiratory tract infections in dogs{R-1}.

[There is evidence to suggest that enrofloxacin is as effective as

chloramphenicol or tetracycline in the treatment of Rocky Moun-

tain spotted fever in dogs{R-84}.]1

Pneumonia (treatment)1—Cattle: Enrofloxacin injection is indicated in

the treatment of bovine respiratory disease caused by susceptible

organisms, including Mannheimia (Pasteurella) haemolytica, Pasteurella

multocida, and Haemophilus somnus{R-2; 57}.

ACCEPTANCE NOT ESTABLISHEDInfections, bacterial (treatment)—

[Bustards, camels, ducks, emus, llamas, oryx, red pacu, African grey

parrots, and pythons]1: In the U.S., for use only in animals not to be

used for food production—Although the safety and efficacy of

enrofloxacin have not been established, dose recommendations for

use in the treatment of susceptible bacterial infections have been

made, based on pharmacokinetic data, for bustards{R-41}, camels{R-45},

ducks{R-42}, emus{R-43}, llamas{R-46}, oryx{R-47}, red pacu{R-44},

FLUOROQUINOLONES Veterinary—Systemic 87


African grey parrots{R-39; 40}, and pythons{R-48}. Further

clinical studies are necessary. See also the Regulatory Considerations

section.

[Horses]1: For use only in animals not to be used for food produc-

tion—Although the safety and efficacy of enrofloxacin and orbiflox-

acin in the treatment of susceptible bacterial infections in horses

have not been established, pharmacokinetic evidence and case

reports are available to suggest that they may be safe and effec-

tive{R-25–27; 79–80; 136}. Due to reports of articular cartilage damage

in foals from administration of enrofloxacin, neither enrofloxacin nor

orbifloxacin should be administered to horses less than 3 years of

age, except as a last resort for severe infections not treatable with

other medications{R-25; 26; 85}. Although there have been reports of

unpublished studies showing articular damage from enrofloxacin

administration to adult horses, subsequent studies have shown no

effect on cartilage in adults when used continuously for up to 21

days{R-86}.

[Pigs, potbellied and minature]1: In the U.S., for use only in animals

not to be used in food production—Although the safety and efficacy

of enrofloxacin in the treatment of susceptible bacterial infections in

pigs have not been established, there is some pharmacokinetic

evidence to suggest that this therapy may be effective{R-29}. See also

the Regulatory Considerations section.

[Sheep, pet and research]1: In the U.S., for use only in animals not to be

used in food production—Although the safety and efficacy of

enrofloxacin in the treatment of susceptible bacterial infections in

sheep have not been established, there is some pharmacokinetic

evidence to suggest that this therapy may be effective{R-28}. See also

the Regulatory Considerations section.

[Bartonella infections (treatment)]1; or

[Hemobartonella felis infections (treatment)]1—Cats: Although the safety

and efficacy have not been established, enrofloxacin has been used in

an attempt to eradicate Bartonella bacteremia in cats{R-72; 73}.

Controlled therapeutic trials investigating the efficacy of enrofloxacin

in clearing Bartonella from cats show a positive response in some

animals, but tests used to document that an infection has been

cleared remain unreliable, making the results difficult to interpret{R-72}.

It should not be assumed that a Bartonella infection is cleared by a

course of enrofloxacin. Long-term monitoring is necessary{R-72; 73}.

Although the safety has not been clearly established, a controlled,

randomized study demonstrated the efficacy of enrofloxacin in the

treatment of Hemobartonella felis infection, by showing it more quickly

resolved clinical signs, raised hematocrit, and decreased organism

counts than in control animals. In this study, some cats treated with a

high dose of enrofloxacin or with doxycycline were apparently cleared

of the organism{R-83; 148}.

[Brucellosis (treatment)]1—Dogs: Historically, the treatment of dogs

infected with Brucella canis has been controversial. Due to the

zoonotic potential and the difficulty in clearing the infection, some

have advocated euthanasia of infected animals. Studies using a

combination of tetracycline and dihydrostreptomycin did demon-

strate that infected animals, following neutering, could be cured of

the infection{R-139}. However, dihydrostreptomycin is no longer

available in the US. The Centers for Disease Control recommend a

combination of doxycycline and rifampin for the treatment of

brucellosis in human patients{R-140}. In a clinical trial, rifampin plus

ciprofloxacin, a metabolite of enrofloxacin, was shown to be as

effective as the standard rifampin and doxycyline regimen in the

treatment of human brucellosis{R-137}. It is not known whether the

fluoroquinolones have any efficacy in the treatment of canine

brucellosis.

[Chlamydial infections (treatment)]1—Cats: There are no studies to

document the effectiveness of the veterinary fluoroquinolones, diflox-

acin, enrofloxacin, marbofloxacin, and orbifloxacin, in the treatment of

chlamydial infections in cats. Clinical trials of related human-labeled

fluoroquinolones in the treatment of genital, respiratory, or ocular

chlamydial infections in human patients have shown efficacy; how-

ever, concern exists that the organisms are not eradicated and

recrudecense is common.

[Endophthalmitis, bacterial (treatment)]1—Cats and dogs: There are no

specific studies to document the effectiveness of the veterinary

fluoroquinolones, difloxacin, enrofloxacin, marbofloxacin and orbiflox-

acin, in the treatment of bacterial endophthalmitis due to susceptible

organisms. However, these bactericidal drugs have been shown to

produce aqueous and vitreous humor concentrations within the

therapeutic range for many pathogens{R-1; 102}. Also, related human-

labeled fluoroquinolones, including ciprofloxacin (a metabolite of

enrofloxacin), have been reported as efficacious in several small

studies and case reports in human patients{R-120–125}.

[Meningitis, bacterial (treatment)]1—Cats and dogs: There are no studies

to document the effectiveness of the veterinary fluoroquinolones,

difloxacin, enrofloxacin, marbofloxacin, and orbifloxacin, in the

treatment of bacterial meningitis due to susceptible organisms.

However, these bactericidal drugs have been shown to obtain central

nervous system concentrations within the therapeutic range for many

pathogens{R-1; 102}. Also, related human-labeled fluoroquinolones,

including ciprofloxacin (a metabolite of enrofloxacin), have been

reported as efficacious in several small studies and case reports in

human patients{R-126–132}. Although the potential for fluoroquinol-

ones to induce seizures has been suggested as a reason to avoid these

drugs in the treatment of meningitis, the above mentioned human

studies, as well as disease models in animals, have failed to indicate an

increased incidence of seizures in fluoroquinolone-treated subjects.

Careful monitoring for seizures is nevertheless advised if fluoroquinol-

ones are used in such infections.

[Mycobacterial infections (treatment)]1—Cats: Although the safety and

efficacy have not been established, enrofloxacin and ciprofloxacin have

been used in the treatment of mycobacterial infections in cats, based

on case reports of successful treatment of cutaneous lesions of

opportunistic mycobacteria{R-75; 76; 142}. There is some evidence to

suggest that fluoroquinolones are effective in the treatment of

tubercular mycobacteriosis, an often serious but also often asymp-

tomatic or insidious disease in cats. Cats are also prone to infection

with Mycobacterium lepraemurium, which is a nontubercular form of

mycobacteria. Safety and efficacy of fluoroquinolones have not yet

been proven in the treatment of M. lepraemurium, but successful

treatment of the cutaneous form of mycobacterial infection with

enrofloxacin indicates possible efficacy in the treatment of nontuber-

cular forms.{R-142}

[Mycoplasmal infections (treatment)]1—Although the efficacy has not

been established, fluoroquinolones have been used to treat infections

caused by Mycoplasma species in animals. Activity of these antibiotics

against Mycoplasma can be variable but enrofloxacin and danofloxacin

have been shown to be consistently more active in vitro (minimum

inhibitory concentrations [MIC] of 0.05 to 1.0 mcg/mL) against

veterinary isolates than flumequine{R-143}.

88 FLUOROQUINOLONES Veterinary—Systemic


[Pasteurellosis (treatment)]1—Rabbits, pet and research: In the U.S., for

use only in animals not to be used for food production—Although the

safety and efficacy have not been established, there are some research

data suggesting that parenteral enrofloxacin can resolve clinical signs

of pasteurellosis in many naturally infected rabbits, even though the

organism is not consistently eradicated{R-67–69}. See also the Regula-

tory Considerations section.

UNACCEPTED[Ehrlichiosis (treatment)]1—Cats and dogs: The American College of

Veterinary Internal Medicine Infectious Disease Study Group has

stated that the treatment of choice for ehrlichiosis is doxycycline and

that enrofloxacin has not been found to be an effective treat-

ment{R-149}. A small, short-term (15-day) study without follow-up

showed that enrofloxacin can be as effective as doxycycline in the

treatment of naturally aquired ehrlichiosis in dogs{R-77}; however,

another study of experimentally induced disease in which dogs were

monitored after 21-day enrofloxacin therapy showed poor efficacy in

clearing the infection{R-138}.




Federal law prohibits the extralabel use of fluoroquinolones in

food-producing animals (21 CFR 530.41). The prohibition is

based on a finding by the Food and Drug Administration that the

extralabel use of these antibiotics in food-producing animals presents

a risk to the public health because such use could increase the level

of drug-resistant zoonotic pathogens at the time of slaughter{R-106}.

Some researchers are concerned that such use can lead to the

transfer of pathogens resistant to fluoroquinolones from animals to

human beings.

Difloxacin, enrofloxacin, marbofloxacin, and orbifloxacin are restricted

to use by or on the order of a licensed veterinarian{R-1; 2; 94; 96–98}.

Ciprofloxacin is not labeled for veterinary use.

Canada—

Difloxacin, enrofloxacin, marbofloxacin, and orbifloxacin are restricted

to use by or on the order of a licensed veterinarian. They are not

labeled for use in food-producing animals.

Ciprofloxacin is not labeled for veterinary use.

CHEMISTRYChemical group: Quinolone carboxylic acid derivatives{R-1}.

Chemical name:

Ciprofloxacin—3-Quinolinecarboxylic acid, 1-cyclopropyl-6-fluoro-1,

4-dihydro-4-oxo-7-(1-piperazinyl)-{R-7}.

Difloxacin hydrochloride—3-Quinolinecarboxylic acid, 6-fluoro-1-(4-flu-

orophenyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo, monohy-

drochloride{R-7}.

Enrofloxacin—3-Quinolinecarboxylic acid, 1-cyclopropyl-7-(4-ethyl-

1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-{R-7}.

Marbofloxacin—9-Fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperaz-

inyl)-7-oxo-7H-pyrido[3,2,1-ij][4,1,2]benzoxadiazine-6-carboxylic

acid{R-7}.

Orbifloxacin—1-Cyclopropyl-7-(cis-3,5-dimethyl-1-piperazinyl)-5,6,8-tri-

fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid{R-7}.

Molecular formula:

Ciprofloxacin—C17H28FN3O3{R-7}.

Difloxacin hydrochloride—C21H19F2N3O3ÆHCl{R-7}.

Enrofloxacin—C19H22FN3O3{R-7}.

Marbofloxacin—C17H19FN4O4{R-7; 97}.

Orbifloxacin—C19H20F3N3O3{R-7; 98}.

Molecular weight:

Ciprofloxacin—331.34{R-7}.

Difloxacin hydrochloride—435.85{R-7}.

Enrofloxacin—359.39{R-7}.

Marbofloxacin—362.36{R-7; 97}.

Orbifloxacin—395.38{R-7; 98}.

Description:

Ciprofloxacin Hydrochloride USP—Faintly yellowish to light yellow

crystals{R-105}.

Difloxacin hydrochloride—White to light yellow powder.

Enrofloxacin—Pale yellow crystals with a melting point of 219 to

221 �C.Orbifloxacin—White to pale yellow crystalline powder{R-82}.

pKa:

Ciprofloxacin—Carboxylic acid group, 6.1; tertiary amine, 7.8{R-95}.

Difloxacin—Carboxylic acid group, 4.33; methyl substituted nitrogen

group, 9.05{R-96}.

Enrofloxacin—Carboxylic acid group, 6.0; tertiary amine, 8.8{R-95}.

Orbifloxacin—5.95 and 9.01{R-98}.

Solubility:

Ciprofloxacin hydrochloride—Sparingly soluble in water; slightly soluble

in acetic acid and in methanol; very slightly soluble in dehydrated

alcohol; practically insoluble in acetone, in acetonitrile, in ethyl

acetate, in hexane, and in methylene chloride{R-105}.

Difloxacin—Poorly water soluble at neutral pH, more soluble under

acidic conditions, and highly water soluble under basic condi-

tions{R-96}.

Enrofloxacin—Slightly soluble in water at pH 7.

Marbofloxacin—Soluble in water; less soluble under alkaline condi-

tions{R-97}.

Orbifloxacin—Slightly soluble in water; more soluble in both acidic and

alkaline conditions{R-98}.

PHARMACOLOGY/PHARMACOKINETICSNote: See also Table 1 and Table 2 at the end of this monograph.

Mechanism of action/effect: Bactericidal{R-2; 95–100}. The fluoroqui-

nolones inhibit bacterial DNA gyrase or topoisomerase IV (a type II

topoisomerase), thereby preventing DNA supercoiling and replica-

tion{R-1; 2; 86}. Cell respiration and division end, and other processes

are interrupted, including membrane integrity{R-1}. Mammalian cell

topoisomerase II is not affected by fluoroquinolones until drug con-

centrations are at least 100 times higher than concentrations rec-

ommended to inhibit the bacteria{R-95}.

Fluoroquinolones enter cells via porins and accumulate rapidly in

susceptible bacteria{R-9}. Some bacteria are able to pump the antibiotic

agent back out of the cell by an energy-dependent efflux transport

system{R-9}.



The efficacy of the fluoroquinolones is concentration dependent as

measured by either the maximum concentration above MIC (Cmax:

MIC) or the area under the curve above MIC (AUC : MIC; AUIC){R-9}.

A post-antibiotic effect, in which growth of pathogens may remain

inhibited for varying periods after fluoroquinolone concentrations fall

below inhibitory concentrations, has been demonstrated with enro-

floxacin and orbifloxacin in some bacteria{R-9; 82}.

Absorption: Oral absorption of fluoroquinolones is high for most ani-

mals studied{R-1; 10; 97; 98}. It is not affected by administration with

food, although absorption may be delayed{R-95}. Divalent and trivalent

cations can affect absoprtion (see the Drug interactions section in this

monograph){R-96}. In cats, dogs, and pigs, oral absorption of

fluoroquinolones approaches 100%, but in ruminants, it is generally

less.{R-95} The horse may be unique regarding oral absorption patterns

in that while enrofloxacin is well absorbed, ciprofloxacin is poorly

absorbed.{R-144} Other fluoroquinolones have not been studied as to

oral bioavailability in horses.

Absorption from parenteral administration of fluoroquinolones is rapid

and often nearly complete{R-9; 11; 22; 28; 29; 32; 41; 45}. In some

animals, there is delayed absorption from intramuscular or subcuta-

neous administration, producing longer half-lives from these routes

compared to intravenous absorption.{R-95}

Enrofloxacin—

Oral—Rapidly absorbed in monogastric species and preruminant

calves{R-1; 10}. Absorption in adult ruminants is variable and has

ranged from 10 to 50%{R-86}.

Distribution: Fluoroquinolones achieve concentrations that are at least

as high as plasma in a wide range of tissues, with the exception of the

central nervous system and the eye{R-1; 26; 95–98}. This is true in many

species, including cats, cattle, chickens, dogs, horses, and rabbits{R-1; 5;

15; 18; 26; 31; 32}.

Differences in volume of distribution among the fluoroquinolones

however, account for a range of maximum plasma concentrations

among the drugs. Drugs with the lowest volume of distribution are

diluted less in body fluid and produce higher plasma concentrations

than drugs with a higher volume. The consequence of this difference is

reflected in the dose administered; to achieve the same peak serum

concentration, drugs with a high volume of distribution require a

higher dose{R-95}.

Fluoroquinolones are rapidly accumulated in macrophages

and neutrophils. Unlike other antibiotics that concentrate in

subcellular sites within phagocytic cells, the quinolones are

distributed into the cytosol where they can reach intracellular

pathogens{R-20}. This concentration in leukocytes may explain the

higher fluoroquinolone concentrations in infected tissue compared

to healthy tissue{R-95}.

Because of renal elimination, urine concentration of fluoroquinolones

occurs in many species. Enrofloxacin concentration in canine

prostate tissue matches that in the serum and concentration in

urine reaches about 100 times that in the serum{R-18; 19}. The

orbifloxacin concentration in canine prostate tissue exceeds that in

serum and concentration in urine reaches about 50 times that in

serum{R-82}. Even difloxacin, for which less than 5% of the dose is

excreted into the urine in the dog, concentrations in the urine

are 10 times plasma concentration after a single dose of 10 mg

per kg of body weight (mg/kg){R-96}. After multiple oral doses in

horses, urine concentrations are higher than serum concentra-

tions{R-27}.

Marbofloxacin—Dogs: Tissue concentrations of marbofloxacin were

determined in healthy male beagle dogs at 2, 18, and 24 hours after

a single oral dose (2.75 or 5.5 mg/kg). Based on the terminal

elimination half-life and the dosing interval, steady-state levels are

reached after the third dose and are expected to be approximately 25%

greater than those achieved after a single dose.

Protein binding:

Ciprofloxacin—Dogs: 44 ± 3%{R-12}.

Difloxacin—Dogs: 46 to 52%{R-97}.

Enrofloxacin—

Camels: Concentration dependent—

1.7% at 1.8 mcg of enrofloxacin per mL of serum (mcg/mL){R-45}.

5% at 0.6 mcg/mL{R-45}.

24.2% at 0.33 mcg/mL{R-45}.

Cattle, lactating: 36 to 45%{R-11}.

Chickens: 24 ± 2%{R-30}; 21 ± 0.1{R-12}.

Dogs: 72% at 1 mcg/mL{R-86}.

Horses: 22 ± 2%{R-12}.

Pigs: 27 ± 3%{R-12}.

Rabbits:

Up to 30 days of age—40 to 50%{R-34; 35}.

Adult—53 ± 1%{R-12}.

Does, pregnant—35 ± 5%{R-63}.

Marbofloxacin{R-97}—

Cats: 7.3%

Dogs: 9.1%

Orbifloxacin—Dogs: 7.7 to 14.5%{R-82}.

Biotransformation:

Difloxacin—In the dog, difloxacin is metabolized to an ester glucuronide

and the desmethyl derivative{R-96}.

Enrofloxacin—Enrofloxacin is de-ethylated to form ciprofloxacin, an

antimicrobically active metabolite in many species{R-11; 13; 18; 22; 24;

28; 29; 31; 39; 42; 46; 71; 72}. Therefore, microbiologic assays in

pharmacokinetic studies are likely to measure the activity of both

enrofloxacin and ciprofloxacin combined. Because minimum

inhibitory concentrations for some pathogens are lower for ciproflox-

acin than for enrofloxacin{R-13}, therapeutic concentrations of cipro-

floxacin can be reached with dosing calculated to achieve effective

enrofloxacin concentrations{R-16; 25; 28}. Ciprofloxacin can be consid-

ered an important contributor to the activity of enrofloxacin{R-16; 28}.

Evaluations of enrofloxacin activity based on serum or tissue concen-

trations should consider the contributions of both enrofloxacin and

ciprofloxacin. It is also possible that other as yet undiscovered

metabolites have antimicrobial activity{R-16}.

Cats: After oral administration, the half-time for conversion of

enrofloxacin to ciprofloxacin is about 13 minutes{R-22}. Ciprofloxacin

serum concentration is about 20% of the enrofloxacin concentration

in the serum at any one time; about 10% at maximum serum

concentrations{R-22; 72; 86}.

Cattle, lactating: The serum concentration of ciprofloxacin is 35% that

of enrofloxacin during the elimination phase, after an intravenous

dose of 5 mg/kg{R-11}.

Chickens: Enrofloxacin is extensively metabolized to ciprofloxacin{R-31}.



Dogs: Overall, 40% of the oral or intravenous enrofloxacin dose

administered is metabolized to ciprofloxacin{R-23}. Ciprofloxacin

makes up about 20% of the total serum concentration of enro-

floxacin and ciprofloxacin after enrofloxacin administration;

ciprofloxacin makes up about 35% of the total body concentration

when calculated based on the area under the concentration-time

curve (AUC){R-16; 18; 86}.

Ducks: Less than 10% of the administered enrofloxacin dose is

converted to ciprofloxacin after a 10 mg/kg dose{R-42}.

Horses: The concentration of ciprofloxacin in the serum reaches 20 to

35% of the enrofloxacin concentration in adult horses{R-24}. In foals,

the amount of ciprofloxacin measured is negligible{R-85}.

Llamas: Approximately 36% of enrofloxacin administered is converted

to ciprofloxacin in llamas{R-46}.

Macaques, long-tailed: Ciprofloxacin makes up about 22% of the total

amount of active drug measured in the serum after intramuscular

administration of 5 mg/kg of enrofloxacin{R-71}.

Parrots, African grey: Ciprofloxacin concentration in the serum

reaches 3 to 78% of the enrofloxacin dose administered{R-39}. The

ratio of ciprofloxacin to enrofloxacin in the serum increases with

multiple dosing over 10 days{R-39}.

Pigs: The concentration of ciprofloxacin in the plasma comprises less

than 10% of the amount of enrofloxacin present in the plasma{R-29}.

Sheep: In one study, the concentration of ciprofloxacin in the plasma

reached 35 and 55% of the serum enrofloxacin concentrations, with

intravenous and intramuscular administration, respectively, of a 2.5

mg/kg dose{R-28}. Another study found the concentration of cipro-

floxacin in the plasma to be 10 to 20% of the serum drug

concentration{R-86}.

Marbofloxacin—Dogs: 10 to 15% of the dose is metabolized in the

liver{R-97}.

Serum concentrations:

Chickens—

Mean plasma concentrations at 6, 12, and 24 to 168 hours after

beginning oral administration of enrofloxacin at a dose of 25 parts

per million (ppm) in the drinking water were 0.241, 0.317, and

0.381 mcg/mL, respectively{R-3}.

Mean plasma concentrations at 6, 12, and 24 to 168 hours after

beginning oral administration of enrofloxacin at a dose of 50 ppm in

the drinking water were 0.464, 0.653, and 0.712 mcg/mL,

respectively{R-3}.

Turkeys—

Mean plasma concentrations at 6 hours and 24 to 168 hours after

beginning oral administration of enrofloxacin at a dose of 25 ppm

in the drinking water were 0.204 and 0.240 mcg/mL, respec-

tively{R-3}.

Mean plasma concentrations at 6 hours and 24 to 168 hours

after beginning oral administration of enrofloxacin at a dose of

50 ppm in the drinking water were 0.352 and 0.458 mcg/mL,

respectively{R-3}.

Elimination:

Difloxacin—Dogs: Primarily through glucuronidation and subsequent

biliary secretion. The glucuronide metabolite may be hydrolyzed back

to the parent compound and reabsorbed in the gastrointestinal tract.

After intravenous administration, 80% of the dose is eliminated in the

feces while renal clearance accounts for less than 5% of difloxacin

elimination{R-96}.

Enrofloxacin—Renal. Primarily by glomerular filtration and tubular

secretion{R-10}.

Marbofloxacin—

Cats: Primarily renal. 70% of an oral dose is excreted into the urine as

parent drug and metabolites{R-97}.

Dogs: 40% of an oral or subcutaneous dose is excreted as parent drug

into the urine. Elimination of parent drug into the feces is also a

significant route of elimination{R-97; 115}.

Orbifloxacin—

Cats: Of the orbifloxacin eliminated in urine after subcutaneous

administration, 96% is unchanged parent drug and 4% is N-hydroxy

orbifloxacin, an active metabolite with somewhat higher MICs for

pathogens sensitive to orbifloxacin{R-111}.

Dogs: 40% of an oral dose is excreted as parent drug into the urine{R-97}.

Of the orbifloxacin eliminated in the urine after a subcutaneous dose,

87% is parent compound and 13% is glucuronide metabolite{R-111}.


BACTERIAL RESISTANCEConcerns about the risk of increasing resistance of human pathogens to

fluoroquinolones as well as the ability of infections in animals to resist

treatment should be considered by health practitioners when prescrib-

ing these medications. There have been warnings by infectious disease

experts that widespread use of fluoroquinolones may lead to increased

resistance, and transfer of resistance to humans has been suggested for

Campylobacter species and Salmonella typhimurium type DT-104.

Increased resistance in Campylobacter jejuni infecting people was

reported after 1995, the same period in which fluoroquinolones were

first approved for use in poultry. There has also been discussion about

the appearance of resistant strains of Salmonella typhimurium during

the time fluoroquinolones have been used in livestock. However, some

resistant strains have been traced to farms that were not administering

fluoroquinolones, leading to the suggestion that the resistance may

have arisen spontaneously{R-95}.

As scientists continue to uncover evidence pertaining to the potential

for transfer of fluoroquinolone-resistant pathogens from animals to

man, fluoroquinolones have had limited approval for use in food-

producing animals and extra-label use in these animals is prohibited in

the United States{R-95; 106}.

SPECIES SENSITIVITYCats: Because of the risk of retinal degeneration that has been associated

with enrofloxacin administration at high doses (20 mg per kg of body

weight [mg/kg] a day){R-1}, it has been recommended that adminis-

tration of high doses of all fluoroquinolones be avoided in cats

whenever possible. However, it may be that not all fluoroquinolones

have the same potential to cause retinal damage. Limited studies show

that marbofloxacin caused no retinal changes visible with fundiscopic

or histologic examination when administered to 8-month-old cats at

10 times the recommended dosage for 2 weeks{R-97}, whereas

enrofloxacin has been shown to cause ocular lesions at 4 times the

recommended dosage{R-1}. A study with orbifloxacin showed that no



retinal changes were visible with fundoscopic or histologic examina-

tion when administered to cats at levels which exceeded the highest

recommended dose of 7.5 mg/kg{R-146}.

CARCINOGENICITYEnrofloxacin—No evidence of carcinogenicity was found in studies of

laboratory animal models{R-3}.

PREGNANCY/REPRODUCTIONThe attributes of fluoroquinolones make them likely to cross the placenta

in many species; however, adverse effects have not yet been reported

when fluoroquinolones have been administered to pregnant

animals{R-95}.

Adequate and well-controlled studies of the effects of fluoroquinolones in

pregnant human beings have not been done; however, administration

during human pregnancy is generally not recommended, based on

reports of arthropathy in immature animals{R-107}.

Ciprofloxacin—Ciprofloxacin crosses the human placenta{R-107}. Intra-

venous doses of ciprofloxacin of up to 20 mg per kg of body weight

(mg/kg) in pregnant rats and mice have not shown evidence of

maternal toxicity, embryotoxicity, or teratogenic effects{R-107}.

Difloxacin, marbofloxacin, and orbifloxacin—Safety in breeding or

pregnant animals has not been determined{R-96–98}.

Enrofloxacin—

Cats, cattle, turkeys: Effect on reproduction or pregnancy has not been

established{R-1–3}.

Chickens: No adverse effects were noted in measured reproductive

parameterswhenmale and female chickenswere given an enrofloxacin

dose of 150 parts per million in the drinking water for 7 days. This

regimenwas repeated at five different ages between1 day and 206 days

of age with no reproductive effect noted{R-3}. The parameters measured

included egg production, egg weight, hatchability, chick viability, and

reproductive histology of treated birds and their hatched chicks{R-4}.

Dogs:

No adverse effects were noted in measured reproductive parameters,

including libido, successful pregnancy, and number of pups per

litter, when male dogs were administered 5 to 15 mg/kg a day for

10 days beginning at 90, 45, or 14 days before breeding{R-1; 5}.

No adverse effects were noted in female dogs administered 15 mg/kg

a day for 10 days in the last 30 days before breeding, between the

10th and 30th days of gestation, between the 40th and 60th days

of gestation, or during the first 28 days of lactation{R-1; 5; 6}.

Rabbits: Enrofloxacin is transferred across the placenta in rabbits{R-63};

adverse effects on pups have not been reported. Ciprofloxacin also

crosses the placenta but at a much slower pace (6% of the rate of

enrofloxacin){R-63}.

LACTATIONBecause of the risk of producing arthropathies in immature animals, it

has been recommended that significant levels of fluoroquinolones in

the milk of nursing animals be avoided{R-95; 107}. Fluoroquinolones

can be distributed into milk, sometimes at a higher concentration than

in plasma,{R-11–14; 34} but it is not known under what conditions

significant amounts might be absorbed by nursing animals{R-86}.

Mastitis—It has not been shown that fluoroquinolones are effective in

treating mastitis{R-95}, perhaps because of factors in milk that inhibit

activity{R-11}.

Cattle: Federal law prohibits the extra-label use of fluoroquinolones in

food-producing animals (see the Regulatory Considerations section). The

following information is included in case of accidental dosing.

Enrofloxacin appears rapidly in milk after parenteral administration,

reaching a peak concentration at 30 to 60 minutes after intravenous

injection, followed by a gradual decline in milk concentration similar

to that occurring in serum concentration{R-11; 14}. Approximately

0.2% of a 5 mg per kg of body weight dose of enrofloxacin is

measured in milk in the first 24 hours; therapeutic antimicrobial

concentrations can be reached{R-11}.

The ciprofloxacin metabolite of enrofloxacin also appears rapidly in

milk, but this occurs 4 to 8 hours after parenteral administration.

It concentrates to a higher peak than enrofloxacin

itself{R-11; 14}.

Horses: Following an oral dose of 5 mg/kg to lactating mares,

concentration of ciprofloxacin and enrofloxacin in milk ranged from

0.25 to 0.78 mcg per mL. At this concentration, a nursing foal would

ingest a dose of less than 0.1 mg per kg of body weight a day,

producing plasma concentrations in the foal below detection lim-

its{R-86}.

Rabbits: Therapeutic concentrations of enrofloxacin are reached in milk

following a dose of 7.5 mg per kg of body weight{R-34}.

PEDIATRICSSee also the Side/Adverse Effects section for information on risk of

arthropathies in immature animals.

Enrofloxacin—

Calves: Until at least 1 week of age, the elimination of enrofloxacin is

slower in calves than in adult cattle{R-13}. Adjustment of dosage,

including increased dosing interval, may be necessary{R-13}.

Foals: Elimination of enrofloxacin in foals (half-life = 18 hrs) is slower

than in adult horses and oral absorption in foals is approximately

42%{R-86; 88}. Administering enrofloxacin at a dose of 10 mg per kg

a day caused every one of five healthy foals to have lesions on

articular cartilage{R-85}.

Rabbits: Elimination of enrofloxacin is significantly less in neonates

until at least 16 days of age compared with that in adult

rabbits{R-34}. The ease of penetration of enrofloxacin into milk

should be considered when treating lactating does that continue to

nurse{R-35}. Enrofloxacin pharmacokinetics in 30-day-old rabbits are

similar to those in adult rabbits{R-35}.







medication.

Digoxin: A small study investigating specifically the effect of enroflox-

acin administration on digoxin clearance and serum concentrations in

dogs showed no effect with concomitant administration{R-59}.

Antacids, aluminum-, calcium-, or magnesium-containing or

Laxatives, magnesium-containing or

Multivitamins or

Sucralfate or



Zinc

(compounds containing divalent or trivalent cations, such as

aluminum, calcium, iron, magnesium, or zinc, administered con-

currently with a fluoroquinolone, may reduce the absorption of the

fluoroquinolone{R-1; 96–98})

Theophylline{R-61} or

Hepatically metabolized drugs, other{R-1}

(in dogs, the clearance of theophylline was reduced by 43% with the

concurrent administration of enrofloxacin [5 mg per kg of body

weight every 24 hours]; peak serum concentration of theophylline

was significantly increased; the pharmacokinetics of enrofloxacin

were unaffected{R-62})

(the concurrent administration of a fluoroquinolone with other drugs

metabolized by hepatic enzymes may affect the pharmacokinetics of

one or both drugs{R-1}; enrofloxacin has been shown to inhibit liver

microsomal mixed-function oxidases in broiler chicks, including

aniline hydroxylase and aminopyrine N-demethylase{R-60}; cyto-

chrome P450 activity was not significantly affected in chickens{R-60};

in mice, there is indirect evidence that cytochrome P450 enzymes

may be affected by enrofloxacin administration{R-62}; the effect of

these enzyme inhibitions on specific drugs has not yet been

demonstrated)

HUMAN DRUG INTERACTIONS AND/OR RELATEDPROBLEMS{R-107}



included in the human monograph Fluoroquinolones (Systemic) in USP



fluoroquinolones in animals:

Note: There are no difloxacin, enrofloxacin, marbofloxacin, or orbiflox-

acin products labeled for use in human beings.

Anticonvulsants, hydantoin, especially:

Phenytoin

(concurrent administration of ciprofloxacin with phenytoin has

resulted in a 34 to 80% decrease in the plasma concentration of

phenytoin; caution should be used when administering quinolones,

especially ciprofloxacin, to patients stabilized on phenytoin; careful

monitoring of phenytoin dosage after discontinuation of quinolones

is highly recommended)

Antidiabetic agents, sulfonylurea, especially:

Glyburide or

Insulin

(concurrent use of ciprofloxacin with glyburide or other antidiabetic

agents has, on rare occasions, resulted in hypoglycemia; also,

hyperglycemia and hypoglycemia have been reported in patients

taking quinolone antibiotics and antidiabetic agents concurrently;

since the mechanism is not understood, similar effects with other

sulfonylurea antidiabetic agents may be expected when these

medications are used with fluoroquinolones; careful monitoring of

blood glucose concentrations is recommended when these medica-

tions are used concurrently)

Anti-inflammatory drugs, nonsteroidal (NSAIDs)

(fluoroquinolones are competitive inhibitors of gamma-aminobutyric

acid receptor binding, and some NSAIDs have been shown to

enhance this effect; concurrent administration of NSAIDs with

quinolone antibiotics may increase the risks of CNS stimulation and

convulsions)

Cyclosporine

(concurrent use with ciprofloxacin has been reported to elevate

serum creatinine and serum cyclosporine concentrations; other

studies have not found ciprofloxacin to alter the pharmacokinetics of

cyclosporine; cyclosporine concentrations should be monitored when

used concurrently with fluoroquinolones, and dosage adjustments

may be required)

Probenecid

(concurrent use of probenecid decreases the renal tubular secretion

of fluoroquinolones, resulting in decreased urinary excretion of the

fluoroquinolone, prolonged elimination half-life, and increased risk of

toxicity; this interaction is more significant with fluoroquinolones

excreted largely unchanged in the urine, and of less clinical

significance with fluoroquinolones that have larger nonrenal elim-

ination, such as ciprofloxacin)

Warfarin

(concurrent use of warfarin with ciprofloxacin has been reported to

increase the anticoagulant effect of warfarin, increasing the chance

of bleeding; other studies have not found fluoroquinolones to alter

the prothrombin time [PT] significantly; however, it is recommended

that the PT of patients receiving warfarin and fluoroquinolones

concurrently be monitored carefully)



humans, and are included in the human monograph Fluoroquinolones



applicable to the use of fluoroquinolones in the treatment of animals:

Note: There are no difloxacin, enrofloxacin, marbofloxacin, or orbiflox-

acin products labeled for use in human beings.




Amylase and


Lactate dehydrogenase (LDH)








Hypersensitivity to quinolones{R-1; 3}

(animals with a history of hypersensitivity to quinolones are at risk

for developing reactions to them{R-1; 97; 98})

Immature animals in some species{R-1}

(fluoroquinolone administration during rapid growth has been

associated with arthropathies and cartilage erosions in weight-

bearing joints in immature cats, dogs, and horses{R-1; 4; 5; 25; 26; 85;

96-98}; in dogs, enrofloxacin has been shown to cause abnormal

carriage of the carpal joint and hindlimb weakness, as well as



cartilage lesions; administration of enrofloxacin should be avoided in

small and medium breed dogs during rapid growth, typically 2 to 8

months of age; large or giant breeds may rapidly grow until 18

months of age{R-1})


problems exist:

Central nervous system (CNS) disorders{R-1}

Seizures, history of

(fluoroquinolones have been associated with CNS stimulation that

may lead to seizures in a few rare cases and should be used with

caution{R-1; 2}; the clinical significance of a report of increased

seizure incidence with enrofloxacin administration to dogs with

phenobarbital-controlled seizures is not known{R-10})

Hepatic disease, severe

Renal failure

(fluoroquinolones are primarily eliminated by a combination of renal

clearance and hepatic metabolism, sometimes with significant biliary

secretion; the predominance of one route over another depends on

the quinolone and the animal species; there is little research

information on changes in elimination in various disease states in

animals; the induction of moderate renal impairment in dogs

[glomerular filtration rate decreased 37% and serum creatinine

values increased 85% from normal controls] had only a minor effect

on the clearance of marbofloxacin{R-108})


tests may be warranted in some patients, depending on condition;

» = major clinical significance):

Culture and sensitivity in vitro and



prior to fluoroquinolone administration to determine pathogen

susceptibility)





Multiple species

Arthropathy—in immature animals, especially dogs and foals

Note: The risk of arthropathy increases with increasing dose but has

been reported to occur at recommended dosages in young dogs.

Difloxacin—Articular cartilage lesions were seen in 15- to 16-week-

old puppies administered difloxacin at 5, 25, or 35 mg per kg of body

weight (mg/kg) a day for 90 days{R-96}. Cartilage lesions and

lameness were observed in puppies administered 50 and 125 mg/kg

a day{R-96}.

Enrofloxacin—Cartilage damage has been observed in 10- to 28-

week-old puppies with an oral enrofloxacin dose of 5 to 25 mg/kg a

day for 30 days and 5- to 7-month-old kittens with an oral dose of 25

mg/kg a day for 30 days{R-1; 5}; changes include splitting of the

articular cartilage surface and, in some cases, necrosis of the hyaline

cartilage{R-4}. Arthropathy has been reported in growing horses{R-25; 26}.

In unpublished manufacturer data, a dose of 5 mg/kg administered

to foals once a day was reported to cause cartilage lesions and signs

of arthropathy after 6 days{R-25}; however, studies have shown no

effect on cartilage in adults when used continuously for up to 21

days{R-86; 136}. In 23-day-old calves, a dose of 25 mg/kg a day for 15

days had no measurable effect on articular cartilage in the stifle joint

at 2 and 9 days after the end of treatment{R-2}.

Marbofloxacin—Lameness and articular cartilage lesions were

reported in large breed, 3- to 4-month-old dogs administered 11

mg/kg a day for 14 days{R-97}.

Orbifloxacin—Microscopic cartilage lesions typical of fluoroquino-

lone arthropathy have also been reported with orbifloxacin

administration; in one of eight, 8- to 10-week-old puppies given

12.5 mg/kg a day and all 8 puppies given 25 mg/kg a day{R-98}. Cats

appear to be resistant to this effect, showing no cartilage lesions after

one month of a 25 mg/kg-a-day dose{R-98}.

Cats

Retinal degeneration (acute blindness, mydriasis)—reported with

enrofloxacin at doses higher than 5 mg per kg of body weight

(mg/kg) a day

Note: Administering enrofloxacin to cats at a dose of 20 mg/kg can

cause retinal degeneration{R-1; 103}, often manifested as temporary or

permanent blindness with mydriasis{R-1; 103; 119}. Mild to severe

fundic lesions are observed on ophthalmologic exam of affected cats,

including changes in the color of the fundus and central or

generalized retinal degeneration. There are also abnormal electro-

retinogram results and diffuse light microscopic changes in the

retinas{R-1}. Retinal degeneration has not been reported in cats in

association with other fluoroquinolones; however, caution is recom-

mended when considering high dose therapy of any fluoroquinolone

in cats.

Cats and dogs

Ataxia; seizures—with enrofloxacin

Note: Although ataxia and seizures were not observed during preap-

proval clinical field trials, they have been noted as part of voluntary

postapproval adverse drug experience reporting{R-1}.

Parrots, African grey

Appetite, decreased{R-40}; polydipsia and polyuria{R-39; 40}—with

a dose of 30 mg/kg every 12 hours for 10 days{R-39} or in drinking

water with 1.5 to 3 mg/mL of water{R-40}; may resolve within 2 or 3

days of treatment cessation{R-39}


Cats

Vomiting—with enrofloxacin, occasional vomiting was observed in

up to 75% of 7- to 10-month-old cats administered a 5 to 15 mg/kg

dose for 30 days; however, 25% of untreated cats also vomited

occasionally{R-1}.


Cats

Diarrhea—reported with marbofloxacin (2.1% of cats in one

report){R-97}

Dogs

Decreased activity—reported with marbofloxacin (4.4% of dogs in

one report){R-97}; decreased appetite—reported with marbofloxacin

(5.4%){R-97}; vomiting—reported with marbofloxacin (2.9%){R-97}



Incidence rare

Cats

Vomiting—with marbofloxacin (<1%){R-97}

Dogs

Vomiting—with enrofloxacin (0.7% of dogs){R-1}

Incidence unknown

Cattle{R-2}, horses{R-24}, and rabbits{R-68; 69}

Local tissue reaction, transient—in cattle, can cause trim loss of

edible tissue at slaughter{R-2}

Dogs

Anorexia; decreased appetite; diarrhea; vomiting—with difloxa-

cin

Note: No adverse effects were reported in association with a clinical

study using recommended dosages of difloxacin in dogs. Anorexia,

decreased appetite, diarrhea, and vomiting have been reported in

clinical cases{R-96} but the incidence is unknown.



following side/adverse effects have been reported in humans and are

included in the human monograph Fluoroquinolones (Systemic) in USP



fluoroquinolones in the treatment of animals:

Note: The following human side/adverse effects are those pertaining to

ciprofloxacin or fluoroquinolones in general. Difloxacin, enrofloxacin,

marbofloxacin, and orbifloxacin are not available as products labeled

for human use.

Note: The relative insolubility of ciprofloxacin at an alkaline pH has

resulted in crystalluria, usually when the urinary pH exceeds 7.

Seizures have been reported very rarely with ciprofloxacin therapy;

however, the patients who did have seizures either had a previous

seizure history, were alcoholic, or were taking ciprofloxacin concur-

rently with theophylline.


Central nervous system (CNS) toxicity; gastrointestinal reac-

tions; vaginitis


Arthralgia; back pain; cardiovascular reactions such as palpi-

tation, vasodilation, or tachycardia; central nervous system

(CNS) stimulation; change in sense of taste; dreams, abnormal;

dysuria; headache; hematuria; hepatotoxicity; hypersensitivity

reactions; interstitial nephritis; moniliasis, oral; moniliasis,

vaginal; myalgia; phlebitis—for intravenous ciprofloxacin;

photosensitivity; phototoxicity; pseudomembranous colitis;

Stevens-Johnson Syndrome (blistering, itching, loosening, peeling,

or redness of skin; diarrhea); tendinitis or tendon rupture; vision,

abnormal

Note: Achilles tendinitis and tendon rupture have been reported in

patients receiving fluoroquinolones. The ruptures occurred 2 to 42

days after the start of therapy. Concommitant use of corticosteroids

with fluoroquinolones may increase the risk of tendon disorders or

ruptures. These injuries may require surgical repair or result in

prolonged disability. It is recommended that fluoroquinolone treat-

ment be discontinued at the first sign of tendon pain or inflamma-

tion, and that patients refrain from exercising until the diagnosis of

tendinitis has been excluded.

Some patients note a reduced incidence of nausea and taste perversion

if the dose is administered in the evening.

Photosensitivity reactions generally appear within a few days of the

start of fluoroquinolone treatment but can occur up to 3 weeks after

its discontinuation. The reactions usually subside within 1 month of

discontinuation.

Indicating possible phototoxicity, pseudomembranous colitis, or ten-

dinitis or tendon rupture and the need for medical attention if they

occur after medication is discontinued:

Abdominal or stomach cramps and pain, severe; abdominal

tenderness; blisters; diarrhea, watery and severe, which may

also be bloody; fever; pain in calves, radiating to heels;

sensation of skin burning; skin rash, itching, or redness;

swelling of calves or lower legs






Reported lethal doses of enrofloxacin—

Cats: 125 mg per kg of body weight (mg/kg) a day for 5 days{R-1}.

Dogs: Oral—125 mg/kg a day for up to 11 days{R-1; 5}.

Mice: Oral—LD50 for female mice is 4335 mg/kg and for male mice is

5000 mg/kg{R-4}.

Rabbits: Oral—LD50 for male and female rabbits is 500 to 800 mg/

kg{R-4}.

Rats: Oral—LD50 for male and female rats is more than 5000 mg/kg{R-2;

3; 4}. A dose of 500 parts per million (40 mg/kg) has no observable

effect{R-4}.

Turkey poults, 1-day-old: Oral—626 parts of enrofloxacin per million

parts of drinking water administered for 21 days caused the death of

11 out of 40 birds in the first 10 days{R-3; 4}. Surviving birds showed

signs of listlessness and decreased body weight gain{R-3}.


clinical significance—not necessarily inclusive:

For difloxacin

Dogs, with doses of 5, 15, or 25 mg/kg a day for 30 consecutive

days{R-96}

Decreased appetite; diarrhea; erythema/edema on the facial

area, transient; weight loss

For enrofloxacin

Calves, feeder, with a dose of 15 or 25 mg/kg a day for 10 to 15 days or

a dose of 50 mg/kg a day for 3 days{R-2}

Note: Federal law prohibits the extra-label use of fluoroquinolones in

food-producing animals (see the Regulatory Considerations section).

The following information is included in case of accidental dosing.

Depression; decreased appetite; incoordination; muscle fascicu-

lations

Cats, with a dose of 20 mg/kg a day for 21 days{R-1}

Depression; retinal degenerative effects; salivation; vomiting

Cats, with a dose ‡ 50 mg/kg a day for 6 days{R-1}

Convulsions; depression; incoordination; loss of appetite; reti-

nal degenerative effects; vomiting



Chicks, 1-day-old, with a dose in drinking water of 625 ppm for 21 to

28 days{R-4}

Decreased water consumption; decreased weight

Dogs, with an oral dose of 50 to 125 mg/kg a day for 11 to 14 days{R-1;

5; 8}

Convulsions; depression or excitation; incoordination; loss of

appetite; muscle tremors; salivation; vomiting

For marbofloxacin

Cats, with a dose of 5.5, 16.5, or 27.5 mg/kg a day for 42 days

Dermatitis, perivascular to diffuse (often reddened pinnae);

excessive salivation; softened stools

Cats, with a dose of 55 mg/kg a day for 14 days

Decreased activity; decreased food consumption; dermatitis,

perivascular to diffuse (often reddened pinnae); excessive saliva-

tion; vomiting, occasional

Dogs, with a dose of 5.5, 16.5, or 27.5 mg/kg a day for 42 days

Decreased food consumption; reddened mucous membranes;

reddened skin (usually involving the ears); vomiting; weight loss

Dogs, with a dose of 55 mg/kg a day for 12 days

Decreased food consumption; dehydration; decreased activity;

excessive salivation; facial swelling; reddened skin (usually the

ears); tremors; vomiting; weight loss

For orbifloxacin

Cats, with a dose of 22.5 and 37.5 mg/kg a day{R-98}

Softened stools

Cats, with a dose of 75 mg/kg a day for 10 days{R-98}

Decreased food consumption; diarrhea, vomiting

TREATMENT OF OVERDOSEAlthough there is no specific information available on treatment of

fluoroquinolone overdose in animals, treatment of human overdose

includes induction of vomiting or use of gastric lavage, observation,

and supportive care, including hydration and dialysis.

CLIENT CONSULTATIONCare should be exercised to avoid contact of medication with the eyes or

skin while handling solutions{R-3}.

VETERINARY DOSING INFORMATIONFlouroquinolone antibiotics have concentration-dependent bactericidal

activity or AUIC{R-21}. Serum and tissue concentrations must be high

enough for a long enough period of time to be effective against the

target pathogen. Fortunately, minimum inhibitory concentrations

(MIC) for fluoroquinolones are relatively low. Depending on many

variables, such as the organism treated and the presence of

neutrophils, fluoroquinolones can also produce a post-antibiotic effect,

suppressing bacterial growth after local drug concentrations have

fallen{R-21; 112}.

Cats: Because of the risk of retinal damage associated with high dosages

of enrofloxacin, it is recommended that caution be used when

considering administering fluoroquinolone at dosages higher than

those recommended for cats.

Flexible Labeling—Because there is a wide minimum inhibitory range

among bacteria susceptible to fluoroquinolones, it was possible to

create a ‘‘flexible’’ product label that includes a dosage range allowing

for doses at the low end to be used to treat pathogens susceptible at a

lower MIC and higher doses for less susceptible organisms. The upper

end of the dosage range is determined by safety factors.

Product labeling for veterinary fluoroquinolone products include

MIC data for bacterial pathogens for specific indications in which

efficacy was confirmed, and a dosage range{R-1; 96–98}. It is

recommended that the dose be chosen based on clinical experience,

the type and severity of infection, and susceptibility of the

pathogen{R-1}.

The effective treatment of canine infections caused by Pseudomonas

aeruginosa {R-17} and Staphylococcus species{R-21} may require the high

end of the dosage range.

Breakpoints determined for ciprofloxacin by the National Committee for

Clinical Laboratory Standards{R-95}

MIC (mcg/mL) Interpretation

£ 1.0 Susceptible

2.0 Intermediacate

‡ 4 Resistant

Note: Be aware that ciprofloxacin may not be appropriate for use as a

representative of veterinary fluoroquinolones in susceptibility testing.

Use of specific antibiotic MIC ranges has been recommended{R-110}.

Breakpoints determined for difloxacin for veterinary pathogens by the

National Committee for Clinical Laboratory Standards{R-147}

Zone diameter

(millimeters) MIC (mcg/mL) Interpretation

‡ 21 £ 0.5 Susceptible

18–20 1–2 Intermediate

£ 17 ‡ 4 Resistant

Note: The disk content is 10 mcg.

Breakpoints determined for oral dosing of enrofloxacin for cats and

dogs by the National Committee for Clinical Laboratory Standards{R-87;

88}

Zone diameter


‡ 23 £ 0.5 Susceptible

17–22 1–2 Flexible*


*Flexible indicates the availability of an FDA-approved Flexible Label; the

pathogens originating from dermal, respiratory tract, and other tissues

could be considered susceptible with an MIC £ 2 if appropriate dosing,

explained in the package insert, is used{R-86; 87}.

Breakpoints recommended for marbofloxacin by the manufacturer{R-145}

Zone diameter


‡ 17 £ 1 Susceptible

14–16 2 Intermediate





Breakpoints recommended for orbifloxacin by the National Committee for

Clinical Laboratory Standards{R-147}

Zone diameter


‡ 23 £ 1 Susceptible

18–22 2–4 Intermediate



CIPROFLOXACIN

SUMMARY OF DIFFERENCESRegulatory considerations: Ciprofloxacin is not labeled for use in

animals.




CIPROFLOXACIN FOR ORAL SUSPENSIONUsual dose: Note: [Dogs]1—Although the safety and efficacy have not

been established, an oral dose of 10 to 20mg per kg of bodyweight every

twenty-four hours has been recommended in the treatment of suscep-

tible bacterial infections, based on pharmacokinetic data{R-95; 118; 134}.

For empiric treatment of infections in dogs caused by probable

Pseudomonas aeruginosa or Staphylococcus infections, the higher end of

the dosage range may be preferable, pending susceptibility results.

[Horses]1—Due to poor bioavailability{R-144}, oral ciprofloxacin should

not be used in horses.


U.S.—




250 mg per 5 mL (5%) (Rx) [Cipro].

500 mg per 5 mL (5%) (Rx) [Cipro].

Canada—


Packaging and storage: Prior to reconsitution, store below 25 �C(77 �F). Protect from freezing. After reconstitution, store below 30 �C(86 �F). Protect from freezing.

Preparation of dosage form: To prepare the oral suspension, the small

bottle containing the microcapsules should be emptied into the large

bottle containing the diluent. Water should not be added to the

suspension. The large bottle should be closed and shaken vigorously

for about 15 seconds.

Stability: The suspension is stable for 14 days when stored in a refrig-

erator or at room temperature (below 30 �C [86 �F]).


CIPROFLOXACIN TABLETSUsual dose: See Ciprofloxacin for Oral Suspension.


U.S.—




100 mg (base) (Rx) [Cipro].




Canada—








Packaging and storage: Store below 30 �C (86 �F), in a well-closed

container, unless otherwise specified by manufacturer.

USP requirements: Preserve in well-closed containers. Contain an

amount of ciprofloxacin hydrochloride equivalent to the labeled

amount of ciprofloxacin, within ± 10%. Meet the requirements for

Identification, Dissolution (80% in 30 minutes in 0.01 N hydro-

chloric acid in Apparatus 2 at 50 rpm), and Uniformity of dosage

units{R-105}.






CIPROFLOXACIN INJECTION USPUsual dose:

Note: [Dogs]1—Although the safety and efficacy have not been estab-

lished, an intravenous dose of 10 to 15 mg per kg of body weight,

administered slowly every twenty-four hours has been recommended

in the treatment of susceptible bacterial infections{R-81}.


U.S.—




200 mg per 20 mL (Rx) [Cipro I.V. (in sterile water for injection;

requires dilution prior to administration)].

200 mg per 100 mL (Rx) [Cipro I.V. (in 5% dextrose injection;

premixed)].





400 mg per 200 mL (Rx) [Cipro I.V. (in 5% dextrose injection;

premixed)].



Canada—








Packaging and storage: Store in a cool place (between 8 and 15 �C[46 and 59 �F]) or at controlled room temperature (between 20 and

25 �C [68 and 77 �F]), unless otherwise specified by manufacturer.

Protect from light and freezing.

Preparation of dosage form: To prepare a solution for intravenous

infusion, the concentrate in sterile water for injection should be

withdrawn aseptically from the vial and diluted to a final concentra-

tion of 1 to 2 mg per mL with a suitable intravenous solution (see

manufacturer’s package insert). Solutions that come from the manufac-

turer in 5% dextrose injection should not be diluted prior to intravenous

infusion. The resulting solution should be infused over a period of at

least 60 minutes by direct infusion or through a Y-type intravenous

infusion set. It is recommended that administration of any other

solutions be discontinued during infusion of ciprofloxacin.

Stability: When diluted with appropriate intravenous fluids (see man-

ufacturer’s package insert) to concentrations from 0.5 to 2 mg per mL,

solutions retain their potency for up to 14 days when refrigerated or

stored at room temperature.

Incompatibilities: Ciprofloxacin is incompatible with aminophylline,

amoxicillin, cefepime, clindamycin, dexamethasone, floxacillin, furo-

semide, heparin, and phenytoin.

If ciprofloxacin is to be given concurrently with another medication, each

medication should be administered separately according to the recom-

mended dosage and route of administration for each medication.

USP requirements: Preserve in single-dose containers, preferably of

Type I glass, in a cool place or at controlled room temperature.

Avoid freezing and exposure to light. A sterile solution of Cipo-

floxacin in Sterile Water for Injection, in 5% Dextrose Injection, or

in 0.9% Sodium Chloride Injection prepared with the aid of Lactic

Acid. The label indicates whether the vehicle is Sterile Water for

Injection, 5% Dextrose Injection, or 0.9% Sodium Chloride Injec-

tion. Label the Injection that has Sterile Water for Injection as the

vehicle to indicate that it is a concentrated form that must be

diluted to appropriate strength (1 to 2 mg per ml) with 5% Dex-

trose Injection or 0.9% Sodium Chloride Injection before adminis-

tration, and that the resulting solution is stable for up to 14 days

when stored in a cool place or at controlled room temperature.

Contains the labeled amount, within ± 10%. Meets the require-

ments for Color (where it is labeled as being in a concentrated

form), Identification, Pyrogen, Sterility, pH (3.5–4.6, except that

where the Injection is labeled as being a concentrated form, its pH

is between 3.3 and 3.9), Particulate matter, Limit of ciprofloxacin

ethylenediamine analog (not more than 0.5%), Lactic acid content

(0.288–0.352 mg per mg of ciprofloxacin claimed on label, except

that where the Injection is labeled as being a concentrated form, it

contains between 0.335 and 0.409 mg per mg of ciprofloxacin

claimed on the label), Dextrose content (if present), and Sodium

chloride content (if present), and for Volume in Container under

Injections.{R-105}.



DIFLOXACIN

ORAL DOSAGE FORMS

DIFLOXACIN HYDROCHLORIDE TABLETSUsual dose: Bacterial infections—Dogs: Oral, 5 to 10 mg per kg of body


Note: The 5 mg per kg dose was found to be clinically effective in the

treatment of susceptible skin, soft tissue, and urinary tract infec-

tions{R-99}.

For empiric treatment of probable Pseudomonas aeruginosa or Staph-

ylococcus infections in dogs, the higher end of the dosage range may

be preferable, pending susceptibility results.


U.S.{R-96}—


11.4 mg (Rx) [Dicural Tablets].


136 mg (Rx) [Dicural Tablets].

Canada{R-99}—




136 mg (Rx) [Dicural Tablets].



manufacturer.


ENROFLOXACIN

SUMMARY OF DIFFERENCESPharmacology/pharmacokinetics: Biotransformation—Enrofloxacin is

de-ethylated to form ciprofloxacin; therapeutic concentrations of

ciprofloxacin can be reached with dosing calculated to achieve

effective enrofloxacin concentrations.

Side/adverse effects: Cats—Retinal degeneration (acute blindness, mydri-

asis) has been reported with enrofloxacin at doses higher than 5 mg

per kg of body weight a day.






ENROFLOXACIN ORAL SOLUTIONUsual dose:

Escherichia coli infection1—Chickens and turkeys: Oral, 25 to 50 parts

enrofloxacin per million parts water (ppm), administered as the only

source of drinking water for three to seven days{R-3}.

Fowl cholera1—Turkeys: Oral, 25 to 50 parts enrofloxacin per million

parts water (ppm), administered as the only source of drinking water

for three to seven days{R-3}.

Note: Medication should be initiated as soon after diagnosis as

possible{R-3}. The effects of environment and other factors on water

consumption should be considered{R-3}.


U.S.—


32.3 mg per mL (Rx) [Baytril 3.23% Concentrate Solution].

Canada—



Withdrawal times:

U.S.{R-3}—

Withdrawal time

Species Meat (days)

Chickens, turkeys 2

Note: This product is not labeled for use in laying hens producing eggs for

human consumption{R-3}.



manufacturer. Store container in an upright position{R-3}.

Preparation of dosage form: Product labeling recommends that stock

solutions be prepared fresh daily{R-3}. Once stock solution or medicated

water is prepared, protect it from freezing or direct sunlight{R-3}. This

product should not be used in automatic water proportioners if the

water hardness is greater than 196 parts per million (ppm){R-3}. Gal-

vanized metal watering systems or containers should not be used to

carry or store this product and chlorinators should not be operated

while administering this medication{R-3}.

Additional information: Product labeling recommends that poultry

litter from treated flocks spread on agricultural land be incorporated

into the soil whenever possible{R-3}. It also recommends a 10- to 14-

day interval between flocks, top dressing with clean litter, and an

increased frequency of removal of caked litter from each house{R-3}.

Poultry litter from treated flocks should not be used in cattle feed.

Caution: Those who administer medication should avoid contact with

their eyes and skin. If contact occurs, immediately flush eyes with

copious amounts of water for 15 minutes. In case of dermal contact,

wash skin with soap and water. Consult a physician if irritation persists

following exposure. In human beings, there is a risk of user photo-

sensitization within a few hours of significant exposure to quinolones.


ENROFLOXACIN TABLETSUsual dose: Bacterial infections—

Cats: Oral, 5 mg per kg of body weight a day{R-1}. The dose may be

administered as a single daily dose or divided into two equal doses

administered every twelve hours{R-1}.

Note: The above dose recommendation is based on risk of retinal

damage in cats administered doses higher than 5 mg/kg{R-1}.

Dogs: Oral, 5 to 20 mg per kg of body weight a day{R-1}. The dose may

be administered as a single daily dose or divided into two equal doses

administered every twelve hours{R-1}.

Note: For empiric treatment of probable Pseudomonas aeruginosa or

Staphylococcus infections in dogs, the higher end of the dosage

range may be preferable, pending susceptibility results.

Note: [Bustards]1—Although the safety and efficacy have not been

established, an oral dose of 10 mg per kg of body weight every twelve

hours has been suggested for the treatment of susceptible bacterial

infections, based on pharmacokinetic data{R-41}.

Cats—Although the efficacy has not been established, if enrofloxacin is

used in the treatment of [Bartonella henselae]1 infection or [hemobart-

onellosis]1 in cats, the USP Veterinary Medicine Committee currently

recommends the administration of 5 mg per kg of body weight a day.

Limited research studies on the treatment of these infections have

sometimes led to recommendations for higher dosages; however, there

is concern about the occurrence of retinal degeneration when a dose of

20 mg/kg is administered to cats and the lack of information on relative

risk of retinal damage at dosages between 5 and 20 mg/kg a day.

The following information is provided in the event other therapies

have failed:

[An oral dose of 5 to 8 mg per kg of body weight every twelve hours

(10 to 16 mg per kg a day) for four to six weeks has been

recommended in the treatment of Bartonella henselae infection, based

on efficacy trials{R-72}.]1

[An oral dose of 5 to 10 mg per kg of body weight every twenty-four

hours for two weeks has been recommended in the treatment of

hemobartonellosis{R-148}. Cats apparently completely cleared of infec-

tion were treated with the high end of this dosage range; however, the

low end is the labeled dose.1

Dogs—Although the efficacy has not been established, an oral dose of 5

mg per kg of body weight every twenty-four hours for fifteen days has

been used in the treatment of [ehrlichiosis]1 in dogs, based on a

comparative, randomized therapeutic trial{R-77}.

An oral dose of 3 mg per kg of body weight every twelve hours for

seven days has been used in the treatment of [Rocky Mountain spotted

fever]1 in dogs, based on a controlled therapeutic trial using disease

models{R-84}.

[Ducks, pet or research]1—In the U.S., for use only in animals not to be

used for food production: Although the safety and efficacy have not

been established, an oral dose of 10 mg per kg of body weight a day

has been suggested for the treatment of susceptible bacterial infections

in Muscovy ducks, based on pharmacokinetic data{R-42}.

[Foals]1—Although the safety and efficacy have not been established,

an oral dose of 2.5 mg per kg of body weight once a day for eight days

has been recommended in the treatment of susceptible bacterial



infections in foals. Because of the potential for arthropathy in

immature animals, use is recommended in foals only when other

antimicrobials are inappropriate{R-85}.

[Horses]1—In the U.S., for use only in animals not to be used for food

production—Although the safety and efficacy have not been estab-

lished, an oral dose of 7.5 to 10 mg per kg of body weight every

twenty-four hours has been recommended{R-24–27; 93}. Tablets have

been crushed and suspended in water for administration{R-27} or

ground into a powder and mixed in sugar syrup{R-25}.

[Pacu, red]1—Although the safety and efficacy have not been

established, administration of enrofloxacin by immersion of fish in a

bath of a 2.5 mg per liter solution of enrofloxacin for five hours, every

twenty-four to forty-eight hours, has been suggested for the treatment

of susceptible bacterial infections in red pacu fish, based on pharma-

cokinetic data{R-44}.

[Parrots, African grey]1—Although the safety and efficacy have not

been established, an oral dose of 7.5 to 30 mg per kg of body weight

every twelve hours has been suggested in the treatment of susceptible

bacterial infections in African grey parrots, based on pharmacokinetic

data{R-39}. The risk of side effects increases with higher doses; polyuria

and polydipsia have been reported at the 30 mg per kg of body weight

dose{R-39}.

[Rabbits, pet or research]1—In the U.S., for use only in animals not to be

used for food production: Although the safety and efficacy have not been

established, an oral dose of 5 mg per kg of body weight every twelve

hours for fourteen days has been recommended in the treatment of

pasteurellosis in rabbits, based on clinical efficacy studies{R-67–69}.


U.S.—


22.7 mg (Rx) [Baytril Tablets (film-coated){R-1}; Baytril Taste Tabs].

68 mg (Rx) [Baytril Tablets (film-coated){R-1}; Baytril Taste Tabs].

136 mg (Rx) [Baytril Taste Tabs{R-1}].

Canada—


15 mg (Rx) [Baytril Tablets{R-102}].












ENROFLOXACIN INJECTIONUsual dose:

Bacterial infections—

Dogs:

Intramuscular—2.5 mg per kg of body weight{R-86}. U.S. product

labeling recommends that this be an initial single dose, to be

followed by a dosage regimen using enrofloxacin tablets; this was

based on studies establishing the efficacy of 2.5 mg per kg of body

weight every twelve hours{R-104}. Canadian product labeling

recommends a maximum of six doses{R-102}.

[Intravenous]1—5 to 20 mg per kg of body weight a day. The dose

may be administered as a single daily dose or divided into two

equal doses administered every twelve hours. To avoid adverse

effects, the drug should be diluted in a 2X volume of saline and

infused over 15 to 20 minutes.


Staphylococcus infections, the higher end of the dosage range may

be preferable, pending susceptibility results.

[Cats]1:

Intramuscular—2.5 mg per kg of body weight. For dogs, U.S. product

labeling recommends that this be an initial single dose, to be

followed by a dosage regimen using enrofloxacin tablets; this was

based on studies establishing the efficacy of 2.5 mg per kg of body

weight every twelve hours{R-104}.

Intravenous—5 mg per kg of body weight a day. The dose may be

administered as a single daily dose or divided into two equal doses

administered every twelve hours. To avoid adverse effects, the

drug should be diluted in a 2X volume of saline and infused over

15 to 20 minutes.

Note: The above dosage recommendations are based on risk of retinal

damage in cats administered doses higher than 5 mg/kg a day{R-1}.

Bacterial pneumonia1—Cattle: Subcutaneous, 7.5 to 12.5 mg per kg of

body weight as a single dose or 2.5 to 5 mg per kg of body weight

every twenty-four hours for three to five days{R-2}.

Note: Up to at least 1 week of age, calves eliminate enrofloxacin and

the active metabolite ciprofloxacin more slowly than do adult

cattle{R-13}.

Note: [Bustards]1—Although the safety and efficacy have not been

established, a parenteral dose of 10 mg per kg of body weight every

twelve hours or 15 mg per kg of body weight every twenty-four hours

has been suggested for the treatment of susceptible bacterial infections,

based on pharmacokinetic data{R-41}.

[Camels]1—Although the safety and efficacy have not been established,

an intramuscular or subcutaneous dose of 2.5 mg per kg of body


susceptible bacterial infections in camels, based on pharmacokinetic

data{R-45}.

[Ducks, pet or research]1—In the U.S., for use only in animals not to be

used for food production: Although the safety and efficacy have not

been established, a parenteral dose of 10 mg per kg of body weight

every twenty-four hours has been suggested for the treatment of

susceptible bacterial infections, based on pharmacokinetic data{R-42}.

[Emus, pet or research]1—In the U.S., for use only in animals not to

be used for food production: Although the safety and efficacy have

not been established, a parenteral dose of 2.2 mg per kg of body


susceptible bacterial infections in emus, based on pharmacokinetic

data{R-43}.

[Horses]1—In the U.S., for use only in animals not to be used for food

production: Although the safety and efficacy have not been estab-

lished, an intravenous dose of 5 mg per kg of body weight every

twenty-four hours has been used in the treatment of susceptible



bacterial infections in horses.{R-93} If a dose higher than 5 mg per kg of

body weight is administered, slow injection by indwelling catheter is

recommended to avoid adverse effects; dilution in 500 mL of sterile

saline solution may also be necessary{R-136}.

[Llamas, pet or research]1—In the U.S., for use only in animals not to

be used for food production: Although the safety and efficacy have not

been established, an intramuscular or subcutaneous dose of 5 mg per

kg of body weight every twelve hours has been suggested for the

treatment of susceptible bacterial infections in llamas, based on

pharmacokinetic data{R-45}.

[Oryx]1—Although the safety and efficacy have not been established, a

parenteral dose of 1.6 mg per kg of body weight every six to eight


infections in oryx, based on pharmacokinetic data{R-45}.

[Pacu, red]1—Although the safety and efficacy have not been

established, an intramuscular dose of 5 mg per kg of body weight

every forty-eight hours has been suggested for the treatment of

susceptible bacterial infections in the red pacu, based on pharmaco-

kinetic data{R-44}.

[Parrots, African grey]1—Although the safety and efficacy have not

been established, an intramuscular dose of 7.5 to 30 mg per kg of body

weight every twelve hours has been suggested in the treatment of

susceptible bacterial infections in African grey parrots, based on

pharmacokinetic data{R-39}. The risk of side effects increases with

higher doses; polyuria and polydipsia have been reported with the 30

mg per kg of body weight dose{R-39}.

[Pigs, potbellied and minature]1—In the U.S., for use only in animals

not to be used in food production: Although the safety and efficacy

have not been established, an oral dose of 10 mg per kg of body weight

every 24 hours has been recommended for pigs in the treatment of

susceptible bacterial infections, based on pharmacokinetic data{R-25}.

See also the Withdrawal times section.

[Pythons]1—Although the safety and efficacy have not been estab-

lished, an intramuscular dose of 10 mg per kg of body weight as a

loading dose followed by 5 mg per kg of body weight every forty-eight


infections in pythons{R-48}. For the treatment of Pseudomonas species

infections, 10 mg per kg of body weight every forty-eight hours has

been suggested, based on pharmacokinetic data{R-48}.

[Rabbits, pet or research]1—In the U.S., for use only in animals not to

be used in food production: Although the safety and efficacy have not

been established, a subcutaneous dose of 5 mg per kg of body weight

every twelve hours for fourteen days has been recommended in the

control of pasteurellosis in rabbits{R-33; 67–69}.

[Sheep, pet or research]1—In the U.S., for use only in animals not to

be used in food production—Although the safety and efficacy have

not been established, an intramuscular or intravenous dose of 2.5 to

5 mg per kg of body weight every twenty-four hours has been

recommended for sheep in the treatment of susceptible bacterial

infections{R-28}, based on pharmacokinetic data. See also the

Withdrawal times section.


U.S.—


22.7 mg per mL (Rx) [Baytril Injectable Solution 2.27%{R-104}].

100 mg per mL (Rx) [Baytril 100 Injectable Solution{R-2}].

Note: The more concentrated enrofloxacin injection, 100 mg per mL, is

labeled only for use in cattle{R-2}, while the less concentrated

injection, 22.7 mg per mL, is labeled for use in dogs{R-104}. The

product used for cattle contains different excipients than the

injectable solution for dogs; the safety of using the cattle product

in other species has not been demonstrated{R-2}.

Canada—


50 mg per mL (Rx) [Baytril Injectable Solution{R-102}].

Withdrawal times:

U.S.{R-2}—Federal law prohibits the extralabel use of enrofloxacin in

food-producing animals and restricts enrofloxacin to use by or on the

order of a licensed veterinarian.

Withdrawal time

Species Meat (days)

Cattle 28

Note: Not labeled for use in cattle intended for dairy production or in

calves to be processed for veal{R-2}. Subcutaneous injection can cause a

local tissue reaction that is transient but can cause trim loss of edible

tissue at slaughter{R-2}.

Canada—There is no established withdrawal time for cattle in Canada

because enrofloxacin is not labeled for use in cattle.


15 and 30 �C (59 and 86 �F), unless otherwise specified by manufac-

turer. Protect from direct sunlight{R-1; 2}. Do not freeze{R-1; 2}.

Caution: Those who administer medication should avoid contact with

their eyes and skin. If contact occurs, immediately flush eyes with

copious amounts of water for 15 minutes. In case of dermal contact,

wash skin with soap and water. A physician should be consulted if

irritation persists following exposure. In human beings, there is a risk

of user photosensitization within a few hours of significant exposure to

quinolones.




MARBOFLOXACIN

ORAL DOSAGE FORMS

MARBOFLOXACIN TABLETSUsual dose: Bacterial infections—Cats and dogs: Oral, 2.75 to 5.5 mg

per kg of body weight every twenty-four hours{R-97; 101}.

Note: The 2.75 mg per kg dose was found to be clinically effective in

the treatment of susceptible skin, soft tissue, and urinary tract

infections{R-97}.

For empiric treatment of probable Pseudomonas aeruginosa or Staph-

ylococcus infections, the higher end of the dosage range may be

preferable, pending susceptibility results.




U.S.{R-97}—


25 mg (Rx) [Zeniquin Tablets].




Canada{R-101}—








manufacturer.


ORBIFLOXACIN




ORBIFLOXACIN TABLETSUsual dose: Bacterial infections—Cats and dogs: Oral, 2.5 to 7.5 mg per



Staphylococcus infections, the higher end of the dosage range may be

preferable, pending susceptibility results.

Note: [Horses]1—In the U.S., for use only in animals not to be used

for food production: Although the safety and efficacy have not

been established, an oral dose of 5 to 7.5 mg per kg of body

weight every twenty-four hours has been recommended for the

treatment of susceptible bacterial infections in adult horses{R-133}.

Tablets have been crushed and suspended in water for adminis-

tration{R-133}.


U.S.{R-98}—


5.7 mg (Rx) [Orbax Tablets].


68 mg (Rx) [Orbax Tablets].

Canada{R-100}—




68 mg (Rx) [Orbax Tablets].

Packaging and storage: Store between 2 and 30 �C (36 and 86

�F){R-98}, unless otherwise specified by manufacturer.




Developed: 02/17/00

Revised: 09/30/02

Interim revision: 03/28/03

Table 1. Pharmacology/Pharmacokinetics—Intravenous administration.

Species Dose (mg/kg)

Compound

measured

Elimination half-life

(hours)

VolDArea (L/kg)

VolD, Steady state

(L/kg)

Clearance

(mL/min/kg)

CIPROFLOXACIN

Dogs{R-117} 2.5 to 10 2.2 3.06 ± 0.75 O.26 ± 0.11

ENROFLOXACIN

Birds

Bustards{R-41} 10 Enrofloxacin 5.63 ± 0.54 2.82 ± 0.37 2.98 ± 0.32 5.71 ± 0.41

Chickens{R-30} 10 Enrofloxacin 4.16 ± 0.19 2.20 ± 0.17 2.43 ± 0.19 2.2 ± 0.09

Chickens{R-31} 10 Enrofloxacin 10.29 ± 0.45 4.31 ± 0.15 2.77 ± 0.09 4.8 ± 0.17

Emus{R-43} 2.2 Enrofloxacin 3.33 1.49 ± 0.52 1.62 ± 1.04 6.00 ± 3.17

Calves{R-13}

One day of age 2.5 Enrofloxacin 6.61 ± 1.12 1.81 ± 0.1 3.16 ± 0.5

2.5 Ciprofloxacin 9.19 ± 1.46

One week old 2.5 Enrofloxacin 4.87 ± 0.68 2.28 ± 0.14 6.5 ± 1


Cattle, lactating{R-11} 5 Enrofloxacin 1.68 ± 0.18 > 1{R-15} 5 Enrofloxacin 1.09 2.1 21

5 Ciprofloxacin 2.67

Camels{R-45} 2.5 Enrofloxacin 3.6 ± 0.89 1.13 ± 0.126 4.61 ± 1.03

Cats{R-22} 5 Enrofloxacin 6.7 ± 2.3 4.0 ± 0.3 9.5 ± 0.7

Ciprofloxacin 6.1 ± 1.3

Dogs{R-5} 1.25 to 5 Enrofloxacin > 3 9{R-16} 5 Enrofloxacin 2.4 ± 0.87 7.0 ± 6.4 27.1 ± 16.2

5 Ciprofloxacin 3.9 ± 1.3{R-18} 5.8 Enrofloxacin 4.4 ± 1 3.7 ± 0.6 10.88 ± 0.68




Table 1. (Contd.)

Species Dose (mg/kg)

Elimination half-life

(hours)

VolDArea (L/kg)

VolD, Steady state

(L/kg)

Clearance

(mL/min/kg)

Fish

Salmon{R-37} 10 Enrofloxacin 34.2 6.1 2.3

Trout, rainbow{R-36} 5 Enrofloxacin 24.4 3.22 2.77 1.52

10 Enrofloxacin 30.4 2.56 2.34 0.97

Foals{R-85} 5 Enrofloxacin 17.10 ± 0.09 2.49 ± 0.43 2.47 ± 0.04 1.73 ± 0.001

Horses{R-27} 2.5 Enrofloxacin 5.94 1.22 ± 0.07 2.33 ± 0.17

5 Enrofloxacin 6.09 0.77 ± 0.11 1.50 ± 0.17{R-24} 5 Enrofloxacin 4.4 2.3 ± 0.5 0.51 ± 0.11

Ciprofloxacin 5.1 ± 2.1

Llamas{R-46} 5 Enrofloxacin 3.38 ± 2.13 3.46 ± 0.98 11.7 ± 3.5

Oryx (antelope){R-47} 1.3 Enrofloxacin 0.69 ± 0.46 0.80 ± 0.3 12.07 ± 7.12

Pigs{R-29} 5 Enrofloxacin 3.9 ± 0.5 6.17 ± 1.83

Neonatal rabbits{R-35}

1 day of age 7.5 (IP) Enrofloxacin 5.01 2.03 4.7

8 days 7.5 (IP) Enrofloxacin 8.5 2.02 2.7

16 days 7.5 (IP) Enrofloxacin 6.1 2.52 4.8

30 days 7.5 (IP) Enrofloxacin 2 6.52 33.8

Rabbits{R-32} 5 Enrofloxacin 2.19 ± 0.29 4.4 ± 1.4 3.4 ± 0.9 22.8 ± 6.8{R-33} 5 Enrofloxacin 2.5 2.12 0.93 10.1{R-33} 7.5 Enrofloxacin 1.9 3.97 ± 0.9 23.9 ± 3.5

Sheep{R-46} 2.5 Enrofloxacin 3.73 ± 0.44 3.02 ± 0.22 9.17 ± 2.3

MARBFLOXACIN

Dogs{R-108} 2 10.8 ± 1.3 1.33 ± 0.10 1.60 ± 0.21{R-115} 2 12.4 ± 2.6 1.90 ± 0.76 1.37 ± 0.19{R-97} 5.5 9.5 ± 0.7 1.19 ± 0.08 1.56 ± 0.13

ORBIFLOXACIN

Cats{R-98} 2.5 4.5 ± 1.8 1.3 ± 0.13

Dogs{R-98} 2,5 5.4 ± 1.1 1.2 ± 0.2

Note: IP = Intraperitoneal

Table 2. Pharmacology/Pharmacokinetics: Other systemic data

Species

Dose

(mg/kg)/Route,

Water

temperature Number of doses

Compound

measured

Absorption

half-life

(hours)

Peak

serum

concentration

(mcg/mL)

Time to peak

serum

concentration

(hours)

Half-life,

terminal

(hours)

Bioavailability

(%)

CIPROFLOXACIN

Dogs{R-134} 10/PO Single 1.4 (fr. graph) 2(fr. graph) 4.91 ± 1.26

20/PO Single 2.8 (fr. graph) 2(fr. graph) 5.30 ± 1.15

40/PO Single 6.6 (fr. graph) 6(fr. graph) 8.86 ± 2.78{R-118} 11/PO Single 4.65

Every 12 hours

for 7 doses

7.48

23/PO Single 3.95

Every 12 hours

for 7 doses

5.68 ± 0.54 1.53 ± 0.52 4.48

DIFLOXACIN

Dogs{R-96} 5/PO Single 1.8 2.8 9.3 >80{R-113} 5/PO Single 1.11 ± 0.07 2.84 ± 0.31 6.94 ± 0.54{R-116} 5/PO Every 24 hours

for 5 days

1.79 ± 0.11 2.17 ± 0.26 8.52 ± 0.84

ENROFLOXACIN

Birds

Bustards{R-41} 10/IM Single Enrofloxacin 0.23 ± 0.07 2.75 ± 0.11 1.72 ± 0.19 6.39 ± 1.49 97

10/PO Single Enrofloxacin 0.17 ± 0.02 1.84 ± 0.16 0.66 ± 0.05 6.80 ± 0.79 62

Chickens{R-30} 10/IM Single Enrofloxacin 1.83 ± 0.04 2.45 ± 0.1 1.43 ± 0.02 4.06 ± 0.06 88

10/PO Single Enrofloxacin 0.92 ± 0.05 1.69 ± 0.08 2.52 ± 0.08 4.29 ± 0.1 60

10/SC Single Enrofloxacin 0.36 ± 0.02 2.41 ± 0.06 1.46 ± 0.06 4.48 ± 0.04 81

Chickens{R-31} 10/PO Single Enrofloxacin 0.67 ± 0.05 2.44 ± 0.64 1.64 ± 0.04 14.23 ± 0.46 64

Ducks{R-42} 10/IM Single Enrofloxacin 1.67 ± 0.29 0.94 ± 0.18

10/PO Single Enrofloxacin 0.99 ± 0.08 1.38 ± 0.18

Parrots{R-39} 15/IM Single Enrofloxacin 3.87 ± 0.27 1 2.31 ± 0.09

3/PO Single Enrofloxacin 0.31 ± 0.11 4 2.59 ± 0.36 48

15/PO Single Enrofloxacin 1.12 ± 0.11 2 2.52 ± 0.33

30/PO Single Enrofloxacin 1.69 ± 0.23 4 2.74 ± 0.37



Table 2. (Contd.)

Species

Dose

(mg/kg)/Route,

Water


Compound

measured

Absorption

half-life

(hours)

Peak

serum

concentration

(mcg/mL)

Time to peak

serum

concentration

(hours)

Half-life,

terminal

(hours)

Bioavailability

(%)

Camels{R-45} 2.5/IM Single Enrofloxacin 0.76 ± 0.46 1.44 ± 0.8 1 6.36 ± 2.03 85

2.5/PO Single Enrofloxacin Not detected

2.5/SC Single Enrofloxacin 0.5 ± 0.12 1.23 ± 0.27 1 10.58 ± 6.78 92

Cats {R-22} 5/PO

Every 24 hours

for 10 days

Enrofloxacin 0.2 ± 0 1.67 ± 0.11 0.6 ± 0.1

5/PO Every 24 hours

for 10 days

Ciprofloxacin 0.13 ± 0.01 2.3 ± 0.5

Cattle, lactating 5/IM Single Enrofloxacin 0.73 ± 0.12 2.4 ± 0.68 5.9 ± 1.44 82{R-45} 5/SC Single Enrofloxacin 0.98 ± 0.2 3.2 ± 1.09 5.55 ± 0.52 137

Dogs{R-8} 1.25/IM Single Enrofloxacin 1.09 0.5{R-5} 1.25/PO Single Enrofloxacin 0.25 (from graph) 1 > 3

2.5/PO Single Enrofloxacin 1 (from graph) 1 > 3

5/PO Single Enrofloxacin 1.5 (from graph) 1 > 3{R-16} 5/PO Single Enrofloxacin 1.16 ± 0.6 0.9 ± 0.8 2.4 ± 0.5

5/PO Single Ciprofloxacin 0.29 ± 0.19 3.6 ± 0.3 3.9 ± 3.2{R-17} 2.75/PO Every 12 hours

for 7 doses

Enrofloxacin 1.03 ± 0.28 1.88 ± 0.72 3.07 ± 1

5.5/PO Every 12 hours

for 7 doses

Enrofloxacin 2.45 ± 0.84 1.55 ± 0.56 4.04 ± 0.78

11/PO Every 12 hours

for 7 doses

Enrofloxacin 4.56 ± 0.49 2.31 ± 0.82 4.26 ± 1.03

{R-18} 5.8/PO Every 12 hours

for 15 days

Enrofloxacin 1.43 ± 0.12 1.8 ± 0.2 83

5.8/PO Every 12 hours

for 15 days

Ciprofloxacin 0.36 ± 0.03 2.2 ± 0.3

{R-21} 2.5/SC Single Active drug* 0.6 ± 0.03 2.25 ± 0.09 2.61 ± 0.15

25/SC Single Active drug 5.77 ± 0.41 3.92 ± 0.16 6.42 ± 0.29

Fish

Pacu{R-44} 5/IM Single Enrofloxacin 1.64 ± 0.92 4 28.9

Ciprofloxacin 0.05 ± 0.01 4 53

5/PO Single Enrofloxacin 0.8 ± 1.17 36

Ciprofloxacin 0.02 ± 0.008 36

2.5 mg per Single 5 hour Enrofloxacin 0.17 ± 0.04 2

Liter/bath dose Ciprofloxacin 0.024 ± 0.001 2

immersion

Salmon{R-38} 5/PO, 9.7 �C Single Enrofloxacin 0.53 2.87 48.2 46

10/PO, 9.7 �C Single Enrofloxacin 0.27 0.42 105.1 49{R-37} 10/PO (in feed),

10 �CSingle Enrofloxacin 1.54 6 56

Trout{R-36} 5/PO, 10 �C Single Enrofloxacin 0.37 24 44.2 35

10/PO, 10 �C Single Enrofloxacin 0.55 6 29.5 24

50/PO, 10 �C Single Enrofloxacin 1.93 6 29.5 17

Foals{R-85} 10/PO Single Enrofloxacin 2.12 ± 0.51 2.20 ± 2.17 18.4 ± 0.06 42

Horses{R-24} 5/IM Single Enrofloxacin 9.9{R-5} 2.5/PO Every 12 hours

for 3 days

Enrofloxacin 0.89 2.62 ± 0.61 1 ± 0.35 57

5/PO Every 12 hours

for 3 days

Enrofloxacin 0.8 5.97 ± 1.56 1.25 ± 0.43 63

{R-5} 5/PO Single Enrofloxacin 1.85 ± 0.86 0.92 ± 0.59 7.75

Mice{R-21} 1.56/SC Single Active drug 0.57 ± 0.06 0.37 ± 0.02 0.3 ± 0.03

25/SC Single Active drug 6.44 ± 0.46 0.54 ± 0.06 0.54 ± 0.04

Pigs{R-39} 10/PO Single Enrofloxacin 1.4 ± 0.5 4.8 ± 1.9 83

Pythons{R-24} 5/IM Single Enrofloxacin 1.66 ± 0.42 5.75 ± 1.47 6.37

5/IM Single Ciprofloxacin 0.35 ± 0.21 13 ± 5.9

Rabbits{R-32} 5/IM Single Enrofloxacin 0.07 ± 0.02 3.04 ± 0.34 0.17 1.81 ± 0.3 92{R-33} 5/PO Single Enrofloxacin 0.452 2.3 2.41 61

5/SC Single Enrofloxacin 2.07 0.9 72

Sheep{R-28} 2.5/IM Single Enrofloxacin 0.78 ± 0.07 1.25 ± 0.11 3.65 ± 0.31 85

2.5/IM Single Ciprofloxacin 0.14 ± 0.02 5 ± 0.45 9.98 ± 2.33

MARBOFLOXACIN

Cats{R-97} 6.2/PO Single 4.8 ± 0.7 1.2 ± 0.6 12.7 ± 1.1

Dogs{R-115} 1/PO Single 0.38 ± 0.35 0.83 ± 0.26 1.7 ± 1.2 14.7 ± 4.9 �100

2/PO Single 0.53 ± 0.24 1.38 ± 0.40 2.5 ± 1.2 14.0 ± 4.9

4/PO Single 0.68 ± 0.59 2.93 ± 0.58 2.0 ± 1.1 12.5 ± 2.7



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Table 2. (Contd.)

Species

Dose

(mg/kg)/Route,

Water


Compound

measured

Absorption

half-life

(hours)

Peak

serum

concentration

(mcg/mL)

Time to peak

serum

concentration

(hours)

Half-life,

terminal

(hours)

Bioavailability

(%)

Dogs 1/SC Single 0.20 ± 0.11 0.78 ± 0.08 1.0 ± 0.6 11.5 ± 1.9 �100

2/SC Single 0.20 ± 0.07 1.52 ± 0.13 0.9 ± 0.2 13.0 ± 3.3

4/SC Single 0.25 ± 0.12 3.04 ± 0.24 1.3 ± 0.61 13.4 ± 2.8{R-113} 2/PO Single 1.47 ± 0.09 1.83 ± 0.17 9.07 ± 1.90{R-108} 2/PO Every 24 hours

for 8 days

1.37 ± 0.21 1.97 ± 0.97

{R-108} 2.7/PO Single 2.0 ± 0.2 1.5 ± 0.3 10.7 ± 1.6

5.6/PO Single 4.2 ± 0.5 1.8 ± 0.3 10.9 ± 0.6 94

ORBIFLOXACIN

Cats{R-98} 2.5/PO Single 2.06 ± 0.6 1 ± 0.45 5.52 ± 2.66

Dogs{R-98} 2.5/PO Single 2.3 ± 0.3 0.77 ± 0.45 5.6 ± 1.1 97{R-113} 2.5/PO Single 1.37 ± 0.01 2.42 ± 0.36 7.14 ± 0.42

Mares{R-133} 7.5/PO Single 2.41 ± 0/03 1.5 9.06 ± 1.33

Note IM¼Intramuscular administration, PO¼Oral administration, SC¼Subcutaneous administration.

*These agar plate diffusion assays used bacillus subtills or Klebsiella pneumoniae as the test organism and, therefore, measured enrofloxacin, cigrofloxacin, and any other

unidentified metabolites with antimicrobial activity against it.



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LINCOSAMIDES Veterinary—Systemic

This monograph includes information on the following: Clindamycin;

Lincomycin.


For veterinary-labeled products—AmTech Clindamycin Hydrochloride Lincomix 50 Feed Medication

Capsules [Clindamycin] [Lincomycin]

AmTech Clindamycin Hydrochloride Lincomix Injectable

Oral Liquid [Clindamycin] [Lincomycin]

Antirobe [Clindamycin] Lincomix Injectable Solution [Lincomycin]

Antirobe Aquadrops [Clindamycin] Lincomix 44 Premix [Lincomycin]

Clincaps [Clindamycin] Lincomix 110 Premix [Lincomycin]

ClindaCure [Clindamycin] Lincomix Soluble Powder [Lincomycin]

Clinda-Guard [Clindamycin] Lincomycin 44 Premix [Lincomycin]

Clindrops [Clindamycin] Lincomycin 44G Premix [Lincomycin]

Lincocin [Lincomycin] Lincomycin 110 Premix [Lincomycin]

Lincocin Aquadrops [Lincomycin] Lincomycin 110G Premix [Lincomycin]

Lincocin Injectable [Lincomycin] Lincomycin Soluble [Lincomycin]

Lincocin Sterile Solution Moorman’s LN 10

[Lincomycin] [Lincomycin]

Lincomix 20 Feed Medication nvClindamycin Capsules

[Lincomycin] [Clindamycin]







GENERAL CONSIDERATIONSThe lincosamides have activity against many gram-positive bacteria and

many anaerobic bacteria, but are not effective against most gram-

negative organisms.

Lincomycin has been shown to have efficacy against Staphylococcus

species, Streptococcus species (except Streptococcus faecalis), Erysipelo-

thrix insidiosa, Leptospira pomona, and Mycoplasma species.{R-3; 4} The

activity of lincomycin against obligate anaerobes is seldom addressed

in published literature. According to the National Committee for

Clinical Laboratory Standards in the United States, clindamycin is the

class antibiotic for the lincosamide family and the clindamycin disk is

used in in vitro testing to assess susceptibility to both clindamycin and

lincomycin{R-31}. Therefore, it is presumed that most anaerobes

susceptible to clindamycin would likewise be susceptible to lincomycin,

provided compensations for potency and kinetic disposition are

made{R-39}.

Clindamycin has a spectrum of activity that includes Staphylococcus

species, Streptococcus species (except Streptococcus faecalis), and Myco-

plasma species, as well as anaerobic organisms, such as Bacteroides

species, Fusobacterium species, Clostridium perfringens (but not neces-

sarily other clostridia), Actinomyces species, Peptostreptococcus species,

and many Propionibacterium species.{R-1}

ACCEPTEDDysentery, swine (treatment)—Pigs: Lincomycin hydrochloride for med-

icated feed and soluble powder are indicated in the treatment and

control of swine dysentery caused by susceptible organisms.{R-21; 28;

38; 41; 63}

Enteritis, necrotic (treatment)—Chickens: Lincomycin hydrochloride for

medicated feed1 and soluble powder are indicated in the control of

necrotic enteritis in chickens caused by susceptible organisms, such as

Clostridium perfringens.{R-22; 28; 38; 41; 42; 56}

Growth promotion and feed efficiency, increased—Chickens and pigs1:

Lincomycin hydrochloride for medicated feed is indicated for increased

weight gain in growing-finishing pigs and for increased weight gain

and feed efficiency in broiler chickens.{R-38; 63}

Joint infections (treatment)—Pigs: Lincomycin injection is indicated in

the treatment of infectious arthritis caused by susceptible organisms,

including susceptible Staphylococcus species, Streptococcus species,

Erysipelothrix rhusiopathiae, and Mycoplasma species.{R-4; 5}

Metritis (treatment)1—Dogs: Lincomycin injection, syrup, and tablets are

indicated in the treatment of metritis caused by susceptible organ-

isms.{R-3}

Osteomyelitis (treatment)—Dogs: Clindamycin capsules and oral solution

are indicated in the treatment of osteomyelitis caused by susceptible

organisms,{R-1; 2} such as Staphylococcus aureus.{R-35; 36; 62}

Periodontal infections (treatment)—

Cats: Clindamycin oral solution is indicated in the treatment of

periodontal infections caused by susceptible bacteria{R-2; 30; 62}.

Dogs: Clindamycin capsules and oral solution are indicated in

the treatment of periodontal infections caused by susceptible

bacteria.{R-1; 2; 62}

Porcine proliferative enteropathies (treatment)1—Pigs: Lincomycin hydro-

chloride for medicated feed is indicated in the control of porcine prolif-

erative enteropathies (ileitis) caused by Lawsonia intracellularis{R-38}.

Pneumonia, bacterial (treatment)—Pigs: Lincomycin injection1 and

lincomycin hydrochloride for medicated feed are indicated in the

treatment of pneumonia caused by susceptible Mycoplasma species.{R-4;

5; 63}

Respiratory tract infections (treatment)1—

Cats: Lincomycin injection, syrup, and tablets are indicated in the


organisms.{R-3}

Dogs: Lincomycin injection, syrup, and tablets are indicated in the


organisms.{R-3}

Skin infections (treatment)1—Dogs: Lincomycin injection, syrup, and

tablets are indicated and [clindamycin]{R-20} is effective in the

treatment of skin infections, such as pustular dermatitis, caused by

susceptible organisms.{R-3} To assure efficacy in the treatment of skin

infections, underlying primary disorders, such as allergic inhalant

dermatitis, should be identified and controlled{R-1; 30}.

Soft tissue infections (treatment)—

Cats: Clindamycin oral solution and lincomycin injection1, syrup1, and

tablets1 are indicated in the treatment of soft tissue infections,

including abscesses, caused by susceptible organisms.{R-2; 3; 30; 62}

LINCOSAMIDES Veterinary—Systemic 109


Dogs: Clindamycin capsules and oral solution, and lincomycin injec-

tion1, syrup1, and tablets1 are indicated in the treatment of soft tissue

infections, including abscesses and infected wounds, caused by

susceptible organisms.{R-1–3; 62}

ACCEPTANCE NOT ESTABLISHEDMetritis (treatment)—Dogs: There are insufficient data to confirm

specifically the efficacy of [clindamycin]1 in the treatment of metritis

in dogs; however, because lincomycin is indicated for this use,

clindamycin can be expected to be at least equally effective{R-15}.

Osteomyelitis (treatment)—[Cats]1: There are insufficient data to confirm

specifically the efficacy of clindamycin in the treatment of osteomyelitis

in cats; however, the safety and predicted antimicrobial efficacy are

supported by research.{R-24; 53; 54; 57}

Respiratory tract infections (treatment)—Cats and dogs: There are

insufficient data to confirm specifically the efficacy of [clindamycin]1

in the treatment of respiratory infections in cats and dogs; however,

because lincomycin is indicated for this use, clindamycin can be

expected to be at least equally effective{R-15}.

[Abscesses, laryngeal (treatment)]1—Cattle: There are insufficient data to

confirm the efficacy and safety of lincomycin injection in the treatment

of laryngeal abscesses in cattle. Reports of three cases showed a good

response in laryngeal abscesses treated{R-44}.

[Arthritis, septic (treatment)]1—Cattle and sheep: There are insufficient

data to confirm the efficacy and safety of lincomycin injection in the

treatment of septic arthritis in cattle and sheep. Case reports of a dozen

cases show a resolution of clinical signs in approximately one-half of

refractory joint infections treated (mixed infections of streptococci,

staphylococci, and Corynebacterium pyogenes).{R-44}

[Mastitis (treatment)]1—Cattle: There are insufficient data to confirm the

efficacy and safety of parenteral lincomycin in the treatment of mastitis

in cattle; however, there is evidence of distribution into milk in

ruminants in concentrations sufficient to treat susceptible infections

that are refractory to other antimicrobials.{R-14; 58} Although no

studies have been performed to demonstrate the efficacy of lincomycin

against gram-positive mastitis pathogens such as Staphylococcus or

Corynebacterium, given lincomycin’s distribution and the susceptibility

patterns of these organisms, lincomycin therapy may be a legitimate

choice when other conventional treatments are deemed unlikely to be

effective.

[Toxoplasmosis (treatment)]1—Cats: There are insufficient data to

establish the efficacy of clindamycin in the treatment of Toxoplasma

gondii infection in cats; however, it is considered to have fewer side

effects and perhaps to be more effective in treating some aspects of the

disease than is pyrimethamine{R-17–19; 34; 59}. Clindamycin may not

effectively clear organisms from areas such as the central nervous

system in chronically infected animals{R-18} and, in some cases, may

be ineffective in resolving clinical signs involving the eye.{R-17}


Withdrawal times have been established for the use of lincomycin in

chickens and pigs (see the Dosage Forms section). Lincomycin is not

labeled for use in chickens producing eggs for human consump-

tion.{R-4; 38; 42}

Canada—

Withdrawal times have been established for the use of lincomycin in

chickens and pigs (see the Dosage Forms section). Lincomycin is not

labeled for use in chickens producing eggs for human consump-

tion.{R-6; 41}

CHEMISTRYSource:

Clindamycin hydrochloride—7(S)-Chloro derivative of lincomycin.{R-27}

Lincomycin hydrochloride—Produced by the growth of a member of the

lincolnensis group of Streptomyces lincolnensis (family Streptomyceta-

ceae).{R-3}

Chemical name:

Clindamycin hydrochloride—l-threo-alpha-d-galacto-octopyranoside,

methyl 7-chloro-6,7,8-trideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl)-

carbonyl]amino]-1-thio-, (2s-trans)-, monohydrochloride.{r-25}

Lincomycin hydrochloride—d-erythro-alpha-d-galacto-octopyranoside,

methyl 6,8-dideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl)carbonyl]-

amino]-1-thio-, monohydrochloride, monohydrate, (2s-trans)-.{r-25}

Molecular formula:

Clindamycin hydrochloride—C18H33ClN2O5S Æ HCl.{R-25}

Lincomycin hydrochloride—C18H34N2O6SÆHCl Æ H2O.{R-25}

Molecular weight:

Clindamycin hydrochloride—461.44.{R-25}

Lincomycin hydrochloride—461.01.{R-25}

Description:

Clindamycin Hydrochloride USP—White or practically white, crystalline

powder. Is odorless or has a faint mercaptan-like odor. Is stable in the

presence of air and light. Its solutions are acidic and are dextrorota-

tory.{R-26}

Lincomycin Hydrochloride USP—White or practically white, crystalline

powder. Is odorless or has a faint odor. Is stable in the presence of air

and light. Its solutions are acid and are dextrorotatory.{R-26}

Lincomycin Hydrochloride Injection USP—Clear, colorless to slightly

yellow solution, having a slight odor.{R-26}

pKa:

Clindamycin—7.7.{R-14}

Lincomycin—7.6.{R-14}

Solubility:

Clindamycin Hydrochloride USP—Freely soluble in water, in dimethyl-

formamide, and in methanol; soluble in alcohol; practically insoluble

in acetone.{R-26}

Lincomycin Hydrochloride USP—Freely soluble in water; soluble in

dimethylformamide; very slightly soluble in acetone.{R-26}


Mechanism of action/effect: The lincosamides inhibit protein

synthesis in susceptible bacteria by binding to the 50 S ribosomal

subunits of bacterial ribosomes and preventing peptide bond forma-

tion.{R-43} The lincosamides are usually considered bacteriostatic{R-43};

however, when clindamycin is present at sufficient concentra-

tions, it may act as a bactericidal antibiotic against sensitive organ-

isms.{R-43}

Other actions/effects: Clindamycin may interfere with the attachment

and entry of Toxoplasma gondii tachyzoites into host cells.{R-33}



110 LINCOSAMIDES Veterinary—Systemic


Absorption: Oral absorption of the lincosamides is rapid, but orally

administered lincomycin is less well absorbed than clindamycin.

Clindamycin—Oral absorption of clindamycin is high{R-1}and is

unaffected by food.

Lincomycin—Oral absorption of lincomycin may be greatly reduced by

the presence of food in the stomach.{R-48}

Oral absorption:

Pigs—20 to 50%.{R-49}

Rats—45 to 60%.{R-49}

Intramuscular absorption: Lincomycin hydrochloride is rapidly ab-

sorbed after intramuscular administration.{R-3}

Distribution: Clindamycin and lincomycin are widely distributed into

most tissues, including respiratory tissue, soft tissue, bones, and

joints{R-13; 23; 24}. The lincosamides are weak bases (commercial

preparations are acidic) and are very lipid soluble at physiologic pH

(7.4). Tissue concentrations may be higher than serum concentra-

tions.{R-48} Small amounts are distributed into pancreatic and prostatic

secretions.{R-48} There is evidence that clindamycin hydrochloride

accumulates in polymorphonuclear granulocytes.{R-20} The lincosa-

mides do not penetrate cerebrospinal fluid (CSF) well;{R-24} however, in

healthy cats, concentrations of clindamycin in brain tissue after 10

days of therapy were 10 to 20% of serum concentration and were

consistently higher than CSF concentrations.{R-24}

Volume of distribution (area)—Intravenous administration:

Clindamycin phosphate—Dogs: 1.4 L per kg (L/kg).{R-16}

Lincomycin—Calves:

6 weeks of age—1 to 1.2 L/kg (healthy calves or calves with induced

Pasteurella haemolytica pneumonia).{R-46; 47}

9 months of age—1.3 L/kg.{R-47}

Protein binding:

Clindamycin—Sheep: Moderate (40 to 50%).{R-14; 51}

Lincomycin—

Cows—Low to moderate (26 to 46%).{R-52}

Sheep—Low (30 to 40%).{R-14; 51}

Note: Human protein binding of lincomycin decreases with increased

plasma concentrations; the range of protein binding varies from low

to high.

Biotransformation:

Clindamycin—Active metabolites of clindamycin measured in urine

along with parent compound include N-demethylclindamycin and

clindamycin sulfoxide.{R-1}

Lincomycin—The percentage of administered lincosamide metabolized

by the liver is unknown.{R-49}

Half-life: Elimination—Intravenous administration:

Clindamycin phosphate—Dogs: 3.2 hours.{R-16}

Lincomycin:

Calves, newborn to 2 weeks of age—3 hours.{R-47}

Calves, 4 weeks to 9 months of age—2 to 2.5 hours.{R-46; 47}

Time to peak concentration:

Clindamycin hydrochloride—

Dogs: Oral—1.3 hours (single dose of 5.5 to 11 mg per kg of body

weight [mg/kg]).{R-1}

Sheep: Intramuscular—1 hour (dose of 20 mg/kg).{R-14}

Clindamycin phosphate—Dogs: Intramuscular—1 hour (dose of 11 mg/

kg).{R-16}

Lincomycin hydrochloride—

Dogs:

Intramuscular—10 minutes to 2 hours (dose of 22 mg/kg).{R-3}

Oral—2 to 4 hours (dose of 22 mg/kg).{R-3}

Sheep: Intramuscular—1 hour (dose of 20 mg/kg).{R-14}

Serum concentrations:

Peak serum concentration—

Clindamycin hydrochloride: Sheep—Intramuscular: 13.8 mcg/mL

(single dose of 20 mg/kg).{R-14}

Clindamycin phosphate: Dogs—Intramuscular: 5.3 mcg/mL (dose of

11 mg/kg){R-16}.

Lincomycin: Sheep—Intramuscular: 12.6 mcg/mL (dose of 20 mg/

kg).{R-14}

Serum concentration after multiple dosing—Clindamycin hydrochloride

(sample 12 hours after the last dose of an every-twelve-hour oral dose

for 10 days): Cats—{R-53}

3.5 mcg/mL (dose of 5.5 mg/kg).

5.4 mcg/mL (dose of 11 mg/kg).

6.5 mcg/mL (dose of 22 mg/kg).

Duration of action:

Clindamycin—Cats and dogs:{R-15}

12 hours, with an oral dose of 11 mg/kg.

24 hours, with an oral dose of 22 mg/kg.

Lincomycin—Dogs: Oral—For gram-positive organisms: 6 to 8 hours (22

mg/kg dose).{R-3}

Note: Efficacy studies based on a 22 mg/kg dose every 12 hours for 3

weeks in dogs show that duration of action for lincomycin is sufficient

for it to be effective when administered every twelve hours{R-20}.

Elimination:

Parent drug and metabolites are primarily excreted in the urine and the

bile.{R-1; 3; 24; 48; 49} Small amounts are excreted in intestinal contents

and pancreatic and prostatic fluids.{R-48}

When lincomycin is administered orally to dogs, 77% of the dose is

excreted in the feces and 14% of the dose is excreted in the urine.

When administered intramuscularly, 38% of the dose is excreted in the

feces and 49% is excreted in the urine.{R-3}

Less clindamycin than lincomycin is excreted in the urine.{R-50}

Clearance—Intravenous administration:

Clindamycin phosphate—Dogs: 5.3 mL per minute per kg (mL/min/

kg).{R-16}

Lincomycin—Calves:

6 weeks of age—3.9 to 8.1 mL/min/kg.{R-46}

9 months of age—4.4 mL/min/kg.{R-46}


CROSS-SENSITIVITY AND RELATED PROBLEMSAnimals sensitive to clindamycin may be sensitive to lincomycin and the

reverse may also be true.

SPECIES SENSITIVITYChinchillas, guinea pigs, hamsters, horses, ponies, and rabbits:{R-7–9; 11} The

use of oral clindamycin or lincomycin is generally contraindicated in



these species because of the risk of altering the gastrointestinal

microflora and causing serious or fatal enterocolitis and diarrhea.

Overgrowth of organisms such as Clostridium or Salmonella species has

been suspected as the cause in many species. Cecal Escherichia coli, but

not Clostridium species, have been cultured from rabbits showing

adverse effects after lincomycin exposure.{R-9} Contamination of feed

with lincomycin at or below feed additive concentrations used for

pigs has caused severe or fatal diarrhea in rabbits, ponies, and

horses.{R-7–9}

Ruminants: Ruminants exposed to oral lincomycin have also been

reported to have side effects such as anorexia, ketosis, and sometimes

severe diarrhea,{R-10; 12; 55} possibly caused by overgrowth of

nonsusceptible bacteria; however, case reports and research studies

using parenteral lincomycin have reported that only a small percent-

age of treated animals developed diarrhea and/or decreased milk

production.{R-44–47}

Feeds contaminated with 3 to 24 parts per million (ppm) of lincomycin

have caused ketosis and diarrhea in dairy cows{R-12}. After treatment

with oral lincomycin for Campylobacter, two thirds of a range flock of

sheep died; however, the flock had a history of Salmonella infections

and grazed in an area with some oxalate-containing range plants, both

of which were believed to play a role in the losses.{R-10}

PREGNANCY/REPRODUCTIONThe safety of clindamycin in pregnant or breeding animals has not been

established.{R-1; 2; 13}

When lincomycin was given to pregnant dogs at 50 mg per kg of body

weight (mg/kg) per day, no evidence of teratogenic effects on the

embryos was seen.{R-3} Also, 75 mg of lincomycin per kg a day

administered to breeding male and female rats during a breeding cycle

had no observed effect on breeding or teratogenic effects on

offspring.{R-3}

LACTATIONClindamycin and lincomycin are distributed into milk{R-14} in therapeu-

tic concentrations.{R-40} With constant serum lincomycin concentra-

tions, milk concentrations range from 2.5 to 6.2 times the serum

concentration, depending on the pH of the milk.{R-14}

PEDIATRICSNo evidence of side effects was noted in newborn puppies and rats given

lincomycin at doses of 30 to 90 mg/kg a day.{R-3}







medication.

» Anesthetics, hydrocarbon inhalation, such as:

Enflurane

Halothane

Isoflurane

Methoxyflurane, or

» Neuromuscular blocking agents

(concurrent use of these medications with clindamycin or lincomycin

may enhance the neuromuscular blockade, resulting in respiratory

depression or paralysis;{R-1; 48} caution is also recommended during

surgery or the postoperative period; treatment with cholinesterase

agents or calcium salts may help reverse the blockade{R-48})




included in the human monographs Clindamycin (Systemic) and

Lincomycin (Systemic) in USP DI Volume I; these drug interactions

are intended for informational purposes only and may or may not be

applicable to the use of clindamycin and lincomycin in the treatment of

animals:

Antidiarrheals, adsorbent

(concurrent use of kaolin- or attapulgite-containing antidiarrheals

with oral lincomycin may significantly decrease absorption of oral

lincomycin; concurrent use with oral clindamycin may delay

absorption; concurrent use should be avoided or patients should be

advised to take adsorbent antidiarrheals not less than 2 hours before

or 3 to 4 hours after oral lincosamides)

Antidiarrheals, antiperistaltic

(antiperistaltic agents, such as opiates, difenoxin, diphenoxylate, or

loperamide, may prolong or worsen pseudomembranous colitis by

delaying toxin elimination)

Antimyasthenics

(concurrent use of medications with neuromuscular blocking action

may antagonize the effect of antimyasthenics on skeletal muscle;

temporary dosage adjustments of antimyasthenics may be necessary

to control symptoms of myasthenia gravis during and following

concurrent use)

Chloramphenicol or

Erythromycins

(may displace clindamycin or lincomycin from or prevent their

binding to 50 S subunits of bacterial ribosomes, thus antagonizing

the effects of the lincosamides; concurrent use is not recommended)

Opioid (narcotic) analgesics

(respiratory depressant effects of drugs with neuromuscular blocking

activity may be additive to central respiratory depressant effects of

opioid analgesics, possibly leading to increased or prolonged respi-

ratory depression or paralysis [apnea]; caution and careful monitor-

ing of the patient are recommended)




Note: No significant laboratory value alterations have been reported in

animals. Human laboratory value alterations have been reported and

are included in this monograph.



humans, and are included in the human monographs Clindamycin

(Systemic) and Lincomycin (Systemic) in USP DI Volume I; these




only and may or may not be applicable to the use of clindamycin and

lincomycin in the treatment of animals:


Alanine aminotransferase (ALT [SGPT]), serum, and

Alkaline phosphatase, serum, and

Aspartate aminotransferase (AST [SGOT]), serum







problems exist:

» Hepatic function impairment, severe

(because clindamycin and lincomycin are metabolized by the

liver{R-1; 49}, it is possible that severe hepatic function impairment

could prolong the half-lives of these medications; adjustments in

dosage might be required{R-37})

» Hypersensitivity to clindamycin or lincomycin{R-1; 3}

(sensitivity or cross-sensitivity may occur)

» Renal function impairment, severe

(lincomycin is eliminated by the kidneys of dogs to a greater degree

than is clindamycin{R-50}; very severe renal impairment may require

dosage adjustments)







prior to lincosamide administration to determine pathogen suscep-

tibility)

Note: The clindamycin disk is used for in vitro susceptibility testing to

assess susceptibility to both clindamycin and lincomycin{R-31}.

SIDE/ADVERSE EFFECTSNote: The pseudomembranous colitis reported in people as an adverse

reaction to lincosamides as well as the colitis and diarrhea side effects

reported in chinchillas, guinea pigs, horses, rabbits, and ruminants are

considered to be caused by overgrowth of resistant organisms.

Resistant Clostridium species are suspected, but other organisms or

even other mechanisms may also be involved.{R-8–11; 48}

The following side/adverse effects have been selected on the basis of their




Chinchillas, guinea pigs, hamsters, horses, ponies, and rabbits{R-7–9; 11}

Enterocolitis (anorexia; collapse; dehydration; diarrhea, watery and

sometimes hemorrhagic)


Cats and dogs

Anorexia; diarrhea; vomiting{R-1; 3; 54}

Note: Anorexia, diarrhea, and vomiting in cats and dogs are believed to

result from local irritation because side effects have not been seen

with parenteral treatment. Side effects are more likely with higher

doses.{R-54}

Ruminants

With lincomycin—

Anorexia; decreased milk production; diarrhea; ketosis

Note: Anorexia, decreased milk production, ketosis, and severe diarrhea

have been reported to be most likely in ruminants administered

lincomycin orally.{R-10; 12} However, some animals may develop

adverse effects with parenterally administered lincomycin.{R-45}

Incidence unknown

All species

Hypersensitivity reactions{R-1; 3}


Cats

Lip smacking—with clindamycin oral solution{R-53}; saliva-

tion—with clindamycin oral solution{R-53}


Pigs

Anal swelling{R-41; 42}; diarrhea{R-41; 42}—transient; irritable

behavior{R-41; 42}; skin reddening{R-41; 42}

Note: Anal swelling, diarrhea, irritable behavior, and skin reddening are

generally self-limiting within 5 to 8 days.




included in the human monographs Clindamycin (Systemic) and

Lincomycin (Systemic) in USP DI Volume I; these side/adverse effects


applicable to the use of clindamycin and lincomycin in the treatment of

animals:


Gastrointestinal disturbances; pseudomembranous colitis


Fungal overgrowth; hypersensitivity; neutropenia; thrombocy-

topenia

Indicating possible pseudomembranous colitis and the need for medical

attention if they occur after medication is discontinued

Abdominal or stomach cramps and pain, severe; abdominal

tenderness; diarrhea, watery and severe, which may also be

bloody; fever





drug manufacturer.



CLIENT CONSULTATIONMedication should be administered for the full length of time prescribed.

Any signs of anorexia, diarrhea, or vomiting should be reported to the

veterinarian.

CLINDAMYCIN

SUMMARY OF DIFFERENCESIndications: Has wider spectrum of activity than does lincomycin.

Indicated in the treatment of osteomyelitis, periodontal infections, and

soft tissue infections. Used in the treatment of skin infections.

Pharmacology/pharmacokinetics: Highly absorbed after oral administra-

tion. Absorption is unaffected by the presence of food in the stomach.





in terms of the clindamycin base (not the hydrochloride salt).

CLINDAMYCIN HYDROCHLORIDE CAPSULES USPUsual dose:

Osteomyelitis—Dogs: Oral, 11 to 33 mg (base) per kg of body weight

every twelve hours{R-1}.

Periodontal infections and soft tissue infections—Dogs: Oral, 5.5 to 33

mg (base) per kg of body weight every twelve hours{R-1}.

[Skin infections]1—Dogs: Oral, 11 mg (base) per kg of body weight

every twenty-four hours.{R-20}

Note: The above dose for the treatment of skin infections in dogs is

based upon a clinical comparative efficacy study of clindamycin

and lincomycin{R-20}.


U.S.{R-1; 6}—


25 mg (base) (Rx) [AmTech Clindamycin Hydrochloride Capsules;

Antirobe; Clincaps; generic].





300 mg (base) (Rx) [Antirobe].

Canada{R-2; 6}—


25 mg (base) (OTC) [Antirobe; nvClindamycin Capsules].





manufacturer. Preserve in tight containers.

USP requirements: Preserve in tight containers. Contain an amount of

clindamycin hydrochloride equivalent to the labeled amount of clin-

damycin, within –10% to +20%. Meet the requirements for Identifi-

cation, Dissolution (80% in 30 minutes in phosphate buffer [pH 6.8] in

Apparatus 1 at 100 rpm), Uniformity of dosage units, and Water (not


CLINDAMYCIN HYDROCHLORIDE ORAL SOLUTION USPUsual dose:

Osteomyelitis; or

[Skin infections]1—Dogs: See Clindamycin Hydrochloride Capsules USP.

Periodontal infections and soft tissue infections—

Cats: Oral, 11 to 33 mg (base) per kg of body weight every twenty-

four hours{R-1}.

Dogs: Oral, 5.5 to 33 mg (base) per kg of body weight every twelve

hours{R-1}.

Note: Cats—Based on dosing studies, the following dosages have been

used in cats for treatment of [osteomyelitis]1 and [skin infections]1:

Staphylococcal infections—Oral, 5.5 mg (base) per kg of body weight

every twelve hours.{R-53}

Anaerobic bacterial infections—Oral, 11 mg (base) per kg of body

weight every twelve hours or 22 mg per kg of body weight every

twenty-four hours.{R-53}

Based on clinical efficacy and pharmacokinetic studies, the following

dose has been used in cats for the treatment of [toxoplasmosis]1—Oral,

12.5 to 25 mg (base) per kg of body weight every twelve hours for two

to four weeks.{R-17; 18; 53; 54; 57; 59}


U.S.{R-6}—


25 mg (base) per mL (Rx) [AmTech Clindamycin Hydrochloride Oral

Liquid; Antirobe Aquadrops; ClindaCure; Clinda-Guard; Clindrops;

generic].

Canada{R-6}—


25 mg (base) per mL (Rx) [Antirobe Aquadrops].




USP requirements: Preserve in tight containers. Label oral solution to

indicate that it is intended for veterinary use only. Contains the

equivalent of the labeled amounts, within ±10%. Meets the require-

ments for Identification, Uniformity of dosage units, Deliverable vol-

ume, and pH (3.0–5.5){R-26}.

LINCOMYCIN

SUMMARY OF DIFFERENCESIndications: Indicated in the treatment of swine dysentery; growth

promotion and feed efficiency in chickens and pigs; joint infections in

pigs; metritis in dogs; pneumonia in pigs; respiratory tract infections in

cats and dogs; skin infections in dogs; and soft tissue infections in cats

and dogs. Indicated in the control of necrotic enteritis in chickens.

Pharmacology/pharmacokinetics: Oral lincomycin is less well absorbed

than intramuscular lincomycin; dosages are adjusted to compensate.

Elimination of lincomycin is affected to a greater extent by severe renal





function impairment than is clindamycin. Absorption is reduced by the

presence of food in the stomach.


expressed in terms of lincomycin base (not the hydrochloride salt).

LINCOMYCIN HYDROCHLORIDE FOR MEDICATED FEEDUsual dose:

Growth promotion—

Chickens: Oral, 2 to 4 grams (base) per ton of feed, fed as the only

ration.{R-38}

Pigs1: Oral, 20 grams (base) per ton of feed, fed as the only

ration.{R-38}

Mycoplasma pneumonia—Pigs: Oral, 200 grams (base) per ton of feed,

fed as the only ration for twenty-one days.{R-38}

Necrotic enteritis1—Chickens: Oral, 2 grams (base) per ton of feed, fed

as the only ration.{R-48}

Porcine proliferative enteropathies (control)1—Pigs: Oral, 100 grams

(base) per ton of feed, fed as the only ration for twenty-one days or

until signs of disease disappear. A dose of 40 grams (base) per ton of

feed, fed as the only ration, may follow the above dose or be used in

place of the 100-gram dose in animals that have not yet had

symptoms{R-38}.

Swine dysentery—Pigs:

Control—Oral, 40 grams (base) per ton of feed, fed as the only

ration.{R-38; 42}

Treatment—Oral, 100 grams (base) per ton of feed (approximately

4.4 to 8.8 mg [base] per kg of body weight), fed as the only ration

for twenty-one days or until signs of disease disappear.{R-38; 42}


U.S.{R-6}—


10 grams (base) per pound of premix (OTC) [Moorman’s LN 10].

20 grams (base) per pound of premix (OTC) [Lincomix 20 Feed

Medication].

50 grams (base) per pound of premix (OTC) [Lincomix 50 Feed

Medication].

Canada{R-6}—


44 grams (base) per kg of premix (OTC) [Lincomix 44 Premix;

Lincomycin 44 Premix; Lincomycin 44G Premix].

110 grams (base) per kg of premix (OTC) [Lincomix 110 Premix;

Lincomycin 110 Premix; Lincomycin 110G Premix].

Withdrawal times:

U.S.{R-38; 42}—

Withdrawal time

Species Meat (days)

Chickens 0

Pigs 0 or 6, depending on product

Canada{R-63}—

When mixed at 2.2 grams of lincomycin (base) per metric ton (1000 kg)

of feed for chickens and 44 grams (base) of lincomycin per metric ton

of feed for pigs:

Withdrawal time

Species Meat (days)

Chickens 0

Pigs 0

When mixed at 110 or 220 grams (base) of lincomycin per metric ton of

feed for pigs:

Withdrawal time

Species Meat (days)

Pigs 2



manufacturer. Store in a dry place.{R-42}

Preparation of dosage form: Premix should be mixed into the com-

plete feed following manufacturer’s directions to produce 2, 3, 4, 20,

40, 100, or 200 grams of lincomycin (base) per ton of feed.

Additional information:

Not for use in breeding swine or laying chickens.{R-38; 42}

In preparing feeds, appropriate cleanout procedures should be followed to

prevent cross-contamination of other feeds.{R-42}


LINCOMYCIN HYDROCHLORIDE SOLUBLE POWDERUSPUsual dose:

Necrotic enteritis—Chickens: Oral, 64 mg (base) per gallon of water,

administered as the only source of drinking water for seven days.{R-22;

28; 41; 56}

Swine dysentery—Pigs: Oral, 250 mg (base) per gallon of water

(approximately 8.4 mg [base] per kg of body weight) a day,

administered as the only source of drinking water for five to ten

days{R-28; 41}.


U.S.—{R-6}


400 mg (base) per gram of powder (OTC) [Lincomix Soluble Powder;

Lincosol Soluble Powder; generic].

Canada—{R-6}


400 mg (base) per gram of powder (OTC) [Lincomix Soluble Powder;

generic].

Withdrawal times:

U.S.—{R-41}

Withdrawal time

Species Meat (days)

Chickens 0




Canada—{R-28}

When mixed at concentrations of 16 mg of lincomycin (base) per liter

of water (61 mg per gallon) for chickens or 33 mg of lincomycin

(base) per liter of water (125 mg per gallon) for pigs:

Withdrawal time

Species Meat (days)

Chickens 0

Pigs 1



manufacturer.

Preparation of dosage form: Powder should be mixed into the

drinking water following manufacturer’s directions to produce 61, 64,

125, or 250 mg (base) per gallon. Fresh stock solutions should be

prepared on the day of use and unused medicated water discarded after

2 days.

USP requirements: Preserve in tight containers. Label it to indicate

that it is for veterinary use only. Contains an amount of Lincomycin

Hydrochloride equivalent to the labeled amount of lincomycin, within

±10%. Meets the requirements for Identification, Water, and Minimum

fill{R-26}.

LINCOMYCIN HYDROCHLORIDE SYRUP USPUsual dose:

Metritis1; or

Skin infections1—Dogs: Oral, 22 mg (base) per kg of body weight every

twelve hours or 15.4 mg (base) per kg of body weight every eight

hours.{R-3}

Respiratory tract infections1—Cats and dogs: Oral, 22 mg (base) per kg

of body weight every twelve hours or 15.4 mg (base) per kg of body

weight every eight hours{R-3}.

Soft tissue infections1—Cats and dogs: Oral, 22 mg (base) per kg of

body weight every twelve hours or 15.4 mg (base) per kg of body

weight every eight hours.{R-3}


U.S.{R-3; 6}—


50 mg (base) per mL (Rx) [Lincocin Aquadrops].

Canada{R-6}—



Packaging and storage: Store between 15 and 30 �C (59 and 86 �F),

unless otherwise specified by manufacturer.{R-33} Store in a tight

container.

USP requirements: Preserve in tight containers. Contains an amount

of Lincomycin Hydrochloride equivalent to the labeled amount of

lincomycin, within –10% to +20%, and one or more suitable colors,

flavors, preservatives, and sweeteners in water. Meets the require-

ments for Uniformity of dosage units (for syrup packaged in single-unit

containers), Deliverable volume (for syrup packaged in multiple-unit

containers), and pH (3–5.5).{R-26}

LINCOMYCIN HYDROCHLORIDE TABLETSUsual dose:

Metritis1; or

Skin infections1—Dogs: Oral, 22 mg (base) per kg of body weight every

twelve hours or 15.4 mg (base) per kg of body weight every eight

hours.{R-3}

Respiratory tract infections1—Cats and dogs: Oral, 22 mg (base) per kg

of body weight every twelve hours or 15.4 mg (base) per kg of body

weight every eight hours{R-3}.

Soft tissue infections1—Cats and dogs: Oral, 22 mg (base) per kg of

body weight every twelve hours or 15.4 mg (base) per kg of body

weight every eight hours.{R-3}


U.S.—{R-3; 6}


100 mg (base) (Rx) [Lincocin].



Canada—{R-6}





manufacturer.






in terms of lincomycin base (not the hydrochloride salt).

LINCOMYCIN INJECTION USPUsual dose:

Joint infections; or

Mycoplasma pneumonia1—Pigs: Intramuscular, 11 mg (base) per kg of

body weight every twenty-four hours for three to seven days.{R-4}

Metritis1; or

Skin infections1—Dogs: Intramuscular or intravenous, 22 mg (base)

per kg of body weight every twenty-four hours or 11 mg (base) per

kg of body weight every twelve hours.{R-3}

Respiratory tract infections1; or

Soft tissue infections1—Cats and dogs: Intramuscular or intravenous,

22 mg (base) per kg of body weight every twenty-four hours or 11

mg (base) per kg of body weight every twelve hours.{R-3}

Note: For intravenous administration, the injection should be diluted

with 5% glucose or normal saline and administered as a drip

infusion.{R-3}

Note: [Cattle]1—Although the safety and efficacy have not been

established for treatment of laryngeal abscesses, mastitis, or septic

arthritis in cattle, a dose of 5 mg (base) lincomycin per kg of body





weight every twenty-four hours, administered intramuscularly for five

to seven days, has been used.{R-44; 45; 60} For deep-seated or severe

infections, a dose of 10 mg (base) per kg of body weight every twelve

hours has been recommended{R-46; 48}.

[Sheep]1—Although the safety and efficacy have not been established

for treatment of septic arthritis in sheep, cases have been reported that

responded to 5 mg (base) per kg of body weight, administered

intramuscularly every twenty-four hours for three to five days.{R-44}


U.S.{R-6}—


25 mg (base) per mL (OTC) [Lincocin Injectable; Lincocin Sterile

Solution; Lincomix Injectable].

100 mg (base) per mL [Lincocin Sterile Solution [cats and dogs] (Rx);

Lincocin Sterile Solution [pigs] (OTC); Lincomix Injectable (OTC)].

300 mg (base) per mL (OTC) [Lincocin Injectable; Lincocin Sterile

Solution; Lincomix Injectable].

Canada{R-6}—


100 mg (base) per mL (OTC) [Lincomix Injectable Solution].

Withdrawal times:

Note: There are no established withdrawal times for cattle or sheep in the

United States or Canada because lincomycin is not approved for use in

these species.

If lincomycin is administered to cattle at the dose of 5 mg (base) per kg of

body weight for four days, evidence has been compiled by the Food Animal

Residue Avoidance Databank (FARAD) that suggests a milk withholding

time of 96 hours{R-45; 60} and a meat withdrawal time of 7 days{R-60}

would be sufficient to avoid residues. There is no available information to

make recommendations for withdrawal times when lincomycin is

administered to cattle concurrently with other medications or when doses

greater than 5 mg (base) per kg of body weight every twenty-four hours are

administered. Also, no recommendations can be made for withdrawal

times when lincomycin is administered to sheep. If it is necessary to

administer these doses, extended withdrawal times are recommended.

U.S.—{R-4}

Withdrawal time

Species Meat (days)

Pigs 2

Canada—{R-6}

Withdrawal time

Species Meat (days)

Pigs 2



manufacturer.


tainers, preferably of Type I glass. Contains benzyl alcohol as a pre-

servative. Contains an amount of Lincomycin Hydrochloride in Water

for Injection equivalent to the labeled amount of lincomycin, within –

10% to +20%. Meets the requirements for Bacterial endotoxins,

Sterility, pH (3.0–5.5), and Particulate matter, and for Injections.{R-26}

Developed: 07/17/96


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resulting from the feeding of antibiotic-contaminated feed. J Am Vet Med Assoc

1981; 179(4): 360–2.

8. Raisbeck MF, Holt GR, Osweiler GD. Lincomycin-associated colitis in horses.

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9. Maiers JD, Mason SJ. Lincomycin-associated enterocolitis in rabbits. J Am Vet

Med Assoc 1984 Sep 15; 185(6): 670–2.

10. Bulgin MS. Losses related to the ingestion of lincomycin-medicated feed in a

range sheep flock. J Am Vet Med Assoc 1988 Apr 15; 192(8): 1083–6.

11. Staempfli JR, Prescott JF, Brash ML. Lincomycin-induced severe colitis in

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168–9.

12. Rice DA, McMurray CH. Ketosis in dairy cows caused by low levels of

lincomycin in concentrated feed. Vet Rec 1983; 113: 495–6.

13. Havari J, Lincoln J. Pharmacologic features of clindamycin in dogs and cats.

J Am Vet Med Assoc 1989 Jul 1; 195(1): 124–5.

14. Ziv G, Sulman FG. Penetration of lincomycin and clindamycin into milk in

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16. Budsberg SC, Kemp DT, Wolski N. Pharmacokinetics of clindamycin phosphate

in dogs after single intravenous and intramuscular administrations. Am J Vet

Res 1992 Dec; 53(12): 2333–6.

17. Lappin MR, Greene CE, Winston S, et al. Clinical feline toxoplasmosis. J Vet Int

Med 1989 Jul/Sep; 3(3): 139–43.

18. Greene CE, Cook JR, Mahaffey EA. Clindamycin for treatment of Toxoplasma

polymyositis in a dog. J Am Vet Med Assoc 1985 Sep 15; 187(6): 631–4.

19. Dubey JP, Yeary RA. Anticoccidial activity of 2-sulfa-moyl-4,4-diaminophe-

nylsulfone, sulfadiazine, pyrimethamine and clindamycin in cats infected with

toxoplasma gondii. Can Vet J 1977 Mar; 18(3): 51–7.

20. Harvey RG, Noble WC, Ferguson EA. A comparison of lincomycin hydrochlo-

ride and clindamycin hydrochloride in the treatment of superficial pyoderma

in dogs. Vet Rec 1993; 132: 351–3.

21. Hamdy AH, Kratzer DD. Therapeutic effects of parenteral administration of

lincomycin on experimentally transmitted swine dysentery. Am J Vet Res

1981 Feb; 42(2): 178–82.

22. Hamdy AH, Thomas RW, Yancey RJ. Therapeutic effect of optimal lincomycin

concentration in drinking water on necrotic enteritis in broilers. Poult Sci

1983 Apr; 62(4): 589–91.

23. Swenson GH, Barbiers AR. The distribution and depletion of lincomycin in

swine following parenteral administration. International Pig Veterinary

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24. Brown SA, Zaya MJ, Dieringer TM, et al. Tissue concentrations of clindamycin

after multiple oral doses in normal cats. J Vet Pharm Ther 1990; 13(3):

270–7.





States Pharmacopeial Convention, Inc.; 2002. p. 471, 472, 1082, 1083,

2555, 2567.





27. Clindamycin package insert (Cleocin HCL, Pharmacia—US), Rev 9/02, Rec

1/14/03.

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Pharmacia—Canada). Downloaded 2/26/03 from www. pharmaciaah.ca.

29. Veterinary Advisory Panel meeting, 2/1/96.

30. Telecommunication (Upjohn—US), 1/30/96.

31. National Committee for Clinical Laboratory Standards publication. Villanova,

PA: NCCLS, 1983; 3(14): M2-T3, M31-P.

32. DSD comment, 8/91.

33. Blais J, Tardif C, Chamberland S. Effect of clindamycin on intracellular

replication, protein synthesis, and infectivity of Toxoplasma gondii. Antimic-

rob Agents Chemother 1993 Dec; 37(12): 2571–7.

34. Peterson JL, Willard MD, Lees GE, et al. Toxoplasmosis in two cats with inflam-

matory intestinal disease. J Am Vet Med Assoc 1991 Aug 15; 199(4): 473–6.

35. Braden TD, Johnson CA, Wakerell P, et al. Efficacy of clindamycin in the

treatment of Staphylococcus aureus osteomyelitis in dogs. J Am Vet Med Assoc

1988 Jun 15; 192(12): 1721–5.

36. Braden TD, Johnson CA, Gabel CL, et al. Posologic evaluation of clindamycin,

using a canine model of post-traumatic osteomyelitis. Am J Vet Res 1987;

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37. Mann HJ, Townsend RJ, Fuhs DW, et al. Decreased hepatic clearance of

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41. Lincomycin package insert (Lincomix Soluble Powder, Pharmacia Animal

Health—US). Downloaded from www.pharmaciaah.com on 8/9/02.

42. Lincomycin package insert (Lincomix 44, Pharmacia Animal Health—-

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CD ed. Port Huron, MI: North American Compendiums, Inc. 2002.

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44. Plenderleith RWJ. Treatment of cattle, sheep, and horses with lincomycin: case

studies. Vet Rec 1988; 122: 112–3.

45. Pearson A. Determination of milk withholding time in cattle following use of

intramuscular lincomycin. Vet Rec 1989; 125(24): 601.

46. Burrows GE, Barto PB, Weeks BR. Chloramphenicol, lincomycin and oxytet-

racycline disposition in calves with experimental pneumonic pasteurellosis.

J Vet Pharm Ther 1986; 9: 213–22.

47. Burrows GE, Barto PB, Martin B, et al. Comparative pharmacokinetics of

antibiotics in newborn calves: chloramphenicol, lincomycin, and tylosin. Am J

Vet Res 1983 Jun; 44(6): 1053–7.

48. Burrows GE. Pharmacotherapeutics of macrolides, lincomycins and spectino-

mycin. J Am Vet Med Assoc 1980 May 15; 176(10): 1072–7.

49. Hornish RE, Gosline RE, Nappier JM. Comparative metabolism of lincomycin in

the swine, chicken and rat. Drug Metab Rev 1987; 18(2 & 3): 177–214.

50. Brown RB, Barza M, Brusch JL, et al. Pharmacokinetics of lincomycin and

clindamycin phosphate in a canine model. J Infect Dis 1975 Mar; 131(3):

252–60.



52. Gyrd-Hansen N, Rasmussen F. Renal og mammaer ekskretion af lincomycin

hos hoer. Nordisk Veterinaermedicin 1967; 19: 11–6.

53. Brown SA, Dieringer TM, Hunter RP, et al. Oral clindamycin disposition after

single and multiple doses in normal cats. J Vet Pharm Ther 1989; 12:

209–16.

54. Greene CE, Lappin MR, Marks A. Effect of clindamycin on clinical, hemato-

logical and biochemical parameters in clinically healthy cats. J Am Anim Hosp

Assoc 1992 Jul/Aug; 28: 323–6.

55. Vomand KC, Sumano H. Adverse drug reactions in cattle. J Am Vet Med Assoc

1990 Oct; 197(7): 899–905.

56. Hamdy AH, Thomas RW, Kratzer DD, et al. Lincomycin dose response for

treatment of necrotic enteritis in broilers. Poult Sci 1983; 62: 585–8.

57. Jacobs G, Lappin M, Marks A, et al. Effect of clindamycin on Factor-VII activity

in healthy cats. Am J Vet Res 1989 Mar; 50(3): 393–5.

58. Brown MB, Scasserra AE. Antimicrobial resistance in streptococcal species

isolated from bovine mammary glands. Am J Vet Res 1990 Dec; 51(12):

2015–8.

59. Lappin MR, Roberts SM, Davidson MG, et al. Enzyme-linked immunosorbent

assays for the detection of Toxoplasma gondii-specific antibodies and antigens

in the aqueous humor of cats. J Am Vet Med Assoc 1992 Oct 1; 201(7):

1010–4.




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cia—Canada). Downloaded 2/26/03 from www. pharmaciaah.ca.

63. Lincomycin product overview for poultry and pigs (Lincomix 44, Pharma-

cia—Canada). Downloaded 2/26/03 from www. pharmaciaah.ca.



MACROLIDES Veterinary—Systemic

This monograph includes information on the following: Azithromycin;

Clarithromycin; Erythromycin; Tilmicosin; Tylosin.


For veterinary-labeled products—Erymycin-100 [Erythromycin

Thiocyanate]

Tylan 10 [Tylosin Phosphate]

Erythro-200 [Erythromycin Base] Tylan 40 [Tylosin Phosphate]

Gallimycin [Erythromycin Phosphate] Tylan 50 [Tylosin Base]

Gallimycin-50 [Erythromycin

Thiocyanate]

Tylan 100 [Tylosin Phosphate]

Gallimycin-100 [Erythromycin Base] Tylan 200 [Tylosin Base]

Gallimycin-200 [Erythromycin Base] Tylan Soluble [Tylosin Tartrate]

Gallimycin PFC [Erythromycin

Phosphate]

Tylocine 200 [Tylosin Base]

Gallistat [Erythromycin Phosphate] Tylosin 10 Premix [Tylosin Phosphate]

Micotil [Tilmicosin Phosphate] Tylosin 40 Premix [Tylosin Phosphate]

Pulmotil 90 [Tilmicosin Phosphate] Tyloved [Tylosin Base]

Pulmotil Premix [Tilmicosin Phosphate]

For human-labeled products—Apo-Erythro [Erythromycin Base] Ery-Tab [Erythromycin Base]

Apo-Erythro E-C [Erythromycin Base] Erythro [Erythromycin Ethylsuccinate]

Apo-Erythro-ES [Erythromycin

Ethylsuccinate]

Erythrocin [Erythromycin Lactobionate;

Erythromycin Stearate]

Apo-Erythro-S [Erythromycin Stearate] Erythrocot [Erythromycin Stearate]

Biaxin [Clarithromycin] Erythromid [Erythromycin Base]

Biaxin XL [Clarithromycin] Ilosone [Erythromycin Estolate]

E-Base [Erythromycin Base] Ilotycin [Erythromycin Base;

Erythromycin Gluceptate]

E.E.S. [Erythromycin Ethylsuccinate] My-E [Erythromycin Stearate]

E-Mycin [Erythromycin Base] Novo-Rythro [Erythromycin

Ethylsuccinate]

Erybid [Erythromycin Base] Novo-rythro [Erythromycin Estolate;

Erythromycin Stearate]

ERYC [Erythromycin Base] Novo-rythro Encap [Erythromycin Base]

ERYC-250 [Erythromycin Base] PCE [Erythromycin Base]

ERYC-333 [Erythromycin Base] Wintrocin [Erythromycin Stearate]

EryPed [Erythromycin Ethylsuccinate] Zithromax [Azithromycin]







GENERAL CONSIDERATIONSMacrolides are considered bacteriostatic at therapeutic concentrations

but they can be slowly bactericidal, especially against streptococcal

bacteria; their bactericidal action is described as time-dependent. The

antimicrobial action of some macrolides is enhanced by a high pH and

suppressed by low pH, making them less effective in abscesses, necrotic

tissue, or acidic urine.{R-119}

Erythromycin is an antibiotic with activity primarily against gram-

positive bacteria, such as Staphylococcus and Streptococcus species,

including many that are resistant to penicillins by means of beta-

lactamase production. Erythromycin is also active against myco-

plasma and some gram-negative bacteria, including Campylobacter

and Pasteurella species.{R-1; 10–12} It has activity against some

anaerobes, but Bacteroides fragilis is usually resistant. Some strains

of Actinomyces and Chlamydia are inhibited by erythromycin.{R-1; 2}

Most Pseudomonas, Escherichia coli, and Klebsiella strains are resistant

to erythromycin{R-2}. Cross-resistance to the other macrolides can

also occur{R-1}.

Tilmicosin has in vitro activity against gram-positive organisms and

mycoplasma and is active against certain gram-negative organisms{R-53},

such as Haemophilus somnus{R-89}, Mannheimia (Pasteurella) haemoly-

tica, and Pasteurella multocida.{R-53} However, M. haemolytica is more

sensitive than P. multocida to tilmicosin. Other gram-negative organ-

isms tested{R-91}, including Enterobacter aerogenes, Escherichia coli,

Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella{R-99}, and

Serratia species, are very resistant to tilmicosin{R-91}. Some strains of

Actinomyces also are extremely resistant to tilmicosin{R-99}.

Tylosin has a spectrum of activity similar to that of erythromycin but is

more active than erythromycin against certain mycoplasmas{R-51;

105}.

Azithromycin, a macrolide labeled for human use, has some advan-

tages over erythromycin in the treatment of infections in animals,

including better oral absorption, a longer half-life, and a broader

spectrum of activity than erythromycin{R-120; 122}. However, the

activity of azithromycin against staphylococci is not as good as that

of erythromycin. Azithromycin concentrates in tissues, particularly

in leukocytes, macrophages and fibroblasts and is slowly released

from leukocytes{R-119; 121}. The intracellular reservoir of azithromy-

cin apparently produces effective drug concentrations in interstitial

fluids even after the plasma concentrations have declined below

detectable levels; plasma pharmacokinetic parameters have little

correlation to the in vivo efficacy of azithromycin. Azithromycin

can be delivered to infected tissues and early abscesses via

leukocytes.{R-119}

Clarithromycin, also labeled for human use, is tolerated better than

erythromycin by human patients, has a broader spectrum of activity

than erythromycin, and, like azithromycin, it also concentrates in

leukocytes. In dogs, clarithromycin has a shorter half-life than

azithromycin{R-119; 124} and there is limited information for its clinical

use in animals.

ACCEPTEDAbscesses, hepatic (prophylaxis)1—Cattle, beef: Tylosin phosphate for

medicated feed is indicated for reduction in incidence of hepatic

abscesses caused by susceptible Fusobacterium necrophorum and Acti-

nomyces pyogenes.{R-48; 49}

Atrophic rhinitis (treatment)1—Pigs: Tylosin phosphate for medicated

feed is indicated for maintaining weight gain and feed efficiency in the

presence of atrophic rhinitis infections.{R-49}

Arthritis, infectious (treatment)1—Pigs: Tylosin injection is indicated in

the treatment of swine arthritis caused by susceptible Mycoplasma

hyosynoviae.{R-51; 52}

Coryza, infectious (prophylaxis)—Chickens: Erythromycin thiocyanate for

medicated feed1 and [erythromycin phosphate powder for oral

solution] are indicated as aids in the prevention of infectious coryza

caused by susceptible organisms.{R-9; 54}

Coryza, infectious (treatment)—Chickens: Erythromycin phosphate pow-

der for oral solution is indicated as an aid in the control of infectious

MACROLIDES Veterinary—Systemic 119


coryza caused by susceptible organisms, including Haemophilus galli-

narum.{R-3; 9}

Diphtheria (treatment)1—Cattle, beef and nonlactating dairy: Tylosin

injection is indicated in the treatment of diphtheria caused by

susceptible Fusobacterium necrophorum.{R-51; 52}

Dysentery, swine (prophylaxis)—Pigs: Tylosin phosphate for medicated

feed is indicated in the prevention of swine dysentery{R-48; 49}.

Dysentery, swine (treatment)—Pigs: Tylosin phosphate for medicated

feed is indicated in the control of swine dysentery caused by susceptible

organisms.{R-48; 49} Tylosin injection is indicated in the treatment of

acute swine dysentery caused by susceptible Treponema hyodysenteriae,

when followed by appropriate feed or water medication.{R-51; 52}

Tylosin tartrate powder for oral solution is indicated in the control and

treatment of swine dysentery{R-50; 66}.

Enteritis (treatment)—

Piglets, one week of age or older: Erythromycin injection is indicated in

the treatment of scours, caused by susceptible organisms, in young

pigs{R-7; 111}.

Turkeys: Erythromycin phosphate powder for oral solution is indicated

in the control of enteritis (bluecomb) caused by susceptible organ-

isms.{R-3; 9}

Enterotoxemia (prophylaxis)—Lambs, newborn: Erythromycin injection

is indicated in the prevention of dysentery in lambs{R-7; 111}.

Erysipelas (treatment)—Pigs: Tylosin injection is indicated in the

treatment of erysipelas caused by susceptible Erysipelothrix rhusiopa-

thiae{R-51; 52}; however, penicillin is considered the primary treatment

of choice for this indication{R-88}.

Feed efficiency, improvement of1; or

Weight gain, increased rate1—

Chickens, including laying chickens: Tylosin phosphate for medicated

feed is indicated for increased rate of weight gain and improving feed

efficiency.{R-49}

Pigs: Tylosin phosphate for medicated feed is indicated for improving

feed efficiency and growth promotion{R-48; 49}.

Leptospirosis—Sows, farrowing: Erythromycin injection is indicated in

the management of leptospirosis in sows at farrowing time{R-7; 111}.

Metritis (treatment)—

Cattle, beef and nonlactating dairy: Erythromycin injection and tylosin

injection are indicated in the treatment of metritis caused by

susceptible organisms{R-7; 51; 52; 111}; however, therapeutic regi-

mens often emphasize evacuation of uterine contents as the primary

treatment.

Sows, at farrowing time: Erythromycin injection is indicated in the

treatment of metritis caused by susceptible organisms{R-7; 111};

however, therapeutic regimens often emphasize evacuation of

uterine contents as the primary treatment.


Cattle: Erythromycin injection is indicated in the treatment of

pneumonia and bovine respiratory disease caused by susceptible

bacteria, including Pasteurella multocida.{R-6; 7; 111} Tylosin injection

is indicated in the treatment of pneumonia and bovine respiratory

disease caused by susceptible bacteria, including Pasteurella multocida

and Actinomyces pyogenes.{R-51} Tilmicosin injection is indicated in

the control of bovine respiratory disease in cattle at high risk for

infection and in the treatment of bovine respiratory disease caused by

susceptible bacteria, including Mannheimia haemolytica{R-53}. In some

regions, tilmicosin has been more effective than oxytetracycline{R-75}

in clinical resolution of calf pneumonia.

Pigs: Erythromycin injection is indicated in the treatment of

respiratory syndrome (pneumonia, bronchitis, and rhinitis){R-7;

111}. Tilmicosin for medicated feed is indicated in the control of

swine respiratory disease associated with Actinobacillus pleuropneu-

moniae and Pasteurella multocida{R-107}; however, parenteral tilmic-

osin should not be administered to pigs because of the risk of

cardiovascular toxicity{R-53}. Tylosin injection is indicated in the

treatment of pneumonia caused by susceptible bacteria, including

P. multocida.{R-51; 52}

[Calves]: Tilmicosin injection is indicated in Canadian product labeling

for the treatment of bovine respiratory disease associated with

susceptible M. haemolytica or Pasteurella multocida during the first 30

days in the feedlot{R-65; 112}.

[Foals]1: Erythromycin is used in the treatment of pneumonia caused

by Rhodococcus equi{R-83}. Some clinicians recommend the use of

rifampin in combination with erythromycin in the treatment of this

infection{R-4; 13; 14}; however, comparative efficacy studies of

erythromycin administered with and without rifampin have not

been performed. See also Pneumonia under Acceptance not established

below.

[Lambs]: Tilmicosin injection is indicated in Canadian product labeling

for the treatment of pneumonic pasteurellosis in lambs associated

with susceptible M. haemolytica{R-65; 112}.

Pododermatitis (treatment)1—Cattle, beef and nonlactating dairy: Eryth-

romycin injection and tylosin injection are indicated in the treatment

of pododermatitis caused by susceptible organisms.{R-7; 51; 52; 111}

Proliferative enteropathy, porcine (prophylaxis and treatment)1—Pigs:

Tylosin phosphate for medicated feed is indicated in the prevention and

control of porcine proliferative enteropathy (ileitis) associated with

susceptible Lawsonia intracellularis{R-49}.

Respiratory disease, chronic (prophylaxis)1—Chickens and turkeys: Eryth-

romycin thiocyanate for medicated feed and [erythromycin phosphate

powder for oral solution] are indicated as aids in the prevention of

chronic respiratory disease.{R-54}

Respiratory disease, chronic (treatment)—

Chickens, broiler and replacement: Erythromycin thiocyanate for

medicated feed and erythromycin phosphate powder for oral solution

are indicated in the control of chronic respiratory disease in chickens

due to susceptible Mycoplasma gallisepticum.{R-3; 9; 54; 64} Tylosin

tartrate powder for oral solution{R-50; 66} is indicated in the control

of and as an aid in the treatment of chronic respiratory disease, and

tylosin phosphate for medicated feed1 is indicated as an aid in the

control of chronic respiratory disease caused by susceptible

M. gallisepticum.{R-49}

Turkeys: Erythromycin thiocyanate for medicated feed1 and [erythro-

mycin phosphate powder for oral solution] are indicated for

reduction of lesions and to decrease the severity of chronic

respiratory disease.{R-9; 54; 64}

Respiratory tract infections, bacterial (treatment)—

Pigs: Erythromycin injection is indicated in the treatment of respiratory

syndrome (bronchitis, pneumonia, and rhinitis){R-7; 111}. Tilmicosin

for medicated feed is indicated in the control of swine respiratory

disease associated with Actinobacillus pleuropneumoniae and Pasteu-

rella multocida{R-107}; however, parenteral tilmicosin should not

be administered to pigs because of the risk of cardiovascular

toxicity{R-53}.

Sheep: Erythromycin injection is indicated in the treatment of upper

respiratory tract infections{R-7; 111}.

120 MACROLIDES Veterinary—Systemic


Sinusitis, infectious (treatment)—Turkeys: Tylosin tartrate powder for

oral solution is indicated to maintain weight gain and feed efficiency in

the presence of infectious sinusitis caused by susceptible M. gallisept-

icum.{R-50}

[Enteritis, Campylobacter (treatment)]1—Dogs: Erythromycin stearate is

used in the treatment of diarrhea believed to be caused by susceptible

Campylobacter species. Erythromycin treatment stops the shedding of

Campylobacter in the feces; however, shedding often recurs shortly after

discontinuation of therapy.{R-10–12} See also Enteritis, Campylobacter

under Acceptance not established below.

[Pyoderma (treatment)]1—Dogs: Erythromycin tablets are used in the

treatment of pyoderma caused by susceptible Staphylococcus species.

However, because drug-induced vomiting is a common side effect of

administration, erythromycin is not considered the treatment of

choice.{R-42–44}

[Synovitis, infectious (prophylaxis)]—Chickens and turkeys: Erythromycin

phosphate powder for oral solution is indicated in the management of

infectious synovitis{R-9}.

ACCEPTANCE NOT ESTABLISHED[Chlamydial infections (treatment)]1—Cats: There are no clinical studies

to document the effectiveness of azithromycin in the treatment of

chlamydial infections in cats. In vitro studies and clinical trials of

azithromycin in urinary and respiratory tract chlamydial infections in

human patients have demonstrated efficacy{R-33–35; 113} and a

pharmacokinetic study of azithromycin in cats allows for prediction

of potentially effective dosing regimens{R-120}.

[Colitis, chronic (treatment)]1—Dogs: There are insufficient data to

establish the efficacy of tylosin in the treatment of chronic colitis in

dogs and there is no available information on the mechanism of action

for alleviation of colitis. However, tylosin tartrate powder for oral

solution has been used in the U.S. in the treatment of chronic colitis in

dogs. The use of tylosin in the treatment of colitis is typically reserved

for patients that are not responsive to other forms of therapy, such as

diet change, and for patients with chronic colitis for which specific

causes have been ruled out.{R-84–86; 101; 102}

[Cryptosporidiosis (treatment)]1—Cats and dogs: There is no treatment

that has been clearly demonstrated to eradicate Cryptosporidium

species infection in human beings{R-32; 40} or animals; the zoonotic

potential of this organism should be considered. Azithromycin can be

administered to shorten the length of time oocysts are shed in cats and

dogs; however, there are no clinical studies in these species to

document efficacy in the treatment of cryptosporidiosis. There are

studies of immunocompromised, human immunodeficiency virus

(HIV)-positive patients that show some evidence of the efficacy of

azithromycin in prevention, remission, and possibly eradication of

infection with long-term administration{R-41; 97}. Because of insuffi-

cient data, it is not possible at this time to recommend long-term

dosing regimens that might be useful in the treatment of this infection

in cats and dogs.

[Enteritis, Campylobacter (treatment)]1—Dogs: In vitro studies have

demonstrated that azithromycin may have up to 6 times the activity

of erythromycin against susceptible Campylobacter strains, making it a

potential treatment for this type of enteritis in dogs; however, no

clinical studies have been performed{R-57; 110}.

[Mastitis (treatment)]1— Cattle: There are insufficient data to establish

the efficacy of systemic erythromycin in the treatment of acute

and peracute mastitis caused by susceptible Staphylococcus and

Streptococcus species; however, studies have shown that erythromycin

is distributed into milk at antimicrobial concentrations under certain

pH conditions and may be clinically effective{R-45–47}.

[Pneumonia, bacterial, (treatment)]1—Foals: Although there is insuffi-

cient evidence to establish efficacy, pharmacokinetic studies suggest

that azithromycin may be as effective as erythromycin, with less

frequent dosing and fewer side effects, in the treatment of pneumonia

caused by Rhodococcus equi in foals{R-121; 122}.

[Respiratory tract infections (treatment)]1, including,

[Bronchitis (treatment)]1

[Laryngitis (treatment)]1

[Pneumonia (treatment)]1

[Tracheobronchitis (treatment)]1, or

[Tracheitis (treatment)]1—Cats and dogs: Although at one time

Canadian tylosin tablets were available for the treatment of

pneumonia and tracheobronchitis{R-56}, and the use of tylosin

injection in the treatment of respiratory tract infections in cats

and dogs has been approved by the U.S. Food and Drug

Administration{R-108}, these uses are not included in United States

or Canadian product labeling for tylosin. Studies performed during

the original approval process showed that tylosin injection can be

effective in the treatment of bronchitis, laryngitis, pneumonia,

tracheobronchitis, or tracheitis in dogs and upper respiratory tract

infections or pneumonitis in cats when the infection is caused by

susceptible organisms{R-108}.

[Rocky Mountain spotted fever]1—Dogs: There are insufficient data at

this time to establish the efficacy of azithromycin in the treatment of

Rocky Mountain spotted fever in dogs. A comparative therapeutic

study of induced Rocky Mountain spotted fever in dogs showed that

azithromycin, when given for a 3-day treatment regimen, was effective

in improving platelet counts, slowing vascular leakage, and reducing

fever; however, retinal vascular lesions remained unchanged. Overall,

the response was not as good as the administration of doxycycline for 7

days. If azithromycin is administered to dogs for the treatment of

Rocky Mountain spotted fever, longer term treatment may be be more

effective.{R-123–125}


Erythromycin thiocyanate and tylosin tartrate are not labeled for use

in chickens or turkeys producing eggs for human consump-

tion.{R-8; 50; 54} Tilmicosin is not labeled for use in female dairy cattle

20 months of age or older{R-53}, veal calves, calves less than 1 month

of age, or calves fed an all-milk diet. Tylosin injection is not labeled

for use in lactating dairy cattle or preruminating calves.{R-51; 52}

Withdrawal times have been established for erythromycin injection,

erythromycin phosphate powder for oral solution, erythromycin

thiocyanate, tilmicosin phosphate, tylosin injection, tylosin phos-

phate, and tylosin tartrate (see the Dosage Forms section).

Azithromycin and clarithromycin are not labeled for use in animals.

Canada—

Erythromycin phosphate, erythromycin thiocyanate, and tylosin

tartrate are not labeled for use in chickens or turkeys producing

eggs for human consumption.{R-8; 9} Neither tilmicosin nor tylosin

base injection is labeled for use in lactating dairy cattle.{R-55; 65}





Withdrawal times have been established for erythromycin injection,

erythromycin phosphate powder for oral solution, erythromycin

thiocyanate, tilmicosin phosphate, tylosin injection, tylosin phos-

phate, and tylosin tartrate (see the Dosage Forms section).

Azithromycin and clarithromycin are not labeled for use in animals.

CHEMISTRYSource:

Azithromycin and clarithromycin—Semisynthetically derived from

erythromycin{R-116; 119}.

Erythromycin—Produced from a strain of Saccharopolyspora erythraeus{R-7}.

Tilmicosin—Produced semisynthetically{R-53} by chemical modifications

of desmycosin{R-1}.

Tylosin—Produced by a strain of the actinomycete Streptomyces fradiae{R-55}.

Chemical group:

Azalide antibiotic, a subclass of macrolides—Azithromycin{R-116}.

Macrolide antibiotics (macrocyclic lactones){R-1; 117}—Clarithromycin,

erythromycin, tilmicosin, and tylosin.

Chemical name:

Azithromycin—1-Oxa-6-azacyclopentadecan-15-one, 13-[(2,6-dideoxy-

3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-

trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dim-

ethylamino)-beta-D-xylo-hexopyranosyl]oxy]-, dihydrate, [2R-(2R*,

3S*,4R*,5R*,8R*,10R*,11R*,12S*,13S*,14R*)]-{R-16}.

Clarithromycin—Erythromycin, 6-O-methyl-{R-16}.

Erythromycin—Erythromycin{R-16}.

Erythromycin estolate—Erythromycin, 2¢-propanoate, dodecyl sulfate

(salt){R-16}.

Erythromycin ethylsuccinate—Erythromycin 2¢-(ethyl butanedio-

ate){R-16}.

Erythromycin gluceptate—Erythromycin monoglucoheptonate

(salt){R-16}.

Erythromycin lactobionate—Erythromycin mono(4-O-beta-D-galacto-

pyranosyl-D-gluconate) (salt){R-16}.

Erythromycin stearate—Erythromycin octadecanoate (salt){R-16}.

Tilmicosin phosphate—Tylosin, 4A-O-de(2,6-dideoxy-3-C-methyl-alpha-

L-ribo-hexopyranosyl)-20-deoxo-20-(3,5-dimethyl-1-piperidinyl)-,

[20(cis)]-, phosphate (1:1) (salt){R-16}.

Tylosin—(10E,12E)-(3R,4S,5S,6R,8R,14S,15R)-14-[(6-deoxy-2,3-di-

O-methyl-beta-D-allopyranosyl)oxymethyl]-5-[[3,6-dideoxy-4-O-(2,6-

dideoxy-3-C-methyl-alpha-L-ribo-hexopyranosyl)-3-dimethylamino-

beta-D-glycopyranosyl]oxy]-6-formylmethyl-3-hydroxy-4,8,12-tri-

methyl-9-oxoheptadeca-10,12-dien-15-olide{R-100}.

Molecular formula:

Azithromycin—C38H72N2O12Æ2H2O{R-16}.

Clarithromycin—C38H69NO13{R-16}.

Erythromycin—C37H67NO13{R-16}.

Erythromycin estolate—C40H71NO14ÆC12H26O4S{R-16}.

Erythromycin ethylsuccinate—C43H75NO16{R-16}.

Erythromycin gluceptate—C37H67NO13ÆC7H14O8{R-16}.

Erythromycin lactobionate—C37H67NO13ÆC12H22O12{R-16}.

Erythromycin stearate—C37H67NO13ÆC18H36O2{R-16}.

Tilmicosin phosphate—C46H80N2O13ÆH3O4P{R-16}.

Tylosin—C46H77NO17{R-100}.

Molecular weight:

Azithromycin—785.02{R-16}.

Clarithromycin—747.95{R-16}.

Erythromycin—733.93{R-16}.

Erythromycin estolate—1056.39{R-16}.

Erythromycin ethylsuccinate—862.05{R-16}.

Erythromycin gluceptate—960.11{R-16}.

Erythromycin lactobionate—1092.22{R-16}.

Erythromycin stearate—1018.40{R-16}.

Tilmicosin phosphate—967.13{R-16}.

Tylosin—916.1{R-100}.

Description:

Azithromycin dihydrate—White, crystalline powder{R-116}.

Clarithromycin USP—White to off-white, crystalline powder{R-22}.

Erythromycin USP—White or slightly yellow, crystalline powder. Is

odorless or practically odorless{R-22}.

Erythromycin Estolate USP—White, crystalline powder. Is odorless or

practically odorless{R-22}.

Erythromycin Ethylsuccinate USP—White or slightly yellow crystalline

powder. Is odorless or practically odorless{R-22}.

Erythromycin Gluceptate—White powder. Is odorless or practically

odorless, and is slightly hygroscopic. Its solution (1 in 20) is neutral

or slightly acid.

Erythromycin Lactobionate for Injection USP—White or slightly yellow

crystals or powder, having a faint odor. Its solution (1 in 20) is neutral

or slightly alkaline{R-22}.

Erythromycin Stearate USP—White or slightly yellow crystals or powder.

Is odorless or may have a slight, earthy odor{R-22}.

Tilmicosin USP—White to off-white amorphous solid{R-22}.

Tylosin USP—White to buff-colored powder{R-22}.

pKa:

Erythromycin base—8.8{R-18; 19}.

Tilmicosin—7.4; 8.6{R-94}.

Tylosin—7.1{R-5; 58}.

Solubility:

Azithromycin—39 mg soluble per mL of water (pH 7.4 ) at 37 �C{R-118}.

Clarithromycin USP—Soluble in acetone; slightly soluble in dehy-

drated alcohol, in methanol, and in acetonitrile; practically insoluble

in water. Slightly soluble in phosphate buffer at pH values of 2

to 5{R-22}.

Erythromycin USP—Slightly soluble in water; soluble in alcohol, in

chloroform, and in ether{R-22}.

Erythromycin Estolate USP—Soluble in alcohol, in acetone, and in

chloroform; practically insoluble in water{R-22}.

Erythromycin Ethylsuccinate USP—Very slightly soluble in water; freely

soluble in alcohol, in chloroform, and in polyethylene glycol

400{R-22}.

Erythromycin Gluceptate—Freely soluble in water, in alcohol, and in

methanol; slightly soluble in acetone and in chloroform; practically

insoluble in ether.

Erythromycin Lactobionate for Injection USP—Freely soluble in water, in

alcohol, and in methanol; slightly soluble in acetone and in chloro-

form; practically insoluble in ether{R-22}.

Erythromycin Stearate USP—Practically insoluble in water; soluble in

alcohol, in chloroform, in methanol, and in ether{R-22}.

Tilmicosin USP—Slightly soluble in water and in n-hexane{R-22}.

Tylosin USP—Freely soluble in methanol; soluble in alcohol, in amyl

acetate, in chloroform, and in dilute mineral acids; slightly soluble in

water{R-22}.

Tylosin tartrate—Readily soluble in water, up to 600 mg per mL{R-61}.



PHARMACOLOGY/PHARMACOKINETICSNote: See also Table 1. Pharmacology/Pharmacokinetics at the end of this

monograph.

Mechanism of action/effect: Bacteriostatic, with potential for a time-

dependent bactericidal action, particularly with high concentrations{R-

1; 5; 119}. The macrolides are thought to enter the cell and reversibly

bind to the 50 S ribosomal subunit, inhibiting translocation of pep-

tides, thereby inhibiting protein synthesis.{R-5} Bacterial resistance

occurs by alteration of the ribosome receptor site and/or by prevention

of the antibiotic from entering the cell. Although macrolides bind to

mitochondrial ribosomes, as does chloramphenicol, macrolides are

unable to cross the mitochondrial membrane and so do not produce

bone marrow suppression in mammals{R-119}.

Absorption:

Azithromycin—Oral administration: Shown to be fairly well absorbed

orally in cats (bioavailability of 58%), dogs (bioavailability of >90%),

and foals (bioavailability of 39 to 56%){R-120–123}.

Erythromycin—Oral administration:

Many oral erythromycin base preparations are coated to prevent

degradation in the stomach. The higher pH of the intestine then

permits absorption.{R-1; 2} However, absorption of enteric-coated and

delayed-release dosage forms can be unpredictable in animals{R-21}.

Erythromycin estolate and erythromycin ethylsuccinate are absorbed

as inactive esters from the duodenum and then undergo hydrolysis to

the free base. The stearate salt dissociates in the duodenum and is

absorbed as the free base. It has been suggested that erythromycin

phosphate also dissociates and is absorbed as the free base. Food in

the stomach does not seem to affect significantly the absorption of

the base or salt.

It is unclear whether any of the oral erythromycin preparations is

absorbed more effectively than any other when administered to

animals{R-1}; however, it does appear that oral absorption in

horses may be different from human absorption. In horses, oral

erythromycin stearate and erythromycin phosphate produced

peak plasma concentrations more quickly than did the ester

formulations; the effect is the opposite of that seen in human

studies.{R-18}

Tylosin—Intramuscular administration: Bioavailability—Goats: 72.6%

(15 mg per kg of body weight [mg/kg] dose){R-72}.

Distribution:

Widely distributed in the body{R-1; 68}. Ion trapping and the high lipid

solubility of the macrolides generally causes tissue concentrations to be

higher (often many times higher) than serum concentrations.{R-1; 70}

Azithromycin—Tissue concentrations can be as much as 100 times

serum concentrations and concentrations in leukocytes can be 200 to

300 times serum concentrations{R-115; 119}.

Cats: Azithromycin appears to distribute well, although sometimes

slowly, into a variety of tissues. High tissue to plasma ratios are

produced. In one study, lung, femur, eye, skin, and brain tissue

concentrations of azithromycin were still rising when the last sample

was taken, 72 hours after the dose{R-120}.

Dogs: A single dose of azithromycin produced high tissue concentra-

tions, often with a tissue to serum ratio of 100 to one; azithromycin

concentrations in eye and brain tissue exceeded serum concentra-

tions by 20- and 1.2-fold, respectively{R-123}.

Foals: Azithromycin peak concentration in polymorphonuclear leuko-

cytes (PMN) was 27.3 mcg per mL (mcg/mL) while peak plasma

concentration was 0.72 mcg/mL after a single 10 mg/kg oral dose.

The drug persisted in PMNs for 120 hours while it was only detected

in plasma for about 24 hours.{R-121}

Clarithromycin—Widely distributed into tissues and enters leukocytes

and macrophages{R-115}.

Erythromycin—In the calf, lung tissue erythromycin concentrations

were found to be approximately three times higher than serum

concentrations from 8 to 24 hours after intramuscular administra-

tion{R-28}.

Tilmicosin and tylosin—Tylosin concentrations in lung tissue are many

times higher than in serum from 2 to 36 hours after a single

intramuscular administration{R-70}; tilmicosin concentrations in lung

tissue are many times higher than in serum for at least 96 hours after

a single subcutaneous administration{R-104}.

Half-life: Azithromycin in leukocytes—

Foals: 49.2 hours{R-121}.

Human data: 34 to 57 hours{R-115}.

Elimination:

Azithromycin—

Cats: More than 50% of the drug is eliminated unchanged in the bile.

One major metabolite resulting from N-demethylation and two

minor metabolites also appear in the bile{R-120}.

Human information: More than 50% of the drug is eliminated

unchanged through biliary excretion while 4 to 14%, depending

on route of administration, is eliminated unchanged in the

urine{R-115}.

Clarithromycin—Human information: 20 to 40% is eliminated unchanged

in the urine{R-115}.

Erythromycin—Primarily hepatic; metabolite and a small amount of

active drug are excreted to a large degree in the bile but are also

excreted in urine and milk. After oral administration, high concen-

trations of erythromycin may be eliminated in the feces.{R-1; 29}

Tilmicosin—Cattle: Of the total subcutaneous dose administered, 24%

has been recovered in the urine and 68% in the feces.{R-53}

Duration of action:

Tilmicosin—Cattle, healthy or acutely pneumonic: 3 days, minimum

(based on maintenance of >3.12 mcg/mL lung concentration [min-

imum inhibitory concentration 95% for M. haemolytica] with a

subcutaneous dose of 10 mg/kg){R-53; 103; 104}.

Tylosin—Goats: 12 hours (based on maintenance of >1 mcg/mL serum

concentration with an intramuscular dose of 15 mg/kg).{R-72}


SPECIES SENSITIVITYErythromycin:

Cattle—Oral administration of erythromycin phosphate or erythromy-

cin stearate has caused severe diarrhea in ruminating calves.{R-28}

Because of this adverse effect and poor absorption, oral erythromycin

administration in cattle is not recommended.

Horses—In foals treated with erythromycin, mild self-limiting diarrhea

may develop.{R-26} In adult horses, the risk of severe diarrhea makes

the use of erythromycin controversial.{R-2}



Tilmicosin:

All species—To avoid cardiotoxicity, tilmicosin should not be admin-

istered intravenously{R-81}.

Human—Injection of tilmicosin may be lethal. Although there is little

information on the effects of tilmicosin in people, a variable

susceptibility to cardiotoxic reactions in other species warrants

caution with human exposure and close monitoring of the cardio-

vascular system, particularly after accidental injection{R-81}. A

physician should be consulted immediately in cases of accidental

injection.{R-53}

Dogs—In laboratory dogs, tachycardia and decreased cardiac contrac-

tility have been noted in response to tilmicosin injection{R-100}.

Goats—Administration of tilmicosin to goats at intramuscular or

subcutaneous doses >10 mg per kg of body weight (mg/kg) is likely

to lead to toxicity{R-81; 100}.

Horses—Administration of tilmicosin to horses at intramuscular

or subcutaneous doses >10 mg/kg is likely to lead to

toxicity{R-81; 100}.

Pigs—Injection of tilmicosin into swine can be fatal as a result of

cardiovascular toxicity. Administration of epinephrine to treat

cardiovascular toxicity due to intravenous tilmicosin administration

has been associated with an increased risk of death.{R-53; 100}

Tylosin: Horses—Injection of tylosin has been fatal to horses.{R-51; 52}

CROSS-SENSITIVITY AND/OR RELATED PROBLEMSPatients that are hypersensitive to one macrolide may be hypersensitive

to a different macrolide{R-116; 117}.

PREGNANCY/REPRODUCTIONAzithromycin:

Fertility and reproduction—Rats and mice given azithromycin at doses

of up to 200 mg/kg a day have shown no evidence of impaired

fertility or harm to the fetus{R-116}.

FDA human pregnancy category B.

Clarithromycin:

Fertility and reproduction—Male and female rats administered up to

160 mg/kg a day have shown no effect on estrous cycle, fertility,

parturition, or viability of offspring{R-117}.

Pregnancy—Monkeys administered oral doses of 150 mg/kg a day had

embryonic loss, which was attributed to marked maternal toxicity at

this dose. In utero fetal loss occurred in rabbits given intravenous

doses of 33 mg per square meter of body surface area, which is

equivalent to 17 times less than the maximum recommended human

daily dose.

Clarithromycin was not found to be teratogenic in four rat studies or

in two rabbit studies. Two additional studies in a different rat strain

demonstrated a low incidence of cardiovascular anomalies at oral

doses of 150 mg/kg a day administered during gestation days 6

through 15. Cleft palate was seen at doses of 500 mg/kg a day. Fetal

growth retardation was seen in monkeys given an oral dose of 70

mg/kg a day, which produced plasma concentrations that were

equivalent to two times the human serum concentrations.

FDA human pregnancy category C{R-115}.

Erythromycin: Erythromycin crosses the placenta; however, there is no

evidence of teratogenicity or other effects when female rats are fed

erythromycin base during pregnancy.{R-17} In people, erythromycin

estolate has been associated with reversible hepatotoxicity in some

women during pregnancy.

Tilmicosin{R-53} and tylosin: Safety in breeding or pregnant animals has

not been established.

LACTATIONClarithromycin is excreted into milk{R-117}. The distribution of azithro-

mycin into milk has not yet been demonstrated{R-116}.

Erythromycin, tilmicosin, and tylosin concentrations in milk can be

much higher than concentrations in serum.{R-26; 72; 74}

In cattle, tilmicosin is distributed into milk at effective antibacterial

concentrations for susceptible pathogens, but detectable concentra-

tions in milk are maintained for many weeks (up to 42 days){R-87}.

Tilmicosin should not be administered to lactating dairy cattle because

of impractical withdrawal times.{R-74}

In mastitis-free cattle, systemic tylosin is distributed into milk at

concentrations that are therapeutic for some mastitis pathogens;

however, tylosin is distributed into milk more readily as the pH of milk

decreases. The pH of mastitic milk can approach 7.4 and decrease the

diffusion of tylosin, interfering with the medication’s ability to reach

therapeutic concentrations in milk against some organisms{R-79; 80}.

PEDIATRICSIn animals up to 1 month of age, the hepatic clearance of macrolides may

be slower than in adult animals{R-1}.

DRUG INTERACTIONS AND/OR RELATEDPROBLEMSThe following drug interactions and/or related problems have been






Beta-adrenergic antagonists, such as

Propranolol

(propranolol and other beta-adrenergic antagonists exacerbate the

negative inotrophy of tilmicosin-induced tachycardia in

dogs{R-53})

» Chloramphenicol or

» Florfenicol or

» Lincosamides or

» Macrolide antibiotics, other

(chloramphenicol, florfenicol, and the lincosamides have mechanisms

of action similar to the macrolides; they may be prevented from

binding, or prevent a macrolide from binding, to the 50 S subunits of

bacterial ribosomes; concurrent use is not recommended{R-1})

» Epinephrine

(in pigs, the intravenous administration of epinephrine potentiates the

lethality of intravenously administered tilmicosin{R-53})

Phenobarbital or

Medications metabolized by microsomal mixed-function oxidases, other

(concurrent use with erythromycin may decrease the effects of these

medications because of induction of hepatic microsomal enzy-

mes{R-87})






included in the human monographs Azithromycin (Systemic), Clari-

thromycin (Systemic), or Erythromycins (Systemic) in USP DI Volume I;

these drug interactions are intended for informational purposes only

and may or may not be applicable to the use of macrolides in the

treatment of animals:

Note: There are no tilmicosin or tylosin products labeled for use in people.

Anticoagulants, coumarin- or indanedione-derivative or

Warfarin

(concurrent administration with macrolide antibiotics has been

associated with increased anticoagulant effects; prothrombin time

should be monitored carefully in patients receiving anticoagulants

and macrolides concurrently)

Carbamazepine or

Cyclosporine or

Digoxin or

Hexobarbital or

Phenytoin or

Valproic acid

(concurrent use with macrolide antibiotics has been associated with

increased serum concentration of these medications; monitoring of

serum concentrations of medications administered concurrently is

recommended to avoid toxicity)

(although no clinical cases of toxicity have been reported,

concurrent use of oral antibiotics may increase serum digoxin

concentrations in some individuals; in these individuals, alteration

of gut flora by antibiotics may diminish digoxin conversion to

inactive metabolites, resulting in increased serum digoxin concen-

trations; although limited data are available, this interaction has

been reported with oral use of erythomycins, neomycin, and

tetracyclines)

Midazolam or

Triazolam

(concurrent use with macrolide antibiotics may decrease the

clearance of these medications, increasing the pharmacologic effect

of midazolam or triazolam)

Penicillins

(since bacteriostatic drugs may interfere with the bactericidal effect

of penicillins in the treatment of meningitis or in other situations in

which a rapid bactericidal effect is necessary, it is best to avoid

concurrent therapy)

Rifabutin or

Rifampin

(concurrent use of rifabutin with azithromycin causes a 15%

decrease in serum concentration of rifabutin{R-116})

(concurrent use of rifabutin or rifampin with clarithromycin causes a

decrease in the serum concentration of clarithromycin by greater

than 50%)

Xanthines, such as:

Aminophylline

Caffeine

Oxtriphylline

Theophylline

(concurrent use of the xanthines [except dyphylline] with

macrolides may decrease hepatic clearance of xanthines, result-

ing in increased serum concentrations and/or toxicity; dosage

adjustment of the xanthines may be necessary during and after

therapy with macrolides)

(concurrent administration of theophylline with clarithromycin

has been shown to increase the area under the plasma concentra-

tion–time curve [AUC] of theophylline by 17%; monitoring of

theophylline serum concentrations is recommended in patients

receiving high doses of theophylline or in patients with theophyl-

line serum concentrations in the upper therapeutic range)

(with erythromycin, this effect may be more likely to occur after 6

days of concurrent therapy because the magnitude of theophylline

clearance reduction is proportional to the peak serum erythromycin

concentrations)

For azithromycin

Antacids, aluminum- and magnesium-containing

(concurrent use with antacids decreases the peak serum concentra-

tion [Cmax] of azithromycin by approximately 24%, but has no effect

on the area under the plasma concentration–time curve [AUC]; oral

azithromycin should be administered at least 1 hour before or 2

hours after aluminum- and magnesium-containing antacids)

For clarithromycin

Pimozide

(concurrent administration of pimozide with clarithromycin has

resulted in cardiac arrhythmias, including QTc-interval prolonga-

tion, ventricular tachycardia, ventricular fibrillation, and torsades de

pointes; fatalities have also occurred; the most likely cause is the

inhibition of hepatic metabolism of pimozide by clarithromycin;

concurrent use is contraindicated)

Zidovudine

(concurrent administration with clarithromycin causes a decrease in

the steady state concentration of zidovudine; doses of clarithromycin

and zidovudine should be taken at least 4 hours apart)

For erythromycin

Hepatotoxic medications, other

(concurrent use of other hepatotoxic medications with erythromycin

may increase the potential for hepatotoxicity)

Ototoxic medications, other

(concurrent use with high-dose erythromycin in patients with renal

function impairment may increase the potential for ototoxicity)




Note: Laboratory value alterations relating specifically to use of macro-

lides in animals are rarely described. Human laboratory value

alterations have been reported for erythromycin and are included in

the following section.



humans, and are included in the human monographs Azithromycin

(Systemic), Clarithromycin (Systemic), or Erythromycins (Systemic) in

USP DI Volume I; these laboratory value alterations are intended for

informational purposes only and may not be applicable to the use of

macrolides in the treatment of animals:


For azithromycin






Creatine kinase and

Gamma-glutamyltransferase and

Lactate dehydrogenase



Potassium, serum


For clarithromycin



Aspartate aminotransferase (AST [SGOT])

(rarely, serum values may be increased)

Blood urea nitrogen (BUN)

(rarely, concentration may be elevated)

For erythromycin



(use of erythromycin may interfere with AST [SGOT] determina-

tions if azonefast violet B or diphenylhydrazine colorimetric tests

are used)

Catecholamines, urinary

(erythromycin may produce false elevations of urinary catechol-

amines because of interference with the fluorometric determina-

tion)





Bilirubin, serum

(values may be increased by all erythromycins, but more

commonly by erythromycin estolate)






problems exist:

Hepatic function impairment

(macrolides are hepatically metabolized{R-29}; although hepatotoxic-

ity has not been reported in animals, erythromycin estolate has, on

uncommon occasions, been associated with hepatotoxicity in people;

therefore, consideration of risk is recommended{R-1})

Renal function impairment, severe

(clarithromycin elimination is reduced in human patients with renal

function impairment, particularly those with a creatinine clearance

< 30 mL per minute; it is recommended that the dose be reduced by

one-half or that the dosage interval be doubled{R-115})




Culture and susceptibility in vitro and



prior to macrolide administration to determine pathogen suscepti-

bility)




THOSE INDICATING NEED FOR MEDICALATTENTIONIncidence unknown

All species

Allergic reactions—considered rare{R-1}

Cats and dogs

Gastrointestinal effects (anorexia, diarrhea, vomiting)—particularly

with erythromycin{R-1; 2; 96}

Note: In dogs, it has been shown that intravenous erythromycin

produces an increase in the electrical and motor activity of the

stomach; this effect most likely occurs through cholinergic pathways.

The effect produces an abrupt, powerful increase in gastric motility

causing retrograde contractions leading to gastrointestinal effects,

such as vomiting and retching.{R-59; 60} In one survey, 41% of pet

owners reported that their dogs (19 of 46) vomited following

administration of oral erythromycin stearate.{R-96} This increase in

gastric motility has not been shown to occur in response to tylosin{R-67}

and, although vomiting may occur in response to tylosin adminis-

tration, it occurs infrequently.

Cattle

Diarrhea—associated with oral erythromycin dosage forms{R-28}

Horses

Diarrhea, severe—with erythromycin; considered more likely in adult

horses{R-2}

Pigs

Diarrhea, erythema, and pruritis—with tylosin;{R-51} edema,

rectal, and partial anal prolapse{R-2; 51}—with erythromycin and

tylosin

THOSE INDICATING NEED FOR MEDICALATTENTION ONLY IF THEY CONTINUE OR AREBOTHERSOMEAll species

Pain and/or swelling at the site of injection—with subcutaneous

injection in cattle, swelling is transient and usually mild{R-2; 29; 53}




included in the human monographs Azithromycin (Systemic), Clari-

thromycin (Systemic), or Erythromycins (Systemic) in USP DI Volume I;

these side/adverse effects are intended for informational purposes only

and may or may not be applicable to the use of macrolides in the

treatment of animals:


For azithromycin

Incidence more frequent—for injection form only



Thrombophlebitis


Gastrointestinal disturbances

Incidence rare

Acute interstitial nephritis; allergic reactions; dizziness; head-

ache; pseudomembranous colitis

For clarithromycin


Abnormal sensation of taste; gastrointestinal disturbances;

headache

Incidence rare

Hepatotoxicity; hypersensitivity reaction; pseudomembranous

colitis; thrombocytopenia

For erythromycin


Gastrointestinal disturbances


Hepatotoxicity; hypersensitivity; inflammation or phlebitis at

the injection site—with parenteral erythromycins only; oral

candidiasis; vaginal candidiasis

Incidence rare

Cardiac toxicity, especially QT prolongation and torsades de

pointes; loss of hearing, usually reversible; pancreatitis

Note: Hepatotoxicity has been associated rarely with all erythromycin

salts, but more frequently with erythromycin estolate. Reports

suggest that a hypersensitivity mechanism may be involved. Liver

function tests often indicate cholestasis. Symptoms typically appear

within a few days to 1 or 2 weeks after the start of continuous

therapy and are reversible when erythromycin is discontinued.

However, hepatotoxicity reappears promptly on readministration to

sensitive patients.

Loss of hearing is more likely to occur with administration of high

doses (‡ 4 grams per day) in patients with renal or hepatic disease

and/or in elderly patients. It appears to be related to high peak

plasma concentrations, usually exceeding 12 mcg per mL. Hearing

loss is usually reversible, although irreversible deafness has

occurred. It occurs 36 hours to 8 days after treatment is started

and begins to dissipate within 1 to 14 days after erythromycin is

discontinued.






For azithromycin: Mice and rats—The LD50 for oral administration is

3000 to 4000 mg/kg{R-118}.

For tilmicosin: Greater susceptibility to toxicity from parenterally

administered tilmicosin has been shown in goats, horses, and pigs

than in cattle.{R-81}. In all species tested, the primary toxic effect is

cardiotoxicity{R-53; 81}.

Intravenous administration of tilmicosin is not recommended for use in

any species because an intravenous dose of 10 mg or less per kg of

body weight (mg/kg) causes signs of toxicity and, in some cases, death

in calves, cattle, goats, horses, and sheep{R-81}. Subcutaneous doses of

up to 30 mg/kg every 3 days for a total of three doses in cattle have

been specified as the highest nontoxic dose in healthy cattle because

the mild evidence of myocardial necrosis seen with three 50 mg/kg

doses administered 72 hours apart{R-53} was not found with a 30 mg/

kg dosage regimen. Repeated subcutaneous doses of 150 mg/kg every

3 days resulted in one death following the third treatment and one

death following the fourth treatment in cattle{R-53; 100}. In contrast,

three of four pigs administered a 20 mg/kg intramuscular dose of

tilmicosin and four of four pigs given a 30 mg/kg dose died. In goats

and horses, subcutaneous or intramuscular doses above 10 mg/kg

may cause signs of toxicosis{R-81; 100}.

Oral tilmicosin caused no ill effects in pigs when they were administered

2000 parts per million (ppm) in the only ration for 42 days or 4000

ppm for 21 days{R-107}. Oral doses of 4 mg/kg a day administered to

dogs for up to a year caused no observable adverse effects{R-107}. The

median lethal dose of oral tilmicosin in fasted rats is 800 mg/kg and in

nonfasted rats is 2250 mg/kg{R-107}.




For tilmicosin—in order of their appearance

Dogs

Cardiovascular changes, including sinus tachycardia, myocar-

dial depression, and reduced arterial pulse pressure (tremors,

rapid respiration, convulsions, and in severe cases, death)—noted

with an intravenous dose of 2.5 mcg/kg{R-81}.

TREATMENT OF OVERDOSEFor tilmicosin: The treatment of tilmicosin-induced cardiotoxicosis is not

yet well established. Tachycardia is believed to result in part from

stimulation of cardiac beta-receptors. In dogs, this effect is partially

blocked by propranolol; however, propranolol also potentiates the

decreased cardiac contractility induced by tilmicosin{R-81}. Dobuta-

mine may partially remedy the cardiac depression in dogs{R-81}.

Epinephrine potentiated the lethality of intravenously administered

tilmicosin in pigs{R-53}.

VETERINARY DOSING INFORMATIONActivity of the macrolides is highest in tissues and in environments with

elevated pH.{R-1}

Organisms that develop resistance to one macrolide antibiotic may also

be resistant to other macrolide antibiotics; this cross-resistance should

be considered when alternative antibacterials are chosen{R-1}. Bacte-

rial resistance to erythromycin seems to be more of a problem with

repeated or continuous use; resistance decreases rapidly when

medication is discontinued.{R-1}

FOR ORAL DOSAGE FORMS ONLYTylosin is more stable than erythromycin in acid environments

and therefore can be administered orally without enteric coating.{R-58}

FOR PARENTERAL DOSAGE FORMS ONLYOnly the gluceptate and the lactobionate salts of erythromycin can be

administered intravenously. Other parenteral dosage forms must be

administered by the intramuscular route only.



Cattle: The intramuscular route of administration for erythromycin is

recommended to avoid the poor absorption and intestinal side effects

associated with oral dosing and the poor absorption and more severe

local reactions associated with subcutaneous administration{R-28}.

Even with intramuscular injection, the effect of erythromycin on edible

tissues should be considered before administration{R-95}. High-dose

intravenous administration should be avoided unless the gluceptate or

lactobionate forms are used{R-82} because immediate side effects have

been reported with such administration.


Recommended treatment consists of the following:




Note: Parenteral epinephrine is not recommended treatment for

tilmicosin toxicity because of adverse effects noted in pigs (see

Overdose section); however,{R-53} epinephrine is not contraindicated

for anaphylaxis due to tilmicosin{R-100}.

AZITHROMYCIN

SUMMARY OF DIFFERENCESPharmacology/pharmacokinetics: Distribution—Azithromycin concen-

trates in tissues, particularly in leukocytes, macrophages and fibroblasts

and is slowly released from leukocytes{R-120; 121}. The intracellular

reservoir of azithromycin produces effective drug concentrations in

interstitial fluids even after the plasma concentrations have declined

below detectable levels{R-121}. Azithromycin can be delivered to infected

tissues and early abscesses via leukocytes{R-119}.




AZITHROMYCIN FOR ORAL SUSPENSION USPUsual dose:

Note: Dosing recommendations for the use of azithromycin in the

treatment of animals are given with some caution advised. Unlike

other antibiotics for which there is limited clinical efficacy and safety

data, the ability of azithromycin to concentrate in tissues makes the

typical dosing estimation based on pharmacokinetic data more

challenging. The following are current recommendations for dosing;

however, these may be supplanted as knowledge about azithromycin

increases:

[Cats]1 and [dogs]1—Although the safety and efficacy have not been

established, an oral dose of 3 to 5 mg per kg of body weight every

twenty-four hours for three to four days has been used to treat

susceptible bacterial infections, based on pharmacokinetic data{R-120;

123; 125–7}. For infections that require longer-term treatment,

azithromycin has been administered for a maximum of 3 or 4 days

a week; this is done either by administering the 3 to 5 mg per kg dose

every other day or by administering the same dose once on three

subsequent days (Monday, Tuesday, and Wednesday) each week,

with no treatment on the other four days of the week.

[Foals]1—Although the safety and efficacy have not been established,

an oral dose of 10 mg per kg of body weight every twenty-four hours for

five days, followed by 10 mg per kg of body weight every forty-eight

hours has been recommended in the treatment of Rhodococcus equi

pneumonia, based on pharmacokinetic data{R-121; 122}. Erythromycin

has typically been used in combination with rifampin in the treatment

ofR. equi pneumonia and the same might be expected for azithromycin;

however, many clinicians are administering azithromycin without

rifampin in the treatment of this infection.


U.S.—




20 mg per mL (when reconstituted according to manufacturer’s

instruction) (available in 300-mg bottles) (Rx) [Zithromax (sucrose)].


instruction) (available in 600-, 900-, and 1200-mg bottles) (Rx)

[Zithromax (sucrose)].

Canada—





instruction) (available in 300-mg bottles) (Rx) [Zithromax

(sucrose)].


instruction) (available in 600- and 900-mg bottles) (Rx) [Zithro-

max (sucrose)].

Packaging and storage:

Prior to reconstitution, store between 5 and 30 �C (41 and 86 �F) in a

tight container.

After reconstitution, the pediatric oral suspension should be stored

between 5 and 30 �C (41 and 86 �F) and used within 10 days.

Preparation of dosage form: For the pediatric suspension, add the

volume of water indicated on manufacturer’s product labeling to the

bottle and shake well.


Azithromycin and one or more buffers, sweeteners, diluents, antica-

king agents, and flavors. Contains the labeled amount, within ±10%.

Meets the requirements for Identification, Uniformity of dosage units

(for solid packaged in single-unit containers), Deliverable volume, pH

(9.0–11.0 [for solid packaged in single-unit containers], 8.5–11.0 [for

solid packaged in multiple-unit containers], in the suspension con-

stituted as directed in the labeling), and Water not more than

1.5%).{R-22}

AZITHROMYCIN TABLETSUsual dose: See Azithromycin For Oral Suspension USP.


U.S.—






250 mg (Rx) [Zithromax].


Canada—







tween 15 and 30 �C (59 and 86 �F), in a well-closed container.



AZITHROMYCIN FOR INJECTIONUsual dose:

Note: There are no data at this time to recommend dosing for

parenteral azithromycin in animals.


U.S.—





Canada—







manufacturer.

Preparation of dosage form: To prepare the initial solution for

intravenous infusion, add 4.8 mL of sterile water for injection to each

500-mg vial and shake until all of the medication is dissolved. Further

dilute this solution by transferring it into 250 or 500 mL of a suitable

diluent (see manufacturer’s package insert) to provide a final con-

centration of 2 or 1 mg per mL, respectively.

Stability: After reconstitution with sterile water for injection, the solu-

tion is stable for 24 hours when stored below 30 �C (86 �F). After

dilution to 1 or 2 mg per mL in suitable diluent, solutions are stable for

24 hours at or below room temperature (30 �C [86 �F]), or for 7 days if

stored at 5 �C (41 �F).


CLARITHROMYCIN




CLARITHROMYCIN FOR ORAL SUSPENSION USPUsual dose:

Note: Dosing recommendations for the use of clarithromycin in the

treatment of animals are given with caution advised. Unlike other

antibiotics for which there is limited clinical efficacy and safety data,

the ability of clarithromycin to concentrate in tissues makes the

typical dosing estimation based on pharmacokinetic data more

challenging. One pharmacokinetic study suggested that 10 mg per

kg a day may be an effective dose for [dogs]1, but did not attempt to

recommend duration of therapy{R-124}. There are no reports of

specific dosing regimens in common usage.

Strength(s) usually available{R-115}: When reconstituted according to


U.S.:




25 mg per mL (Rx) [Biaxin].


Canada:







in a well-closed container. Protect from light.

Preparation of dosage form: Add the total volume of water indicated

on manufacturer’s product labeling, in two portions, shaking well after

each addition.

Stability: After reconstitution, suspension retains its potency for 14

days. Do not refrigerate.


Clarithromycin, dispersing agents, diluents, preservatives, and flavor-

ings. Contains the labeled amount, within –10 to +15%, labeled

amount being 25 mg or 50 mg per mL when constituted as directed in

the labeling. Meets the requirements for Identification, pH (4.0–5.4, in

the suspension constituted as directed in the labeling), Loss on drying

(not more than 2.0%), and Deliverable volume.{R-22}

CLARITHROMYCIN TABLETS USPUsual dose: See Clarithromycin for Oral Suspension USP.


U.S.—








250 mg (Rx) [Biaxin].


Canada—







unless otherwise specified by the manufacturer. Protect from light.

Preserve in tight containers.


amount, within ±10%. Meet the requirements for Identification, Dis-

solution (80% in 30 minutes in 0.1 M Sodium acetate buffer in

Apparatus 2 at 50 rpm), Uniformity of dosage units, and Loss on

drying (not more than 6.0%).{R-22}

CLARITHROMYCIN EXTENDED-RELEASE TABLETSUsual dose:

Note: There is no specific evidence that human extended-release

dosage forms are completely absorbed by animals; therefore, reliable

dose recommendations cannot be made.


U.S.—




500 mg (Rx) [Biaxin XL].

Canada—




500 mg (Rx) [Biaxin XL].


unless otherwise specified by the manufacturer. Protect from light.


ERYTHROMYCIN BASE




ERYTHROMYCIN DELAYED-RELEASE CAPSULES USPUsual dose:

Note: There is no specific evidence that human delayed-release dosage

forms are completely absorbed by animals; therefore, reliable dose

recommendations cannot be made.


U.S.—




250 mg (Rx) [ERYC; generic].

Canada—




250 mg (Rx) [Apo-Erythro E-C; ERYC-250; Novo-rythro Encap].

333 mg (Rx) [Apo-Erythro E-C; ERYC-333].





amount, within –10% to +15%. Meet the requirements for Identifi-

cation, Drug release (Method B: 80% in 60 minutes for Acid stage and

60 minutes for Buffer stage in Apparatus 1 at 50 rpm), and Water (not


ERYTHROMYCIN TABLETS USPUsual dose: [Pyoderma]1—Dogs: Oral, 10 to 20 mg per kg of body

weight every eight to twelve hours.{R-30; 42–44; 60}

Note: The above dose recommendation is based on current clinical practice

rather than specific canine pharmacokinetic data. The absorption of

enteric-coated tablets in dogs can be unpredictable.{R-21}


U.S.—




250 mg (Rx) [generic].

500 mg (Rx) [generic].

Canada—




250 mg (Rx) [Apo-Erythro; Erythromid].





amount, within –10% to +20%. Meet the requirements for Identifi-

cation, Dissolution (70% in 60 minutes in 0.05 M phosphate buffer

[pH 6.8] in Apparatus 2 at 50 rpm), Uniformity of dosage units, and

Loss on drying (not more than 5.0%).{R-22}

Note: Tablets that are enteric-coated meet the requirements for

Erythromycin Delayed-release Tablets.{R-22}

ERYTHROMYCIN DELAYED-RELEASE TABLETS USPUsual dose:

Note: There is no specific evidence that human delayed-release dosage

forms are completely absorbed by animals; therefore, reliable dose

recommendations cannot be made.






U.S.—




250 mg (Rx) [E-Mycin; Ery-Tab; Ilotycin; generic].

333 mg (Rx) [E-Base; E-Mycin; Ery-Tab; PCE; generic].

500 mg (Rx) [E-Base; Ery-Tab; PCE].

Canada—




250 mg (Rx) [E-Mycin; generic].

333 mg (Rx) [PCE].

500 mg (Rx) [Erybid].




USP requirements: Preserve in tight containers. The label indicates

that Erythromycin Delayed-release Tablets are enteric-coated. The

labeling indicates the Drug Release Test with which the product

complies. Contain the labeled amount, within –10% to +20%. Meet the

requirements for Identification, Drug Release (Method B: 75% in 60

minutes for Acid stage and 60 minutes for Buffer stage in Apparatus 1

at 100 rpm for Test 1 and in Apparatus 2 at 75 rpm for Test 2),

Uniformity of dosage units, and Water (not more than 6.0%).{R-22}




ERYTHROMYCIN INJECTION USPUsual dose:

Enteritis (scours)—Piglets, one week of age or older: Intramuscular, 11

mg per kg of body weight every twenty-four hours{R-111}.

Enterotoxemia (lamb dysentery) (prophylaxis)—Lambs, newborn:

Intramuscular, 5.5 mg per kg of body weight every twenty-four

hours, as soon after birth as is practical{R-111}.

Leptospirosis—Sows, farrowing: Intramuscular, 1.1 to 3.3 mg per kg of

body weight every twenty-four hours{R-111}.

Metritis—

Cattle: Intramuscular, 1.1 to 2.2 mg per kg of body weight every

twenty-four hours{R-111}.

Sows, farrowing: Intramuscular, 1.1 to 3.3 mg per kg of body weight


Pneumonia, bacterial—

Cattle: Intramuscular, 2.2{R-111} to 8.8{R-6} mg per kg of body weight

every twenty-four hours.

Note: See product labeling for the above dosing recommendations

with applicable withdrawal times.

For pneumonic pasteurellosis—[Intramuscular, 15 mg per kg of body

weight every twelve hours.{R-24; 28}]1

Note: The above dose is higher than those stated on U.S. or


Pigs (treatment of respiratory syndrome): Intramuscular, 1.1 to 3.3


Note: Injections should be made deep into the muscle.{R-6} Erythro-

mycin injection should not be administered intravenously or

subcutaneously.

Pododermatitis—Cattle: Intramuscular, 1.1 to 2.2 mg per kg of body



Pigs (treatment of respiratory syndrome): Intramuscular, 1.1 to 3.3


Sheep (treatment of upper respiratory tract infections): Intramus-

cular, 1.1 mg per kg of body weight every twenty-four

hours{R-111}.


U.S.—{R-6; 8}


100 mg per mL (OTC) [Gallimycin-100].

200 mg per mL (OTC) [Gallimycin-200].

Canada—{R-7; 8}


200 mg per mL (OTC) [Erythro-200; Gallimycin-200].

Withdrawal times:

U.S.—

For Gallimycin-200{R-6}:

Withdrawal time

Species Meat (days)

Cattle 6

Note: Product labeling listing the above withdrawal time states that it

applies to a dose of 8.8 mg per kg of body weight every 24 hours

and a course of therapy not exceeding 5 days. Higher doses or

longer duration of treatment may increase withdrawal times. This

product is not labeled for use in lactating dairy cattle. To avoid

excessive trim, cattle should not be slaughtered for 21 days after the

last injection.

For Gallimycin-100{R-111}:

Withdrawal time


Cattle 14 72

Pigs 7

Sheep 3


apply to a dose of 1.1 to 2.2 mg per kg of body weight for cattle, 1.1 to

3.3 mg per kg of body weight for pigs, and 1.1 mg per kg of body

weight for sheep.

Canada—{R-7}

Withdrawal time


Cattle 14 72

Pigs 7

Sheep 3





Note: Product labeling listing the above withdrawal times states that the

recommended withdrawal times apply to doses of 2.2 to 4.4 mg per kg

of body weight in cattle, 22 mg per kg of body weight in piglets, 2.2 to

6.6 mg per kg of body weight in pigs, 11 mg per kg of body weight in

lambs, and 2.2 mg per kg of body weight in sheep; administered every

24 hours in each species. To avoid excessive trim, cattle should not be

slaughtered for 21 days after the last injection; for pigs and sheep, the

waiting period is 10 days.




USP requirements: Preserve in multiple-dose containers. A sterile

solution of Erythromycin in a polyethylene glycol vehicle. Label it to

indicate that it is for veterinary use only. Label it to state that it is for

intramuscular administration only. Contains the labeled amount,


Water (not more than 1.0%), and Sterility, and for Injections.{R-22}

ERYTHROMYCIN ESTOLATE

SUMMARY OF DIFFERENCESPharmacology/pharmacokinetics: Absorption—Erythromycin estolate is

absorbed as the ester from the duodenum and is hydrolyzed to free base

in the body.{R-1; 18}

Side/adverse effects: In humans, erythromycin estolate has been asso-

ciated with an increased risk of subclinical hepatotoxicity during

pregnancy and an increased risk of cholestatic jaundice at any time.

These effects have not been reported in animals; however, periodic

liver function tests for animals receiving long-term erythromycin

estolate therapy have been recommended.{R-2}





in terms of erythromycin base (not the estolate salt).

ERYTHROMYCIN ESTOLATE CAPSULES USPUsual dose: [Rhodococcus equi pneumonia]1—Foals: Oral, 25 mg (base)

per kg of body weight every six hours.{R-13; 14; 26}

Note: The above dose has also been administered concurrently with 5 mg

rifampin per kg of body weight.{R-13; 14} The doses recommended are

based on pharmacokinetic and clinical efficacy studies in foals.{R-13; 14;

26}


U.S.—




250 mg (base) (Rx) [Ilosone; generic].

Canada—




250 mg (base) (Rx) [Ilosone; Novo-rythro].





erythromycin estolate equivalent to the labeled amount of erythro-

mycin, within –10% to +15%. Meet the requirements for Identifica-

tion, Disintegration (30 minutes), Uniformity of dosage units, and


ERYTHROMYCIN ESTOLATE ORAL SUSPENSION USPUsual dose: See Erythromycin Estolate Capsules USP.


U.S.—




25 mg (base) per mL (Rx) [Ilosone; generic].

50 mg (base) per mL (Rx) [Ilosone; generic].

Canada—




25 mg (base) per mL (Rx) [Ilosone; Novo-rythro].

50 mg (base) per mL (Rx) [Ilosone; Novo-rythro].

Packaging and storage: Store between 2 and 8 �C (36 and 46 �F).

Store in a tight container.

Auxiliary labeling:

• Refrigerate.

• Shake well.

USP requirements: Preserve in tight containers, in a cold place. Con-

tains one or more suitable buffers, colors, diluents, dispersants, and

flavors. Contains an amount of erythromycin estolate equivalent to the

labeled amount of erythromycin, within –10% to +15%. Meets the

requirements for Identification, Uniformity of dosage units (single-unit

containers), Deliverable volume, and pH (3.5–6.5){R-22}.

ERYTHROMYCIN ESTOLATE TABLETS USPUsual dose: See Erythromycin Estolate Capsules USP.

Strength(s) usually available.

U.S.—




250 mg (base) (Rx) [generic].

500 mg (base) (Rx) [Ilosone].

Canada—








500 mg (base) (Rx) [Ilosone].


tween 15 and 30 �C (59 and 86 �F), unless otherwise specified by the



indicate whether they are to be chewed before swallowing. Contain an

amount of erythromycin estolate equivalent to the labeled amount of

erythromycin, within –10% to +20% (+15%, if chewable). Meet the

requirements for Identification, Disintegration (30 minutes [Note:

Chewable tablets are exempt from this requirement]), Uniformity of

dosage units, and Water (not more than 5.0%; if chewable, not more

than 4.0%).{R-22}

ERYTHROMYCIN ETHYLSUCCINATE

SUMMARY OF DIFFERENCESPharmacology/pharmacokinetics: Absorption—

Absorbed as the ester, then hydrolyzed to free base in the body.{R-1}

Pigeons: Orally administered erythromycin ethylsuccinate has a

relative bioavailability of less than 10%.{R-27}

ORAL DOSAGE FORMSNote: The strengths of the dosage forms available are expressed in terms

of the ethylsuccinate salt. In people, 400 mg of erythromycin

ethylsuccinate produces approximately the same blood concentrations

as 250 mg of erythromycin base.

1.17 grams of erythromycin ethylsuccinate equal 1 gram of erythro-

mycin base{R-90}.

ERYTHROMYCIN ETHYLSUCCINATE ORALSUSPENSION USPUsual dose:

Note: There are no dose recommendations specific to animals for this

dosage form.


U.S.—




40 mg per mL (Rx) [E.E.S.; Erythro; generic].

80 mg per mL (Rx) [E.E.S.; Erythro; generic].

Canada—



Store in a tight container.

Stability: After dispensing, suspensions do not require refrigeration if

used within 14 days. Some manufacturers recommend storage in

light-resistant containers to prevent discoloration.{R-36}

USP requirements: Preserve in tight containers, and store in a cold

place. A suspension of Erythromycin Ethylsuccinate containing one or

more suitable buffers, colors, dispersants, flavors, and preservatives.

Contains an amount of erythromycin ethylsuccinate equivalent to the

labeled amount of erythromycin, within –10% to +20%. Meets the

requirements for Identification, Uniformity of dosage units (single-unit

containers), Deliverable volume, and pH (6.5–8.5).{R-22}

ERYTHROMYCIN ETHYLSUCCINATE FOR ORALSUSPENSION USPUsual dose: See Erythromycin Ethylsuccinate Oral Suspension USP.



U.S.:




40 mg per mL (Rx) [E.E.S.; EryPed; generic].

80 mg per mL (Rx) [EryPed; generic].

Canada:




20 mg per mL (Rx) [Novo-Rythro].

40 mg per mL (Rx) [E.E.S.; Novo-Rythro].

80 mg per mL (Rx) [E.E.S.].


(104 �F), preferably between 15 and 30� C (59 and 86 �F), unless

otherwise specified by manufacturer. Store in a tight container.

Stability: After reconstitution, depending on the manufacturer or the

specific product, suspensions do not require refrigeration if used within

14 days.


Erythromycin Ethylsuccinate with one or more suitable buffers, colors,

diluents, dispersants, and flavors. Contains an amount of erythromy-

cin ethylsuccinate equivalent to the labeled amount of erythromycin,


Uniformity of dosage units (single-unit containers), Deliverable vol-

ume, pH (7.0–9.0, in the suspension constituted as directed in the

labeling), and Loss on drying (not more than 1.0%).{R-22}

ERYTHROMYCIN ETHYLSUCCINATE TABLETS USPUsual dose: See Erythromycin Ethylsuccinate Oral Suspension USP.

Strength(s) usually available.

U.S.—




400 mg (Rx) [E.E.S.; generic].

Canada—




600 mg (Rx) [Apo-Erythro-ES; E.E.S.].








USP requirements: Preserve in tight containers. Label the chewable

Tablets to indicate that they are to be chewed before swallowing.

Contain an amount of erythromycin ethylsuccinate equivalent to the

labeled amount of erythromycin, within –10% to +20%. Meet the


0.01 N hydrochloric acid in Apparatus 2 at 50 rpm for nonchewable

tablets and 75% in 60 minutes in 0.1 M acetate buffer [pH 5.0] in

Apparatus 2 at 75 rpm for Tablets labeled as chewable), Uniformity of

dosage units, Loss on drying (not more than 4.0% [Note: Chewable

Tablets are exempt from this requirement]), and Water (Chewable

Tablets only, not more than 5.0%).{R-22}

ERYTHROMYCIN ETHYLSUCCINATE TABLETS(CHEWABLE) USPUsual dose: See Erythromycin Ethylsuccinate Oral Suspension USP.


U.S.—




200 mg (Rx) [EryPed].

400 mg (Rx) [Erythro].

Canada—




200 mg (Rx) [E.E.S. (scored); EryPed].




USP requirements: Preserve in tight containers. Label the chewable

Tablets to indicate that they are to be chewed before swallowing.

Contain an amount of erythromycin ethylsuccinate equivalent to the

labeled amount of erythromycin, within –10% to +20%. Meet the


0.01 N hydrochloric acid in Apparatus 2 at 50 rpm for nonchewable

tablets and 75% in 60 minutes in 0.1 M acetate buffer [pH 5.0] in

Apparatus 2 at 75 rpm for Tablets labeled as chewable), Uniformity of

dosage units, Loss on drying (not more than 4.0% [Note: Chewable

Tablets are exempt from this requirement]), and Water (Chewable

Tablets only, not more than 5.0%).{R-22}

ERYTHROMYCIN GLUCEPTATE





in terms of erythromycin base (not the gluceptate salt).

STERILE ERYTHROMYCIN GLUCEPTATE USPUsual dose: [Antibacterial]1—Foals: Intravenous, 5 mg (base) per kg of

body weight every four to six hours.{R-26}


U.S.—




1 gram (base) (Rx) [Ilotycin].

Canada—




500 mg (base) (Rx) [Ilotycin].

1 gram (base) (Rx) [Ilotycin].




Preparation of dosage form:{R-37}

To prepare solution, add at least 10 mL of sterile water for injection to

each 500-mg vial and at least 20 mL of diluent to each 1-gram vial.

After initial dilution, solution may be further diluted to a concentration of

1 gram per L in 0.9% sodium chloride injection or 5% dextrose

injection for slow, continuous infusion.

Stability: After reconstitution, initial dilutions (25 to 50 mg per mL)

retain their potency for 7 days if refrigerated.{R-37}

USP requirements: Preserve in Containers for Sterile Solids. It is

Erythromycin Gluceptate suitable for parenteral use. Has a potency

equivalent to not less than 600 mcg of erythromycin per mg, calcu-

lated on the anhydrous basis. In addition, where packaged for dis-

pensing, contains an amount of erythromycin gluceptate equivalent to

the labeled amount of erythromycin, within –10% to +15%. Meets the

requirements for Identification, Bacterial endotoxins, Sterility, pH

(6.0–8.0, in a solution containing 25 mg per mL), Water (not more

than 5.0%), and Particulate matter, and, where packaged for dis-

pensing, Uniformity of dosage units, Constituted solutions, and

Labeling under Injections.{R-22}

ERYTHROMYCIN LACTOBIONATE

PARENTERAL DOSAGE FORMSNote: The strengths of the dosage forms available are expressed in terms

of erythromycin base (not the lactobionate salt).

ERYTHROMYCIN LACTOBIONATE FOR INJECTION USPUsual dose:

Note: There are no dose recommendations specific to animals for this

dosage form.


U.S.—{R-39}








500 mg (base) (Rx) [Erythrocin; generic].

1 gram (base) (Rx) [Erythrocin; generic].

Canada—




500 mg (base) (Rx) [Erythrocin].

1 gram (base) (Rx) [Erythrocin].




Preparation of dosage form: See manufacturer’s product labeling.

Stability:

After reconstitution, initial dilutions (50 mg per mL) retain their potency

for 14 days if refrigerated, or for 24 hours at room temperature.

Infusions prepared in piggyback infusion bottles retain their potency for 8

hours at room temperature, for 24 hours if refrigerated, or for 30 days

if frozen.

Acidic infusions are unstable and lose potency rapidly. A pH of at least

5.5 is recommended for final dilutions, which should be administered

completely within 8 hours after dilution.

USPrequirements: Preserve in Containers for Sterile Solids. A sterile, dry

mixture of erythromycin lactobionate and a suitable preservative. Con-

tains an amount of erythromycin lactobionate equivalent to the labeled

amount of erythromycin, within –10% to +20%. Meets the requirements

for Constituted solution, Identification, Bacterial endotoxins, pH (6.5–

7.5, in a solution containing the equivalent of 50 mg of erythromycin per

mL), Water (not more than 5.0%), Particulate matter, and Heavy metals

(not more than 0.005%), and for Injections.{R-22}

ERYTHROMYCIN PHOSPHATE

SUMMARY OF DIFFERENCESPharmacology/pharmacokinetics: Absorption—

Erythromycin phosphate is presumed to dissociate in the duodenum

and be absorbed as the free base.{R-18}

Horses: Erythromycin phosphate is absorbed at least as well as

erythromycin estolate when administered orally.{R-18}

ORAL DOSAGE FORMSNote: The dosing and strengths of the dosage form available are expressed

in terms of erythromycin phosphate (not erythromycin base).

1.12 grams of erythromycin phosphate equal 1 gram of erythromycin

base{R-8}.

ERYTHROMYCIN PHOSPHATE POWDER FOR ORALSOLUTIONUsual dose:

Chronic respiratory disease—Chickens: Oral, 500 mg per gallon of

water, administered as the only source of drinking water every

twenty-four hours for five days{R-3}.

Coryza, infectious—Chickens: Oral, 500 mg per gallon of water,

administered as the only source of drinking water for seven

days.{R-3}

Enteritis—Turkeys: Oral, 500 mg per gallon of water, administered as

the only source of drinking water for seven days.{R-3}

Note: Dosage ranges for birds are approximate, based on variable water

consumption and animal size.


U.S.—{R-3; 6; 8}


260 mg (231.2 mg erythromycin base) per gram (OTC) [Gallimycin

PFC].

Canada—{R-8; 9}


130 mg (115.6 mg base) per gram (OTC) [Gallimycin; Gallistat].

260 mg (231.2 mg base) per gram (OTC) [Gallimycin PFC].

Withdrawal times:

U.S. and Canada—{R-3; 9}

Withdrawal time

Species Meat (days)

Chickens and turkeys 1

Note: Products are not labeled for use in birds producing eggs for human

consumption or in replacement pullets over 16 weeks of age{R-3; 9}.

Canadian product labeling lists the dose as 116 mg (base) per liter of

water for chickens and turkeys.



manufacturer.

Stability: Solutions should be discarded after 3 days.{R-8}


ERYTHROMYCIN STEARATE

SUMMARY OF DIFFERENCESPharmacology/pharmacokinetics: Absorption—Erythromycin stearate

dissociates in the duodenum and is absorbed as the free base.{R-18}





in terms of erythromycin base (not the stearate salt).

ERYTHROMYCIN STEARATE ORAL SUSPENSIONUsual dose: [Enteritis, Campylobacter]1—Dogs: Oral, 10 mg (base) per

kg of body weight every eight hours.{R-10}


U.S.—


Canada—




25 mg (base) per mL (Rx) [Erythrocin; Novo-rythro].

50 mg (base) per mL (Rx) [Erythrocin; Novo-rythro].






Auxiliary labeling:

• Refrigerate.

• Shake well.


ERYTHROMYCIN STEARATE TABLETS USPUsual dose: See Erythromycin Stearate Oral Suspension.


U.S.—




250 mg (base) (Rx) [Erythrocin; Erythrocot; My-E;Wintrocin; generic].

500 mg (base) (Rx) [Erythrocin; generic].

Canada—




250 mg (base) (Rx) [Apo-Erythro-S; Erythrocin; Novo-rythro].

500 mg (base) (Rx) [Apo-Erythro-S; Erythrocin].




Note: Some manufacturers recommend storage in light-resistant con-

tainers to prevent discoloration.


erythromycin stearate equivalent to the labeled amount of erythro-

mycin, within –10% to +20%. Meet the requirements for Identifica-

tion, Dissolution (75% in 120 minutes in 0.05 M phosphate buffer [pH

6.8] in Apparatus 2 at 100 rpm), Uniformity of dosage units, and Loss

on drying (not more than 5.0%).{R-22}

ERYTHROMYCIN THIOCYANATE

ORAL DOSAGE FORMSNote: 1.08 grams of thiocyanate salt equal 1 gram of erythromycin

base{R-54}.

ERYTHROMYCIN THIOCYANATE FOR MEDICATED FEEDUsual dose:

Coryza, infectious (prophylaxis)1—Chickens: Oral, 100 grams (93

grams of base) per ton of feed, fed as the only ration for seven to

fourteen days.{R-54}

Respiratory disease, chronic (prophylaxis)1—Chickens and turkeys: Oral,

100 grams (93 grams of base) per ton of feed, fed as the only ration from

two days before stress until three to six days after stress.{R-54}

Respiratory disease, chronic (treatment)—Chickens and turkeys1: Oral,

200 grams (185 grams of base) per ton of feed, fed as the only

ration.{R-54}


U.S.—{R-8; 54}


220 grams (203 grams of base) per kg of premix (OTC) [Erymycin-100].

Canada—{R-8; 64}


110 grams (102 grams of base) per kg of premix (OTC) [Gallimycin-50].

Withdrawal times:

U.S.—{R-54}

With a dose of 200 grams (185 grams of base) per ton of feed:

Withdrawal time

Species Meat (days)

Chickens 2

Turkeys 0

Note: Product is not labeled for use in birds producing eggs for human

consumption{R-54}.

With a dose of 100 grams (93 grams of base) per ton of feed:

Withdrawal time

Species Meat (days)

Chickens 1

Turkeys 0

Note: Product is not labeled for use in birds producing eggs for human

consumption{R-54}.

Canada—

Withdrawal time

Species Meat (days)

Chickens 1


applies to a dose of 220 grams per metric ton (1000 kg) of feed, fed as

the only ration, to chickens.{R-64}

Not labeled for use in chickens producing eggs for human consump-

tion.


15 and 30 �C (59 and 86 �F), unless otherwise specified by manufacturer.


TILMICOSIN PHOSPHATE

ADDITIONAL DOSING INFORMATIONTilmicosin injection should be given only by subcutaneous administra-

tion because intravenous administration is fatal with doses as low as 5

mg per kg of body weight.{R-53}

Parenteral administration of tilmicosin to pigs by any route often is fatal.{R-53}







ORAL DOSAGE FORMSNote: The dosing and strengths of the dosage form available are

expressed in terms of tilmicosin base (not the phosphate salt).

TILMICOSIN FOR MEDICATED FEEDUsual dose: Pneumonia, bacterial—Pigs: Oral, 181 to 383 grams per

ton of feed, fed as the only ration for twenty-one days, beginning

approximately seven days before an anticipated disease outbreak, if

possible{R-107; 114}.


U.S.—


200 grams (base) per kg (90.7 grams [base] per pound) of premix

(Rx) [Pulmotil 90].

Canada—


200 grams (base) per kg (OTC) [Pulmotil Premix].

Withdrawal times:

U.S.{R-107}—

Withdrawal time

Species Meat (days)

Pigs 7

Canada{R-114}—

Withdrawal time

Species Meat (days)

Pigs 7



manufacturer.

Preparation of dosage form: Tilmicosin should not be mixed in con-

centrates or feeds containing bentonite because bentonite may reduce

the efficacy of tilmicosin{R-107}. Premix should be thoroughly mixed in

feed before administration{R-107}.

Caution: Inhalation, oral exposure, and direct contact with eyes should

be avoided{R-107}.





The dosing and strengths of the dosage form available are expressed in

terms of tilmicosin base (not the phosphate salt).

TILMICOSIN INJECTION USPUsual dose: Pneumonia, bacterial—

Cattle: Subcutaneous, 10 mg (base) per kg of body weight as a single

dose{R-53}.

[Calves] and [lambs]: Subcutaneous, 10 mg (base) per kg of body

weight as a single dose{R-65; 112}.

Note: Tilmicosin should not be administered intravenously. Intramus-

cular administration should be avoided. No more than 15 mL should

be administered per injection site.{R-53}


U.S.—


300 mg (base) per mL (Rx) [Micotil].

Canada—


300 mg (base) per mL (Rx) [Micotil].

Withdrawal times:

U.S.—

Withdrawal time

Species Meat (days)

Cattle 28


applies to a dose of 10 mg (base) per kg of body weight administered

once to cattle.

Not labeled for use in lactating cattle.

Tilmicosin should not be used in lactating dairy cows because of its

extended antimicrobial activity in milk. A single subcutaneous

tilmicosin dose of 10 mg per kg of body weight resulted in tilmicosin

concentrations detectable in milk for 19 to 31 days when measured by

high performance liquid chromatography or 14 to 21 days when

measured by Bacillus stearothermophilus assay{R-74}.

Canada—

Withdrawal time

Species Meat (days)

Calves, cattle, lambs 28


applies to a dose of 10 mg (base) per kg of body weight administered

once to cattle or lambs{R-112}.

Not labeled for use in lactating dairy cattle, veal calves, calves

weighing less than 70 kg, or lactating sheep{R-92}.

Packaging and storage: Store at or below 30 �C (86 �F). Protect from

light.{R-53}

Caution: Injection of tilmicosin in humans may be fatal. Caution should

be exercised to avoid self-injection. An automatically powered syringe

should not be used for administration.{R-53}

Auxiliary labeling:

• Keep out of the reach of children.

• Avoid contact with eyes.

USP requirements: Preserve in light-resistant Containers for Injec-

tions. Store at or below 30�. A sterile solution of Tilmicosin in a

mixture of Propylene Glycol and Water for Injection, solubilized with

the aid of Phosphoric Acid. Label the Injection to indicate that it is for

veterinary use only. Contains the labeled amount, within ±10%. Meets

the requirements for Identification, Bacterial endotoxins, Sterility, pH



(5.5–6.5), Particulate matter, and Content of propylene glycol (within

±20% of labeled amount){R-22}.

TYLOSIN BASE

SUMMARY OF DIFFERENCESPharmacology/pharmacokinetics: Tylosin is stable enough in acid envi-

ronments to be administered orally without enteric coating.{R-58}




TYLOSIN INJECTIONUsual dose:

Arthritis, infectious1;

Erysipelas; or

Swine dysentery—Pigs: Intramuscular, 8.8 mg per kg of body weight

every twelve hours{R-51}.

Note: When used to treat swine dysentery, tylosin injection should be

followed by administration of medication in feed or drinking

water.{R-51}

Diphtheria1;

Metritis; or

Pododermatitis1—Cattle, beef and nonlactating dairy: Intramuscular,

17.6 mg per kg of body weight every twenty-four hours.{R-51; 52; 55}.


Cattle, beef and nonlactating dairy: Intramuscular, 17.6 mg per kg of

body weight every twenty-four hours{R-51; 55}.

Pigs: Intramuscular, 8.8 mg per kg of body weight every twelve

hours{R-51}.

Note: In pigs, no more than 5 mL per injection site is recommended;

in cattle, no more than 10 mL per injection site.{R-51; 52}

Note: [Cats]1 and [dogs]1—A dose of 6.6 to 11 mg per kg of body weight

every twelve to twenty-four hours has been used in the treatment of

respiratory tract infections in cats and dogs{R-108}.


U.S.—


50 mg per mL (OTC) [Tylan 50].

200 mg per mL (OTC) [Tylan 200; TyloVed; generic].

Canada—{R-55}


200 mg per mL (OTC) [Tylan 200; Tylocine 200].

Withdrawal times:

U.S.—{R-51; 52}

Withdrawal time

Species Meat (days)

Cattle 21

Pigs 14


apply to a maximum treatment period of 5 days in cattle and

maximum treatment period of 3 days in pigs{R-51; 52}. Not for use in

lactating dairy cattle{R-51} or preruminant calves.

If tylosin-medicated drinking water is used as a follow-up treatment for

swine dysentery, feed containing 40 to 100 grams of tylosin phosphate

for medicated feed per ton of feed is recommended to assure depletion

of tissue residues.{R-51; 52}

Canada—{R-55}

Withdrawal time

Species Meat (days)

Cattle 21

Pigs 14


apply to a dose of 17.6 mg per kg of body weight (mg/kg) for cattle and

2.2 to 8.8 mg/kg every 24 hours for pigs. Not for use in lactating dairy

cattle.

To avoid excessive trim, swine should not be slaughtered for 21 days

after treatment; cattle should not be slaughtered for 42 days after

treatment.{R-55}



manufacturer.

Incompatibilities: To avoid precipitation, tylosin injection should not

be mixed with other injectables.{R-51}

Caution:

Contact with human skin should be avoided.

Injection into pigs weighing less than 6.25 pounds should not be attempted

unless the syringe is capable of accurately delivering 0.1 mL. Adverse

reactions may occur from overdosage in piglets.{R-51; 52}


TYLOSIN PHOSPHATE

ORAL DOSAGE FORMS

TYLOSIN GRANULATED USPUsual dose:

Abscesses, hepatic (prophylaxis)1—Cattle, beef: Oral, 8 to 10 grams per

ton of feed (approximately 60 to 90 mg per animal a day), fed as the

only ration{R-49}.

Atrophic rhinitis1—Pigs: Oral, 100 grams per ton of feed, fed as the

only ration{R-49}.

Dysentery, swine—Pigs:

Prophylaxis—Oral, 100 grams per ton of feed, fed as the only ration

for at least three weeks, followed by 40 grams per ton of feed, fed

as the only ration{R-49}.

Treatment—Oral, 40 to 100 grams per ton of feed, fed as the only

ration for two to six weeks{R-48; 49}.

Note: The dose shown for treatment with tylosin phosphate for

medicated feed should follow an initial treatment with tylosin

powder for oral solution in the drinking water for three to ten

days{R-49; 100}.





Feed efficiency, improvement of1; or

Increased weight gain1—

Chickens: Oral, 4 to 50 grams per ton of feed, fed as the only ration{R-

49}.

Chickens, laying: Oral, 20 to 50 grams per ton of feed, fed as the only

ration{R-49}.

Pigs: Oral, 10 to 40 grams per ton of feed, fed as the only ration{R-48;

49}.

Proliferative enteropathy, porcine (prophylaxis and treatment)1—Pigs:

Oral, 100 grams per ton of feed, fed as the only ration for three

weeks{R-49}.

Respiratory disease, chronic1—

Chickens, broiler: Oral, 800 to 1000 grams per ton of feed, fed as the

only ration.

Chickens, replacement: Oral, 1000 grams per ton of feed, fed as the

only ration.

Note: Medication should be administered in feed to chickens up to 5

days of age, then administered again for twenty-four to forty-eight

hours to chickens 3 to 5 weeks of age.


U.S.—


22 grams per kg (10 grams per pound) of premix (OTC) [Tylan 10].



Canada—


22 grams per kg of premix (OTC) [Tylan 10; Tylosin 10 Premix].

88 grams per kg of premix (OTC) [Tylan 40; Tylosin 40 Premix].

220 grams per kg of premix (OTC) [Tylan 100].

Withdrawal times:

U.S.{R-49; 100}—

When fed at doses of 10 to 100 grams of tylosin phosphate per ton of

feed:

Withdrawal time

Species Meat (days)

Pigs 0

When fed at doses of 800 to 1000 grams of tylosin phosphate per ton of

feed:

Withdrawal time

Species Meat (days)

Chickens 5

Canada—

When fed at a dose of 110 grams of tylosin phosphate per metric ton

(1000 kg) of feed:

Withdrawal time

Species Meat (days)

Pigs 0

Note: Product labeling listing the above withdrawal time states that

when tylosin premix is administered concurrently with tylosin

tartrate in drinking water, a withdrawal time of two days is

necessary.



manufacturer.

Preparation of dosage form: Medication should be thoroughly mixed

in feed before use. It should not be used in any feed containing more

than 2% bentonite.{R-49}

Caution: When handling and mixing medication, protective clothing

and impervious gloves should be used. Contact with human skin

should be avoided.{R-49}

USP requirements: Preserve in well-closed, polyethylene-lined or

polypropylene-lined containers, protected from moisture and excessive

heat. Contains tylosin phosphate mixed with suitable carriers and

inactive ingredients. Label it to indicate that it is for animal use only.

Label it also to indicate that it is for manufacturing, processing, or

repackaging. Contains the labeled amount, within ± 20%. Meets the

requirement for Identification, Loss on drying (not more than 12.0%),

Powder fineness, and Content of tylosins.{R-22}

TYLOSIN TARTRATE




1.1 grams of tylosin tartrate equals 1 gram of tylosin base{R-90}. The

dosing and strengths of the dosage forms available are expressed in

terms of the base.

TYLOSIN TARTRATE POWDER FOR ORAL SOLUTIONUsual dose:

Dysentery, swine—Pigs: Oral, 250 mg per gallon of water, as the only

source of drinking water for three to ten days.{R-50}

Respiratory disease, chronic—Chickens: Oral, 2 grams (base) per gallon

(approximately, 110 mg per kg of body weight a day) in the only

source of drinking water for three to five days.{R-50}

Sinusitis, infectious—Turkeys: Oral, 2 grams per gallon (approximately

132 mg per kg of body weight a day) in the only source of drinking

water for three to five days.{R-50}

Note: [Dogs]1—There are insufficient data to establish the efficacy of

tylosin in the treatment of chronic colitis in dogs; however, an oral

dose of 11 mg per kg of body weight every eight hours has been

recommended{R-84}.

Note that reformulation is necessary for administration to dogs{R-

109}.

Size(s) usually available{R-8; 50}:

U.S.—


100 grams (base) of powder (OTC) [Tylan Soluble].





Canada—


100 grams (base) of powder (OTC) [Tylan Soluble].

Withdrawal times{R-8}:

U.S.—

Withdrawal time

Species Meat (days)

Chickens 1

Turkeys 5


apply to a dose of 250 mg per gallon of drinking water for pigs and 2

grams per gallon of drinking water for chickens and turkeys. Product

is not labeled for use in birds producing eggs for human consump-

tion{R-50}.

Canada—

Withdrawal time

Species Meat (days)

Chickens 1

Pigs 2

Turkeys 3


they apply to a dose of 1 gram per 4 L (approximately 1 gallon) of

drinking water for 3 to 10 days for pigs, 2 grams per 4 L of drinking

water for 3 to 5 days for chickens, and 2 grams per 4 L of drinking

water for 3 to 5 days for turkeys.{R-66}



manufacturer.

Preparation of dosage form: A fresh solution of tylosin tartrate should

be prepared every 3 days. Water should be added to powder (not

powder added to water) when preparing the solution.{R-50}

Caution: Contact with human skin should be avoided. Protective

clothing and impervious gloves should be worn when mixing and

handling solutions.{R-50}


Developed: 07/22/97

Revised: 09/30/02


Table 1. Pharmacology/pharmacokinetics.

Drug

Protein

binding

(%)

Elimination

half-life

(hr)

Volume of

distribution

(L/kg)

Clearance

(mL/min/kg)

Route; Dose

(mg/kg)

Tmax

(hr)

Cmax

(mcg/mL)

Bioavailablity

(%)

Azithromycin

Cats{R-120} Terminal: 35 Steady state: 23 10.7 IV; 5

PO; 5 0.85 0.97 58

Dogs (beagles) 16–26* 29 Steady state: 12 IV; 24 0.33 4.2 97{R-123} PO; 24

Foals, 8- to 14- 16 Area: 12.4 10 IV; 5

weeks{R-121} Terminal: 16.3 Steady state: 11.6 PO; 10 1.4 0.72 39

Foals, 6- to 10- 20.3 Area: 22.3 10.4 IV; 10

weeks{R-122} Steady state: 18.6 PO; 10 1.8 0.57 56

Human data{R-115} 7–50� 11 to 14 Steady state: 33 PO: 500 mg

total dose

2 to 3 0.4 37

Rats{R-123} 14–29* 32 Steady state: 84 IV; 20

PO; 20 2.0 0.29 46

Clarithromycin

Dogs (crossbred

beagles){R-124}Terminal: 3.9 Steady state: 1.4 4.3 IV; 10

Fed PO; 10 1.6 3.3 70

Fasted PO; 10 1.7 3.5 79

Erythromycin

Calves{R-23} 2.2 Area: 1.5 7.8 IV; 15

Cattle{R-21} 18 IV/IM; 20{R-25} 3.2 Area: 0.79 2.9 IV; 12.5

Dogs{R-62} 1.7 Steady state: 2.7 21 IV; 10

Horses, foals{R-26} 1 Area: 2.3 to 7.2 IV; 5 to 20

Mice{R-62} 0.7 Steady state: 3.6 77 IV; 10

Pigeons{R-27} 0.9 IV; 20

PO; 100 10

Rabbits{R-62} 0.7 Steady state: 6.8 53 IV; 10

Rats{R-62} 0.7 Steady state: 9.3 73 IV; 25

Sheep{R-21} 23 IV/IM; 20





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2nd ed. Ames, IA: Iowa State University Press, 1993: 119–26; 187–203.

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02.

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Table 1. (Contd.)

Drug

Protein

Binding

(%)

Elimination

Half-life

(hr)

Volume of

Distribution

(L/kg)

Clearance

(mL/min/kg)

Route; Dose

(mg/kg)

Tmax

(hr)

Cmax

(mcg/mL)

Bioavailablity

(%)

Tilmicosin

Cattle{R-91} SC; 10 1.8 0.13{R-104} SC; 10 1 0.71

Tylosin

Calves,

newborn{R-73}

2.3 Area: 4.4 24.5 IV; 10

Calves, 1 week

to 9 months

1 to 15 Area: 3.6 to 4.4 32 to 48 IV: 10

Calves, 7

weeks{R-69}1.2 Area: 2.5 23.7 IV; 10

Chickens{R-71} 30

Cattle{R-20} 33.5 IV/IM; 20{R-25; 80} 1.6 Area: 1.1 7.8 IV; 12.5{R-79} 2.1 IV; 20

Dogs{R-68} 0.9 Area: 1.7 22 IV; 10

IM; 10 0.5 1.5

Goats{R-72} 38 3 Area: 1.7 6.8 IM; 15 4.2 2.4 73

Sheep{R-20} 38 IV/IM; 20{R-79} 2.1 IV; 20

*Protein binding is concentration dependent, reported as increasing with decreasing concentration from 10 to 0.02 mg/L.

�Protein binding is concentration dependent, reported as increasing with decreasing concentration from 1 to 0.2 mcg/mL.



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METRONIDAZOLE Veterinary—Systemic

Some commonly used brand names for human-labeled products are: Apo-

Metronidazole; Flagyl; Flagyl I.V.; Flagyl I.V. RTU; Metric 21; Metro I.V.;

Novonidazol; Protostat; and Trikacide.



CATEGORY:Antibacterial (systemic); antiprotozoal.

INDICATIONSNote: In other USP DI monographs, bracketed information in the

Indications section refers to uses that are not included in U.S. product

labeling, and superscript 1 refers to uses that are not included in

Canadian product labeling. However, since metronidazole is not

specifically approved for veterinary use, there is no product labeling

identifying approved indications.

GENERAL CONSIDERATIONSMetronidazole is effective in the treatment of systemic and enteric

obligate anaerobic bacterial infections, including Clostridium species,

Fusobacterium species{R-1}, and penicillinase-producing strains of

Bacteroides{R-2; 3}. Surgical therapy may be necessary to completely

resolve isolated infections{R-3}.

Metronidazole is not clinically effective against facultative anaerobes or

obligate aerobes{R-1; 4}. However, it is often combined with another

antibiotic or antibiotics effective against aerobes to treat mixed

bacterial infections{R-2}.

Metronidazole is considered effective in the treatment of some protozoal

infections in animals.

ACCEPTED[Giardiasis (treatment)]1—Cats and dogs: Metronidazole is used to

eliminate shedding of giardial cysts and treat associated diarrhea in

cats and dogs{R-6; 7; 36}. Environmental eradication is necessary for

effective treatment. The infection may not be completely cleared in all

animals{R-7}.

ACCEPTANCE NOT ESTABLISHED[Amebiasis, intestinal (treatment)]1;

[Balantidiasis, intestinal (treatment)]1; or

[Trichomoniasis, intestinal (treatment)]1—Cats and dogs: In human

patients, metronidazole is used in the treatment of susceptible Balan-

tidium coli, Entamoeba histolytica, and Trichomonas species{R-1; 4; 5}.

Metronidazole is also recommended in the treatment of enteric

protozoal infections in cats and dogs, although the relationship

between infection and clinical signs can be difficult to define.

[Bowel disease, inflammatory (treatment)]1—Cats and dogs: Although

there are insufficient data to establish efficacy, metronidazole is used in

the treatment of inflammatory bowel disease.

[Colitis, antibiotic-associated (treatment)]1; or

[Colitis, clostridial (treatment)]1—Horses: Although there are insufficient

data to establish efficacy, metronidazole is used in the treatment of

bacterial colitis caused by susceptible organisms, including Clostridium

difficile{R-10–12}.

[Encephalopathy, hepatic (treatment)] —Cats and dogs: Although there

are insufficient data to establish efficacy, metronidazole is used to

reduce gastrointestinal bacterial production of ammonia thought to

contribute to clinical signs in hepatic encephalopathy.

[Endometritis (treatment)]1—Horses: Although there are insufficient data

to establish efficacy, metronidazole is used in combination with other

antibiotics in the treatment of endometritis, including infections

caused by penicillinase-producing anaerobic bacteria{R-13}.

[Helicobacter species infections (treatment)]1—Cats and dogs: Although

the treatment of Helicobacter pylori in human gastrointestinal disease

has had major clinical impact, there is currently little evidence to

suggest that these organisms significantly affect gastrointestinal

function in cats and dogs or that metronidazole, in combination

with another antibiotic and bismuth subsalicylate or subcitrate,

will produce long-term eradication of Helicobacter species in these

species{R-22–26}.

[Infections, bacterial (treatment)]1, including

[Bone and joint infections (treatment)]1;

[Central nervous system infections (treatment)]1;

[Intra-abdominal infections (treatment)]1;

[Perioperative infections, colorectal (prophylaxis)]1;

[Respiratory tract infections, lower (treatment)]1;

[Septicemia, bacterial (treatment)]1; or

[Skin and soft tissue infections (treatment)]1—Cats, dogs, and horses:

Although there are insufficient clinical research data to establish

efficacy, metronidazole is used in the treatment of many types of

anaerobic bacterial infections in animals. In human patients,

metronidazole is indicated, usually in combination with other

antibiotics, in the prevention of perioperative infections during

colorectal surgery and in the treatment of bone and joint infections;

central nervous system infections; intraoperative infections; lower

respiratory tract infections, including pleuropneumonia and

lung abscess; septicemia; and skin and soft tissue infections

caused by susceptible species, including Bacteroides and Clostridium

species{R-1; 4}. There are limited pharmacokinetic data and case

reports available pertaining to the use of metronidazole in the treatment

of these types of infections in animals{R-8; 9; 12; 14; 16; 19–21; 28}.

[Periodontal infections (treatment)]1—Cats and dogs: Metronida-

zole is used in the treatment of periodontal infections in cats and

dogs{R-15; 17; 18} It may be administered for destructive periodontal

diseases as part of a treatment plan that also includes one or more of

the following: dental scaling, gingival crevicular lavage, periodontal

surgery, or regular teeth cleaning{R-17}.


The Food and Drug Administration has not approved the use of

metronidazole in animals. The use of nitroimidazoles in food animals

is strictly prohibited.{R-27}

Canada—

Metronidazole is not approved for use in food-producing animals.

There are no established withdrawal times.

144 METRONIDAZOLE Veterinary—Systemic


CHEMISTRYChemical group: Nitroimidazoles.

Chemical name:

Metronidazole—1H-Imidazole-1-ethanol, 2-methyl-5-nitro-.{R-29}

Metronidazole hydrochloride—1H-Imidazole-1-ethanol, 2-methyl-5-

nitro-, hydrochloride.{R-29}

Molecular formula:

Metronidazole—C6H9N3O3.{R-29}

Metronidazole hydrochloride—C6H9N3O3 Æ HCl.{R-29}

Molecular weight:

Metronidazole—171.15.{R-29}

Metronidazole hydrochloride—207.61.{R-29}

Description: Metronidazole USP—White to pale yellow, odorless crys-

tals or crystalline powder. Is stable in air, but darkens on exposure to

light.{R-30}

Solubility: Metronidazole USP—Sparingly soluble in water and in alco-

hol; slightly soluble in ether and in chloroform.{R-30}


Mechanism of action/effect: Metronidazole is reduced as it enters the

target cell where it interacts with bacterial or protozoal DNA, causing

a loss of helical structure and strand breakage in the DNA; these effects

inhibit nucleic acid synthesis and cause death of the cell.

Absorption: Metronidazole is moderately well absorbed from the gas-

trointestinal tract.{R-21; 33; 37}

Distribution: Horses—In one pharmacokinetic study of horses, peak

metronidazole concentrations in peritoneal fluid, synovial fluid, and

cerebrospinal fluid were 65%, 92%, and 30% of peak serum concen-

trations.{R-21} With an oral dose of 7.5 mg/kg every 6 hours, endo-

metrial penetration was poor{R-21}.

Biotransformation: Hepatic, metabolized primarily by side-chain

oxidation and glucuronide synthesis.

Pharmacokinetic data:


CARCINOGENICITY/MUTAGENICITYMetronidazole has been shown to be a carcinogen in mice and rats with

chronic oral administration. It has also been shown to be mutagenic in

in vitro assays.{R-1; 4}

PREGNANCY/REPRODUCTIONPregnancy—Metronidazole readily crosses the placenta and enters the

fetal circulation{R-1}. No teratogenic effects were seen in the pups of rats

that had received 250 mg per kg of body weight (mg/kg) a day for 1 to

12 days, or 100 mg/kg a day for 40 days. However, spermatogenesis in

male rats was affected by the administration of 100 mg/kg a day.

LACTATIONMetronidazole is distributed into milk at concentrations similar to plasma

concentrations{R-1; 4}. Risk-benefit should be considered carefully

when metronidazole is used in nursing animals.

DRUG INTERACTIONS AND/OR RELATED PROBLEMSThe followingdrug interactions and/or related problemshavebeen selected

on the basis of their potential clinical significance (possiblemechanism in

parentheses where appropriate)—not necessarily inclusive:


ing on the amount present, may also interact with metronidazole.

Cimetidine

(hepatic metabolism of metronidazole may be decreased when

metronidazole and cimetidine areused concurrently, possibly resulting

in delayed elimination and increased serum metronidazole concen-

trations{R-5}; dosage of metronidazole may need to be adjusted)

Phenobarbital

(phenobarbital may induce microsomal liver enzymes, increasing

metronidazole’s metabolism and resulting in a decrease in half-life

and plasma concentration{R-5}; dosage of metronidazole may need to

be adjusted)




THOSE INDICATING NEED FOR MEDICAL ATTENTIONNeurologic disturbances (ataxia, nystagmus, seizures, tremors,

weakness)—with high dosage in cats, dogs, and horses{R-31; 32}

THOSE INDICATING NEED FOR MEDICAL ATTENTIONONLY IF THEY CONTINUE OR ARE BOTHERSOMEAnorexia; neutropenia; vomiting

THOSE NOT INDICATING NEED FOR MEDICALATTENTIONReddish brown urine




Table 1. Intravenous administration.

Species

Half-life of

elimination (hours)

Volume of

distribution (L/kg)

Clearance

(mL/kg/min)

Dogs{R-37} 4.48 ± 0.89 Area: 0.95 ± 0.10 2.49 ± 0.54

Horses{R-33} 2.9 Area: 1.70 ± 0.24 6.67 ± 0.83{R-21} 3.11 ± 0.21 Area: 0.74 ± 0.01 2.8 ± 0.18

Steady state: 0.69 ± 0.01{R-39} 3.27 ± 0.65 Steady state: 0.68 ± 0.16 2.8 ± 0.8

Table 2. Oral administration.

Species

Dose

(mg/kg)

Cmax

(mcg/mL)

Tmax

(hour)

Bioavailability

(%)

Dogs{R-37} 44 42* 1* 59 to 100

Horses{R-33} 25 12.6 ± 2.4 1 to 2 85.0 ± 18.6{R-39} 20 22 ± 8 1.1 ± 0.6 74 ± 18{R-21}� 15 13.9 ± 2.18 0.67 97 ± 5.7

*Read from graph.

�Two horses with pleuropneumonia yielded similar kinetic results to that of healthy

mares in this study.

METRONIDAZOLE Veterinary—Systemic 145


included in the human monograph Metronidazole (Systemic) in USP DI



metronidazole in the treatment of animals:


Central nervous system (CNS) effects; gastrointestinal distur-

bance


Change in taste sensation; CNS toxicity, including ataxia and

encephalopathy; dark urine; dryness of mouth; hypersensitiv-

ity; leukopenia; pancreatitis; peripheral neuropathy—usually

with high doses or prolonged use; seizures—usually with high doses;

thrombocytopenia—reversible; thrombophlebitis; unpleasant or

sharp metallic taste; urinary tract effects, including frequent

or painful urination and inability to control urine flow;

vaginal candidiasis





drug manufacturer.

Lethal dose—Dogs: 250 mg per kg of body weight (mg/kg) a day induced

central nervous system dysfunction within 4 to 6 days and death

within a week of onset of signs{R-32}.


clinical significance—not necessarily inclusive:

Dogs, with doses of 65 to 129 mg/kg a day.{R-32}

Ataxia; head tilt; nystagmus (spontaneous, positional, vertical);

seizures

Note: Ataxia and nystagmus were noted consistently in a report on five

cases of toxicosis. Signs appeared within 7 to 12 days of initiating

therapy. In dogs that survived complications of neurologic dysfunc-

tion, signs gradually resolved over 1 to 2 weeks after ending

metronidazole administration{R-32}.

ORAL DOSAGE FORMSNote: In other USP DI monographs, bracketed uses in the Dosage Forms

section refer to categories of use and/or indications that are not

included in U.S. product labeling, and superscript 1 refers to categories

of use and/or indications that are not included in Canadian product

labeling. However, since metronidazole is not specifically approved for

veterinary use, there is no product labeling identifying approved

indications.


in terms of metronidazole base.

METRONIDAZOLE CAPSULESUsual dose:

[Bacterial infections, anaerobic]1; or

[Protozoal infections]1—

Cats and dogs: Oral, 15 mg (base) per kg of body weight every twelve

hours{R-38}.

Horses: Oral, 15 to 25 mg (base) per kg of body weight every six

hours{R-33}.

Note: Anorexia may occur in horses treated with the above dose;

therefore, some clinicians recommend use of a lower oral dose of

10 mg per kg of body weight every twelve hours{R-40}.

For susceptible gram-negative anaerobic infections in horses, one

study recommended an alternative dosage regimen of 15 mg per

kg of body weight as an initial dose, followed by 7.5 mg per kg of

body weight every six hours{R-21}.

Contents of the capsule can be mixed with molasses or adminis-

tered via nasogastric tube.{R-31; 33; 34}

[Hepatic encephalopathy]1; or

[Inflammatory bowel disease]1—Cats and dogs: Oral, 7.5 mg (base) per

kg of body weight every twelve hours.


U.S.—

Veterinary product(s):


Human product(s):

375 mg (base) (Rx) [Flagyl].

Canada—




500 mg (base) (Rx) [Flagyl; Trikacide].


15 and 30 �C (59 and 86 �F), in a well-closed container, unless other-

wise specified by manufacturer. Store in a light-resistant container.


METRONIDAZOLE TABLETS USPUsual dose: See Metronidazole Capsules.

Note: Cats—The typical way to give 15 mg per kg of body weight to a

nine-pound cat is to administer one-fourth of a 250-mg tablet.


U.S.—




250 mg (base) (Rx) [Flagyl; Metric 21; Protostat (scored; lactose)].

500 mg (base) (Rx) [Flagyl; Protostat (scored; lactose)].

Canada—




250 mg (base) (Rx) [Apo-Metronidazole; Flagyl; Novonidazol (scored);

Trikacide].


15 and 30 �C (59 and 86 �F), in a well-closed container, unless other-

wise specified by manufacturer. Store in a light-resistant container.

Additional information: For cats, tablets should not be crushed for

administration, because metronidazole is bitter and often unpalatable.



USP requirements: Preserve in well-closed, light-resistant containers.

Contain the labeled amount, within ±10%. Meet the requirements

for Identification, Dissolution (85% in 60 minutes in 0.1 N hydro-

chloric acid in Apparatus 1 at 100 rpm), and Uniformity of dosage

units{R-30}.

PARENTERAL DOSAGE FORMSNote: In other USP DI monographs, bracketed uses in the Dosage Forms




labeling. However, since metronidazole is not specifically approved for


indications.


in terms of metronidazole base.

METRONIDAZOLE INJECTION USPUsual dose:

Note: Reliable dosing information is not available for the use of

parenteral metronidazole in animals. However, for situations in

which oral administration is not a viable option, injectable forms are

used by following dosing regimens similar to oral dosage forms.


U.S.—




500 mg (base) per 100 mL (Rx) [Flagyl I.V. RTU; Metro I.V.;

generic].

Canada—




500 mg (base) per 100 mL (Rx) [Flagyl; generic].

Withdrawal times: There are no established withdrawal times since

metronidazole is not approved for use in food-producing animals.



manufacturer. Protect from light. Protect from freezing.

Incompatibilities: Intravenous admixtures of metronidazole and other

medications are not recommended.{R-35}

Additional information: Metronidazole Injection USP is an isotonic

(297 to 310 mOsm per L), ready-to-use solution, requiring no dilution

or buffering prior to administration.{R-35}

USP requirements: Preserve in single-dose containers of Type I or Type

II glass, or in suitable plastic containers, protected from light. A sterile,

isotonic, buffered solution of Metronidazole in Water for Injection.

Contains the labeled amount, within ±10%. Meets the requirements

for Identification, Bacterial endotoxins, pH (4.5–7.0), and Particulate

matter, and for Injections{R-30}.

METRONIDAZOLE HYDROCHLORIDE FOR INJECTIONUsual dose: See Metronidazole Injection USP.


U.S.—




500 mg (base) (Rx) [Flagyl I.V.].

Canada—


Packaging and storage: Prior to reconstitution, store below 30 �C(86 �F), in a light-resistant container, unless otherwise specified by

manufacturer.


Metronidazole hydrochloride for injection must not be given by direct

intravenous injection, since the initial dilution has an extremely low

pH (0.5 to 2.0). It must be diluted further and neutralized prior to

administration.{R-35}

To prepare initial dilution for intravenous infusion, add 4.4 mL of sterile

water for injection, bacteriostatic water for injection, 0.9% sodium

chloride injection, or bacteriostatic sodium chloride injection to each

500-mg vial, to provide a concentration of 100 mg per mL (pH 0.5 to

2.0). The resulting solution should be further diluted in 100 mL of

0.9% sodium chloride injection, 5% dextrose injection, or lactated

Ringer’s injection. The final dilution must be neutralized with

approximately 5 mEq of sodium bicarbonate injection per 500 mg of

metronidazole (final pH 6 to 7). Since carbon dioxide gas is produced

during neutralization, it may be necessary to relieve the pressure in the

final container. The final concentration should not exceed 8 mg per

mL, since neutralization decreases the solubility of metronidazole and

precipitation may occur.{R-35}

Stability:

After reconstitution, solutions retain their potency for 96 hours if stored

below 30 �C (86 �F) in room light. Diluted and neutralized solutions

retain their potency for 24 hours.

Neutralized solutions should not be refrigerated, because precipitation

may occur.

Incompatibilities:{R-35}

Metronidazole should not be used with aluminum (needles or hubs) that

would come into contact with the medication.

Intravenous admixtures of metronidazole with other medications are not

recommended.


Revised: 07/28/94; 09/30/02


04/05/03

REFERENCES1. Flagyl 375 (capsules) package insert (Pharmacia—US), Rev 9/01. Downloaded

from www.pharmacia.com on 4/15/02.

2. Boothe DM. Anaerobic infections in small animals. Probl Vet Med 1990 Jun;

2(2): 330–47.

METRONIDAZOLE Veterinary—Systemic 147


3. Dow SW. Management of anaerobic infections. Vet Clin North Am Small Anim

Pract 1988 Nov; 18(6): 1167–82.

4. Flagyl tablets package insert (Pharmacia—US), Rev 9/01. Downloaded from

www.pharmacia.com on 4/15/02.



6. Zimmer JF. Treatment of feline giardiasis with metronidazole. Cornell Vet 1987

Oct; 77(4): 383–8.

7. Zimmer JF, Burrington DB. Comparison of four protocols for the treatment of

canine giardiasis. J Am Anim Hosp Assoc 1986; 22: 168–72.

8. Tisdall PL, Hunt GB, Beck JA, et al. Management of perianal fistulae in five

dogs using azathioprine and metronidazole prior to surgery. Aust Vet J 1999

Jun; 77(6): 374–8.

9. Carlson GP, O’Brien MA. Anaerobic bacterial pneumonia with septicemia in

two racehorses. J Am Vet Med Assoc 1990 Mar 15; 196(6): 941–3.

10. Jones RL. Clostridial enterocolitis. Vet Clin North Am Equine Pract 2000 Dec;

16(3): 471–85.

11. Weese JS, Parsons DA, Staempfli HR. Association of Clostridium difficile with

enterocolitis and lactose intolerance in a foal. J Am Vet Med Assoc 1999 Jan

15; 214(2): 229–32, 205.

12. McGorum BC, Dixon PM, Smith DG. Use of metronidazole in equine acute

idiopathic toxaemic colitis. Vet Rec 1998 Jun 6; 142(23): 635–8.

13. Ricketts SW, Mackintosh ME. Role of anaerobic bacteria in equine endome-

tritis. J Reprod Fertil Suppl 1987; 35(2): 343–51.

14. Mair TS. The medical management of eight horses with grade 3 rectal tears.

Equine Vet J Suppl 2000 Jun; 16(32): 104–7.

15. Heijl L, Lindhe J. Effect of selective antimicrobial therapy on plaque and

gingivitis in the dog. J Clin Periodontol 1980 Dec; 7(6): 463–78.

16. Sweeney RW, Sweeney CR, Weiher J. Clinical use of metronidazole in horses:

200 cases (1984-1989). J Am Vet Med Assoc 1991 Mar 15; 198(6): 1045–8

17. Norris JM, Love DN. In vitro antimicrobial susceptibilities of three Porphyro-

monas spp and in vivo responses in the oral cavity of cats to selected

antimicrobial agents. Aust Vet J 2000 Aug; 78(8): 533–7.

18. Heijl L, Lindhe J. The effect of metronidazole on established gingivitis and

plaque in beagle dogs. J Periodontol 1982 Mar; 53(3): 180–7.

19. Chou S, Richards GK, Brown RA. A new approach to antibiotic therapy in

colon surgery based on bioassay tissue concentrations. Can J Surg 1982 Sep;

25(5): 527–31.

20. Piek CJ, Robben JH. Pyothorax in nine dogs. Vet Q 2000 Apr; 22(2): 107–11.

21. Specht TE, Brown MP, Gronwall RR, et al. Pharmacokinetics of metronidazole

and its concentration in body fluids and endometrial tissues of mares. Am J Vet

Res 1992 Oct; 53(10): 1807–12.

22. Neiger R, Seiler G, Schmassmann A. Use of a urea breath test to evaluate short-

term treatments for cats naturally infected with Helicobacter heilmannii. Am J

Vet Res 1999 Jul; 60(7): 880–3.

23. Perkins SE, Yan LL, Shen Z, et al. Use of PCR and culture to detect Helicobacter

pylori in naturally infected cats following triple antimicrobial therapy.

Antimicrob Agents Chemother 1996 Jun; 40(6): 1486–90.

24. Happonen I, Linden J, Westermarck EJ. Effect of triple therapy on eradication of

canine gastric helicobacters and gastric disease. Small Anim Pract 2000 Jan;

41(1): 1–6.

25. Simpson KW, Strauss-Ayali D, McDonough PL, et al. Gastric function in dogs

with naturally acquired gastric Helicobacter spp. infection. J Vet Intern Med

1999 Nov-Dec; 13(6): 507–15.

26. Cornetta AM, Simpson KW, Strauss-Ayali D, et al. Use of a [13C]urea breath

test for detection of gastric infection with Helicobacter spp in dogs. Am J Vet

Res 1998 Nov; 59(11): 1364–9.

27. Extralabel drug use in animals. Fed Regist 1996 Nov 7; 61(217): 57731–46.

28. Bartlett JG, Louie TJ, Gorbach SL, et al. Therapeutic efficacy of 29 antimicrobial

regimens in experimental intra-abdominal sepsis. Rev Infect Dis 1981 May-

Jun; 313: 535–42.





States Pharmacopeial Convention, Inc., 2002. p. 1227, 1228, 2570.

31. Panel comment, Rec. 5/93.

32. Dow SW, LeCouteur RA, Poss ML, et al. Central nervous system toxicosis

associated with metronidazole treatment of dogs: five cases (1984–1987). J Am

Vet Med Assoc 1989; 195(3): 365–8.

33. Sweeny RW, Sweeney CR, Soma LR, et al. Pharmacokinetics of metronidazole

given to horses by intravenous and oral routes. Am J Vet Res 1986 Aug;

47(5): 1726–9.

34. Sweeny RW, Sweeney CR, Weiher J. Clinical use of metronidazole in horses:

200 cases (1984-1989). J Am Vet Med Assoc 1991; 198(6): 1045–8.

35. Flagyl IV and IV RTU package insert (SCS Pharmaceuticals—US), Rev 7/16/

98. In: PDR Physician’s Desk Reference. 54th ed. 2000. Montvale, NJ: Medical

Economics Company, 2000. p. 2878–80.

36. Kirkpatrick CE, Farrell JP. Feline giardiasis: observations on natural and

induced infections. Am J Vet Res 1984 Oct; 45(10): 2182–8.

37. Neff-Davis CA, Davis LE, Gillette EL. Metronidazole: a method for its

determination in biological fluids and its disposition kinetics in the dog. J Vet


38. Committee comment, Rec. 5/27/02.

39. Steinman A, Gips M, Lavy E, et al. Pharmacokinetics of metronidazole in

horses after intravenous, rectal, and oral administration. J Vet Pharmacol Ther

2000; 23: 353–7.

40. Panel comment, Rec. 11/29/94.



PENICILLIN G Veterinary—Intramammary-Local�

Some commonly used brand names for veterinary-labeled products are

Go-dry and Masti-Clear.




INDICATIONS

GENERAL CONSIDERATIONSThe spectrum of activity of penicillin G includes many aerobic and

anaerobic gram-positive organisms. Penicillin G is highly susceptible to

beta-lactamases and has little activity against organisms that can

produce these enzymes. In addition, penicillin G is ineffective against

bacteria that are resistant by certain other mechanisms, such as having

a relatively impermeable cell wall. Therefore, penicillin G has little

activity against many staphylococci and most gram-negative bacteria.

ACCEPTEDMastitis (treatment)1—Cattle: Penicillin G is indicated in the treatment of

mastitis in cattle{R-1; 2; 7} caused by susceptible organisms such as

Streptococcus agalactiae{R-7; 20}. Intramammary therapy alone is indi-

cated only in the treatment of subacute mastitis manifested by mild

inflammatory changes in the milk or udder. Acute or peracute mastitis,

in which gross inflammatory changes in the milk or udder or systemic

signs appear, requires administration of other medications also, which

may include systemic antibiotics and/or supportive therapy.{R-5}


Withdrawal times have been established for penicillin G procaine

intramammary infusion (see the Dosage Forms section{R-1}).

CHEMISTRYSource: Produced by the mold Penicillium.{R-8}


Chemical name: Penicillin G procaine—4-Thia-1-azabicyclo[3.2.0]hep-

tane-2-carboxylic acid, 3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-,

[2S-(2 alpha,5 alpha,6 beta)]-, compd. with 2-(diethylamino)ethyl

4-aminobenzoate (1:1) monohydrate.{R-10}

Molecular formula: Penicillin G procaine

C16H18N2O4S Æ C13H20N2O2 Æ H2O.{R-10}

Molecular weight: Penicillin G procaine—588.72.{R-10}

Description: Penicillin G Procaine USP—White crystals or white, very

fine, microcrystalline powder. Is odorless or practically odorless, and is

relatively stable in air. Its solutions are dextrorotary. Is rapidly inac-

tivated by acids, by alkali hydroxides, and by oxidizing agents{R-17}.

pKa: 2.7.{R-11; 12}

Solubility: Penicillin G Procaine USP—Slightly soluble in water; soluble

in alcohol and in chloroform{R-17}.


Mechanism of action/effect: The penicillins produce their bactericidal

effect by inhibiting cross-linkages during bacterial cell wall synthesis.{R-9}

Pencillin G must penetrate the cell wall to attach to specific proteins on

the inner surface of the bacterial cell membrane. In actively growing

cells, the binding of penicillin within the cell wall leads to interference

with production of cell wall peptidoglycans and subsequent lysis of the

cell in a hypo- or iso-osmotic environment.{R-9; 13}





lation causes uneven distribution.{R-14} After penicillin G procaine is

infused into a mammary gland, it is also partially distributed into the

other quarters of the gland,{R-4; 15} into the local lymph circulation,

and to some degree into the plasma and other tissues.{R-16}

Peak serum concentration: In healthy animals, after intramammary

administration of 400 mg (404,000 Units) of penicillin G procaine in

combination with the same amount of dihydrostreptomycin sulfate,

the peak serum concentration of penicillin G is 0.07 mcg/mL at 4

hours.{R-16}





Bacteriologic pathogen identification in milk

(milk samples should be tested 3 weeks after the end of treatment;

mastitis is not considered bacteriologically cured until samples show

an absence of the mastitis-causing organisms{R-2})

Clinical signs

(although a resolution of clinical signs of mastitis is not an indication


clinical condition of the mammary gland, teat, and milk produced

can aid in diagnosis of a recurrence of mastitis or initial diagnosis of


Somatic cell count


used primarily to maintain milk quality, but also to approximately

assess the overall effectiveness of mastitis control programs that may

include antibiotic treatment of cows){R-5}





Cows

Allergic reactions—theoretically possible locally or systemically




PENICILLIN G Veterinary—Intramammary-Local 149






drug manufacturer.



focus. The program should include good maintenance of milking

equipment and constant evaluation of milking procedures and teat

health as well as strategic treatment of clinical cases of mastitis.{R-7}

VETERINARY DOSING INFORMATIONAntibiotic therapy in the dry cow is measurably more effective than

treatment during lactation.{R-7; 18}

Choice of antibiotic for treatment of mastitis should be based on

knowledge of culture and sensitivity of pathogens causing mastitis in

the cow and the dairy herd.{R-19}

Before administration of intramammary penicillin G procaine, the

following steps should be performed:{R-1}



washing excess dirt down from the udder onto the teat ends.{R-6}

The area should be dried thoroughly. An effective germicidal teat dip


separate cotton ball soaked with an antiseptic such as 70% alcohol.




possible{R-6} and the contents of the syringe should be injected into

each streak canal while the teat is held firmly. The medication

should then be gently massaged up the teat canal into the udder.

An effective teat dip is recommended on all teats following treatment.

For the lactating cow, treated quarters should not be milked for at least

six hours after treatment but should be milked at regular intervals

thereafter.{R-2}


PENICILLIN G PROCAINE INTRAMAMMARYINFUSION USPUsual dose: Antibacterial1—Cattle:

Dry cow (nonlactating)—Intramammary, 100,000 Units into each

quarter of the udder at the time of drying-off.{R-1}

Lactating cow—Intramammary, 100,000 Units into each affected

quarter of the udder every twelve hours for a maximum of three

doses.{R-2}


U.S.—{R-1; 2}


100,000 Units per 10 mL (OTC) [Go-dry (dry cow only); Masti-Clear

(lactating cow only)].

Canada—{R-3}



Withdrawal times:

U.S.{R-1; 2}—


unless otherwise specified by manufacturer.{R-1; 2}

USP requirements: Preserve in well-closed disposable syringes. A sus-

pension of Penicillin G Procaine in a suitable vegetable oil vehicle.

Label it to indicate that it is for veterinary use only. Contains an

amount of penicillin G procaine equivalent to the labeled amount of

penicillin G, within –10% to +15%. Meets the requirements for Iden-

tification and Water (not more than 1.4%).{R-17}

Developed: 03/08/95

Interim revision: 04/24/96; 05/19/97; 07/08/98; 10/15/99; 06/30/02

02/28/03

REFERENCES1. Go-dry (G.C. Hanford Mfg. Co—US), Rev 10/92, Rec 7/22/94.

2. Masti-Clear (G.C. Hanford Mfg. Co—US), Rec 2/19/03.



4. Hawkins GE, Cannon RY, Paar CF. Concentration of penicillin in milk from

noninfused quarters following infusion of one quarter. J Dairy Sci 1962; 45:

1020–2.





Vet Med Assoc 1993 Jul; 203(2): 210–20.

8. Watson ADJ. Penicillin G and the alternatives. Vet Annu. 1985; 25: 277–83.


419–26.



11. Prescott JF, Baggot JD. Antimicrobial therapy in veterinary medicine, 2nd ed.

Ames, IA: Iowa State University Press, 1993. p. 81–9.

12. Ziv G, et al. Pharmacokinetic evaluation of penicillin and cephalosporin

derivatives in serum and milk of lactating cows and ewes. Am J Vet Res 1973;

34(12): 1561–5.




15. Anifantakis EM. Excretion rates of antibiotics in milk of sheep and their effect

on yogurt production. J Dairy Sci 1982; 65: 426–9.

16. Franklin A, Rantzien M, Obel N, et al. Concentrations of penicillin, strepto-

mycin, and spiramycin in bovine udder tissue liquids. Am J Vet Res 1986 Apr;

47(4): 804–7.



States Pharmacopeial Convention, Inc., 2002. p. 1415, 2573.



19. Panel comment , Rec 11/18/94.


Withdrawal time


Cows

Nonlactating 14 72

Lactating 3 60



150 PENICILLIN G Veterinary—Intramammary-Local


PENICILLIN G Veterinary—Systemic


For veterinary-labeled products—Agri-cillin; Ambi-pen; Aquacillin; Benz-

apro; Combicillin; Combicillin AG; Depocillin; Derapen SQ/LA; Duo-Pen;

Duplocillin LA; Durapen; Hi-Pencin 300; Longisil; Microcillin; Pen-

Aqueous; Pen G Injection; Penmed; Penpro; Pot-Pen; Propen LA; R-Pen;

Twin-pen; and Ultrapen LA.

For human-labeled products—Pfizerpen.





GENERAL CONSIDERATIONSThe spectrum of activity of penicillin G includes many aerobic and

anaerobic gram-positive organisms. Aerobes susceptible to penicillin

G include most beta-hemolytic streptococci, beta-lactamase-negative

staphylococci, Actinomyces species, some Bacillus anthracis, Coryne-

bacterium species, and Erysipelothrix rhusiopathiae. Most species of

anaerobes, including Clostridium species, but excluding beta-lactam-

ase-producing Bacteroides species, are also susceptible to penicillin G.

Penicillin G is easily inactivated by beta-lactamases and has little

efficacy against organisms that can produce these enzymes. In

addition, penicillin G is ineffective against those bacteria that are

resistant by other mechanisms, such as having a relatively

impermeable cell wall. Therefore, penicillin G has little activity

against many staphylococci and most gram-negative bacteria.{R-3; 4}

ACCEPTEDBlackleg (treatment)—Cattle and [sheep]: Penicillin G is indicated in the

treatment of blackleg caused by susceptible organisms such as

Clostridium chauvoei in cattle and sheep.{R-5; 6}

Erysipelas (treatment)—Pigs and turkeys: Penicillin G is indicated in the

treatment of infections caused by Erysipelothrix rhusiopathiae (insidiosa)

in pigs and turkeys.{R-6–9}

Pharyngitis (treatment); or

Rhinitis (treatment)—Cattle: Penicillin G is indicated in the treatment of

bacterial rhinitis or pharyngitis caused by susceptible organisms such

as Actinomyces pyogenes.{R-5}

Pneumonia, bacterial (treatment)—Cattle,{R-6; 7} sheep{R-6; 7}, [horses]{R-6},

and [pigs]{R-10}: Penicillin G is indicated in the treatment of bacterial

pneumonia caused by susceptible organisms in cattle, sheep, [horses],

and [pigs]; however, for bacterial pneumonia in cattle, sheep, and pigs,

penicillin G is not considered the drug of first choice pending culture and

sensitivity results.{R-85; 87}

Strangles (treatment)—Horses: Penicillin G is indicated in the treatment

of strangles caused by Streptococcus equi;{R-7} however, it may be

effective only during the acute phase of the infection.{R-13}

[Actinomycosis (treatment)]—Cattle: Penicillin G is indicated in the

treatment of actinomycosis, and may be most effective for infections in

which pathogens other than Actinomyces species are not yet

involved.{R-6; 14}

[Arthritis, septic (treatment)]—Cattle, horses, pigs, and sheep:{R-6} Peni-

cillin G is indicated in the treatment of septic arthritis caused by

susceptible bacteria in cattle, horses, pigs, and sheep.{R-15; 16}

[Leptospirosis (treatment)]—Cattle,{R-6} dogs{R-6; 17}, horses1{R-18}, and

pigs:{R-6} Penicillin G is indicated in the treatment of acute leptospirosis

in cattle, dogs, horses, and pigs. The chronic shedding stage of

leptospirosis is often treated with tetracycline; penicillin G adminis-

tered alone will not clear the carrier state.{R-73; 85}

[Malignant edema (treatment)]—Cattle:{R-6} Penicillin G is indicated in

the treatment of malignant edema caused by susceptible Clostridium

septicum in cattle.

[Metritis (treatment)]—Cattle, horses, pigs, and sheep:{R-6} Penicillin G is

indicated in the treatment of metritis caused by susceptible organisms

in cattle, horses, pigs, and sheep{R-20; 21}; however, therapeutic

regimens often emphasize evacuation of uterine contents as the

primary treatment.{R-85}

[Pyelonephritis (treatment)]—Cattle: Penicillin G is indicated in the

treatment of pyelonephritis caused by susceptible organisms such as

Corynebacterium renale in cattle.{R-6; 22; 23}

[Skin and soft tissue infections (treatment)]—

Cattle: Penicillin G is indicated in the treatment of skin and soft tissue

infections caused by susceptible organisms, including those associ-

ated with calf diphtheria, foot rot, the umbilicus, and wounds.{R-10}.

Horses: Penicillin G is indicated in the treatment of skin and soft tissue


ated with the umbilicus and with wounds.{R-6}

Pigs: Penicillin G is indicated in the treatment of skin and soft tissue


ated with the umbilicus.{R-6}

Sheep: Penicillin G is indicated in the treatment of skin and soft tissue


ated with post-surgical tail docking and castration site infections,

and also those associated with the umbilicus.{R-6; 10}

[Tetanus (treatment)]—Cats, cattle, dogs, horses, and pigs1: Penicillin G is

indicated in the treatment of Clostridium tetani in cats, cattle, dogs,

horses, and pigs in conjunction with tetanus antitoxin and supportive

therapy.{R-6}


Administration of penicillin G procaine to animals may produce

procaine concentrations in the blood and urine that violate equine

and greyhound racing commission prohibitions.{R-91; 92}

Penicillin G is not for use in turkeys producing eggs for human

consumption or for use in horses intended for food.{R-7; 8}

Penicillin G Benzathine and Penicillin G Procaine Injectable Suspen-

sion USP combination is not labeled for use in lactating cattle or

preruminating calves.{R-5}

Some brands of Penicillin G Procaine Injectable Suspension USP are

not labeled for use in preruminating cattle.{R-53}



PENICILLIN G Veterinary—Systemic 151


Withdrawal times have been established for Penicillin G Potassium

USP, Penicillin G Benzathine and Penicillin G Procaine Injectable

Suspension USP, and Penicillin G Procaine Injectable Suspension

USP (see the Dosage Forms section).{R-5; 7; 8; 26}

Canada—

Administration of penicillin G procaine to animals may produce

procaine concentrations in the blood and urine that violate equine

and greyhound racing commission prohibitions.{R-84}

Penicillin G is not labeled for use in turkeys producing eggs for human

consumption.{R-9}

Penicillin G Benzathine and Penicillin G Procaine Injectable

Suspension USP combination is not labeled for use in lactating

cattle.{R-27; 28}

Withdrawal times have been established for Penicillin G Potassium

USP, Penicillin G Benzathine and Penicillin G Procaine Injectable

Suspension USP, and Penicillin G Procaine Injectable Suspension

USP (see the Dosage Forms section).{R-9; 27; 28}

CHEMISTRYSource: Produced by the mold Penicillium.{R-1}


Chemical name:

Penicillin G benzathine—4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic

acid, 3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-, [2S-(2alpha,5alpha,

6beta)]-, compd. withN,N’-bis(phenylmethyl)-1,2-ethanediamine (2:1),

tetrahydrate.{R-30}

Penicillin G potassium—4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic

acid, 3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-, monopotassium

salt, [2S-(2alpha,5alpha,6beta)]-.{R-30}

Penicillin G procaine—4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic

acid, 3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-, [2S-(2alpha,5alpha,

6beta)]-, compd. with 2-(diethylamino)ethyl 4-aminobenzoate (1:1)

monohydrate.{R-30}

Penicillin G sodium—4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic

acid, 3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-, [2S-(2alpha,

5alpha,6beta)]-, monosodium salt.{R-30}

Molecular formula:

Penicillin G benzathine—(C16H18N2)4S)2ÆC16H20N2Æ4H2O.{R-30}

Penicillin G potassium—C16H17KN2O4S.{R-30}

Penicillin G procaine—C16H18N2O4SÆC13H20N2O2ÆH2O.{R-30}

Penicillin G sodium—C16H17N2NaO4S.{R-30}

Molecular weight:

Penicillin G benzathine—981.19.{R-30}

Penicillin G potassium—372.48.{R-30}

Penicillin G procaine—588.72.{R-30}

Penicillin G sodium—356.37.{R-30}

Description:

Penicillin G Benzathine USP—White, odorless, crystalline powder.{R-51}

Penicillin G Potassium USP—Colorless or white crystals, or white,

crystalline powder. Is odorless or practically so, and is moderately

hygroscopic. Its solutions are dextrorotatory. Its solutions retain

substantially full potency for several days at temperatures below 15 �C,

but are rapidly inactivated by acids, by alkali hydroxides, by glycerin,

and by oxidizing agents.{R-51}

Penicillin G Procaine USP—White crystals or white, very fine, micro-

crystalline powder. Is odorless or practically odorless, and is relatively

stable in air. Its solutions are dextrorotatory. Is rapidly inactivated by

acids, by alkali hydroxides, and by oxidizing agents.{R-51}

Penicillin G Sodium USP—Colorless or white crystals or white to slightly

yellow, crystalline powder. Is odorless or practically odorless, and is

moderately hygroscopic. Its solutions are dextrorotatory. Is relatively

stable in air, but is inactivated by prolonged heating at about 100 �C,

especially in the presence of moisture. Its solutions lose potency fairly

rapidly at room temperature, but retain substantially full potency for

several days at temperatures below 15 �C. Its solutions are rapidly

inactivated by acids, alkali hydroxides, oxidizing agents, and penicil-

linase.{R-51}

pKa: 2.7.{R-2; 32}

Solubility:

Penicillin G Benzathine USP—Very slightly soluble in water; sparingly

soluble in alcohol.{R-51}

Penicillin G Potassium USP—Very soluble in water, in saline TS, and in

dextrose solutions; sparingly soluble in alcohol.{R-51}

Penicillin G Procaine USP—Slightly soluble in water; soluble in alcohol

and in chloroform.{R-51}

PHARMACOLOGY/PHARMACOKINETICSSee also Table 1. Pharmacokinetic Parameters at the end of this

monograph.

Note: With the exception of information in Table 1, pharmacokinetic data

in this section are based on intravenous administration of potassium or

sodium penicillin G.

Mechanism of action/effect: The penicillins produce their bactericidal

effect by inhibition of bacterial cell wall synthesis.{R-29} Pencillin G

must penetrate the cell wall to attach to specific proteins on the inner

surface of the bacterial cell membrane. In actively growing cells, the

binding of penicillin within the cell wall leads to interference with

production of cell wall peptidoglycans and subsequent lysis of the cell

in a hypo- or iso-osmotic environment.{R-4; 29; 33}

Absorption:

Gastric absorption of penicillin G is poor in many species because it is

rapidly hydrolyzed in the acid environment of the stomach or

abomasum.{R-4} Only 15 to 30% of penicillin G may be absorbed by

the oral route in a fasted animal and that percent decreases when

there is food in the stomach.{R-34}

The sodium and potassium salts of penicillin G are the only dosage forms

that are suitable for intravenous administration. They are also the

most quickly absorbed from intramuscular or subcutaneous sites of

administration.{R-4; 34; 35} Procaine penicillin G is more slowly

absorbed from intramuscular administration than are the sodium or

potassium salts and so produces more sustained but lower plasma

concentrations.{R-4; 35} Benzathine penicillin G is the least soluble of

the dosage forms and so is the most slowly absorbed; the longest

sustained but lowest plasma concentrations of penicillin G are

produced.{R-4; 35} The rate of absorption from intramuscular injections

of some penicillin dosage forms, such as procaine penicillin G, can vary

depending on the injection site; injections into the neck muscle in

cattle and horses produce more rapid absorption and higher plasma

concentrations than do injections into the gluteal muscle. Also,

procaine penicillin G is more completely absorbed in steers when

injected intramuscularly than when administered subcutaneously.

Distribution: Volume of distribution—

Dromedaries: 0.34 ± 0.079 liter per kg (L/kg).{R-59}

152 PENICILLIN G Veterinary—Systemic


Horses: 0.72 ± 0.16 L/kg.{R-44}

Sheep: 0.604 ± 0.205 L/kg.{R-59}

Protein binding:

Cattle—Low (28.5%).{R-38; 39}

Dogs—Moderate (60%).{R-40}

Horses—Moderate (52–54%).{R-39; 41}

Rabbits—Low (35%).{R-39; 42}

Sheep—Low (30.4%).{R-38; 39}

Half-life: Elimination—

Calves, newborn to 15 days: 26.6 minutes.{R-60}

Dogs: 30 minutes.{R-39}

Dromedaries: 49 minutes.{R-59}

Horses: 48 to 53 minutes.{R-41; 57}

Sheep: 42 minutes.{R-59}

Turkeys: 30 minutes.{R-62}

Elimination: Primarily renal{R-2; 4}; active renal tubular secretion

occurs.{R-89} From 60 to 100% of the dose is recoverable from urine

following injection of an aqueous solution of penicillin G.{R-43}

Total clearance—

Dromedaries: 4.87 ± 0.63 mL/min/kg.{R-59}

Horses: 8.5 ± 1.33 mL/min/kg.{R-44}

Sheep: 9.17 ± 1.39 mL/min/kg.{R-59}

Calves:

Newborn—2.98 ± 0.52 mL/min/kg.{R-60}

Five days—4.83 ± 1.45 mL/min/kg.{R-60}

Ten days—3.11 ± 1 mL/min/kg.{R-60}

Fifteen days—4.65 ± 1.18 mL/min/kg.{R-60}


CROSS-SENSITIVITY AND/OR RELATED PROBLEMSIn humans, patients allergic to other penicillins may also be allergic to

penicillin G; in addition, patients allergic to cephalosporins may be

allergic to penicillin G.{R-52} The incidence of these occurrences in

animals is unknown, but it is recommended that penicillin use be

avoided in animals that have had a previous severe reaction.{R-2}

Animals allergic to procaine or other ester-type local anesthetics may

also be allergic to penicillin G procaine.{R-6; 75}

PREGNANCY/REPRODUCTIONPenicillins have been shown to cross the placenta; however, no

teratogenic problems have been associated with the use of penicillin

G during pregnancy in studies of mice, rabbits, and rats, or during

clinical use in many species. No well-controlled studies have been

performed for most species.{R-75}

LACTATIONPenicillin G is distributed into milk{R-2}; in food animals the distribution is

sufficient to cause violative residues. However, the concentrations of

penicillin produced in milk are subtherapeutic for most bacteria.{R-85}

In sheep, 0.11% of an intramuscular injection of sodium penicillin G

was distributed into the milk.{R-31}

PEDIATRICSIn neonates that have not yet developed full renal function, excretion

of penicillin G occurs at a slower rate than it does in a mature

animal.{R-60; 75}

DRUG INTERACTIONS AND/OR RELATEDPROBLEMSThe following drug interactions and/or related problems have been






Antibacterials, bacteriostatic, such as:

Chloramphenicol or

Tetracycline

(because penicillin G acts only on cells that are actively reproducing,

bacteriostatic antibiotics such as chloramphenicol or tetracycline

may decrease the efficacy of penicillin G by depressing the activity of

target cells{R-43}; however, the clinical significance of this interfer-

ence is not well documented{R-66})

Phenylbutazone

(the concomitant administration of phenylbutazone with penicillin G

may cause higher plasma concentrations of penicillin G, resulting in

lower distribution of penicillin G to the tissues{R-44})







» Hypersensitivity to penicillin

(some reactions, such as hemolytic anemia in horses{R-49}, may be

much more likely to occur in an animal that has had a previous

reaction to penicillin G)

» Hypersensitivity to procaine{R-6}

(some sources recommend intradermal procaine testing of animals

suspected of procaine sensitivity before administering procaine

penicillin G{R-6})


problems exist:

Erysipelas in pigs

(administration of procaine penicillin has caused recurrence or

exacerbation of signs of erysipelas including abortion, cyanotic ears,

fever of 39.5 to 41 �C, inappetance, lassitude, vomiting, and

shivering{R-50})

Renal function impairment

(because penicillin G is primarily excreted by the kidneys, unneces-

sary accumulation of medication in the plasma and tissues may

occur{R-45}; also, the sodium or potassium content of intravenous

penicillin G dosage forms should be considered)









prior to penicillin administration to determine pathogen susceptibil-

ity)

Potassium or sodium, serum

(determination of concentrations of serum sodium or potassium may

be necessary in animals receiving high doses or long-term therapy

with potassium or sodium penicillin G, particularly in those patients

with severe renal function impairment, other pre-existing electrolyte

imbalance, or congestive heart failure{R-75})





All species

Allergic reactions, specifically anaphylaxis,{R-6} contact derma-

titis,{R-6} serum sickness–like syndromes,{R-6} and urticaria{R-6};

overgrowth of nonsusceptible organisms{R-7}; procaine toxic-

ity—with procaine-containing dosage forms only

Note: Multiple cases of procaine toxicity have been reported in pig herds

being treated for erysipelas{R-50; 77}. Signs included abortion,

cyanotic ears, fever of 39.5 to 41 �C, inappetance, lassitude,

vomiting, and shivering.

Horses

Allergic reactions, specifically anaphylaxis{R-6; 48} (hemorrhagic

enterocolitis, progressive respiratory distress from coughing to dyspnea

to apnea);{R-48} immune-mediated hemolytic anemia (icterus,

inappetance, listlessness, paleness of mucous membranes, red-brown

urine, splenomegaly, tachycardia);{R-49} procaine toxicity (signs in

reported order of occurrence: fright, sudden backing, aimless galloping,

loss of coordination, muscle tremors, apnea, cardiac arrest)—with

high doses of procaine-containing dosage forms{R-48}


All species

Pain at site of injection—with higher doses{R-69}




included in the human monograph Penicillins (Systemic) in USP DI


purposes only and may or may not be applicable to the use of penicillin

G in the treatment of animals:



candidiasis


Allergic reactions, specifically anaphylaxis; exfoliative derma-

titis; serum sickness–like reactions; skin rash, hives, or itching

Incidence rare

Clostridium difficile colitis; hepatotoxicity; interstitial nephri-

tis; leukopenia or neutropenia; mental disturbances; pain at site

of injection; platelet dysfunction or thrombocytopenia; seizures



Interstitial nephritis is seen primarily with methicillin, and to a lesser

degree with nafcillin and oxacillin, but may occur with any penicillin.

Mental disturbances are toxic reactions to the procaine content of

penicillin G procaine; this reaction may be seen in patients who

receive a large single dose of the medication, as in the treatment of

gonorrhea.







drug manufacturer.

VETERINARY DOSING INFORMATION

FOR PARENTERAL DOSAGE FORMS ONLYTo prevent procaine toxicity, keeping procaine penicillin at proper

storage temperature and following shelf life recommendations are

recommended to avoid any degradation of the product.{R-48}


For anaphylaxis

• Parenteral epinephrine.{R-6}


For procaine toxicity{R-76}

• If seizures occur, sedation with diazepam{R-48} and/or barbitu-

rates{R-6}.

• Oxygen administration and respiratory support as needed.

• Treatment for cardiovascular collapse if necessary.

ORAL DOSAGE FORMS

PENICILLIN G POTASSIUM FOR ORAL SOLUTION USPUsual dose: Antibacterial—Turkeys: Oral, administered as the sole

source of drinking water at a concentration of 1,500,000 Units per

gallon (395,000 Units per L) for five days.{R-8}

Size(s) usually available{R-46}:

U.S.—{R-8}


384,000,000 Units (OTC) [R-Pen].

500,000,000 Units (OTC) [R-Pen; generic].



Canada—{R-9}


100,000,000 Units (OTC) [Pot-Pen].

500,000,000 Units (OTC) [Pot-Pen; generic].

15,000,000,000 Units (OTC) [generic].

Withdrawal times:

U.S.{R-8; 26} and Canada{R-9}—

Withdrawal time

Species Meat (days)

Turkeys 1



the manufacturer. Store in a tight container.


U.S.—Dissolve 384,000,000 Units in 256 Gallons (969 L) to produce the

final 1,500,000 Units per Gallon (3.8 L) solution.{R-8}

Canada—Dissolve 100,000,000 Units in 88.7 Gallons (337 L) to produce

the final 1,128,600 Units per Gallon (3.8 L) solution.{R-9}

Stability: Gravity flow water systems require preparation of fresh solu-

tions every 12 hours. Automatic watering systems require fresh

solution preparation every 24 hours.{R-8}


Penicillin G Potassium and one or more suitable buffers, colors, dilu-

ents, flavors, and preservatives. Contains the labeled number of Peni-

cillin G Units when constituted as directed in the labeling, within –10%

to +30%. Meets the requirements for Identification, Uniformity of

dosage units (single-unit containers), Deliverable volume (multiple-

unit containers), pH (5.5–7.5, in the solution constituted as directed in

the labeling), and Water (not more than 1.0%).{R-51}




PENICILLIN G BENZATHINE AND PENICILLIN GPROCAINE INJECTABLE SUSPENSION USPNote: Penicillin G benzathine and penicillin G procaine combination has

been replaced by other more effective medications. Although products

containing penicillin G procaine and penicillin G benzathine combined

may be effective in the treatment of extremely sensitive organisms, the

plasma concentration of penicillin G produced by the administration of

recommended doses of penicillin G benzathine drops to such a low level

after 12 to 48 hours that it becomes ineffective in the treatment of

most systemic infections.{R-78; 79} No dosage of these penicillin G

procaine and penicillin G benzathine combinations can be recom-

mended as likely to be effective for many infections caused by

penicillin-sensitive organisms.{R-88} Even when administered at label

doses, the risk exists for residues, which are 30 to 60 times the

maximum limit, to occur at the injection site.{R-80}


U.S.—


150,000 Units of penicillin G benzathine and 150,000 Units of

penicillin G procaine per mL (Rx) [Ambi-pen; Combicillin; Combicillin

AG; Duo-Pen; Durapen; Twin-Pen; generic].

Canada—


150,000 Units of penicillin G benzathine and 150,000 Units of

penicillin G procaine per mL (Rx) [Benzapro; Duplocillin LA;

Longisil].

Withdrawal times:

U.S.—{R-26}

Withdrawal time

Species Meat (days)

Cattle, beef 30

Note: Products bearing labeling listing the above withdrawal time state

that it is based on a dose of 4400 Units of penicillin G benzathine and

4400 Units of penicillin G procaine per kg (2000 Units of each per

pound) of body weight administered subcutaneously every 48 hours

for two treatments and is not applicable to higher doses or longer


Canada—{R-27; 28}

Withdrawal time

Species Meat (days)

Cattle, beef 14

Note: Products bearing labeling listing the above withdrawal time state

that it is based on a dose of 4286 to 4500 Units of penicillin G

benzathine and 4286 to 4500 Units of penicillin G procaine per kg of

body weight administered intramuscularly and is not applicable to

higher doses or longer administration.{R-27; 28; 63}


Protect from freezing.{R-5}

Preparation of dosage form: The vial should be warmed to room tem-

perature and shaken well to insure a uniform suspension.{R-5}


tainers, preferably of Type I or Type III glass. A sterile suspension of

Penicillin G Benzathine and Penicillin G Procaine or when labeled for

veterinary use only, of Penicillin G Benzathine and Penicillin G Pro-

caine, in Water for Injection. Where it is intended for veterinary use

only, it is so labeled. May contain one or more suitable buffers, pre-

servatives, and suspending agents. Contains the labeled amounts,


Crystallinity, pH (5.0–7.5), Limit of soluble penicillin G and procaine

(where it is prepared from penicillin G procaine and is labeled for

veterinary use only, not more than 1%), and for Bacterial endotoxins,

and Sterility under Penicillin G Procaine Suspension, and for Injec-

tions.{R-51}



PENICILLIN G POTASSIUM FOR INJECTION USPUsual dose: [Antibacterial]1—

Cats and dogs: Intravenous or intramuscular, 20,000 to 40,000 Units

per kg of body weight every six to eight hours.{R-54}

Horses: Intravenous or intramuscular, 20,000 Units per kg of body

weight every six to eight hours.{R-57; 65}


U.S.—{R-66; 67}




1,000,000 Units (Rx) [generic].

5,000,000 Units (Rx) [Pfizerpen; generic].


20,000,000 Units (Rx) [Pfizerpen; generic].

Canada—{R-68}











To prepare initial dilution for intramuscular or intravenous use, see

manufacturer’s labeling.

To prepare for further dilution for intravenous use, see manufacturer’s

labeling.

Stability: After reconstitution, solutions retain their potency for 24

hours at room temperature or for 7 days if refrigerated.{R-66; 68}

Incompatibilities:

Penicillin G potassium is rapidly inactivated by oxidizing and reducing

agents, such as alcohols and glycols.{R-68}

Extemporaneous admixtures of beta-lactam antibacterials (penicillins


mutual inactivation. Do not mix these antibacterial agents in the same

intravenous bag, bottle, or tubing.{R-69}


Human guidelines recommend that daily doses of 10,000,000 Units or

more should be administered by slow intravenous infusion or by

intermittent piggyback infusion to avoid causing or exacerbating

possible electrolyte imbalance.{R-68}

The potassium content and sodium content (derived from sodium citrate

buffer) of penicillin G potassium for injection are approximately

1.7 mEq (66.3 mg) and 0.3 mEq (6.9 mg), respectively, per 1,000,000

Units of penicillin G.{R-66}

USP requirements: Preserve in Containers for Sterile Solids. It is sterile

Penicillin G Potassium or a sterile, dry mixture of Penicillin G Potas-

sium with not less than 4.0% and not more than 5.0% of Sodium

Citrate, of which not more than 0.15% may be replaced by Citric Acid.

Has a potency of the labeled number of Penicillin G Units, within –10%

to +20%. In addition, where it contains Sodium Citrate it has a po-

tency of not less than 1335 and not more than 1595 Penicillin G Units

per mg. Meets the requirements for Constituted solution, Identification,

Crystallinity, Bacterial endotoxins, Sterility, pH (6.0–8.5, in a solution

containing 60 mg per mL or, where packaged for dispensing, in the

solution constituted as directed in the labeling), Loss on drying (not

more than 1.5%), and Particulate matter, and for Uniformity of dosage

units and Labeling under Injections.{R-51}

PENICILLIN G PROCAINE INJECTABLE SUSPENSIONUSPUsual dose: Antibacterial—

[Cats] and [dogs]: Intramuscular, 20,000 to 40,000 Units per kg of

body weight every twelve to twenty-four hours.{R-54}

Cattle, pigs, and sheep: Intramuscular, [24,000 to 66,000{R-36; 79}

Units per kg of body weight every twenty-four hours].

Horses: Intramuscular, [20,000 Units per kg of body weight every

twelve to twenty-four hours.{R-56; 58; 65; 69}]

Note: Penicillin G procaine should not be administered subcutaneously

at high doses{R-80} because doing so produces significant local

inflammation and hemorrhage, as well as medication deposits{R-82}

that can contribute to residue problems. The maximum dose

per injection site of penicillin G procaine should be 3,000,000 Units

(10 mL); injection sites should be different for each succeeding

treatment.{R-7; 53} Penicillin G procaine should never be adminis-

tered intravenously.


U.S.—


300,000 Units per mL (OTC) [Agri-cillin; Aquacillin; Microcillin; Pen-

Aqueous; generic].

Canada—


300,000 Units per mL (OTC) [Depocillin; Derapen SQ/LA; Hi-Pencin

300; Pen-Aqueous; Pen G Injection; Penmed; Penpro; Propen LA;

Ultrapen LA; generic].

Note: Some Canadian products, such as Derapen SQ/LA, Propen LA, and

Ultrapen LA, list their strengths and dosing in terms of milligrams

rather than international units (IU){R-46}; procaine penicillin G

contains 1009 penicillin G IU per mg{R-25}.

Withdrawal times:

U.S.—{R-7; 26; 53}

Withdrawal time


Cattle 4 48

Calves (nonruminating) 7

Sheep 8

Swine 6

Note: Products bearing labeling with the above withdrawal times list a

dose of 6600 Units per kg of body weight administered intramuscu-

larly once every 24 hours. Treatment should not exceed five days in

lactating cattle or seven days in sheep, swine, or nonlactating cattle for

these withdrawal times to apply.{R-7; 26}



Withdrawal time


Cattle 10 48

Sheep 9

Swine 7

Note: Products bearing labeling with the above withdrawal times list a

dose of 6600 Units per kg of body weight administered intramuscu-

larly once every 24 hours. Treatment should not exceed four days for

these withdrawal times to apply. These products are not labeled for use

in pre-ruminating calves.{R-26; 53; 70}

Canada—{R-6; 81}

When administered at a dose of 6670 Units per kg of body weight

every twenty-four hours{R-81}:

Withdrawal time


Cattle 5 72

When administered at a dose of 15,000 Units per kg of body weight


Withdrawal time

Species Meat (days)

Pigs 8

When administered at a dose of 21,000 Units per kg of body weight


Withdrawal time


Cattle 10 96

Sheep 10 —

Note: The Canadian Bureau of Veterinary Drugs has published results of

tissue residue studies and calculated withdrawal times for use of

penicillin G procaine administered at doses that are higher than U.S.

label doses{R-80; 82; 83}. Some of these withdrawal times are now listed

in the labeling of Canadian products, as shown above, with the

exception of the withdrawal calculated for the highest dose. If penicillin

G is administered at the extra-label dose of 60,000 Units per kg of body

weight every 24 hours, there is some evidence to suggest that a

withdrawal time of 21 days would be sufficient to avoid residues in

sheep and non-lactating cattle and that a withdrawal time of 15 days

would be sufficient for pigs.

For Derapen SQ/LA, Propen LA, and Ultrapen LA:

Withdrawal time

Species Meat (days)

Cattle

Intramuscular dose 21

Subcutaneous dose 14

Pigs 10

Note: Products bearing labeling with the above withdrawal times list 20

mg per kg of body weight as a single intramusuclar or subcutaneous

dose in cattle or a single intramusuclar dose in pigs. The dose may be

repeated in seventy-two hours.


Protect from freezing.{R-53; 70}

Preparation of dosage form: The vial should be warmed to room

temperature and shaken well to insure a uniform suspension.{R-53}


Some animals may develop procaine toxicity, which can result in acute

neurologic signs{R-48}.

Administration of penicillin G procaine to racing horses may pro-

duce violative procaine concentrations in urine for more than two

weeks.{R-91; 92}


tainers, preferably of Type I or Type III glass, in a refrigerator. A

sterile suspension of Penicillin G Procaine or, where labeled for

veterinary use only, of sterile penicillin G procaine, in Water for

Injection and contains one or more suitable buffers, dispersants, or

suspending agents, and a suitable preservative. It may contain

procaine hydrochloride in a concentration not exceeding 2.0%.

Where it is intended for veterinary use, the label so states. Contains

an amount of penicillin G procaine equivalent to the labeled amount

of penicillin G, within –10% to +15%, the labeled amount being not

less than 300,000 Penicillin G Units per mL or per container. Meets

the requirements for Identification, Crystallinity, Bacterial endotox-

ins, Sterility, pH (5.0–7.5), and Penicillin G and procaine contents,

and for Injections.{R-51}

PENICILLIN G SODIUM FOR INJECTION USPUsual dose: [Antibacterial]1—See Penicillin G Potassium for Injection USP.


U.S.—





Canada—









otherwise specified by the manufacturer.

Preparation of dosage form: To prepare initial dilution for intramus-

cular or intravenous use, see manufacturer’s labeling for instructions.

Stability: After reconstitution, solutions retain their potency for 24

hours at room temperature or for 7 days if refrigerated.{R-68}



Incompatibilities:

Penicillin G sodium is rapidly inactivated by acids, alkalies, and oxidizing

agents and in carbohydrate solutions at alkaline pH.

Extemporaneous admixtures of beta-lactam antibacterials (penicillins


mutual inactivation. Do not mix these antibacterials in the same

intravenous bag, bottle, or tubing.{R-29; 71}

Additional information:{R-68}

Human guidelines recommend that daily doses of 10,000,000 Units or

more should be administered by slow intravenous infusion to avoid

causing or exacerbating electrolyte imbalance.

The sodium content is approximately 2 mEq (2 mmol) per 1,000,000

Units of penicillin G. This should be considered in patients on a

restricted sodium intake.

USP requirements: Preserve in Containers for Sterile Solids. It is

sterile Penicillin G Sodium or a sterile mixture of penicillin G sodium

and not less than 4.0% and not more than 5.0% of Sodium Citrate,

of which not more than 0.15% may be replaced by Citric Acid.

Contains the labeled amount of Penicillin G, within –10% to +20%,

and where it contains Sodium Citrate it has a potency of not less

than 1420 and not more than 1667 Penicillin G Units per mg. Meets

the requirements for Constituted solution, Identification, Crystallinity,

Bacterial endotoxins, Sterility, pH (6.0–7.5, in a solution containing

60 mg per mL), Loss on drying (not more than 1.5%), and Partic-

ulate matter, and for Uniformity of dosage units and Labeling under

Injections.{R-51}

Developed: 04/27/95


04/05/03

Table 1. Pharmacokinetic parameters.

Species

Penicillin G

dosage form

Dose

(Units/kg)

Route/site of

administration*

Cmax

(mcg/mL)

Tmax

(hours)

Duration� of

action (hours)

Target� minimum serum

conc.(mcg/mL)

Disappearance

rate constant

(hour–1)

Calves (6–9 mo.) Potassium{R-55} 10,000 IM/neck 4.71 ± 3.86 1 to 1.5 – – –

Procaine{R-55} 30,000 IM/neck 1.55 ± 0.33 1.5 to 6 – – –

Cattle Procaine{R-36} 66,000 IM/neck 4.24 ± 1.08 6.00 ± 0.00 – – 0.08 ± 0.03

66,000 SC/neck 1.85 ± 0.27 5.33 ± 0.67 – – 0.04 ± 0.01

After 5-day

administration

Procaine{R-36} 24,000 IM/gluteal 0.99 ± 0.04 5.33 ± 0.67 – – 0.04 ± 0.01

66,000 IM/gluteal 2.63 ± 0.27 6.00 ± 0.00 – – 0.04 ± 0.00

During 7-day

administration:

Benzathine with

Procaine{R-69}�11,000 IM/not stated 0.72 2

Horses Sodium{R-57} 10,000 IV/jugular 1.68 0.5

20,000 IV/jugular 2.92 0.5

40,000 IV/jugular 3.90 0.5

Procaine{R-57} 10,000 IM/gluteal 4.90 0.5

20,000 IM/gluteal 18.75 0.5

40,000 IM/gluteal >24 0.5

Procaine{R-56} 22,000 IM/gluteal 1.42 ± 0.22 3

Foals (0–7 days) Procaine{R-58} 22,000 IM/semimem-

branous

2.17 ± 0.27 2

*Legend: IM = intramuscular; IV = intravenous; SC = subcutaneous.

�The durations of action in this study were based on a specific minimum target serum concentration considered by that researcher to be a value high enough to treat

penicillin-susceptible organisms.

�This study gave the stated dose once every 24 hours and monitored serum concentrations for 7 days. The Cmax shown here was the highest measured; values stayed below

0.31 after the first day and went as low as 0.12 mcg/mL.

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49. Blue JT, Dinsmore RP, Anderson KL. Immune-mediated hemolytic anemia

induced by penicillin in horses. Cornell Vet 1987; 77: 263–76.

50. Embrechts E. Procaine penicillin toxicity in pigs. Vet Rec 1982 Oct; 111: 314.



States Pharmacopeial Convention, Inc., 2002. p. 1409, 1410, 1412, 1415,

1421, 2573.

52. Amoxicillin package insert (Trimox, Apothecon—US), Rev 4/90, Rec 7/93.

53. Agri-cillin package insert (Agri Laboritories Ltd.—US), Rec 8/28/94.

54. Kirk RW, Bonagura JD, editors. Current veterinary therapy XI small animal

practice. Philadelphia: W.B. Saunders, 1992: 1244.

55. Bengtsson AF, Luthman J, Jacobsson O. Concentrations of sulphadimidine,

oxytetracycline and penicillin G in serum, synovial fluid and tissue cage fluid

after parenteral administration to calves. J Vet Pharmacol Ther 1989; 12: 37–

45.

56. Stover SM, et al. Aqueous procaine penicillin G in the horse: serum, synovial,

peritoneal, and urine concentrations after single-dose intramuscular admin-

istration. Am J Vet Res 1981; 42: 629–31.

57. Love DN, et al. Serum concentrations of penicillin in the horse after

administration of a variety of penicillin preparations. Equine Vet J 1983;

15(1): 43–8.

58. Brown MP, et al. Aqueous procaine penicillin G in foals: Serum concentrations

and pharmacokinetics after a single intramuscular dose. Equine Vet J 1984;

16(4): 374–5.

59. Oukessou M, et al. Comparative benzylpenicillin pharmacokinetics in the

dromedary Camelus dromedarius and in sheep. J Vet Pharmacol Ther 1990; 13:

298–303.

60. Short CR, et al. Clearance of penicillin G in the newborn calf. J Vet Pharmacol

Ther 1984; 7: 45–8.

61. Ziv G, Shani J, Sulman FG. Pharmacokinetic evaluation of penicillin and

cephalosporin derivatives in serum and milk of lactating cows and ewes. Am J

Vet Res 1973; 34(12): 1561–5.

62. Hirsh, et al. Pharmacokinetics of penicillin G in the turkey. Am J Vet Res 1978;

39(7): 1219–21.

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Port Huron, MI: North American Compendiums Inc., 1993: 398.

64. Howard JL. Current veterinary therapy 3 food animal practice. Philadelphia:

W.B. Saunders Company, 1993: 932.

65. Wilcke J, editor. Practice formulary. In: Veterinary values. 2nd ed. U.S.:

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66. Penicillin G potassium (Pfizerpen, Roerig). In: PDR Physicians’ desk reference.


1994: 1985–7.

67. Penicillin G potassium, Apothecon. Red Book 1994. Montvale, NJ: Medical

Economics Data, 1994: 311.

68. Penicillin G (generic, Wyeth-Ayerst). In: Krogh CME, editor. CPS Compendium

of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical

Association, 1994: 997–8.

69. Sullins KE, Messer NT, Nelson L. Serum concentration of penicillin in the horse

after repeated intramuscular injections of procaine penicillin G alone or in

combination with benzathine penicillin and/or phenylbutazone. Am J Vet Res

1984 May; 45(5): 1003–7.

70. Penicillin G Procaine Aqueous Suspension (G.C. Hanford Mfg. Co—US), Rev

9/93, Rec 8/1/94.

71. St Peter WL, Redic-Kill KA, Halstenson CE. Clinical pharmacokinetics of

antibiotics in patients with impaired renal function. Clin Pharmacokinet 1992;

22(3): 169–210.

72. English PB. Serum penicillin concentrations in the bovine with fortified

benzathine. Aust Vet J 1959 Aug; 35: 353–8.

73. Prescott JF. Leptospirosis. In: Howard JL. Current veterinary therapy 3 food


74. Smith MC, Sherman DM. Goat medicine. Philadelphia, PA: Lea & Febiger,

1994. p. 206–8.

75. Penicillin G procaine (Pfizerpen-AS, Roerig). In: PDR Physicians’ desk

reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production

Company, 1994. p. 1987–9.

76. Kirk RW, Bistner SI. Handbook of veterinary procedures and emergency

treatment. 3rd ed. Philadelphia: W.B. Saunders, 1981. p. 155–6.

77. Nurmio P. Penicillin G procaine: a possible cause of embryonic death in swine.

Vet Rec 1980 Feb; 106 (5): 97–8.

78. Papich MG. Disposition of penicillin G after administration of benzathine

penicillin G, or a combination of benzathine penicillin G and procaine penicillin

G in cattle. Am J Vet Res 1994; 55(6): 825–30.




80. Korsrud GO, et al. Depletion of penicillin G residues in tissues and injection

sites of yearling beef steers dosed with benzathine penicillin G alone or in

combination with procaine penicillin G. Food additives and contaminants

1994; 11(1): 1–6.

81. Penmed product information (Medprodex—Canada). In: Arrioja-Dechert A,



82. Bureau of Veterinary Drugs Overview 1993–94. Food Directorate/Health

Protection Branch/Health Canada. Minister of National Health and Welfare:

Minister of Supplies and Services Canada 1994.

83. Ritter L. Withholding times for procaine penicillin G in cattle [letter]. Can Vet J

1991; 32: 647.

84. Race track division schedule of drugs 1991. Agriculture Canada.







90. Bengtsson B, et al. Distribution of penicillin-G and spiramycin to tissue cages

and subcutaneous tissue fluid in calves. Res Vet Sci 1991; 50: 301–7.


92. Tobin T. Drugs and the performance horse. Charles Thomas, Publishers, 1981.

p. 270–2.

93. Depocillin product information (Intervet—Canada). In: Arrioja-Dechert A,





PIRLIMYCIN Veterinary—Intramammary-Local

Some commonly used brand names are Pirsue Aqueous Gel and Pirsue

Sterile Solution{R-1}.




INDICATIONS

GENERAL CONSIDERATIONSPirlimycin is a lincosamide antibiotic with activity primarily against

gram-positive organisms, including Staphylococcus and Streptococcus

species.{R-1} It is considered more active than clindamycin against

Staphylococcus aureus.{R-5} Pirlimycin is not active against gram-

negative bacteria, such as Escherichia coli.{R-10}

ACCEPTEDMastitis (treatment)—Cows, lactating: Pirlimycin is indicated in the

treatment of clinical and subclinical mastitis caused by Staphylococcus

aureus, Streptococcus agalactiae, Streptococcus dysgalactiae, and Strepto-

coccus uberis.{R-1}

In refractory cases of chronic Staphylococcus aureus mastitis, adminis-

tration of intramammary pirlimycin at recommended doses is sufficient

to control but not eliminate the pathogen.{R-4} Intramammary therapy

alone is indicated only in the treatment of subacute or subclinical

mastitis manifested by mild changes in the milk or udder. Cows with

acute or peracute mastitis, which involves gross changes in the milk

or udder or systemic signs, should be given other medications also,

which may include systemic antibiotics and/or supportive therapy.{R-6}


Withdrawal times have been established for cattle. See the Dosage

Forms section.{R-1}

CHEMISTRYSource: Semisynthetic derivative of lincomycin.{R-3}

Chemical group: Lincosamide antibiotic.

Chemical name: Pirlimycin hydrochloride—L-threo-alpha-D-galacto-

Octopyranoside, methyl 7-chloro-6,7,8-trideoxy-6-[[(4-ethyl-2-piperi-

dinyl)carbonyl]amino]-1-thio-, monohydrochloride, monohydrate,

(2S-cis).{R-2}

Molecular formula: Pirlimycin hydrochloride—

C17H31ClN2O5S Æ HCl Æ H2O.{R-2}

Molecular weight: Pirlimycin hydrochloride—465.43{R-2}.

pKa: 8.5.{R-3}


Mechanism of action/effect: Pirlimycin is bacteriostatic at therapeu-

tic concentrations.{R-3} The lincosamides inhibit protein synthesis in

susceptible bacteria by binding to the 50 S ribosomal subunits of

bacterial ribosomes and preventing peptide bond formation.{R-7}

Absorption: Almost one half of the dose is absorbed systemically after

intramammary administration.{R-5}

Distribution: Pirlimycin is lipophilic and diffuses readily across tissue

membranes.{R-3}

Biotransformation: Pirlimycin is eliminated primarily as parent drug

when administered by the intramammary route; however, 4% of the

dose is oxidized by the liver to pirlimycin sulfoxide{R-5}.

Peak concentrations: Based on two intramammary doses of 50 mg

each, given 24 hours apart—

Blood: 0.025 mcg per mL (mcg/mL) 2 and 6 hours after the second

50-mg intramammary dose{R-14; 15}.

Mammary tissue: 10 mcg per gram (mcg/gram) 10 hours after the

second dose{R-4}.

Milk: > 150 mcg/mL in the first assay sample, taken 4 hours after each

dose{R-4}.

Liver concentration:

Total—The concentration of pirlimycin and metabolites (primarily

pirlimycin sulfoxide) in the liver 4 days after the second 50-mg

intramammary dose is 2.18 mcg/gram{R-11; 13; 14}.

Parent compound (marker residue)—The concentration of pirlimycin in

the liver 2 days after the second 50-mg intramammary dose is 2.33

mcg/gram; the concentration falls below 0.5 mcg/gram by 21 days

after the second dose{R-11; 14}.

Mammary tissue concentration: Based on two intramammary

doses of 50 mg each, given 24 hours apart—The mammary

tissue concentration 4 days after the second dose is 0.927 mcg/

gram{R-14; 15}.

Milk concentration: Based on a 50-mg intramammary dose at 0 and

24 hours, the milk pirlimycin concentration 12 hours after the second

infusion of medication is measured to be 8 to 18 mcg/mL and by 36

hours the concentration is less than 1 mcg/mL{R-11}.

Elimination: When pirlimycin is administered by the intramammary

route, approximately 51% of the original dose is distributed into the

milk, 10% into the urine, and 24% into the feces.{R-5} Of the total dose,

68% is recovered as unchanged pirlimycin.{R-5}






(milk samples should be tested three weeks after treatment with

pirlimycin is discontinued; mastitis is not considered bacterio-

logically cured until samples show an absence of the mastitis-

causing organism; for refractory Staphylococcus aureus mastitis,

in which control, but not elimination, is achieved, S. aureus

PIRLIMYCIN Veterinary—Intramammary-Local 161


can reappear in milk cultures by 10 hours after the second

treatment{R-4})

SIDE/ADVERSE EFFECTSNote: All clinical efficacy and toxicity studies performed with intramam-

mary pirlimycin in cows have shown it to be nonirritating{R-11}. No

serious adverse effects associated with the use of pirlimycin in cows

have been documented. The Food and Drug Administration Adverse

Drug Experience reporting program has received only one report of

urticaria, possibly drug-related, in three cows that responded well to

treatment for the urticaria{R-16}.





drug manufacturer.

CLIENT CONSULTATIONTreatment of mastitis in dairy cattle is best achieved by a comprehen-

sive mastitis control program in which herd management is the

primary focus. The program should include good maintenance of

milking equipment and constant evaluation of milking procedures

and teat health as well as strategic treatment of clinical cases of

mastitis.{R-9}


knowledge of the culture and sensitivity of the pathogens causing

mastitis in the cow and the dairy herd.

Before administration of intramammary pirlimycin, the following steps

should be performed:



washing excess dirt down from the udder onto the teat ends. The

area should be dried thoroughly. An effective germicidal teat dip



alcohol.



• To administer pirlimycin, the tip of the syringe should be inserted

into the teat end as little as possible and the contents of the syringe

should be injected into each streak canal while the teat is held

firmly.

The medication should then be gently massaged up the teat canal into

the gland cistern.

Following treatment, an effective teat dip is recommended on all teats.


PIRLIMYCIN INTRAMAMMARY INFUSIONUsual dose: Mastitis—Cows, lactating: Intramammary, 50 mg admin-

istered into each affected quarter, followed by a second dose admin-

istered twenty-four hours later.{R-1; 17}


U.S.—{R-1; 18; 19}


5 mg per mL (Rx) [Pirsue Sterile Solution].

Canada—{R-12; 18}


5 mg per mL (Rx) [Pirsue Aqueous Gel].

Withdrawal times:

U.S.—{R-17–19}

Canada—{R-12; 18}

Packaging and storage: Store at 25 �C (77 �F) or less, unless otherwise

specified by manufacturer. Protect from freezing.{R-1}


Developed: 07/09/96

Revised: 02/27/98


REFERENCES1. Pirsue Sterile Solution (Pharmacia—US), Rev 1/03. Downloaded 2/17/03

from www.pharmaciaah.com.


MD: The United States Pharmacopeial Convention Inc; 2002.

3. Henke CL, Chester ST, Dame KJ, et al. New developments in lactating cow

preparations—the efficacy of three blind labeled intramammary infusion

formulae in the treatment of clinical mastitis. Proceedings of the 31st annual

meeting of the National Mastitis Council, Inc.; 1992 Feb 10–12; Arlington,

Virginia. Arlington, VA: National Mastitis Council; 1992.

4. Owens WE, Nickerson SC, Watts JL, et al. Milk, serum, and mammary tissue

concentration of pirlimycin following intramuscular, intramammary or

combination therapy of chronic Staphyloccus aureus mastitis. Agri-Practice

1994 Mar; 15(3): 19–23.

5. Hornish RE, Arnold TS, Baczynskyj L, et al. Pirlimycin in the dairy cow:

metabolism and residues. Proceedings of the 202nd national meeting of the

American Chemical Society; 1991 Aug 25–30; New York. Washington, DC:

American Chemical Society; 1992.

6. Heath SE. Bovine mastitis. In: Howard JL, editor. Current veterinary therapy 3.

Food animal practice. Philadelphia: WB Saunders Co; 1993. p. 762–9.

7. Barragry TB. Veterinary drug therapy. Baltimore: Lea & Febiger; 1994.

p. 251–62.


bovine mastitis. Vet Rec 1989; 124: 630–4.


Vet Med Assoc 1993; 203(2): 219–20.

10. Thornsberry C, Marler JK, Watts JL, et al. Activity of pirlimycin against

pathogens from cows with mastitis and recommendations for disk diffusion

tests. Antimicrob Agents Chemother 1993; 37: 1122–6.

11. Freedom of Information Summary. Pirlimycin hydrochloride for intramam-

mary treatment of clinical or subclinical mastitis in lactating dairy cattle.

NADA 141–036. The Upjohn Company. Office of Consumer Affairs, Food and

Drug Administration, Rockville, MD.

12. Pirsue Aqueous Gel package insert (Pharmacia—Canada), Rev 1/01, Rec

1/30/02.

Withdrawal time


Cows 9 36

Withdrawal time


Cows 28 48

162 PIRLIMYCIN Veterinary—Intramammary-Local




15. Upjohn Technical Report (TR) 782-7926-92-002. Metabolism study 2.

In: Freedom of Information Report. Pirlimycin hydrochloride for intramam-

mary treatment of clinical or subclinical mastitis in lactating dairy cattle.

NADA 141-036. The Upjohn Company. Office of Consumer Affairs, Food and

Drug Administration, Rockville, MD.

16. The Food and Drug Administration Center for Veterinary Medicine Adverse

Drug Experience Summaries, Center for Veterinary Medicine, Food and Drug

Administration, Rockville, MD. 10/18/96.

17. Freedom of Information Summary. Pirsue Sterile Solution (new formulation

and withdrawal period). NADA 141-036. Sponsor: Pharmacia & Upjohn

Company. September 7, 2000.



19. Entriken TL, editor. Veterinary pharmaceuticals and biologicals, 12th ed.

Lenexa, KS: Veterinary Healthcare Communications, 2001. p. 1892–3.



States Pharmacopeial Convention, Inc., 2002.

PIRLIMYCIN Veterinary—Intramammary-Local 163


POTENTIATED SULFONAMIDES Veterinary—Systemic

This monograph includes information on the following: Ormetoprim and

Sulfadimethoxine; Pyrimethamine and Sulfaquinoxaline*; Sulfadiazine

and Trimethoprim; Sulfadoxine and Trimethoprim*; Sulfamethoxazole

and Trimethoprim.


For veterinary-labeled products—Bimotrim [Sulfadoxine

and Trimethoprim]

Tribrissen 120 [Sulfadiazine

and Trimethoprim]

Borgal [Sulfadoxine

and Trimethoprim]


and Trimethoprim]

Potensulf [Sulfadoxine

and Trimethoprim]


and Trimethoprim]

Primor 120 [Ormetoprim

and Sulfadimethoxine]

Tribrissen 24% [Sulfadiazine

and Trimethoprim]



Tribrissen 48% [Sulfadiazine

and Trimethoprim]



Tribrissen 400 Oral Paste

[Sulfadiazine and Trimethoprim]



Tribrissen Piglet Suspension


Quinnoxine-S [Ormetoprim


Tribrissen 40% Powder


Rofenaid 40 [Ormetoprim


Trimidox [Sulfadoxine

and Trimethoprim]

Romet 30 [Ormetoprim


Trivetrin [Sulfadoxine

and Trimethoprim]

Romet-30 [Ormetoprim


Tucoprim Powder [Sulfadiazine

and Trimethoprim]

Sulfaquinoxaline-S [Pyrimethamine


Uniprim Powder [Sulfadiazine

and Trimethoprim]


and Trimethoprim]

For human-labeled products—Apo-Sulfatrim [Sulfamethoxazole

and Trimethoprim]

Nu-Cotrimox DS [Sulfamethoxazole

and Trimethoprim]

Apo-Sulfatrim DS [Sulfamethoxazole

and Trimethoprim]

Roubac [Sulfamethoxazole

and Trimethoprim]

Bactrim [Sulfamethoxazole

and Trimethoprim]

Septra [Sulfamethoxazole

and Trimethoprim]

Bactrim DS [Sulfamethoxazole

and Trimethoprim]

Septra DS [Sulfamethoxazole

and Trimethoprim]

Bactrim I.V. [Sulfamethoxazole

and Trimethoprim]

Septra Grape Suspension

[Sulfamethoxazole

and Trimethoprim]

Bactrim Pediatric [Sulfamethoxazole

and Trimethoprim]

Septra I.V. [Sulfamethoxazole

and Trimethoprim]

Cofatrim Forte [Sulfamethoxazole

and Trimethoprim]

Septra Suspension [Sulfamethoxazole

and Trimethoprim]

Cotrim [Sulfamethoxazole

and Trimethoprim]

Sulfatrim [Sulfamethoxazole

and Trimethoprim]

Cotrim DS [Sulfamethoxazole

and Trimethoprim]

Sulfatrim DS [Sulfamethoxazole

and Trimethoprim]

Cotrim Pediatric [Sulfamethoxazole

and Trimethoprim]

Sulfatrim Pediatric [Sulfamethoxazole

and Trimethoprim]

Novo-Trimel [Sulfamethoxazole

and Trimethoprim]

Sulfatrim S/S [Sulfamethoxazole

and Trimethoprim]

Novo-Trimel D.S. [Sulfamethoxazole

and Trimethoprim]

Sulfatrim Suspension [Sulfamethoxazole

and Trimethoprim]

Nu-Cotrimox [Sulfamethoxazole

and Trimethoprim]



CATEGORY:Antibacterial (systemic); antiprotozoal (systemic).


are either not included in U.S. product labeling or are for products not


Information identified by a superscript 1 refers to uses that are either

not included in Canadian product labeling or are for products not

commercially available in Canada.

GENERAL CONSIDERATIONSThe combined and synergistic activities of the two agents in each type

of potentiated sulfonamide produce antibacterial activity against a

wide range of infections caused by gram-positive and gram-negative

bacteria, some protozoa{R-3}, and some anaerobes under certain

conditions{R-44}. The minimum inhibitory concentrations against

specific susceptible bacteria for each antibiotic are generally lowered

when the antibiotics are administered in the potentiated sulfonamide

combination. The resistance developed to the potentiated sulfona-

mides is lower than that to each individual agent{R-20; 23}; this

is an important benefit because of the common resistance to

sulfonamides and rapid development of resistance to diaminopyri-

midines when used alone.{R-20} Cross-resistance between sulfona-

mides is considered complete{R-94} and often occurs between

pyrimidines{R-25}.

ACCEPTEDCoccidiosis (prophylaxis)—

Chickens: Ormetoprim and sulfadimethoxine premix1{R-6} is indicated

in the prevention of coccidiosis caused by susceptible Eimeria

acervulina, E. brunetti, E. maxima, E. mivati, E. necatrix, and E. tenella.

[Pyrimethamine and sulfaquinoxaline combination{R-17} is indicated

in the prevention of coccidiosis, caused by susceptible organisms.]

Potentiated sulfonamides may be more effective in the treatment of

E. acervulina than of E. tenella{R-71}.

Partridges, chukar1: Ormetoprim and sulfadimethoxine premix is

indicated in the prevention of coccidiosis caused by susceptible

Eimeria kofoidi and E. legionensis {R-6; 125}.

Turkeys: Ormetoprim and sulfadimethoxine premix1{R-6} is indicated in

the prevention of coccidiosis caused by susceptible Eimeria adenoeides,

E. gallopavonis, and E. meleagridis. [Pyrimethamine and sulfaquinox-

aline combination{R-17} is indicated in the prevention of coccidiosis

caused by susceptible organisms.]

[Coccidiosis (treatment)]—Chickens and turkeys: Pyrimethamine and

sulfaquinoxaline oral solution{R-17} is indicated to aid in the treatment

of susceptible coccidia.

Colibacillosis (prophylaxis)1—Chickens, broiler and replacement, and

ducks: Ormetoprim and sulfadimethoxine premix{R-6} is indicated in the

prevention of colibacillosis caused by susceptible Escherichia coli.

Colibacillosis (treatment)—

Ducks1: Ormetoprim and sulfadimethoxine premix{R-6} is indicated in

the control of colibacillosis caused by susceptible E. coli.

[Cattle]: Sulfadoxine and trimethoprim injection{R-13; 14} is indicated in

the treatment of colibacillosis caused by susceptible organisms.*Not commercially available in the U.S.

164 POTENTIATED SULFONAMIDES Veterinary—Systemic


[Pigs]: Sulfadiazine and trimethoprim oral suspension{R-10} and

sulfadoxine and trimethoprim injection{R-13} are indicated in the

treatment of neonatal colibacillosis caused by susceptible E. coli{R-10}.

Enteric septicemia (treatment)1—Catfish: Ormetoprim and sulfadime-

thoxine premix{R-7; 16} is indicated in the control of enteric septicemia

caused by susceptible Edwardsiella ictaluri.

Fowl cholera (prophylaxis)1—Chickens and turkeys: Ormetoprim and

sulfadimethoxine premix{R-6} is indicated in the prevention of fowl

cholera caused by susceptible Pasteurella multocida.

Fowl cholera (treatment)1—Ducks: Ormetoprim and sulfadimethoxine

premix{R-6} is indicated in the control of fowl cholera caused by

susceptible Pasteurella multocida.

Furunculosis (treatment)—Salmon and trout: Ormetoprim and sulfadime-

thoxine premix{R-7; 16} is indicated in the control of furunculosis

caused by susceptible Aeromonas salmonicida.

Gastrointestinal tract infections, bacterial (treatment)—Treatment of

gastroenteritis with antimicrobials should rely on a specific diagnosis

and knowledge of pathogen susceptibility.

Dogs: Sulfadiazine and trimethoprim [injection]{R-8; 95} and tablets1{R-

2; 11} are indicated in the treatment of acute gastrointestinal tract

infections.

[Cats]: Sulfadiazine and trimethoprim injection{R-8} and tablets1{R-11}

are indicated in the treatment of acute gastrointestinal tract

infections.

Infectious coryza (prophylaxis)1—Chickens: Ormetoprim and sulfadime-

thoxine premix{R-6} is indicated in the prevention of infectious coryza

caused by susceptible Haemophilus gallinarum.

New duck disease (treatment)1—Ducks: Ormetoprim and sulfadimethox-

ine premix{R-6} is indicated in the control of new duck disease

(infectious serositis) caused by susceptible Riemerella anatipestifer.


Dogs: Sulfadiazine and trimethoprim [injection{R-8; 95}] and tablets1{R-

2} are indicated in the treatment of acute bacterial respiratory tract

infections caused by susceptible organisms.

Horses: Sulfadiazine and trimethoprim injection{R-9; 96; 146}, oral

paste{R-3; 18}, and oral powder1{R-4} are indicated in the treatment of

respiratory tract infections caused by susceptible organisms.


are indicated in the treatment of respiratory tract infections caused



Dogs: Ormetoprim and sulfadimethoxine tablets1{R-5} are indicated in

the treatment of skin and soft tissue infections caused by susceptible

E. coli and Staphylococcus intermedius. Sulfadiazine and trimetho-

prim [injection]{R-8} and tablets1{R-2; 11} are indicated in the

treatment of abscesses and infected wounds caused by susceptible

organisms.

Horses: Sulfadiazine and trimethoprim injection{R-9; 96; 146}, oral

paste{R-3; 18}, and oral powder1{R-4} are indicated in the treatment of

abscesses and infected wounds caused by susceptible organisms.


are indicated in the treatment of bacterial infections, such as

abscesses and wounds, caused by susceptible organisms.

Strangles (treatment)—Horses: Sulfadiazine and trimethoprim injec-

tion{R-9; 96; 146}, oral paste{R-3; 18}, and oral powder1{R-4} are

indicated in the treatment of acute strangles caused by susceptible

organisms.

Urinary tract infections (treatment)—Dogs: Ormetoprim and sulfadime-

thoxine tablets{R-126} and sulfadiazine and trimethoprim tablets1{R-2}

are indicated in the treatment of acute urinary tract infections caused


Urogenital tract infections (treatment)1—Horses: Sulfadiazine and tri-

methoprim injection{R-96; 146}, oral paste, and oral powder{R-4} are

indicated in the treatment of acute urogenital tract infections{R-3}.

[Arthritis, bacterial (treatment)]—Pigs: Sulfadoxine and trimethoprim

injection{R-13–15} is indicated in the treatment of bacterial arthritis

caused by susceptible organisms.

[Enteritis, bacterial (treatment)]—

Cattle: Sulfadoxine and trimethoprim injection{R-13; 14} is indicated

in the treatment of enteritis caused by susceptible E. coli or

Salmonella.

Pigs: Sulfadiazine and trimethoprim oral suspension{R-10} and sulfa-

doxine and trimethoprim injection{R-13; 14} are indicated in the

treatment of post-weaning scours caused by susceptible E. coli.

[Mastitis (treatment)]; or

[Metritis (treatment)]—Sows: Sulfadoxine and trimethoprim injec-

tion{R-13–15} is indicated in the treatment of mastitis-metritis-agalactia

syndrome caused by susceptible organisms.

[Perioperative infections (treatment)]—Horses: Sulfadiazine and trimeth-

oprim oral paste{R-18} and injection{R-9} are indicated in the treatment

of postoperative bacterial infections caused by susceptible organisms.

[Pneumonia, bacterial (treatment)]—

Cattle: Sulfadoxine and trimethoprim injection{R-13; 14} is indicated in

the treatment of bacterial pneumonia, including bovine pneumonic

pasteurellosis (shipping fever), caused by susceptible organisms.

Pigs: Sulfadoxine and trimethoprim combination{R-14; 15} is indicated

in the treatment of bacterial pneumonia caused by susceptible

organisms.

[Pododermatitis (treatment)]—Cattle: Sulfadoxine and trimethoprim

injection{R-13; 14} is indicated in the treatment of pododermatitis


[Septicemia (treatment)]—

Cattle: Sulfadoxine and trimethoprim injection{R-13; 14} is indicated in

the treatment of septicemia caused by susceptible organisms.

Dogs: Sulfadiazine and trimethoprim injection1{R-95} is used in the

treatment of septicemia caused by susceptible organisms.

[Vibrio anguillarum infection]—Salmon: Sulfadiazine and trimethoprim

combination oral powder{R-22} is indicated in the treatment of

infections caused by susceptible Vibrio anguillarum{R-64}.

ACCEPTANCE NOT ESTABLISHEDDistemper, canine (treatment)—Dogs: Although U.S. product labeling

includes the use of sulfadiazine and trimethoprim in the treatment of

secondary bacterial infections associated with canine distemper{R-2},

and this use may be appropriate in bacterial infections that are

susceptible to this medication, the use of these antimicrobials in the

treatment of distemper-associated infections is not considered more

appropriate or more generally accepted than in the treatment of

bacterial infections associated with other viral infections.

Bacterial infections (treatment)—Horses: There are insufficient controlled

studies to support the efficacy and safety of [sulfamethoxazole and

trimethoprim combination]1 in the treatment of bacterial infections in

foals and horses; however, based on pharmacokinetic data, the

combination is used in the treatment of susceptible infections{R-31–33}.

POTENTIATED SULFONAMIDES Veterinary—Systemic 165


[Coccidiosis (treatment)]1—Cats and dogs: There are insufficient data to

support the efficacy of sulfadiazine and trimethoprim or ormetoprim and

sulfadimethoxine{R-136} in the treatment of enteric coccidiosis in cats

and dogs; however, these medications are used to reduce the shedding

of oocysts and may aid in the natural elimination of Isospora species.

[Equine infectious arthritis (treatment)]1—Horses: There are insufficient

data to support the efficacy and safety of sulfadiazine and trimethoprim

combination in the treatment of equine infectious arthritis; however,

pharmacokinetic and clinical studies do lend support to its efficacy in

the treatment of experimentally-induced Staphylococcus aureus joint

infections{R-41; 42}.

[Equine protozoal myeloencephalitis (treatment)]1; or

[Protozoal infections (treatment)]1—Horses: There are insufficient con-

trolled studies to support the efficacy and safety of sulfamethoxazole

and trimethoprim combination in the treatment of protozoal infections

in foals and horses; however, based on pharmacokinetic data, the

combination is used in the treatment of susceptible infections{R-31–33}. Prior to the availability of approved products (ponazuril,

toltrazuril) to treat equine protozoal myeloencephalitis, administration

of sulfamethoxazole and trimethoprim in combination with pyrimeth-

amine was clinically useful in treating horses with this disease{R-147}.

In vitro studies also show efficacy of potentiated sulfonamides against

Sarcocystis neurona{R-148}.

[Meningitis, bacterial (treatment)]1—Dogs: There are insufficient data to

support the efficacy of sulfadiazine and trimethoprim combination in

the treatment of bacterial meningitis in dogs; however, it has been

used for this indication{R-38}.

[Nocardiosis (treatment)]1—Cats and dogs: There are insufficient data to

support the efficacy of sulfadiazine and trimethoprim or sulfamethox-

azole and trimethoprim in the treatment of nocardiosis in cats and

dogs; however, these medications are used in the treatment of

nocardial infections. Sulfonamides have been considered the treatment

of choice and there is some evidence{R-128–133} to suggest that

sulfadiazine and trimethoprim or sulfamethoxazole and trimethoprim

are efficacious in the treatment of these infections{R-128; 131; 133}.

Ormetoprim and sulfadimethoxine combination could also be effective

in the treatment of nocardiosis, based on a pharmacokinetic profile

similar to that of trimethoprim with sulfadiazine or sulfamethoxaz-

ole{R-138}. Because of a variability in the susceptibility of Nocardia

species, culture and sensitivity tests should be performed, if possible.

Surgical drainage should be provided for any abscesses or draining

tracts{R-130; 131}. Sulfonamide and trimethoprim combination admin-

istered alone may not be effective in the treatment of cerebral

nocardiosis{R-132}.

[Pneumonia (treatment)]1—Calves, nonruminating: Until recently, Cana-

dian sulfadiazine and trimethoprim boluses were labeled for use in the

treatment of bacterial pneumonia in calves{R-12}. Such a product has

not been available in the United States. Although there are no

sulfadiazine and trimethoprim products labeled for use in calves in the

United States or Canada at this time, oral sulfadiazine and trimeth-

oprim tablets might be used in the treatment of susceptible infections,

such as bacterial pneumonia, in calves. For more information, see

Sulfadiazine and Trimethoprim Tablets in the Dosage Forms section of

this monograph.

[Prostate infection (treatment)]1—Dogs: There are insufficient data to

support the efficacy of trimethoprim in combination with sulfadiazine

or sulfamethoxazole in the treatment of prostate infections caused by

susceptible organisms in dogs; however, pharmacokinetic studies show

that these trimethoprim and sulfonamide combinations are distributed

into prostate fluid at therapeutic concentrations{R-48}. Ormetoprim and

sulfadimethoxine combination also could be effective in the treatment

of prostatitis, based on a pharmacokinetic profile similar to that of

trimethoprim with sulfadiazine or sulfamethoxazole{R-138}.


Withdrawal times have been established for ormetoprim and sulfa-

dimethoxine for medicated feed (see the Dosage Forms section).

Canada—

Withdrawal times have been established for ormetoprim and sulfa-

dimethoxine for medicated feed; pyrimethamine and sulfaquinoxa-

line oral solution; sulfadiazine and trimethoprim boluses, oral paste,

oral powder, and oral suspension; and sulfadoxine and trimethoprim

injection (see the Dosage Forms section).

CHEMISTRYChemical group:

Ormetoprim, pyrimethamine, and trimethoprim—Diaminopyrimidines.

Sulfadiazine, sulfadimethoxine, sulfadoxine, sulfamethoxazole, and sulf-

aquinoxaline—Sulfonamides.

Chemical name:

Ormetoprim—2,4-Pyrimidinediamine,5-[(4,5-dimethoxy-2-methylphenyl)

methyl]-{R-1}.

Pyrimethamine—2,4-Pyrimidinediamine, 5-(4-chlorophenyl)-6-ethyl-{R-1}.

Sulfadiazine—Benzenesulfonamide, 4-amino-N-2-pyrimidinyl-{R-1}.

Sulfadimethoxine—Benzenesulfonamide, 4-amino-N-(2,6-dimethoxy-4-

pyrimidinyl)-{R-1}.

Sulfadoxine—Benzenesulfonamide, 4-amino-N-(5,6-dimethyoxy-4-pyri-

midinyl)-{R-1}.

Sulfamethoxazole—Benzenesulfonamide, 4-amino-N-(5-methyl-3-isoxaz-

olyl)-{R-1}.

Sulfaquinoxaline—N1-2-Quinoxalinylsulfanilamide{R-1}.

Trimethoprim—2,4-Pyrimidinediamine, 5-[(3,4,5-trimethoxyphenyl)

methyl]-{R-1}.

Molecular formula:

Ormetoprim—C16H18N4O2{R-1}.

Pyrimethamine—C12H13ClN4{R-1}.

Sulfadiazine—C10H10N4O2S{R-1}.

Sulfadimethoxine—C12H14N4O4S{R-1}.

Sulfadoxine—C12H14N4O4{R-1}.

Sulfamethoxazole—C10H11N3O3S{R-1}.

Sulfaquinoxaline—C14H12N4O2S{R-1}.

Trimethoprim—C14H18N4O3{R-1}.

Molecular weight:

Ormetoprim—274.32{R-1}.

Pyrimethamine—248.71{R-1}.

Sulfadiazine—250.28{R-1}.

Sulfadimethoxine—310.34{R-1}.

Sulfadoxine—310.33{R-1}.

Sulfamethoxazole—253.28{R-1}.

Sulfaquinoxaline—300.34{R-1}.

Trimethoprim—290.32{R-1}.





Description:

Ormetoprim—White powder{R-5}.

Pyrimethamine USP—White, odorless, crystalline powder{R-117}.

Sulfadiazine USP—White or slightly yellow powder. Odorless or nearly

odorless and stable in air, but slowly darkens on exposure to

light{R-117}.

Sulfadimethoxine USP—Practically white, crystalline powder{R-117}.

Sulfadoxine—White or yellowish-white crystalline powder, melting at

197–200 �C{R-118}.

Sulfamethoxazole USP—White to off-white, practically odorless, crystal-

line powder{R-117}.

Sulfaquinoxaline—Yellow, odorless powder{R-118}.

Trimethoprim USP—White to cream-colored, odorless crystals, or

crystalline powder{R-117}.

pKa:

Sulfadiazine—6.4{R-25}.

Sulfadimethoxine—6.2{R-97; 98}.

Sulfadoxine—6.3{R-25}.

Sulfamethoxasole—5.7{R-25}.

Sulfaquinoxaline—5.5{R-99; 100}.

Trimethoprim—7.6{R-73; 90}.

Solubility:

Pyrimethamine USP—Practically insoluble in water; slightly soluble in

acetone, in alcohol, and in chloroform{R-117}.

Sulfadiazine USP—Practically insoluble in water; freely soluble in dilute

mineral acids, in solutions of potassium and sodium hydroxides, and in

ammonia TS; sparingly soluble in alcohol and in acetone; slightly

soluble in human serum at 37 �C{R-117}.

Sulfadimethoxine USP—Soluble in 2 N sodium hydroxide; spar-

ingly soluble in 2 N hydrochloric acid; slightly soluble in alcohol, in

ether, in chloroform, and in hexane; practically insoluble in

water{R-117}.

Sulfadoxine—Very slightly soluble in water; slightly soluble in alco-

hol and in methyl alcohol; practically insoluble in ether. Dissolves

in solutions of alkali hydroxides and in dilute mineral acids{R-118}.

Sulfamethoxazole USP—Practically insoluble in water, in ether, and in

chloroform; freely soluble in acetone and in dilute solutions of sodium

hydroxide; sparingly soluble in alcohol{R-117}.

Sulfaquinoxaline—Practically insoluble in water; very slightly soluble in

alcohol; practically insoluble in ether; freely soluble in aqueous

solutions of alkalis{R-118}.

Trimethoprim USP—Very slightly soluble in water; soluble in benzyl

alcohol; sparingly soluble in chloroform and in methanol; slightly

soluble in alcohol and in acetone; practically insoluble in ether and in

carbon tetrachloride{R-117}.

PHARMACOLOGY/PHARMACOKINETICSNote: Unless otherwise noted, pharmacokinetic values are based on

administration of a single intravenous dose and concurrent adminis-

tration of a diaminopyrimidine and a sulfonamide.

When sulfamethoxazole and trimethoprim are administered concur-

rently to horses, the pharmacokinetics of each drug appears to be

unaffected by the presence of the other{R-30; 32}.


Sulfonamides—The sulfonamides are bacteriostatic antimicrobials that

interfere with the biosynthesis of folic acid in bacterial cells; they

compete with para-aminobenzoic acid (PABA) for incorporation into

dihydrofolic acid{R-20}. By replacing the PABA molecule in dihydrofolic

acid, they prevent formation of folic acid required for nucleic acid

synthesis and multiplication of the bacterial cell{R-94; 101}. Sulfona-

mides are effective only in cells that must produce their own folic acid;

mammalian cells do not synthesize folic acid, but get it from outside

sources.

Diaminopyrimidines—Ormetoprim{R-5} and trimethoprim{R-23} are bac-

teriostatic antimicrobials that block a step in folate production just

subsequent to that affected by the sulfonamides. Bacterial production

of tetrahydrofolic acid from dihydrofolate is interrupted by the

diaminopyrimidine as it reversibly binds and inhibits dihydrofolate

reductase. Because the conversion of dihydrofolic acid to tetrahydro-

folic acid is blocked, folate cannot be produced. Pyrimethamine causes

the same inhibition of dihydrofolate reductase in protozoa{R-20}. Like

bacteria and protozoa, animal cells also reduce folic acid to tetrahy-

drofolic acid; however, bacterial and protozoal dihydrofolate reductase

is significantly more tightly bound by trimethoprim than is human

dihydrofolate reductase{R-2}.

Potentiated sulfonamides—Because the diaminopyrimidines exert their

effect on folate biosynthesis at a step immediately subsequent to the

one at which the sulfonamides act, the combination of a sulfonamide

and diaminopyrimidine produces a synergistic effect that deprives the

cell of essential nucleic acids and proteins. The potentiated sulfonamide

combination produces an antimicrobial effect that is bacteriostatic and

sometimes bactericidal against certain bacteria under optimum

conditions.{R-2; 23; 24} The minimal effective ratio of sulfonamide to

diaminopyrimidine in the target tissue is 20 to 1 for synergism. At

equimolar quantities, other ratios are equally effective, depending on

the strain of organism and the minimum inhibitory concentration

(MIC) for each drug. Therefore, 16 to 1, 10 to 1, and other ratios may

be effective, but combinations are formulated to achieve at least 20 to

1 in vivo{R-20}.

Absorption: Oral—

Ormetoprim and sulfadimethoxine:

Calves, 6 weeks of age—The bioavailability of oral ormetoprim is very

poor in ruminating calves{R-86}; the bioavailability of oral sulfa-

dimethoxine in calves is slow but complete and unaffected by

ruminant status{R-81}.

Dogs—Ormetoprim and sulfadimethoxine are rapidly and well

absorbed after oral administration{R-5}.

Horses—Oral absorption of ormetoprim and sulfadimethoxine is

variable. Sulfadimethoxine appears to be more efficiently absorbed

than ormetoprim{R-35; 36}.

Sulfadimethoxine administered alone: Bioavailability—

Catfish, channel: 40 mg/kg dose—{R-68}

Free base: 31%.

Sodium salt: 34%.

Trout, rainbow:

42 mg/kg dose—{R-67}

Free base: 34%.

Sodium salt: 63%.

126 mg/kg dose—Sodium salt: 50%{R-67}.

Sulfadiazine and trimethoprim:

Calves, 6 weeks of age—The bioavailability of oral trimethoprim is

greatly reduced in ruminating calves as compared to preruminating

calves. Therapeutic serum concentrations (> 0.1 mcg/mL) were not



achieved with oral administration of 25 mg of sulfadiazine and 5 mg

of trimethoprim in combination to ruminating calves{R-81}. The

bioavailability of oral sulfadiazine in calves is slow but complete and

unaffected by rumen status{R-81}.

Dogs—Sulfadiazine and trimethoprim are rapidly and well absorbed

following oral administration{R-76}. However, absorption can be

variable among dogs and between different doses given to the same

dog{R-46}.

Horses—The absorption of trimethoprim is delayed when a horse has

free access to feed{R-27}. Initial serum concentrations will be lower in

a fed horse than in a fasted horse; however, the effect is greatly

decreased by the third day of treatment{R-27}.

Pigs—Bioavailability: Dose of 40 mg of sulfadiazine and 4 mg of

trimethoprim per kg—Fasted or fed:

Sulfadiazine—85 to 89%{R-91}.

Trimethoprim—90 to 92%{R-91}.

Sheep—Absorption of sulfadiazine in sheep is comparable to that in

dogs; however, trimethoprim is not as well absorbed orally in sheep

as in dogs{R-76}.

Sulfamethoxazole and trimethoprim: Bioavailability—Quail: Dose of

50 mg of sulfamethoxazole and 10 mg of trimethoprim per kg of

body weight—

Sulfamethoxazole: 81%{R-93}.

Trimethoprim: 41%{R-93}.

Distribution: Potentiated sulfonamides are widely distributed

throughout body tissues{R-2; 3}. In general, the diaminopyrimidine

concentration in plasma peaks early and is quickly found in high

concentrations in tissues{R-76}; therefore, concentrations are generally

higher in the tissues than in the serum{R-25}. The sulfonamide com-

ponent generally is found at higher concentrations in plasma for a

much longer time and tissue distribution is slower{R-76}. Initial con-

centrations of sulfonamides in tissues are generally lower than those in

plasma{R-25}.

Calves, preruminating—Sulfadiazine and trimethoprim are distributed

well into cerebrospinal fluid (CSF){R-79} and synovial fluid{R-80}.

Dogs—Potentiated sulfonamides are rapidly and widely distributed in

the tissues. Trimethoprim and sulfadiazine are distributed into the

aqueous and vitreous humors of the eye at concentrations that are 30

to 50% of serum concentrations{R-45}. Trimethoprim is distributed into

prostatic fluid at concentrations that are up to three times the serum

concentration and are higher when trimethoprim is administered

concurrently with sulfadiazine or sulfamethoxazole{R-48}. Sulfadiazine

and sulfamethoxazole are distributed into prostatic fluid at about 10%

of the concurrent serum concentration{R-48}.

Horses—Distribution of potentiated sulfonamides has been broadly

investigated in the horse. Ormetoprim and sulfadimethoxine{R-35},

sulfadiazine and trimethoprim{R-29}, and sulfamethoxazole and

trimethoprim{R-31; 33} are all well distributed into peritoneal fluid,

CSF, synovial fluid, and urine. Ormetoprim and sulfadimethoxine also

have been shown to be well distributed into the endometrium{R-35}.

Inflammation in the meninges or synovium does not significantly

affect distribution into the respective fluids{R-31}.

Ormetoprim and sulfadimethoxine: Equine endometrial tissue and

synovial and peritoneal fluid concentrations of ormetoprim were

similar to concurrent serum concentrations and concentrations of

sulfadimethoxine in those fluids were 25 to 30% of serum concen-

tration{R-35}.

Sulfadimethoxine and trimethoprim: After 4-day dosing in mares,

trimethoprim was measured in CSF at 50% of serum concentrations,

but sulfadimethoxine was measured at 2.7% of serum concentra-

tions{R-35}.

Sulfamethoxazole and trimethoprim: A single dose of 36 mg of

sulfamethoxazole and 7.5 mg of trimethoprim per kg of body weight,

administered intravenously to mares, reached concentrations in

serum sufficient to exceed the minimum inhibitory concentrations

(MICs) of common bacterial and protozoal pathogens{R-33}. After

repeated doses, sulfamethoxazole, unlike trimethoprim, accumulated

in the CSF{R-31}.

Fish—Sulfadimethoxine administered alone:

In channel catfish, sulfadimethoxine is distributed into the muscle at

the highest concentration immediately after administration, but

within 48 to 96 hours the highest concentrations are in the

bile{R-68}. At any point in time there can be wide variation in

tissue residues among fish{R-69}.

In rainbow trout, sulfadimethoxine is distributed at the highest

concentrations into the bile, followed by the intestine, liver, blood,

skin, kidney, spleen, gill, muscle, and fat.{R-67}

Volume of distribution (VolD):

Ormetoprim and sulfadimethoxine—Horses:{R-35}

Ormetoprim—

Area: 1.7 Liters per kg (L/kg).

Steady state: 1.2 L/kg.

Sulfadimethoxine—

Area: 0.28 L/kg.

Steady state: 0.27 L/kg.

Sulfadiazine and trimethoprim—

Calves: Area—

Sulfadiazine:

1 day of age—0.72 L/kg{R-79}.

1 week of age—0.66 L/kg{R-79; 80}.

6 weeks of age—0.58 L/kg{R-79}.

Ruminating—0.85 L/kg{R-77}.

Trimethoprim:

1 day of age—1.69 L/kg{R-79}.

1 week of age—2.2 to 2.5 L/kg{R-79; 80}.

6 weeks of age—2.27 L/kg{R-79}.

Ruminating—1.97 L/kg{R-77}.

Horses: Steady state—

Sulfadiazine: 0.58 L/kg{R-43}.

Trimethoprim: 1.68 L/kg{R-43}.

Pigs: Steady state—

Sulfadiazine: 0.54 L/kg{R-91}.


Sulfadimethoxine administered alone—Steady state:

Catfish, channel—0.66 L/kg{R-68}.

Trout, rainbow—0.42 to 0.5 L/kg{R-67; 70}.

Sulfadoxine and trimethoprim—

Cows: Apparent—

Sulfadoxine: 0.37 L/kg{R-82}.


Goats: Apparent—



Horses: Apparent—





Sulfamethoxazole and trimethoprim—

Foals:

Sulfamethoxazole—Area and steady state: 0.73 L/kg{R-32}.

Trimethoprim—Area and steady state: 2.2 L/kg{R-32}.

Horses:

Sulfamethoxazole—

Area: 0.36 L/kg{R-31}.

Steady state: 0.33 L/kg{R-31}; 0.5 L/kg{R-33}.

Trimethoprim—

Area: 2.27 L/kg{R-31}.

Steady state: 1.62 L/kg{R-31}; 2.79 L/kg{R-33}.

Quail:

Sulfamethoxazole—Area: 0.48 L/kg{R-93}.

Trimethoprim—Area: 3.9 L/kg{R-93}.

Protein binding: In general, the binding of sulfonamides to proteins is

concentration-dependent{R-25; 30} and, in general, trimethoprim pro-

tein binding is independent of plasma concentration{R-25; 30}. There

appears to be no interference in protein binding between sulfadoxine

and trimethoprim{R-30}; this may also be true for other potentiated

sulfonamides.

Sulfadiazine—

Cattle: Moderate (50%) (concentration not specified){R-75}.

Sulfadimethoxine—

Cats: High (87.5%) (50 mcg/mL plasma concentration){R-102}.

Catfish, channel: Low (18%), not concentration-dependent{R-68}.

Chickens: Average binding over a range of concentrations—

Moderate (40%), at serum concentrations of 2 to 10 mcg/

mL{R-103}.

Dogs:High (> 75%), at plasma concentrations of 50 to 150 mcg/mL{R-104}.

Goats: Very high (94%), at plasma concentration of 100 micromole/

L{R-98}.

Trout, rainbow: Low (17%), not concentration-dependent{R-67}.

Sulfadoxine—

Horses:

High (72%), at serum concentration of 50 mcg/mL{R-30}.

Moderate (40%), at serum concentration of 150 mcg/mL{R-30}.

Low (14%), at serum concentration of 450 mcg/mL{R-30}.

Cows:

High (65 to 80%), at serum concentration of 100 mcg/mL or

below{R-82; 83}.

Moderate (44 to 51%), at serum concentration of 150 mcg/mL or

more{R-82; 83}.

Trimethoprim—

Cows: Moderate (57%){R-83}.

Goats: Moderate (48%){R-73}.

Horses: Moderate (50%){R-30}.

Pigs: Moderate (33 to 54%){R-90}.

Biotransformation:

Sulfonamides—Sulfonamides are metabolized primarily in the liver, but

metabolism also occurs in other tissues. Biotransformation occurs by

acetylation, glucuronide conjugation, and aromatic hydroxylation in

many species{R-94}. The types of metabolites formed and the amount of

each varies depending on the specific sulfonamide administered; the

species, age, diet, and environment of the animal; the presence of

disease; and, with the exception of pigs and ruminants, the gender of

the animal{R-105–108}. N4-acetyl metabolites have no antimicrobial

activity and hydroxymetabolites have 2.5 to 39.5% of the activity of

the parent compound{R-109}. Metabolites may compete with the parent

drug for involvement in folic acid synthesis. They have little

detrimental effect on the bacterial cell, so their presence could decrease

the activity of the remaining parent drug{R-109}.

Sulfadiazine—Calves: Sulfadiazine is excreted primarily as unchanged drug

in the urine; the percentage of unchanged drug excreted increases from 1

day of age to 42 days of age, changing from 22 to 50%{R-79}.

Sulfadimethoxine:

Catfish, channel—Metabolized primarily by the liver; acetylation is the

major pathway{R-68}.

Dogs—Sulfadimethoxine is not acetylated in the dog as it is in other

species, and it is excreted primarily as unchanged drug{R-5}.

Salmon—Metabolism occurs primarily in the liver{R-66}.

Diaminopyrimidines—Trimethoprim: In many species, including

cows{R-79}, goats, and pigs, trimethoprim is extensively

metabolized{R-25}.

Half-life:

Absorption—Horses: Oral—Sulfadiazine and trimethoprim: Dose of

25 mg of sulfadiazine and 5 mg of trimethoprim per kg of body

weight (mg/kg){R-43}—

Sulfadiazine: 0.35 hour.

Trimethoprim: 0.44 hour.

Distribution—Horses: Oral—Sulfadiazine and trimethoprim: Dose of


weight{R-43}—

Sulfadiazine: 0.27 hour.

Trimethoprim: 0.15 hour.

Elimination—

Ormetoprim and sulfadimethoxine: Horses—

Ormetoprim: 1.7 hours{R-35}.

Sulfadimethoxine: 7.9 hours{R-35}.


Calves—

1 day of age:

Sulfadiazine—5.7 hours{R-79}.

Trimethoprim—8.4 hours{R-79}.

1 week of age:

Sulfadiazine—4.4 hours{R-79; 80}.

Trimethoprim—2.1 hours{R-79; 80}.

6 weeks of age:

Sulfadiazine—3.6 hours{R-79}.

Trimethoprim—0.9 hour{R-79}.

Calves, ruminating—

Sulfadiazine: 3.25 hours{R-77}; 4 hours{R-78}.

Trimethoprim: 1 hour{R-78}; 3.44 hours{R-77}.

Horses—

Sulfadiazine: 2.7 hours{R-29}; 4.65 hours{R-43}; 7 hours{R-3}.

Trimethoprim: 2 to 3 hours{R-3; 29; 32; 43}.

Sulfadoxine and trimethoprim:

Cows, lactating—

Sulfadoxine:

Alpha phase (up to 4 hours postadministration)—0.9

hour{R-82}.

Beta phase (between 4 and 48 hours postadministration)—10.8

hours{R-82}.



Trimethoprim: 1.18 hours{R-82}.

Goats—

2 days of age:

Sulfadoxine—16.5 hours{R-72}.

Trimethoprim—3 hours{R-72}.

40 days of age to adult:


Trimethoprim—0.8 hour{R-72}.

Horses—

Sulfadoxine: 14 hours{R-30}; 9.7 hours{R-37}.

Trimethoprim: 3.2 hours{R-30}; 1.9 hours{R-37}.

Sheep—

1 week of age:



4 months of age to adult:


Trimethoprim—0.75 hour{R-74; 84}.

Sulfamethoxazole and trimethoprim:

Horses—

Sulfamethoxazole: 3.5 hours{R-31}; 4.8 hours{R-33}.

Trimethoprim: 1.9 hours{R-31}; 3.4 hours{R-33}.

Horse foals—

Sulfamethoxazole: 9.9 hours{R-32}.


Pony foals—

Sulfamethoxazole: 5.8 hours{R-32}.


Quail:

Sulfamethoxazole—2.9 hours{R-93}.


Sulfadiazine: Administered alone orally—Dogs: 9.84 hours{R-49}.

Sulfadimethoxine: Administered alone—

Cats: 10.2 hours{R-102}.

Dogs: 13.1 hours{R-104}.

Trout, rainbow: 16 hours{R-67; 70}.

Trimethoprim: Administered alone—

Dogs: Based on oral dosing—2.5 hours{R-30; 49}.

Pigs: 2.4 hours{R-89}.

Peak serum concentration:

Sulfadimethoxine—Administered alone: Oral—

Catfish, channel: 7.83 to 11 mcg/mL at 3 to 6 hours (after 5 days of

dosing 40 to 42 mg/kg every 24 hours){R-68; 69}.

Chickens: 106.3 mcg/mL at 12 hours (single dose of 100 mg/kg).{R-

103}

Cows: 114 ± 10 mcg/mL at 10 hours (dose of 107 mg/kg).{R-111}

Dogs: 67 ± 16 mcg/mL at 3.75 hours (dose of 55 mg/kg).{R-104}

Ormetoprim and sulfadimethoxine—Oral:

Foals, 1 to 3 days of age—0.65 mcg of ormetoprim per mL at 2 hours

and 54.6 mcg of sulfadimethoxine per mL at 8 hours (dose of 3.5 mg

of ormetoprim and 17.5 mg of sulfadimethoxine per kg of body

weight){R-36}.

Horses—80 mcg of sulfadimethoxine per mL at 8 hours and 0.92 mcg

of ormetoprim per mL at 0.5 hour postadministration (loading dose

of 9.2 mg of ormetoprim and 45.8 mg of sulfadimethoxine per kg of

body weight){R-25}.

Sulfadiazine and trimethoprim—Oral:

Calves—

1 week of age: 11.9 mcg of sulfadiazine per mL at 12 hours and 0.41

mcg of trimethoprim per mL at 3 hours (dose of 25 mg of sulfadiazine

and 5 mg of trimethoprim per kg){R-81}.

6 weeks of age:

Milk-fed—17.3 mcg of sulfadiazine per mL at 3 hours and 0.43

mcg of trimethoprim per mL at 1.5 hours (dose of 25 mg sulfadiazine

and 5 mg of trimethoprim per kg of body weight){R-81}.

Grain and fiber–fed—14.9 mcg of sulfadiazine per mL at 8

hours and < 0.1 mcg of trimethoprim per mL (below test limit) for

entire trial (dose of 25 mg of sulfadiazine and 5 mg of

trimethoprim per kg of body weight){R-81}.

Dogs—

12.4 mcg of sulfadiazine per mL at 4 hours and 1.7 mcg of

trimethoprim per mL at 1 hour (dose of 20 mg of sulfadiazine and

4 mg of trimethoprim per kg of body weight){R-49}.

30.1 mcg of sulfadiazine per mL{R-19} and 1.52 mcg of trimethoprim

per mL{R-2; 19} at 3 hours (dose of 25 mg of sulfadiazine and 5 mg

of trimethoprim per kg of body weight).

After 2 days of dosing every 12 hours: 67.4 mcg of sulfadiazine per

mL and 2.98 mcg of trimethoprim per mL at 2 hours{R-46} (dose of

25 mg of sulfadiazine and 5 mg of trimethoprim per kg).

After 4 days of dosing every 24 hours: 84.7 mcg of sulfadiazine at 3

hours and 2.55 mcg of trimethoprim per mL at 2 hours{R-46} (dose

of 25 mg of sulfadiazine and 5 mg of trimethoprim per kg).

Horses—

Fasted: 9 to 13 mcg of sulfadiazine per mL at 3 hours and 1 to 1.5

mcg of trimethoprim per mL at 1 to 2 hours (dose of 25 to 29 mg

of sulfadiazine and 5 to 6 mg of trimethoprim per kg of body

weight){R-27–29}

Fed: 10 mcg of sulfadiazine per mL and 0.5 mcg of trimethoprim per

mL at 6 hours (dose of 29.2 mg of sulfadiazine and 5.8 mg of

trimethoprim per kg of body weight){R-27}.

Pigs—

Fasted: 32 mcg of sulfadiazine per mL at 4.3 hours and 1.9 mcg of

trimethoprim per mL at 2.1 hours (oral dose of 40 mg of sulfadiazine


Fed: 25 mcg of sulfadiazine per mL at 3.2 hours and 1.5 mcg of

trimethoprim per mL at 3.4 hours (oral dose of 40 mg of sulfadiazine


Salmon—20.3 mcg of sulfadiazine per mL at 24 hours and 3.25 mcg of

trimethoprim per mL at 12 hours (oral dose of 83.3 mg of

sulfadiazine and 16.7 mg of trimethoprim per kg of body weight of

fish at 8 �C){R-63}.

Sulfadoxine and trimethoprim—Cattle: Intramuscular administra-

tion—30.3 mcg of sulfadoxine per mL at 2 hours and 0.7 mcg of

trimethoprim per mL at 0.75 to 1 hour (dose of 13.3 mg of sulfadoxine

and 2.7 mg of trimethoprim per kg of body weight){R-85}.

Sulfamethoxazole and trimethoprim—Horses: Oral administration—0.26

mcg/mL of trimethoprim at 0.75 hour and 13.7 mcg/mL of sulfame-

thoxazole at 1.5 hours (dose of 12.5 mg of sulfamethoxazole and 2.5

mg of trimethoprim per kg of body weight){R-31}.

Duration of action: Duration of action may be estimated by the length

of time target serum concentrations are maintained; however, duration

of action for the potentiated sulfonamides is difficult to estimate from

target serum concentrations{R-78} because of the rapid movement of the



diaminopyrimidines into the tissues and the possibly wide range of local

sulfonamide to diaminopyrimidine concentration ratios believed to be

effective and synergistic. Target concentrations should be viewed as

estimates only, and clinical response should be considered one of the

measurements of activity of the medication. Some sources consider

bacteria susceptible if their minimum inhibitory concentration (MIC) is

0.5 mcg/mL for trimethoprim and 9.5 mcg/mL for sulfonamide{R-25}.

However, the National Committee for Clinical Laboratory Standards

(NCCLS) in the U.S. lists MIC breakpoints for animal isolates and tri-

methoprim/sulfamethoxazole as £ 2 mcg per mL/38 mcg per mL for

susceptible organisms and ‡ 4 mcg per mL/76 mcg per mL for resistant

organisms{R-141}. Organisms testing between these values are consid-

ered intermediate and may or may not be inhibited in certain body sites

or with certain antimicrobials with low toxicity in which high concen-

trations can be achieved{R-141}. These breakpoints are also used to test

for susceptibility to sulfadiazine and trimethoprim or ormetoprim and

sulfadimethoxine combination{R-141}.

Sulfadiazine and trimethoprim—Calves:

1 day of age—A single intravenous dose of 25 mg of sulfadiazine and

5 mg of trimethoprim produced therapeutic serum concentrations

> 2 mcg of sulfadiazine per mL of serum for 24 hours and > 0.1

mcg of trimethoprim per mL for 15 hours{R-79}.

7 to 42 days of age—A single intravenous dose of 25 mg of sulfadiazine

and 5 mg of trimethoprim produced therapeutic serum concentra-

tions of > 2 mcg of sulfadiazine per mL of serum for 15 hours and

> 0.1 mcg/mL of trimethoprim for 6 to 8 hours{R-79}.

Sulfadoxine and trimethoprim—Cattle: Sulfadoxine serum concentra-

tions exceeded 9.5 mcg/mL from 12 minutes to 10 hours postinjec-

tion and trimethoprim serum concentrations exceeded 0.5 mcg/mL

from 15 minutes to 2 hours (intramuscular dose of 13.3 mg of

sulfadoxine and 2.7 mg of trimethoprim per kg of body weight)

postinjection{R-85}.

Elimination:

Sulfonamides—Renal excretion is the primary route of elimination for

most nonenteric sulfonamides and it occurs by glomerular filtration of

parent drug, tubular excretion of unchanged drug and metabolites,

and passive reabsorption of nonionized drug.{R-94; 110} Alkalization of

the urine increases the fraction of the dose that is eliminated in the

urine.{R-110} In general, the metabolites of the parent drug are more

quickly eliminated by the kidney than is the original sulfonamide{R-75},

but the proportions of metabolites formed can vary depending on

many factors.

Sulfadimethoxine:

Cattle—Sulfadimethoxine is metabolized to a great degree, so that 40

to 60% of the administered dose is excreted as metabolites in the

urine{R-111}.

Dogs—Sulfadimethoxine is slowly excreted renally because of a high

degree of tubular reabsorption{R-5}.

Sulfadoxine: Horses—Sulfadoxine is excreted by glomerular filtration

and reabsorption{R-34}. The clearance of sulfadoxine increases with

increasing pH{R-34}.

Trimethoprim—Renal excretion occurs by glomerular filtration, active

tubular secretion, and reabsorption{R-25; 89}.

Horses: It is believed that a large percentage of trimethoprim is

metabolized before elimination in urine (46%) and feces (52%){R-25;

26; 30}. The clearance of trimethoprim is affected by urine pH, plasma

concentration, and extent of diuresis{R-34}; however, when sulfadi-

azine and trimethoprim are administered concurrently, neither

antibiotic interferes with the excretion of the other{R-3; 4}.

Dogs: Two-thirds of the total dose is eliminated in the urine as parent

drug in the first 24 hours{R-19}.

Total clearance—

Ormetoprim and sulfadimethoxine: Horses—

Ormetoprim: 11.1 mL per minute per kg (mL/min/kg){R-35}.

Sulfadimethoxine: 0.42 mL/min/kg{R-35}.


Calves—

Sulfadiazine:

1 day of age—1.43 mL/min/kg{R-79}.

1 week of age—1.7 mL/min/kg{R-79; 80}.

6 weeks of age—1.88 mL/min/kg{R-79}.

Trimethoprim:

1 day of age—2.8 mL/min/kg{R-79}.

1 week of age—12 mL/min/kg{R-79; 80}.

6 weeks of age—28.9 mL/min/kg{R-79}.

Calves, ruminating—

Sulfadiazine: 3.15 mL/min/kg{R-77}.

Trimethoprim: 6.6 mL/min/kg{R-77}.

Horses—



Pigs—



Sulfamethoxazole and trimethoprim:

Horses—

Sulfamethoxazole: 1.3 mL/min/kg{R-31; 33}.

Trimethoprim: 11.3 mL/min/kg{R-33}; 14.8 mL/min/kg{R-31}.

Horse foals—

Sulfamethoxazole: 0.83 mL/min/kg{R-32}.


Pony foals—

Sulfamethoxazole: 1.1 mL/min/kg{R-32}.


Sulfadimethoxine: Administered alone—

Cats: 0.32 mL/min/kg{R-102}.

Dogs: 0.36 mL/min/kg{R-104}.

Trout, rainbow: 0.36 mL/min/kg{R-70}.


SPECIES SENSITIVITYDogs: An idiosyncratic sulfonamide toxicosis can occur in any breed of dog,

but this reaction has been reported more frequently in the Doberman

Pinscher than in other breeds. This specific type of drug reaction includes

blood dyscrasias, nonseptic polyarthritis, and skin rash{R-53; 54}. See also

the Side Adverse Effects section in this monograph.

Horses: Trimethoprim with sulfadiazine or with sulfadoxine infused into

the uterus of horses can cause endometrial inflammation, straining, and

expulsion of the medication. Conception rates may be lowered. Because

there is good distribution of these medications when administered by

systemic routes, intrauterine administration is not recommended.{R-27}.

CROSS-SENSITIVITY AND/OR RELATED PROBLEMSPatients allergic to one sulfonamide may be allergic to other sulfona-

mides also.



PREGNANCY/REPRODUCTIONSulfonamides and diaminopyrimidines cross the placenta in pregnant

animals{R-110} and some teratogenic effects have been seen with very

high doses given to pregnant mice and rats{R-110}.

Ormetoprim and sulfadimethoxine: Dogs—Safety in breeding or pregnant

animals has not been established{R-5}.


Dogs—The recommended dose of 25 mg of sulfadiazine and 5 mg of

trimethoprim per kg of body weight administered during pregnancy

had no apparent effect on offspring{R-2; 19}.

Horses—Safety in pregnant animals has not been established{R-4}.

With administration of recommended doses, no changes in sper-

matogenesis in stallions were apparent{R-4}.

LACTATIONSulfonamides are distributed into milk, with 0.5 to 2% of the total dose

found in the milk{R-114; 115}. For example, the milk-to-plasma

concentration ratio for sulfadiazine and sulfadoxine was measured to

be 0.5 in cows{R-75; 82}.

Trimethoprim is distributed into milk{R-35}. Trimethoprim concentrations

in milk were found to be 1.3 to 3.5 times the plasma concentration

measured at the same time in goats{R-73}. The concentration of

trimethoprim in the milk of cows is 1 to 3 times higher than in

plasma{R-82; 83} and the concentration of trimethoprim in the milk of

pigs is 1.3 to 3.5 times higher than in plasma{R-90}.





Note: Combinations containing the following medication, depending on

the amount present, may also interact with this medication.

Detomidine

(a trimethoprim and sulfonamide combination administered to a

detomidine-anesthetized horse can lead to arrhythmias, hypotension,

and death; it is suspected that the antimicrobial potentiates the

cardiac changes reported with detomidine{R-25; 120}).



following drug interactions have been reported in humans and are

included in the human monographs Sulfonamides (Systemic) and

Trimethoprim (Systemic) in USP DI Volume I; these drug interactions


applicable to the use of sulfonamides in the treatment of animals:




Anticonvulsants, hydantoin, or

Antidiabetic agents, oral

(these medications may be displaced from protein binding sites and/

or their metabolism may be inhibited by some sulfonamides,

resulting in increased or prolonged effects and/or toxicity; dosage

adjustments may be necessary during and after sulfonamide therapy)

Bone marrow depressants

(concurrent use of bone marrow depressants with sulfonamides

or aminopyrimidines may increase the leukopenic and/or

thrombocytopenic effects; if concurrent use is required, close

observation for myelotoxic effects should be considered)

Cyclosporine

(concurrent use with sulfonamides or trimethoprim may increase the

metabolism of cyclosporine, resulting in decreased plasma concentrations

and potential transplant rejection, and additive nephrotoxicity; plasma

cyclosporine concentrations and renal function should be monitored)

Dapsone

(concurrent use with trimethoprim will usually increase the plasma

concentrations of both dapsone and trimethoprim, possibly due to an

inhibition in dapsone metabolism, and/or competition for renal

secretion between the two medications; increased serum dapsone

concentrations may increase the number and severity of side effects,

especially methemoglobinemia)

Folate antagonists, other

(concurrent use with trimethoprim or use of trimethoprim between

courses of other folic acid antagonists is not recommended because of

the possibility of an increased risk of megaloblastic anemia)

Hemolytics, other

(concurrent use with sulfonamides may increase the potential for

toxic side effects)


(concurrent use with sulfonamides may result in an increased

incidence of hepatotoxicity; patients, especially those on prolonged

administration or those with a history of liver disease, should be

carefully monitored)

Methenamine

(in acid urine, methenamine breaks down into formaldehyde, which

may form an insoluble precipitate with certain sulfonamides,

especially those that are less soluble in urine, and may also increase

the danger of crystalluria; concurrent use is not recommended)

Methotrexate or

Phenylbutazone or

Sulfinpyrazone

(the effects of methotrexate may be potentiated during concurrent

use with sulfonamides because of displacement from plasma protein

binding sites; phenylbutazone and sulfinpyrazone may displace

sulfonamides from plasma protein binding sites, increasing sulfon-

amide concentrations)

Phenytoin

(trimethoprim may inhibit the hepatic metabolism of phenytoin,

increasing the half-life of phenytoin by up to 50% and decreasing its

clearance by 30%)

Procainamide

(concurrent use with trimethoprim may increase the plasma

concentration of both procainamide and its metabolite NAPA by

decreasing their renal clearance)

Rifampin

(concurrent use may significantly increase the elimination and

shorten the elimination half-life of trimethoprim)

Warfarin

(trimethoprim may potentiate the anticoagulant activity of warfarin

by inhibiting its metabolism)







Thyrotropin stimulation tests or

Total serum thyroxine (T4)

(thyroid function tests may be lowered in dogs with administration of

sulfamethoxazole and trimethoprim combination at high doses [25

mg of sulfamethoxazole and 5 mg of trimethoprim per kg of body

weight every 12 hours for 6 weeks]{R-62} or ormetoprim and

sulfadimethoxine{R-21} [8 weeks of medication with the labeled dose

or with three to five times the labeled dose]; the T4 and thyrotropin

stimulation tests, but not T3, may be significantly reduced{R-61}; this

effect was not shown with labeled doses of sulfadiazine and

trimethoprim{R-62})


Cholesterol, serum

(cholesterol concentrations can be elevated with administration of

sulfonamides, including ormetoprim and sulfadimethoxine combina-

tion; however, this effect is reversible{R-5})


In addition to the above laboratory value alterations reported in animals,

the following laboratory value alterations have been reported in

humans, and are included in the human monographs Sulfonamides

(Systemic) and Trimethoprim (Systemic) in USP DI Volume I; these


only and may or may not be applicable to the use of sulfonamides in

the treatment of animals:


Benedict’s test

(sulfonamides may produce a false-positive Benedict’s test for urine

glucose)

Creatinine determinations

(sulfamethoxazole or trimethoprim may interfere with the Jaffe

alkaline picrate reaction assay for creatinine, resulting in creatinine

values that are approximately 10% higher than actual values)

Sulfosalicylic acid test

(sulfonamides may produce a false-positive sulfosalicylic acid test

for urine protein)

Urine urobilinogen test strip (e.g., Urobilistix)

(sulfonamides may interfere with the Urobilistix test for urinary

urobilinogen)



Aspartate aminotransferase (AST [SGOT]), serum


Bilirubin, serum, and


Creatinine, serum








» Blood dyscrasias{R-25; 99}

(slight to moderate reduction in hematopoietic activity has been

reported with long-term high dosing of potentiated sulfona-

mides{R-99})

» Hypersensitivity to diaminopyrimidines or sulfonamides{R-5; 10; 18; 19}

(animals that have had a previous reaction may be much more likely

to react on subsequent administration)


problems exist:

Hepatic function impairment{R-5; 10; 18; 19; 25}

(delayed biotransformation may increase the risk of adverse effects)

Renal function impairment{R-25}

(delayed elimination could cause accumulation of sulfonamide and

metabolites, increasing the risk of adverse effects)

Urolithiasis{R-25}

(sulfonamides can crystallize in the renal system under certain

conditions{R-25})




Complete blood count (CBC), including platelet count

(some animals have had reductions in hematopoietic activity when

administered potentiated sulfonamides; periodic CBC and platelet

counts are recommended if it is necessary to administer long-term

treatment with potentiated sulfonamides{R-3; 19})




prior to potentiated sulfonamide administration to determine path-

ogen susceptibility)

Schirmer’s tear test

(periodic Schirmer’s tear tests during potentiated sulfonamide

therapy in dogs may be warranted to monitor for early keratocon-

junctivitis sicca{R-124})


potential clinical significance (possible signs and, for humans, symptoms

in parentheses where appropriate)—not necessarily inclusive:


For all species

Crystallization in the urinary tract{R-5}; hypersensitivity, spe-

cifically anaphylaxis{R-4; 5}

Note: Crystallization of sulfonamides is theoretically possible with

administration of potentiated sulfonamides; however, the lower

doses of sulfonamide used in the potentiated sulfonamide combina-

tion makes crystallization less likely to occur than with sulfonamide

administered alone. Sulfonamides can crystallize in the kidneys or

urine in animals with aciduria, with high doses of sulfonamide, or

with dehydration. The amount of drug in the acetylated metabolite

form also can affect solubility. Because dogs do not produce

acetylated metabolites, they may be less susceptible to this adverse

effect{R-123}. Crystallization also can be minimized in susceptible

animals by maintaining a high urine flow and, if necessary,

alkalinizing the urine.



Dogs

Anemia, hemolytic{R-5; 19}; anemia, nonregenerative{R-23; 51};

anorexia{R-5; 19}; cutaneous drug eruption, including erythema

multiforme, perforating folliculitis, and pustular dermati-

tides{R-54; 60}; diarrhea{R-5; 19}; facial swelling{R-5; 19}; fever{R-5;

19}; hepatitis{R-5; 19; 52; 54}; hypothyroidism{R-21; 61; 62}; idiosyn-

cratic toxicosis{R-53; 54; 57–60} (blood dyscrasias, including anemia,

leukopenia, or thrombocytopenia; fever; focal retinitis; lymphadenop-

athy; nonseptic polyarthritis; polymyositis; skin rash); keratocon-

junctivitis sicca{R-5; 19; 55; 56}; neurologic disorders{R-19}

(aggression, ataxia, behavioral changes, hyperexcitability, seizures);

polyarthritis{R-5; 19}; polydipsia/polyuria{R-5; 19}; thrombocyto-

penia—one case reported without other blood lines affected{R-116};

urticaria{R-5; 19}; vomiting{R-5; 19}.

Note: Idiosyncratic toxicosis can occur 8 to 20 days after starting

treatment and is believed to be caused by either an immune-mediated

syndrome or by an idiosyncratic reaction in dogs, perhaps due to toxic

metabolites of the sulfonamide. Of 22 reported cases compiled in one

study, 7 were Doberman Pinschers and it has been theorized that they

are more susceptible than other breeds to this toxicosis{R-53; 54}. A

large majority of the animals in which idiosyncratic toxicosis occurs

have had a previous exposure to a sulfonamide{R-54}. When sulfon-

amide therapy is discontinued, recovery generally occurs within 2 to 5

days.{R-54; 60}

Keratoconjunctivitis sicca is considered a possible side/adverse effect in

any dog administered sulfonamides; it can occur at any time after

therapy is initiated. The most frequent reports have been with

sulfasalazine or trimethoprim and sulfonamide combination{R-55;

56}, perhaps because these medications are most commonly used for

long-term therapy in dogs. As many as 15% (5 out of 33 in one

study) of dogs treated with sulfadiazine and trimethoprim may

develop keratoconjunctivitis sicca{R-124}. While increased risk has

not been linked to higher dose or longer treatment, dogs weighing

less than 12 kg may be at increased risk{R-124}. Lacrimation may

return to normal after discontinuation of sulfonamide treatment.

The nonregenerative anemias seen in response to long-term adminis-

tration of sulfadiazine and trimethoprim combination are, in some

cases, believed to be related to folate reduction with long-term, high-

dose administration (60 to 120 mg/kg a day for many weeks{R-23})

of potentiated sulfonamide{R-23; 50}; these anemias generally respond

well to withdrawal of the medication{R-23}. In the event an animal

does not respond to medication withdrawal, folinic or folic acid

supplementation may be necessary{R-137; 138}.

Iatrogenic hypothyroidism may occur and thyroid function test

results may be lowered with administration of sulfamethoxazole and

trimethoprim combination at high doses (25 mg of sulfamethoxazole

and 5 mg of trimethoprim per kg every 12 hours for 6 weeks){R-62}

or ormetoprim and sulfadimethoxine{R-21} (8-week medication with

the labeled dose or with three to five times the labeled dose). Results

of the T4 and thyrotropin stimulation tests, but not T3, may show

significant reduction{R-61}; this effect was not shown with labeled

doses of sulfadiazine and trimethoprim (12.5 mg of sulfadiazine and

2.5 mg of trimethoprim per kg every 12 hours for 4 weeks){R-62}.

Horses

Diarrhea, transient—approximately 3% of horses treated in one

study{R-3; 139}; hypersensitivity reactions (anorexia; decreased

hematopoiesis{R-3}; loose stool; or muscle tremors)—with intravenous

administration of potentiated sulfonamides{R-25; 26; 35}

Pigs

Thyroid hyperplasia—in gilts, sows and piglets; believed to be in

response to the sulfadimethoxine component of ormetoprim and

sulfadimethoxine combination{R-92}

For sulfaquinoxaline

Chickens and dogs

Hemorrhagic syndrome (anorexia, epistaxis, hemoptysis, lethargy,

pale mucous membranes, death){R-100; 112; 113; 121; 122}

Note: Hemorrhagic syndrome has been reported in chickens and dogs

but may occur in other species. It is most often reported with the

addition of sulfaquinoxaline to feed for chickens, but in dogs,

reports follow administration of products labeled for poultry but

administered to dogs in the water supply.{R-112; 113; 121; 122}

Sulfaquinoxaline is a vitamin K antagonist that inhibits vitamin K

epoxide and vitamin K quinone reductase and causes an effect

similar to that of coumarin anticoagulants.{R-100} Rapid hypopro-

thrombinemia occurs in dogs and an additional adverse effect of

sulfaquinoxaline on specific cell types may explain why supple-

mentation of chicken feeds with vitamin K has not always

prevented the syndrome in chickens.{R-100; 112} Rapid discontin-

uation of medication and initiation of therapy with vitamin K1

may reverse the effects.


Cats

Salivation—with uncoated tablets or broken tablets{R-11}; thyroid

function changes—with prolonged dosages{R-11}; vomiting, tran-

sient—up to 1 hour after administration of sulfadiazine and trimeth-

oprim combination{R-23}

Cattle, horses, or pigs

Local pain and swelling—with intramuscular injection of sulfon-

amide and trimethoprim{R-9; 13; 14}

Pigs

Irritant reactions—with intramuscular injections{R-14}; vomit-

ing—with oral suspension of sulfadiazine and trimethoprim combi-

nation{R-10}



following side/adverse effects have been reported in humans and are

included in the human monographs Sulfonamides (Systemic) and

Trimethoprim (Systemic) in USP DI Volume I; these side/adverse effects


applicable to the use of potentiated sulfonamides in the treatment of

animals:

For sulfonamides—


Central nervous system (CNS) effects; gastrointestinal distur-

bances; hypersensitivity; photosensitivity


Blood dyscrasias; hepatitis; Lyell’s syndrome (difficulty in

swallowing; redness, blistering, peeling, or loosening of skin);

Stevens-Johnson syndrome (aching joints and muscles; redness,

blistering, peeling, or loosening of skin; unusual tiredness or

weakness)



Incidence rare

CNS toxicity; Clostridium difficile colitis; crystalluria or

hematuria; goiter or thyroid function disturbance; interstitial

nephritis or tubular necrosis

Note: Fatalities have occurred, although rarely, due to severe reactions

such as Stevens-Johnson syndrome, fulminant hepatic necrosis, agran-

ulocytosis, aplastic anemia, and other blood dyscrasias. Therapy

should be discontinued at the first appearance of skin rash or any

serious side/adverse effects or if signs of folic acid deficiency occur.

Crystalluria is more likely to occur with a less soluble sulfonamide,

such as sulfadiazine. It occurs most often with the administration of

high doses, and can be minimized by maintaining a high urine flow

and alkalinizing the urine.

C. difficile colitis may occur up to several weeks after discontinuation

of these medications.

For trimethoprim—


Gastrointestinal disturbances; headache; pruritis; skin rash

Incidence rare

Anaphylaxis; aseptic meningitis; blood dyscrasias, such as

leukopenia or neutropenia, megaloblastic anemia, and throm-

bocytopenia; glossitis; methemoglobinemia; phototoxicity; se-

vere skin reactions, such as erythema multiforme, exfoliative

dermatitis, Stevens-Johnson syndrome, and toxic epidermal

necrolysis [Lyell’s syndrome]






Acute toxicities appear to be difficult to induce; those reported below are

in response to a dose five times the loading dose and ten times the

maintenance dose on the product label.




For ormetoprim and sulfadimethoxine{R-21}

Dogs (53 mg ormetoprim and 267 mg sulfadimethoxine per kg of body

weight dose or 160 mg ormetoprim per kg administered alone)

Convulsions; hyperglycemia, mild

TREATMENT OF OVERDOSERecommended treatment consists of the following:

• Discontinuing medication.

• Administering intravenous diazepam or other acute antiseizure

medication as needed.

• Providing fluid replacement therapy as required.

CLIENT CONSULTATIONDosage and length of treatment recommendations should be followed.

High doses or long-term use can increase the risk of side effects.

Animals should have a good water supply and should be monitored to

insure their adequate water consumption during treatment.

VETERINARY DOSING INFORMATIONAlthough the minimum inhibitory concentrations (MICs) of potentiated

sulfonamides are important in determining therapeutic regimens, they

can be misleading because the actual concentrations of drugs at the

therapeutic site can be difficult to pinpoint at any one time.

Trimethoprim goes rapidly into tissues, and sulfonamides often have

measurable serum concentrations for longer periods. The ratio of

sulfonamide to trimethoprim concentrations necessary at the site for

efficacy may vary from the goal of 20 to 1, depending on the tissue and

the local concentrations of other factors, such as thymidine.{R-24}.

Clinical efficacy also should be considered, once pathogen susceptibility

has been determined{R-24; 31}.

The National Committee for Clinical Laboratory Standards (NCCLS) in

the U.S. lists MIC breakpoints for animal isolates and trimethoprim/

sulfamethoxazole as £ 2 mcg per mL/38 mcg per mL for susceptible

organisms and ‡ 4 mcg per mL/76 mcg per mL for resistant

organisms{R-141}. Organisms testing between these values are consid-

ered intermediate and may or may not be inhibited in certain body

sites in which high concentrations can be achieved or with certain

antimicrobial agents with low toxicity{R-141}. These breakpoints are

also used to test for susceptibility to sulfadiazine and trimethoprim or

ormetoprim and sulfadimethoxine combination{R-141}.

FOR ORAL DOSAGE FORMS ONLYHorses: The oral administration of 25 to 100 mg of sulfadiazine and 5 to

20 mg of trimethoprim per kg of body weight a day for 5 days does not

cause the increase in coliform bacteria and Clostridium perfringens type

A associated with induced colitis. Healthy horses do not appear to

develop watery stools within this dosage range. At the highest dose, a

slight decrease in coliform count is noted in healthy horses.{R-40}

Having free access to feed does not significantly affect the horse’s

ability to absorb sulfadiazine during administration of oral sulfadiazine

and trimethoprim combination. The absorption of trimethoprim is

delayed so initial serum concentrations will be lower in a fed horse

than in a fasted horse; however, this effect is greatly decreased by the

third day of treatment{R-27}.


For anaphylaxis



ORMETOPRIM AND SULFADIMETHOXINE




ORMETOPRIM AND SULFADIMETHOXINE FORMEDICATED FEEDUsual dose:

Coccidiosis (prophylaxis)1—

Chickens and partridges, chukar: Oral, 68.1 grams of ormetoprim and

113.5 grams of sulfadimethoxine per ton of feed, fed as the only

ration{R-6; 125}.



Turkeys: Oral, 34 grams of ormetoprim and 56.8 grams of

sulfadimethoxine per ton of feed, fed as the only ration{R-6}.

Colibacillosis (prophylaxis)1—Chickens: Oral, 68.1 grams of ormeto-

prim and 113.5 grams of sulfadimethoxine per ton of feed, fed as the

only ration{R-6}.

Colibacillosis (treatment)1—Ducks: Oral, 272.4 grams of ormetoprim

and 454 grams of sulfadimethoxine per ton of feed, fed as the only

ration for seven days{R-6}.

Enteric septicemia1—Catfish: Oral, 8 mg of ormetoprim and 42 mg of

sulfadimethoxine per kg of body weight a day, administered in the

feed and fed as the only ration for five days{R-7; 16}.

Fowl cholera (prophylaxis)1—

Chickens: Oral, 68.1 grams of ormetoprim and 113.5 grams of


Turkeys: Oral, 34 grams of ormetoprim and 56.8 grams of


Fowl cholera (treatment)1—Ducks:

Routine—Oral, 136.2 grams of ormetoprim and 227 grams of

sulfadimethoxine per ton of feed, fed as the only ration for seven

days{R-6}.

Severe—Oral, 272.4 grams of ormetoprim and 454 grams of

sulfadimethoxine per ton of feed, fed as the only ration for seven

days{R-6}.

Furunculosis—Salmon and trout: Oral, 8 mg of ormetoprim and 42 mg

of sulfadimethoxine per kg of body weight a day, administered in the

feed, and fed as the only ration for five days{R-7; 16}.

Infectious coryza (prophylaxis)1—Chickens: Oral, 68.1 grams of

ormetoprim and 113.5 grams of sulfadimethoxine per ton of feed,

fed as the only ration{R-6}.

New duck disease1—Ducks: Oral, 272.4 grams of ormetoprim and 454

grams of sulfadimethoxine per ton of feed, fed as the only ration for

seven days{R-6}.


U.S.—


50 grams of ormetoprim and 250 grams of sulfadimethoxine per kg

of premix (OTC) [Romet 30 (catfish and salmonids)].


of premix (OTC) [Rofenaid 40 (chickens, ducks, partridges, and

turkeys)].

Canada—



of premix (Rx) [Romet-30 (salmonids)].

Withdrawal times:

U.S.{R-6; 7}—

Withdrawal time

Species Meat (days)

Chickens, ducks, partridges, turkeys 5

Note: Product labeling with the above withdrawal times states that this

combination is not for use in birds producing eggs for food or for

chickens over 16 weeks of age{R-6}.

Withdrawal time

Species Meat (days)

Catfish 3

Salmon, trout 42

Canada{R-16}—

Withdrawal time

Species Meat (days)

Salmon, trout 42

Note: Product labeling with the above withdrawal time states that it

applies to a dose of 15 mg per kg of body weight a day when the water

temperature is ‡ 10 �C.



manufacturer.

Additional information: Canadian labeling states that the product

should not be used when the water temperature is below 10 �C{R-16}.

USP requirements: Not in USP.

ORMETOPRIM AND SULFADIMETHOXINE TABLETSUsual dose:

Skin and soft tissue infections1; or

Urinary tract infections1—Dogs: Oral, 9.2 mg of ormetoprim and 45.8

mg of sulfadimethoxine per kg of body weight as an initial dose,

followed by 4.6 mg of ormetoprim and 22.9 mg of trimethoprim per

kg of body weight every twenty-four hours{R-5}. Administration for

more than twenty-one days is not recommended{R-5}.

Note: Dogs—Although the efficacy has not been established, a dose

of 11 mg of ormetoprim and 55 mg of sulfadimethoxine a day

has been used in the treatment of [enteric coccidiosis]1 in dogs. This

therapy may reduce shedding of oocysts and relieve symp-

toms{R-136}.


U.S.{R-5}—


20 mg of ormetoprim and 100 mg of sulfadimethoxine (Rx) [Primor 120].

40 mg of ormetoprim and 200 mg of sulfadimethoxine (Rx) [Primor

240].

100 mg of ormetoprim and 500 mg of sulfadimethoxine (Rx) [Primor

600].

200 mg of ormetoprim and 1000 mg of sulfadimethoxine (Rx)

[Primor 1200].

Canada—





manufacturer.




PYRIMETHAMINE AND SULFAQUINOXALINE




PYRIMETHAMINE AND SULFAQUINOXALINE ORALSOLUTIONUsual dose: [Coccidiosis (prophylaxis and treatment)]—Chickens and

turkeys: Oral, 14.7 mg of pyrimethamine and 48.8 mg of sulfaqui-

noxaline per liter of water, administered as the only source of drinking

water for two days. Treatment is stopped for three days and then

repeated as necessary to control infection. For existing infection,

treatment should be repeated until symptoms of disease have disap-

peared{R-17}.


U.S.—



Canada{R-17}—


9.8 grams of pyrimethamine and 32.5 grams of sulfaquinoxaline per

liter of solution (OTC) [Quinnoxine-S; Sulfaquinoxaline-S].

Withdrawal times:

Canada{R-17}—

Withdrawal time

Species Meat (days)

Chickens, turkeys 4

Packaging and storage: Store below 23 �C (73 �F), unless otherwise

specified by the manufacturer. Protect from freezing{R-17}.


SULFADIAZINE AND TRIMETHOPRIM




SULFADIAZINE AND TRIMETHOPRIM ORAL PASTEUsual dose:

Respiratory tract infections;

Skin and soft tissue infections;

Strangles;

Urogenital infections1; or

[Perioperative infections]—Horses: Oral, 25 mg of sulfadiazine and

5 mg of trimethoprim per kg of body weight every twenty-four

hours{R-3; 18}.

Note: Horses—Based on pharmacokinetic studies, disease models of

infectious arthritis, and the relatively short half-life of trimethoprim

in the horse, an [oral dose of 25 mg of sulfadiazine and 5 mg of

trimethoprim per kg of body weight every twelve hours has been

used to treat susceptible infections in horses{R-25}, including equine

infectious arthritis]1, in which case the dose is administered for three

to six weeks{R-41; 42}.

The administration of oral sulfadiazine and trimethoprim combi-

nation while a horse has free access to feed does not significantly

affect the absorption of the sulfadiazine{R-25; 27; 28}; however, the

absorption of trimethoprim is delayed so that initial serum

concentrations will be lower in a fed horse than in a fasted horse.

This effect is greatly decreased by the third day of treatment{R-27}.

For horses being treated for less severe, susceptible infections,

allowing free access to food is recommended to decrease the risk of

diarrhea{R-25}.


U.S.{R-3}—


333 mg of sulfadiazine and 67 mg of trimethoprim per gram of paste

(Rx) [Tribrissen 400 Oral Paste].

Canada{R-18}—



Withdrawal times:

U.S.—Sulfadiazine and trimethoprim oral paste is not labeled for use in

food-producing animals, including horses intended for food produc-

tion. See Sulfadiazine and Trimethoprim Tablets for more information.


unless otherwise specified by the manufacturer{R-3}.


SULFADIAZINE AND TRIMETHOPRIM ORALPOWDERUsual dose:

Respiratory tract infections1;


Strangles1; or

Urogenital infections1—Horses: Oral, 25 mg of sulfadiazine and 5 mg of

trimethoprim per kg of body weight every twenty-four hours{R-4}.

Note: Based on pharmacokinetic studies, an [oral dose of 25 mg of

sulfadiazine and 5 mg of trimethoprim per kg of body weight every

twelve hours]1 has also been used in horses{R-25}.

The administration of oral sulfadiazine and trimethoprim combi-

nation while a horse has free access to feed does not significantly

affect the absorption of the sulfadiazine{R-25; 27; 28}; however, the

absorption of trimethoprim is delayed so initial serum concentra-

tions will be lower in a fed horse than in a fasted horse. This

effect is greatly decreased by the third day of treatment{R-27}. For

horses being treated for less severe, susceptible infections, allowing

free access to food is recommended to decrease the risk of

diarrhea{R-25}.

[Vibrio anguillarum infection]—Salmon: Oral, 25 mg of sulfadiazine and

5 mg of trimethoprim per kg of body weight a day, administered in

the feed, and fed as the only ration for seven to ten days{R-22}.


available in Canada




U.S.—


333 mg of sulfadiazine and 67 mg of trimethoprim per gram of

powder (Rx) [Tucoprim Powder; Uniprim Powder (horses)].

Canada—


333 mg of sulfadiazine and 67 mg of trimethoprim per gram of

powder (Rx) [Tribrissen 40% Powder (salmon)].

Withdrawal times:

U.S.—Sulfadiazine and trimethoprim oral powder is not labeled for use in

food-producing animals, including horses intended for food produc-

tion. See Sulfadiazine and Trimethoprim Tablets for more information.

Canada{R-22}—

Withdrawal time

Species Meat (days)

Salmon 80

Note: The half-lives of sulfadiazine and trimethoprim in the deepest layer

of marine sediments can be ninety days or longer{R-65}.


between 15 and 30 �C (59 and 86 �F), in a tight container, unless

otherwise specified by the manufacturer. Protect from light{R-22}.


SULFADIAZINE AND TRIMETHOPRIM ORALSUSPENSIONUsual dose:

[Colibacillosis]; or

[Enteritis, bacterial]—Piglets:Oral, 22.8 mg of sulfadiazine and 4.6 mg of

trimethoprim per kg of body weight every twenty-four hours{R-10}.


U.S.—



Canada—


45.5 mg of sulfadiazine and 9.1 mg of trimethoprim per mL (Rx)

[Tribrissen Piglet Suspension].

Withdrawal times:

Canada{R-10}—

Withdrawal time

Species Meat (days)

Piglets 5





SULFADIAZINE AND TRIMETHOPRIM TABLETSUsual dose:

Gastrointestinal tract infections1;

Respiratory tract infections1; or

Skin and soft tissue infections1{R-46}—Dogs and [cats]: Oral, 12.5 mg of

sulfadiazine and 2.5 mg of trimethoprim per kg of body weight every

twelve hours{R-2; 11; 19} or, less commonly, 25 mg of sulfadiazine

and 5 mg of trimethoprim per kg of body weight every twenty-four

hours.

Note: Only intact tablets should be administered to cats, to avoid

excessive salivation caused by contact of the medication with oral

mucosa{R-11}.

Urinary tract infections1—Dogs: Oral, 12.5 mg of sulfadiazine and

2.5 mg of trimethoprim per kg of body weight every twelve hours or,

less commonly, 25 mg of sulfadiazine and 5 mg of trimethoprim per


Note: For [bacterial prostatitis in dogs, 25 mg of sulfadiazine and 5 mg

of trimethoprim per kg of body weight every twelve hours for two

to four weeks]1 is recommended{R-23; 47; 48}, based on pharma-

cokinetic data.

Product labeling states that administration for more than fourteen

days is not recommended{R-2; 11; 19}.

Note: Although the efficacy has not been established, doses up to [37.5 to

50 mg of sulfadiazine and 7.5 to 10 mg of trimethoprim per kg of body

weight every twelve hours for three to six months have been used in the

treatment of nocardiosis]1 in cats and dogs{R-23; 130; 132}.

For organisms susceptible to both sulfadiazine and trimethoprim,

once-daily dosing is likely to be efficacious for cats and dogs.

However, for organisms that may be resistant to one of the

antimicrobials, twice-daily dosing as above is recommended. For

infections for which susceptibility is unknown or when life-threat-

ening infections are present, 25 mg of sulfadiazine and 5 mg of


used, based on current information about the pharmacokinetics of

this medication in the dog{R-23}.

Note: [Calves, nonruminating]1—Until recently, Canadian sulfadiazine

and trimethoprim boluses were labeled for use in the treatment of

bacterial pneumonia in calves{R-12}. Although there are no sulfadia-

zine and trimethoprim products labeled for use in calves in the United

States or Canada at this time, oral sulfadiazine and trimethoprim

tablets might be used in the treatment of susceptible infections, such as

pneumonia, in calves.

Tablets are not recommended for use in ruminating animals because of

poor bioavailability{R-81} and subsequent lack of efficacy as calves

progress to the ruminant state{R-12}. In ruminating calves, therapeutic

serum concentrations of trimethoprim have not been reached with

oral administration{R-81}. Increased rate of elimination and decreased

absorption of the medication as calves mature lead to a decrease

in resulting serum antibiotic concentration that is measurable at

6 weeks of age in milk-fed calves and becomes so pronounced with

onset of rumination that this medication cannot be administered

effectively{R-79; 81; 143}.

According to some researchers{R-24; 81; 143}, many pathogens

important in calfhood diseases, including Escherichia coli, Salmonella

species, and Haemophilus species, have minimum inhibitory concen-

trations (MICs) that range from 3 to 10 mcg per mL (mcg/mL) for

sulfonamides and 0.1 to 0.5 mcg/mL for trimethoprim. Researchers

have suggested that, in calves less than 1 week of age, oral



administration of 12.5 mg of sulfadiazine and 2.5 mg of trimethoprim

per kg of body weight every 24 hours would be appropriate in the

treatment of infections caused by these organisms{R-81}. They note

that in animals older than 1 week of age, an oral dose of 25 mg of

sulfadiazine and 5 mg of trimethoprim per kg of body weight,

administered every 12 hours, has been necessary to maintain

therapeutic concentrations{R-81}. However, the National Committee

for Clinical Laboratory Standards (NCCLS) lists the breakpoints as

£ 38/2 mcg/mL for sulfonamide and trimethoprim, respectively{R-141}.

It is possible for an organism to be classified as sensitive yet have MICs

above the plasma concentration achieved by the above dosages{R-145}.

Based on pharmacokinetic calculations, an oral dosage of 37.5 mg of

sulfadiazine and 7.5 mg of trimethoprim per kg of body weight every 12

hours in calves older than 1 week of age but younger than 6 weeks of

age may be needed to consistently maintain concentrations greater than

or equal to the NCCLS breakpoints, but the safety and efficacy of such a

dose has not been tested in calves{R-144; 145}.


U.S.—


25 mg of sulfadiazine and 5 mg of trimethoprim (Rx) [Tribrissen 30].

100 mg of sulfadiazine and 20 mg of trimethoprim (Rx) [Tribrissen

120].

400 mg of sulfadiazine and 80 mg of trimethoprim (Rx) [Tribrissen 480].

800 mg of sulfadiazine and 160 mg of trimethoprim (Rx) [Tribrissen

960].

Canada—



Withdrawal times:

U.S. and Canada—Sulfadiazine and trimethoprim tablets are not labeled

for use in food-producing animals.

There is no established withdrawal time for calves in the U.S. and, in

Canada, where a sulfadiazine and trimethoprim bolus was once

available, there is no longer any product labeled for use in calves. If a

sulfadiazine and trimethoprim combination product available in the

U.S. is administered to 1-week-old calves at a dose of 12.5 mg of

sulfadiazine and 2.5 mg of trimethoprim every twelve hours, there is

some evidence to suggest that a meat withdrawal time of 10 days, the

discontinued Canadian product label withdrawal time, would be

sufficient to avoid residues that would violate U.S. standards{R-12; 79;

80; 81; 140; 142}. Estimates for a withdrawal time for dosages larger

than 12.5 mg of sulfadiazine and 2.5 mg of trimethoprim every twelve

hours are not available. It should be considered that substitution of one

oral dosage form for another may result in differences in pharmaco-

kinetic results. Available residue studies{R-140} and pharmacokinetic{R-

81} studies for oral products were performed in calves using boluses

and tablets, respectively.



manufacturer.





SULFADIAZINE AND TRIMETHOPRIM INJECTIONUsual dose:

Respiratory tract infections; or

Skin and soft tissue infections—

[Cats] and [dogs]: Subcutaneous, 12.5 mg of sulfadiazine and 2.5 mg

of trimethoprim per kg of body weight every twelve hours or, less

commonly, 25 mg of sulfadiazine and 5 mg of trimethoprim per kg

of body weight every twenty-four hours{R-8; 95}.

Horses: Intramuscular or intravenous, 20 mg of sulfadazine and 4 mg

of trimethoprim per kg of body weight every twenty-four hours{R-9}.

Strangles; or

Urogenital tract infections1—Horses: Intramuscular or intravenous,



[Gastrointestional tract infections]—Cats and dogs: Subcutaneous,

12.5 mg of sulfadiazine and 2.5 mg of trimethoprim per kg of body

weight every twelve hours or, less commonly, 25 mg of sulfadiazine

and 5 mg of trimethoprim per kg of body weight every twenty-four

hours{R-8}.

Note: Although Canadian labeling recommends intramuscular or

intravenous administration of sulfadiazine and trimethoprim combi-

nation and there are few reports in the literature of adverse reactions

to intravenous administration of this combination, some sources

recommend caution when administering these medications intrave-

nously to horses{R-25}.

Product labeling states that administration for more than fourteen

days in cats and dogs and more than seven days in horses is not

recommended{R-8; 9}.


U.S.—


400 mg of sulfadiazine and 80 mg of trimethoprim per mL (Rx)

[Tribrissen 48% (horses)].

Canada—



[Tribrissen 24% (cats and dogs)].


[Tribrissen 48% (horses)].

Withdrawal times:

U.S. and Canada—Products are not labeled for use in horses to be used

for food production{R-9}.



manufacturer.








SULFADOXINE AND TRIMETHOPRIM




SULFADOXINE AND TRIMETHOPRIM INJECTIONUsual dose:

[Bacterial enteritis];

[Bacterial pneumonia]; or

[Colibacillosis]—Cattle and pigs: Intramuscular or slow intravenous,

13.3 mg of sulfadoxime and 2.7 mg of trimethoprim per kg of body

weight, every twenty-four hours for five days{R-13–15}.

Note: [Cattle]—Based on pharmacokinetic studies, a dose of 13.3 mg

of sulfadoxine and 2.7 mg of trimethoprim per kg of body weight

every twelve hours1 may be necessary to treat infections in cattle

caused by organisms that are less than very sensitive to sulfadox-

ine and trimethoprim{R-85}.

[Bacterial arthritis];

[Mastitis]; or

[Metritis]—Pigs: Intramuscular or slow intravenous, 13.3 mg of

sulfadoxine and 2.7 mg of trimethoprim per kg of body weight every

twenty-four hours for five days{R-13–15}.

[Pododermatitis]; or

[Septicemia]—Cattle: Intramuscular or slow intravenous, 13.3 mg of

sulfadoxine and 2.7 mg of trimethoprim per kg of body weight, every

twenty-four hours for five days{R-13–15}.


U.S.—



Canada—


200 mg of sulfadoxine and 40 mg of trimethoprim per mL (Rx)

[Bimotrim; Borgal; Potensulf; Trimidox; Trivetrin].

Withdrawal times:

Canada{R-13–15}—

Withdrawal time


Cattle 10 96

Pigs 10





SULFAMETHOXAZOLE AND TRIMETHOPRIM




SULFAMETHOXAZOLE AND TRIMETHOPRIM ORALSUSPENSION USPUsual dose:

Note: [Dogs]1—Although the safety and efficacy have not been

established, an oral dose of 25 mg of sulfamethoxazole and 5 mg

of trimethoprim per kg of body weight every twelve hours for two to

four weeks has been used in the treatment of bacterial prostatitis in

dogs, based on pharmacokinetic data{R-47; 48}.

[Horses]1—Although the safety and efficacy have not been estab-

lished, an oral dose of 25 mg of sulfamethoxazole and 5 mg of


used in the treatment of bacterial infections, based on pharmacoki-

netic studies{R-31}.


U.S.—



Human-labeled product(s):{R-119}

40 mg of sulfamethoxazole and 8 mg of trimethoprim per mL (Rx)

[Bactrim Pediatric; Cotrim Pediatric; Septra Grape Suspension; Septra

Suspension; Sulfatrim Pediatric; Sulfatrim Suspension; generic].

Canada—





[Apo-Sulfatrim; Bactrim; Novo-Trimel; Nu-Cotrimox; Septra].



manufacturer. Store in a tight, light-resistant container. Protect from

freezing.


tains the labeled amounts, within ±10%. Meets the requirements for

Identification, pH (5.0–6.5), Chromatographic purity, and Alcohol

content (not more than 0.5%){R-117}.

SULFAMETHOXAZOLE AND TRIMETHOPRIM TABLETSUSPUsual dose: See Sulfamethoxazole and Trimethoprim Oral Suspension USP.


U.S.—




400 mg of sulfamethoxazole and 80 mg of trimethoprim (Rx)

[Bactrim; Cotrim; Septra; Sulfatrim; Sulfatrim S/S].

800 mg of sulfamethoxazole and 160 mg of trimethoprim (Rx)

[Bactrim DS; Cofatrim Forte; Cotrim DS; Septra DS; Sulfatrim DS].

Canada—




100 mg of sulfamethoxazole and 20 mg of trimethoprim (Rx) [Apo-

Sulfatrim].






Sulfatrim; Bactrim; Novo-Trimel; Nu-Cotrimox; Septra].


Sulfatrim DS; Bactrim DS; Novo-Trimel D.S.; Nu-Cotrimox DS;

Roubac; Septra DS].



manufacturer. Store in a well-closed, light-resistant container.

USP requirements: Preserve in well-closed, light-resistant containers.

Contain the labeled amounts, within ±7%. Meet the requirements for

Identification, Dissolution (70% of each active ingredient in 60 min-

utes in 0.1 N hydrochloride acid in Apparatus 2 at 75 rpm), and

Uniformity of dosage units{R-117}.




SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTIONUSPUsual dose:

Note: [Foals]1 and [horses]1—Although the efficacy and safety have not

been established, a slow intravenous dose of 12.5 mg of sulfameth-

oxasole and 2.5 mg of trimethoprim per kg of body weight every


and protozoal infections in foals and horses, based on pharmacokinetic

data{R-31; 32}. However, to reach effective concentrations in the

cerebrospinal fluid (CSF) for bacterial and protozoal infections, higher

doses are required; distribution studies show that an intravenous

dose of 36 mg of sulfamethoxazole and 7.5 mg of trimethoprim per

kg of body weight will produce CSF concentrations sufficient to treat

susceptible bacterial and protozoal infections{R-31; 33}.

Intravenous doses should be administered slowly.


U.S.—





[Bactrim I.V.; Septra I.V.].

Canada—





[Septra].



manufacturer. Store in a light-resistant container. Should not be

refrigerated.

Preparation of dosage form: The contents of each vial (5 mL) must be

diluted to 75 to 125 mL with 5% dextrose injection prior to admin-

istration by intravenous infusion. The resulting solution should be

administered by intravenous infusion over a sixty- to ninety-minute

period.

Stability: After initial dilution with 75 or 125 mL of 5% dextrose

injection, infusion should be administered within two or six hours,

respectively. The solution should not be used if it is cloudy or contains

a precipitate. The solution should not be mixed with other medications

or solutions.

USP requirements: Preserve in single-dose, light-resistant containers,

preferably of Type I glass. May be packaged in 50-mL multiple-dose

containers. A sterile solution of Sulfamethoxazole and Trimethoprim in

Water for Injection which, when diluted with Dextrose Injection, is

suitable for intravenous infusion. Label it to indicate that it is to be

diluted with 5% Dextrose Injection prior to administration. Contains

the labeled amounts, within ±10%. Meets the requirements for Iden-

tification, Pyrogen, pH (9.5–10.5), Particulate matter, and Related

compounds, and for Injections.{R-117}

Developed: 6/10/98

Revised: 6/30/02


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MD: The United States Pharmacopeial Convention, Inc. 2002.

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Schering-Plough—US). Downloaded from www.spah.com on 2/21/03.

3. Sulfadiazine and trimethoprim product information (Tribrissen 400 Oral

Paste, Schering-Plough—US). Downloaded from www.spah.com on 2/21/03.

4. Sulfadiazine and trimethoprim package insert (Tucoprim, Pharmacia—US),

Rev 4/01. Downloaded from www.pharmaciaah.com on 2/21/03.

5. Ormetoprim and sulfadimethoxine package insert (Primor, Pfizer—US), Rev

3/94. Downloaded from www.pfizer.com on 2/21/03.

6. Ormetoprim and sulfadimethoxine package insert (Rofenaid 40 Premix,

Roche—US), Rev 92, Rec 10/30/95.

7. Ormetoprim and sulfadimethoxine package insert (Romet B, Roche—US), Rev

87, Rec 10/30/95.

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Schering-Plough—Canada). Downloaded from Schering-Plough Animal

Health Product Label Retrieval Service on 2/21/03.

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10. Sulfadiazine and trimethoprim package insert (Tribrissen Piglet Suspension,

Mallinckrodt—Canada), Rec 6/1/95.

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rodt—Canada), Rec 6/1/95 [discontinued product].

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rodt—Canada), Rec 6/1/95 [discontinued product].

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14. Sulfadoxine and trimethoprim package insert (Borgal Injection, Hoes-

chst—Canada), Rec 7/5/95.

15. Sulfadoxine and trimethoprim package insert (Trimidox, Sanofi—Canada),

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1995. p. 572.

17. Pyrimethamine and sulfaquinoxaline product label (Quinnoxine-S, A.P.A./

Sanofi—Canada), Rec 10/27/95.

18. Sulfadiazine and trimethoprim package insert (Tribrissen Oral Paste, Mal-

linckrodt—Canada), Rec 6/1/95.

19. Sulfadiazine and trimethoprim package insert (Ditrim, Syntex—US), Rev 5/

93, Rec 3/1/96.

20. Van Miert ASGPAM. The sulfonamide-diaminopyridine story. J Vet Pharma-

col Ther 1994; 17: 309–16.

21. Freedom of information summary. Primor tablets. New Animal Drug

Application (NADA) 100–929. Hoffman-LaRoche Inc.

22. Sulfadiazine and trimethoprim product information (Tribrissen 40% Powder,



23. Wilcke JR. Therapeutic application of sulfadiazine/trimethoprim in dogs and

cats: a review. Companion Anim Pract 1988 Sep: 3–8.

24. Bushby SRM. Sulfonamide and trimethoprim combinations. J Am Vet Med

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PYRIMETHAMINE Veterinary—Systemic

A commonly used brand name for a human-labeled product is Daraprim.



CATEGORY:Antiprotozoal (systemic).




Canadian product labeling. However, since pyrimethamine is not

specifically approved for veterinary use, there is no product labeling

identifying approved indications.

GENERAL CONSIDERATIONSPyrimethamine is a folic acid antagonist{R-1}, active against protozoal

dihydrofolate reductase. It is considered most effective against path-

ogenic protozoa when administered in combination with a sulfon-

amide{R-11; 16; 20}.

The ready availability of combination products containing trimethoprim

and sulfadiazine or trimethoprim and sulfamethoxazole may have

contributed to the frequency of their concurrent administration with

pyrimethamine. While trimethoprim does not increase the efficacy of

therapy against protozoa{R-30}, it is suspected to increase the incidence

of side effects due to folate reduction{R-1; 21}. Whenever possible,

pyrimethamine should be administered in combination with a sulfon-

amide alone in the treatment of susceptible infections.

The development of resistant organisms has been stimulated in in vitro

experiments, and cross-resistance by these cultures to other dihydro-

folate inhibitors has been shown. However, when pyrimethamine was

combined with a sulfonamide in the treatment of pyrimethamine-

resistant Neospora cultures, the combination was completely effec-

tive{R-11}.

In the case of equine protozoal myeloencephalitis, resistance may occur

within an individual horse if inadequate treatment is administered;

however, transmission of resistance to the Sarcocystis neurona

population outside the individual is not considered a problem because

the horse is an aberrant host and does not shed infectious

organisms{R-21; 29}.

ACCEPTED[Equine protozoal myeloencephalitis (treatment)]1—Horses: Pyrimeth-

amine is used in combination with a sulfonamide, such as sulfadiazine

or sulfamethoxazole{R-9}, in the treatment of protozoal myeloenceph-

alitis{R-7; 8; 21}.

ACCEPTANCE NOT ESTABLISHED[Neospora caninum infection (treatment)]1—Dogs: Although the efficacy

and safety have not been established, pyrimethamine is used in

combination with sulfonamides, most typically sulfadiazine, in the

treatment of Neospora caninum infection. This use is based on evidence

of in vitro pathogen susceptibility{R-11; 13} and case reports of

successful treatment outcomes in some dogs, particularly in puppies

in which clinical signs of the infection had not yet progressed to rigid

hindlimb paralysis{R-12; 14; 15}.

[Toxoplasmosis (treatment)]1—Cats: Although the efficacy and safety

have not been established, pyrimethamine is used in combination with

sulfadiazine in the treatment of toxoplasmosis in cats{R-18–20}. Side

effects associated with the administration of pyrimethamine and

sulfadiazine have led clinicians to search for other treatments.

However, this therapy may have some value in the treatment of

infection with nonencysted organisms in cats that can tolerate the

medications.

REGULATORY CONSIDERATIONSU.S. and Canada—Pyrimethamine is not labeled for use in animals,

including food-producing animals; therefore, there are no established

withdrawal times.

CHEMISTRYChemical group: A diaminopyrimidine; structurally related to tri-

methoprim{R-6}.

Chemical name: 2,4-Pyrimidinediamine, 5-(4-chlorophenyl)-6-

ethyl-{R-2}.

Molecular formula: C12H13ClN4{R-2}.


Description: Pyrimethamine USP—White, odorless, crystalline pow-

der{R-3}.

pka: 7.34{R-5}.

Solubility: Pyrimethamine USP—Practically insoluble in water; slightly

soluble in acetone, in alcohol, and in chloroform{R-3}.

PHARMACOLOGY/PHARMACOKINETICSMechanism of action/effect: Pyrimethamine reversibly binds to and

inhibits the enzyme dihydrofolate reductase in protozoa. This inhibi-

tion prevents the production of tetrahydrofolic acid from dihydrofolate

and thereby prevents the metabolism of folate{R-6}. Like protozoa,

mammalian cells reduce folic acid to tetrahydrofolic acid; however, the

therapeutic action of pyrimethamine relies on a greater selectivity for

protozoal dihydrofolate reductase than for the mammalian enzyme{R-1;

16}. Pyrimethamine is generally administered in conjunction with a

sulfonamide to take advantage of the sequential inhibition of enzy-

matic steps in folate synthesis provided by the combination{R-1}.

Absorption: Oral—Human beings: Pyrimethamine is well absorbed

orally{R-1}.

Bioavailability: Oral—Horses: Average, 56% (range, 39 to 78%){R-5}.

Distribution: Rapidly and extensively distributed after intravenous

administration{R-5}.

Horses—Cerebrospinal fluid (CSF) concentrations reached 25 to 50% of

the serum concentrations but did not appear to accumulate in horses

administered daily oral doses of 1 mg per kg of body weight (mg/kg)

for 10 days{R-6}.

Pigs—Distribution occurs in two phases after a 10 mg/kg intravenous

dose; the fast phase has a half-life of 0.11 hour, and the slow phase

has a half-life of 1.6 hours{R-10}.

PYRIMETHAMINE Veterinary—Systemic 185


Rats—Mean CSF concentration was 27% of the plasma concentration

during the first 48 hours after a single oral dose of 2.9 mg/kg (1 mg

per rat){R-24}.

Volume of distribution—Intravenous administration:

Horses—Steady-state: 1.52 liters per kg (L/kg){R-5}.

Pigs—Area: 12.1 ± 2 L/kg{R-10}.

Protein binding:

Dogs—High (85%){R-24}.

Human beings—High (87%){R-24}.

Mice—High (78%){R-24}.

Pigs—High (85%), independent of serum concentration{R-10}.

Rats—High (78%){R-6}.

Biotransformation: Less than 5% of administered doses are excreted

as unchanged drug in the urine in pigs{R-10} and rats{R-24}; five

hours after administration of radiolabeled pyrimethamine to a rat,

less than 50% of radioactivity in the blood was intact parent

drug{R-24}. Therefore, it is believed that pyrimethamine is extensively

metabolized, although metabolites have not been identified in animals.

In human beings, pyrimethamine is believed to be hepatically

metabolized{R-24; 28}.

Half-life: Elimination—Intravenous administration:

Horses—12 ± 3.7 hours{R-5}.

Pigs—13.3 ± 4.9 hours{R-10}.

Concentrations:

Peak serum concentration—Oral administration: Horses—

Single dose: 0.18 ± 0.03 mcg per mL of serum (mcg/mL) with

administration of 1 mg/kg{R-5}.

Multiple doses: 0.32 ± 0.11 mcg/mL after the 5th dose and 0.26 ±

0.07 mcg/mL after the 10th dose of 10 daily doses of 1 mg/kg{R-6}.

Time to peak concentration—Oral administration: Horses—

Single dose: 2.9 ± 2.1 hours after administration of 1 mg/kg{R-5}.

Multiple doses: 2.2 hours after the 5th dose and 2.7 hours after the

10th dose of 10 daily doses of 1 mg/kg{R-6}.

Serum concentrations, other—Oral administration: Horses—

Single dose: 0.09 mcg/mL 24 hours after administration of

1 mg/kg{R-5}.

Multiple doses: Plasma steady state was reached at the 5th day of 10

daily doses of 1 mg/kg; at that time the serum concentrations

fluctuated approximately 65% over each 24-hour period, with the

peak at approximately 0.32 mcg/mL{R-6}.

Elimination: Pigs—Only about 3% of an intravenous dose of pyri-

methamine is excreted in the urine as unchanged drug, although up to

90% of the dose is eliminated in that time{R-10}.

Total clearance—

Horses: 1.6 ± 0.32 mL per minute per kg (mL/min/kg){R-5}.

Pigs: 0.68 ± 0.16 mL/min/kg{R-10}.


CARCINOGENICITYMice: A significant increase in the number of lung tumors per mouse has

been reported with doses of 25 mg per kg of body weight (mg/kg),

administered intraperitoneally{R-1}.

PREGNANCY/REPRODUCTIONReproduction: Rats—The fertility index of rats treated with pyrimeth-

amine is lowered only by the highest doses administered. This suggests

a toxic effect on the whole animal or the conceptus{R-1}.

Pregnancy:

Hamsters—Single doses of 20 mg per pregnant hamster caused

malformation or death in less than 10% of fetuses{R-1}.

Horses—In a group of horses treated with oral pyrimethamine at 1 mg

per kg of body weight (mg/kg) a day, sulfadiazine at 16.7 mg/kg

every twelve hours, and trimethoprim at 3.3 mg/kg every twelve

hours, the three horses that were pregnant during therapy aborted

during the second or third month of treatment{R-21}. Each of the

aborted fetuses was in the fifth month of gestation{R-21}. It is not

certain which of the medications might have caused the abortions.

The horses’ diets had not been supplemented with folate at the time

of the abortions{R-21}.

The administration of oral folic acid to pregnant mares being treated

for equine protozoal myeloencephalitis may not protect the fetus

from the effects of folate deficiency. Reports have been made of

mares delivering foals with congenital defects after oral administra-

tion during pregnancy of pyrimethamine, 0.5 to 1 mg/kg a day,

with sulfadiazine, 25 mg/kg a day; or sulfamethoxazole, 12.5 mg/

kg day, and trimethoprim, 2.5 mg/kg{R-35}. Two of the three

reported mares had been treated in the last 3 months of gestation

and one for 2 years before foaling. These mares had also been

supplemented with oral folic acid, 40 mg as a total daily dose, and

vitamin E, 8000 Units as a total daily dose, during the period of

antibiotic treatment. Each of three mares on this dosage regimen

produced a foal with renal hypoplasia or nephrosis and bone

marrow aplasia or hypoplasia{R-35}. In both mares and foals, serum

folate concentrations were below the laboratory reference range and

in two foals, folate was less than 30% of the minimum reference

range{R-35}. The risk of congenital defects should be considered

when treating pregnant mares with pyrimethamine and sulfon-

amide.

Miniature pigs—A high incidence of malformations (70%), such as cleft

palate, club foot, and micrognathia, was seen in offspring when

pregnant sows were administered pyrimethamine, 3.6 mg/kg a day,

from days 11 to 35 of gestation; however, no abnormalities were

noted in the offspring of sows administered 0.9 to 1.8 mg/kg a day

during the same period of gestation{R-1; 4}.

Rats—Fetal resorption and stunted growth in fetuses have been seen in

pregnant rats given pyrimethamine{R-1}. Rats administered 12.5 mg/

kg from days 7 to 9 of gestation had 66% of fetuses resorbed and

33% stunted, while a dose of 0.5 to 1 mg/kg from days 4 to 13 of

gestation caused resorption of 8 to 15% of fetuses and stunted

growth in 7 to 17% of fetuses{R-1}.

LACTATIONPyrimethamine is distributed into human milk{R-1}. Distribution into

milk in lactating animals has not been determined.

PEDIATRICSDogs: Pyrimethamine has been administered at a dose of 1 mg per kg of

body weight a day for 4 weeks in 8- to 17-week-old puppies, without

any apparent harmful effects{R-14}.

186 PYRIMETHAMINE Veterinary—Systemic






Note: Drug interactions relating specifically to the use of pyrimethamine

in animals are rarely reported in veterinary literature. Human drug

interactions have been reported and are included in the following

section.


The following drug interactions have been reported in humans, and are

included in the human monograph Pyrimethamine (Systemic) in USP



pyrimethamine in the treatment of animals:



medication.


(concurrent use of pyrimethamine with bone marrow depressants

may increase the leukopenic and/or thrombocytopenic effects; if

concurrent use is required, the possibility of increased myelotoxic

effects should be considered, especially when pyrimethamine is used

in large doses, such as those required in the treatment of toxoplas-

mosis)

Folate antagonists, other

(concurrent use of other folate antagonists with pyrimethamine or

use of pyrimethamine between courses of other folate antagonists is

not recommended because of the possible development of megalob-

lastic anemia)







» Anemia or

Bone marrow suppression

(pyrimethamine may cause folate deficiency, resulting in megalob-

lastic anemia and blood dyscrasias, including agranulocytosis and

thrombocytopenia{R-19; 21; 26})


(in human beings, pyrimethamine is metabolized in the liver)


problem exists:

Pregnancy

(the risk of teratogenesis should be considered in planning treatment

with pyrimethamine{R-35})




Complete blood counts (CBCs){R-19; 21; 23} and

Platelet counts

(should be performed on a regular basis, particularly with long-term

or high-dose therapy; periodic packed cell volume evaluation is

recommended in horses being treated for equine protozoal myeloen-

cephalitis to monitor for anemia{R-29})




inclusive:

Note: It is assumed that animals have the same tendency as people to

develop signs of folate deficiency with long-term use or high doses of

folic acid antagonists such as pyrimethamine. Signs of folate deficiency

have been reported frequently in the human literature and include

agranulocytosis, megaloblastic anemia, and thrombocytopenia{R-16}.

Similar signs have been noted in cats, dogs, and horses{R-19; 21; 26}. It

should be considered that signs of folate deficiency may occur in any

species administered pyrimethamine. When administering pyrimeth-

amine with a sulfonamide, the risk of sulfonamide-related side effects

should be considered. See the Sulfonamides (Veterinary—

Systemic) monograph for further information.


Cats

Leukopenia—seen with a dose of 1 mg per kg of body weight (mg/ kg)

a day for 6 days{R-19}

Horses

Anemia{R-21}; congenital defects in offspring (bone marrow aplasia

or hypoplasia; renal nephrosis or hypoplasia; skin lesions){R-35};

diarrhea{R-21}; leukopenia{R-21}




included in the human monograph Pyrimethamine (Systemic) in USP


purposes only, and may or may not be applicable to the use of

pyrimethamine in the treatment of animals:


Agranulocytosis, leukopenia, or thrombocytopenia; atrophic

glossitis; gastrointestinal disturbances (anorexia, diarrhea, nau-

sea, and vomiting)

Incidence rare

Erythema multiforme and/or Stevens-Johnson syndrome;

hypersensitivity


contact the American Society for the Prevention of Cruelty

to Animals (ASPCA) National Animal Poison Control Center

(888-426-4435 or 900-443-0000; a fee may be required for consul-

tation) and/or the drug manufacturer.






Dogs—with a dose of 5 to 10 mg per kg of body weight (mg/kg) a day for

10 to 21 days{R-26}

Chronic effects

Anorexia and/or decreased appetite; ataxia; bone marrow

suppression, including leukopenia and reticulocytopenia; dehy-

dration; gastrointestinal toxicity (diarrhea, occasionally bloody;

vomiting); weakness; weight loss

Note: Bone marrow suppression has been demonstrated by biopsy

in a few dogs receiving extremely high doses of pyrimethamine

(6 mg/kg a day for 10 to 15 days){R-26}. Three of eight dogs

treated had bone marrow suppression, particularly of the erythroid

elements{R-26}.

In dogs, vomiting was reported to be common within 2 to 5 hours of

administration of 7.5 to 10 mg/kg, but vomiting was seen only

occasionally in dogs receiving 5 mg/kg a day for 10 to 21 days{R-26}.

Intestinal lesions, including inflammation, mucoid degeneration,

shortened villi and mucosal atrophy, are visible on histopathologic

examination after administration of 6.2 mg/kg a day for 10 days to

dogs{R-26}.

Respiratory depression and circulatory collapse, as well as neuro-

toxicity leading to seizures, have been reported in people receiving

total doses of 250 to 300 mg of pyrimethamine{R-1}. These specific

signs have not been reported in animals; however, one of four dogs

administered 5 mg/kg a day died on the 17th day of therapy; the

specific cause of death was not reported{R-26}.

TREATMENT OF OVERDOSE{R-1}

• Gastric lavage.

• Control of central nervous system stimulation by administration of

benzodiazepines or short-acting barbiturates, if necessary.

• Respiratory assistance, if necessary.

• Administration of folate to prevent hematopoietic changes (see

Veterinary Dosing Information).

CLIENT CONSULTATIONClients should be advised to watch for signs such as loss of appetite,

weakness, pale mucous membranes or pinpoint blood spots in

membranes, or noticeable bruising.

VETERINARY DOSING INFORMATIONThe administration of sulfadiazine and trimethoprim products labeled for

use in animals in combination with human-labeled pyrimethamine

tablets is commonly discussed in veterinary literature. However, the

low affinity of protozoal dihydrofolate for trimethoprim suggests poor

efficacy of trimethoprim in the treatment of protozoal infections{R-30}.

The concurrent administration of trimethoprim with pyrimethamine

offers no known benefit and may increase the risk of adverse effects

associated with these dihydrofolate reductase inhibitors{R-1; 9; 21}.

Whenever possible, pyrimethamine should be administered in combi-

nation with a sulfonamide alone in the treatment of susceptible

infections.

The administration of folic acid or folinic acid supplements during

treatment with pyrimethamine may help to prevent adverse effects

associated with folate deficiency, which occur as an extension of the

mechanism of action of the drug{R-9; 21}; however, neither oral

supplement has been clearly proven to be effective. Only limited

information on the effectiveness of folic acid or folinic acid in the

prevention of folate deficiency caused by pyrimethamine is avail-

able.

Cats and dogs: No definitive studies are available to confirm that folic

acid or folinic acid supplementation should be used to prevent signs of

folate deficiency that may occur during treatment with pyrimeth-

amine{R-36}. Monitoring animals for signs of folate deficiency is

recommended during treatment with pyrimethamine (see the Patient

monitoring and Side/Adverse Effects sections){R-36}.

Horses: An oral folic acid dose of 0.09 to 0.18 mg per kg of body

weight mg/kg) (40 to 80 mg per horse) every twenty-four hours

has been used{R-29; 31}; however, case reports have shown that a

total dose of 40 mg of folic acid a day given to pregnant mares

being treated with pyrimethamine and sulfonamide is sometimes

not effective in preventing congenital defects in foals caused by

folate deficiency{R-35}. Fresh grass has more than twice the total

folacin concentration of hay{R-32}, and serum folate concentrations

tend to be much higher in pastured horses than in permanently

stabled horses or horses in training{R-33; 34}. It has been

recommended that horses be maintained on feeds containing high

folacin concentrations during pyrimethamine therapy{R-29}. Rather

than supplementing horses with folic acid, some clinicians recom-

mend monitoring the packed-cell volume to detect developing

anemias.

Some clinicians have used the in vitro minimum inhibitory concentration

(MIC) of pyrimethamine considered necessary to inhibit Toxoplasma

gondii{R-5; 21} or the MIC of pyrimethamine necessary to inhibit

Neospora caninum{R-11} as guidelines for target cerebrospinal fluid

concentrations for control of the Sarcocystis species responsible for

equine protozoal myeloencephalitis.{R-5}

DIET/NUTRITIONHorses: Pyrimethamine should be administered 1 hour prior to feeding

hay{R-9}.

Human beings: Information from human product labeling includes the

statement that anorexia and vomiting induced by pyrimethamine may

be minimized by administering it with food{R-1}.

ORAL DOSAGE FORMSNote: In other USP DI monographs, bracketed information in the Dosage

Forms section refers to categories of use and/or indications that are not



labeling. However, since pyrimethamine is not specifically approved for


indications.

PYRIMETHAMINE TABLETS USPUsual dose:

[Equine protozoal myeloencephalitis]1—Horses: Oral, 1 mg per kg of

body weight every twenty-four hours{R-5} in combination with 16.7mg

of sulfadiazine or sulfamethoxazole per kg of body weight every twelve

hours{R-5; 8; 9; 21} has been used. The average duration of treat-

ment necessary to clear the organism may be as long as 130 days



or more{R-21}. Testing cerebrospinal fluid for Sarcocystis neurona

antibodies may help determine when to discontinue treatment{R-21}.

Note: The above dose is based on clinical case reports with successful

outcomes that also included the concurrent administration of 3.3 mg

of trimethoprim per kg of body weight. However, the administration

of pyrimethamine concurrently with trimethoprim generally is not

recommended. To decrease the risk of toxicity, the administration of

pyrimethamine with sulfadiazine alone is preferred, but there are no

specific reports of the efficacy of this combination.

[Neospora caninum infection]1—Dogs: Although the efficacy and safety

have not been established, an oral dose of 1 mg of pyrimethamine per

kg of body weight every twenty-four hours{R-14} in combination with

12.5 mg of sulfadiazine per kg of body weight every twelve hours{R-14}

for four weeks has been used.

Note: The above dose is based on clinical case reports with successful

outcomes that also included the concurrent administration of 2.5

mg of trimethoprim per kg of body weight. However, the admin-

istration of pyrimethamine concurrently with trimethoprim gener-

ally is not recommended. To decrease the risk of toxicity, the

administration of pyrimethamine with sulfadiazine alone is pre-

ferred, but there are no reports of the efficacy of this combination.

[Toxoplasmosis]1—Cats: Although the efficacy and safety have not been

established, an oral dose of 1 mg of pyrimethamine per kg of body

weight every twenty-four hours{R-18} in combination with 25 mg of

sulfadiazine per kg of body weight every twelve hours{R-18} for

fourteen to twenty-eight days has been used.

Note: The above dose was extrapolated from studies evaluating the

efficacy of pyrimethamine and sulfadiazine in ending or reducing shed-

ding of oocysts{R-18; 19} as well as preventing tissue infection{R-19}.

Because pyrimethamine is only available in 25-mg tablets, some

clinicians will arrange for capsules to be formulated in smaller

strengths for easier administration of the unpalatable medication to

cats. Consultation with an experienced pharmacist is recommended.


U.S.—



Human-labeled product(s){R-1}:

25 mg (Rx) [Daraprim (scored)].

Canada—




25 mg (Rx) [Daraprim (scored)].

Withdrawal times:

U.S. and Canada—Pyrimethamine is not labeled for use in animals,

including food-producing animals; therefore, there are no established

withdrawal times.



manufacturer. Store in a tight, light-resistant container.

Auxiliary labeling: • Keep out of the reach of children{R-1}.

Caution: Potential danger of accidental overdose{R-1}.


tain the labeled amount, within ± 7%. Meet the requirements for

Identification, Dissolution (75% in 45 minutes in 0.01 N hydrochloric

acid in Apparatus 2 at 50 rpm), and Uniformity of dosage units{R-3}.

Developed: 07/01/98

Interim revision: 10/14/99; 9/30/02; 03/28/03

REFERENCES1. Pyrimethamine package insert (Daraprim, Burroughs Wellcome—US), Rev

4/94, Rec 10/13/94.





States Pharmacopeial Convention, Inc., 2002. p. 1602, 2579.

4. Misawa J, Kanda S, Kokue E, et al. Teratogenic activity of pyrimethamine in

Gottingen minipig. Toxicol Lett 1982; 10(1): 51–4.

5. Clarke CR, Burrows GE, MacAllister CG, et al. Pharmacokinetics of intrave-

nously and orally administered pyrimethamine in horses. Am J Vet Res 1992

Dec; 53(12): 2292–5.

6. Clarke CR, Burrows GE, MacAllister CG, et al. Pharmacokinetics, penetration

into cerebrospinal fluid, and hematologic effects after multiple oral adminis-

trations of pyrimethamine to horses. Am J Vet Res 1992 Dec; 53(12): 2296–9.

7. Boy MG, Galligan DT, Divers TJ. Protozoal encephalomyelitis in horses: 82

cases (1972-1986). J Am Vet Med Assoc 1990 Feb; 196(4): 632–4.

8. Brewer B, Mayhew IG. Multifocal neurologic disease in a horse. J Equine Vet

Sci 1988 Jul/Aug; 8(4): 302–4.

9. Bertone JJ. Update on equine protozoal myeloencephalitis. FDA Vet 1996

May/Jun; XI(III): 7–9.

10. Shimoda M, Kokue E, Kurebayashi Y, et al. Three-compartment model for

pyrimethamine disposition in the pig. J Vet Pharmacol Ther 1981 Jun; 4(2):

165–70.

11. Lindsay DS, Butler JM, Rippey NS, et al. Demonstration of synergistic effects of

sulfonamides and dihydrofolate reductase/thymidylate synthase inhibitors

against Neospora caninum tachyzoites in cultured cells, and characterization

of mutants resistant to pyrimethamine. Am J Vet Res 1996 Jan; 57(1): 68–72.

12. Knowler C, Wheeler SJ. Neospora caninum infection in three dogs. J Small

Anim Pract 1995; 36: 172–7.

13. Lindsay DS, Rippey NS, Cole RA, et al. Examination of the activities of 43

chemotherapeutic agents against Neospora caninum tachyzoites in cultured

cells. Am J Vet Res 1994 Jul; 55(7): 976–81.

14. Mayhew IG, Smith KC, Dubey JP, et al. Treatment of encephalomyelitis due to

Neospora caninum in a litter of puppies. J Small Anim Pract 1991; 32: 609–

12.

15. Hay WH, Shell LG, Lindsay DS, et al. Diagnosis and treatment of Neospora

caninum infection in a dog. J Am Vet Med Assoc 1990 Jul 1; 197(1): 87–8.

16. St. Georgiev V. Opportunistic/nosocomial infections. Treatment and develop-

mental therapeutics. Toxoplasmosis. Med Res Rev 1993 Sep; 13(5): 529–68.

17. Davidson MG, Lappin MR, Rottman JR, et al. Paradoxical effect of clindamycin

in experimental, acute toxoplasmosis in cats. Antimicrob Agents Chemother

1996 Jun; 40(6): 1352–9.

18. Sheffield HG, Melton ML. Effects of pyrimethamine and sulfadiazine on the

intestinal development of Toxoplasma gondii in cats. Am J Trop Med Hyg 1976

May; 25(3): 379–83.

19. Dubey JP, Yeary RA. Anticoccidial activity of 2-sulfa-moyl-4,4-diaminodiphe-

nylsulfone, sulfadiazine, pyrimethamine and clindamycin in cats infected with

Toxoplasma gondii. Can Vet J 1977 Mar; 18(3): 51–7.

20. Mack DG, McLeod R. New micromethod to study the effect of antimicrobial

agents on Toxoplasma gondii: comparison of sulfadoxine and sulfadiazine

individually and in combination with pyrimethamine and study of clindamy-

cin, metronidazole, and cyclosporin A. Antimicrob Agents Chemother 1984

Jul; 26(1): 26–30.

21. Fenger CK, Granstom DE, Langemeier JL, et al. An epizootic of equine protozoal

myeloencephalitis on a farm. J Am Vet Med Assoc 1997 Apr 1; 210(7): 923–7.

22. McCabe RE, Oster S. Current recommendations and future prospects in the

treatment of toxoplasmosis. Drugs 1989 Dec; 38(6): 973–87.

23. Peterson JL, Willard MD, Lees GE, et al. Toxoplasmosis in two cats with

inflammatory intestinal disease. J Am Vet Med Assoc 1991 Aug; 199(4):

473–6.

24. Cavallito JC, Nichol CA, Brenckman WD, et al. Lipid-soluble inhibitors

of dihydrofolate reductase. I. Kinetics, tissue distribution, and extent of



metabolism of pyrimethamine, metoprine, and etoprine in the rat, dog, and

man. Drug Metab Dispos 1978; 6: 329–37.

25. Bygbjerg IC, Lund JT, Hording M. Effect of folic and folinic acid on cytopenia

occurring during cotrimoxazole treatment of pneumocystis carinii pneumonia.

Scand J Infect Dis 1988; 20: 685–6.

26. Castles TR, Kintner LD, Lee C. The effects of folic or folinic acid on the toxicity

of pyrmethamine in dogs. Toxicol Appl Pharmacol 1971; 20: 447–59.

27. Plumb DC. Veterinary drug handbook, 2nd ed. Ames, IA: Iowa University

Press, 1995. p. 541–3.

28. Weiss LM, Harris C, Berger M, et al. Pyrimethamine concentrations in serum

and cerebrospinal fluid during treatment of acute toxoplasma encephalitis in

patients with AIDS. J Infect Dis 1988 Mar; 157(3): 580–3.

29. Reviewer comment, Rec 7/11/97.


31. Reviewer comment, Rec 6/18/97.

32. National Research Council. Nutrient requirements of horses. Washington,

D.C.: National Academy Press, 1989. p. 29–30.

33. Roberts MC. Serum and red cell folate and serum levels in horses. Aust Vet J

1983 Apr; 60(4): 106–11.

34. Allen BV. Serum folate levels in horses, with particular reference to the English

thoroughbred. Vet Rec 1978; 103: 257–9.

35. Toribio RE, Bain FT, Mrad OR, et al. Congenital defects in newborn foals of

mares treated for equine protozoal myeloencephalitis during pregnancy. J Am

Vet Med Assoc 1998 Mar 1; 212(5): 697–701.






RIFAMPIN Veterinary—Systemic

Some commonly used brand names for human-labeled products are:

Rifadin; Rifadin IV; Rimactane; and Rofact.





Canadian product labeling. However, since rifampin is not specifically

approved for veterinary use, there is no product labeling identifying

approved indications.

GENERAL CONSIDERATIONSRifampin is a broad-spectrum antibiotic, with activity against many

gram-positive and some gram-negative aerobic bacteria{R-7} as well as

facultative anaerobic organisms{R-53; 60}. However, for clinical

purposes, rifampin generally should not be considered broad-spectrum

until proven so in each case. Most gram-negative bacteria should be

considered resistant or to have unpredictable susceptibilities until

susceptibility data are available{R-11}. Because many infections involve

more than one species of bacterium and because resistance can

develop quickly, rifampin is most often administered in combination

with other antimicrobial agents.

Rifampin is considered especially active in the treatment of staphylo-

coccal infections and in the eradication of pathogens located in

difficult to reach target areas, such as inside phagocytic cells{R-20;

62}. The ability of rifampin to reach intracellular bacteria{R-62} can

make it difficult to predict in vivo therapy results based on in vitro

sensitivity tests{R-49}.

Rifampin has been shown to have in vitro activity against equine

Corynebacterium pseudotuberculosis{R-7}, Rhodococcus equi{R-6; 7}, Staph-

ylococcus species{R-7}, Streptococcus equi{R-6; 7}, S. equisimilis{R-7},

and S. zooepidemicus{R-6; 7} isolates. Susceptibility has been variable

for the equine gram-negative nonenteric bacteria. It has shown

moderate activity against Actinobacillus suis, A. equuli, Bordetella

bronchiseptica, and Pasteurella species isolates{R-6; 7}. Equine isolates of

Pseudomonas aeruginosa, Escherichia coli, Enterobacter cloacae, Klebsiella

pneumoniae, Proteus species, and Salmonella species were found to be

resistant{R-7}.

Strains of the porcine pathogen Actinobacillus pleuropneumoniae, isolated

in Spain, were found to be susceptible to rifampin in vitro at a

concentration of 1 mcg/mL or less{R-50}. Rifampin also had activity

against Pasteurella multocida species isolated from pigs with pneumonia

in Spain{R-55}.

Some strains of Mycobacterium paratuberculosis were found to be sensitive

to rifampin in in vitro tests{R-43}.

Anaerobes found to be susceptible in vitro include 132 strains of

Bacteroides species and 25 strains of Fusobacterium species isolated from

goats in Spain; with blood concentrations of 2 mcg/mL, only 18% of

strains were resistant{R-53}. Although in vitro tests showed rifampin to

be active against Clostridium perfringens type A isolates{R-52}, when

higher concentrations of pathogens per milliliter were tested, the

antimicrobial was not very effective{R-51} and in vivo efficacy against

induced infections in mice was only weakly significant{R-52}.

Resistance to rifampin can develop quickly; therefore, it is most often used

in combination with other antimicrobials{R-2; 11; 54}. Resistant mutants

may be concentration-sensitive and contain RNA polymerases with one

of a variety of sensitivities to rifampin{R-12}. Resistance may occur as a

single-step mutation of the DNA-dependent RNA polymerase; therefore,

initial susceptibility can rapidly diminish as small populations of

resistant cells soon outnumber susceptible cells{R-2}. This effect is

diminished when combination antibiotic treatment is administered{R-2;

4}. One case of the development of resistant Rhodococcus equi in a foal

treated with erythromycin and rifampin has been reported{R-39}. Cross-

resistance to other antibiotics{R-2} or transfer of resistance to other local

microorganisms has not been reported{R-4}.

ACCEPTED[Pneumonia, Rhodococcus equi (treatment adjunct)]1 ; or

[Extrapulmonary infection, Rhodococcus equi (treatment adjunct)]1 —

Foals: Rifampin is used in combination with erythromycin in the

treatment of pneumonia caused by Rhodococcus (Corynebacterium) equi

infection in foals{R-33; 34; 36}. Although the lung appears to be most

vulnerable to Rhodococcus equi infection, in some cases susceptible foals

have been found to have abdominal or subcutaneous abscesses,

bacterial endocarditis, diskospondylitis, gastrointestinal infections,

osteomyelitis, or septicemia{R-37–42}. In many, but not all, of these

cases the foal has a concomitant pneumonia{R-37–42}. R. equi are

susceptible in vitro to erythromycin alone{R-66; 67}, and erythromycin

alone has been effective in the treatment of this infection{R-36; 67; 75}.

However, no studies have been performed to compare the efficacy of

erythromycin alone with the combination of erythromycin and

rifampin in foals. The in vitro evidence of synergistic activity for the

combination of erythromycin and rifampin against R. equi{R-10} and

the volume of case reports supporting the efficacy of the combination

make treatment with a combination of erythromycin and rifampin

more commonly recommended for this indication than erythromycin

alone{R-32}.

ACCEPTANCE NOT ESTABLISHED[Infections, bacterial (treatment)]1—Although the safety and efficacy

have not been established, rifampin is used in combination with other

antimicrobials in the treatment of susceptible bacterial infections, and

in particular, staphylococcal infections{R-20} in animals. Rifampin is

particularly suited for the treatment of organisms that are resistant to

other therapies by nature of their intracellular location{R-20; 62}.

Because the pharmacokinetics of rifampin have been well-studied in

horses{R-6; 7; 13} and minimal side effects have been reported in foals{R-

33; 34; 36}, the treatment of these infections in horses may be more

well-defined than for other species. The use of rifampin in other

animals could be based on available pharmacokinetic data for calves{R-

19}, dogs{R-4; 65}, foals{R-16}, rabbits{R-18}, and sheep{R-22}; knowledge

of bacterial susceptibility; case reports describing treatment of infec-

tions in a cat{R-58}, a deer{R-60}, and dogs{R-57}; and also efficacy

studies that have been performed in rats{R-54; 59}. However, there is

RIFAMPIN Veterinary—Systemic 191


limited knowledge about the safety of rifampin use in species other

than horses.

[Brucellosis (treatment)]1—Dogs: Although the safety and efficacy have

not been established, rifampin in combination with doxycycline has

been recommended in the treatment of brucellosis in dogs. This

recommendation is based on demonstrated efficacy in the treatment of

human brucellosis{R-68–72} and evidence of possible canine pathogen

susceptibility to rifampin{R-73}. There are no controlled studies in dogs.

[Paratuberculosis (treatment)]1—Cattle, goats, and sheep: For use in

animals not to be used in food production—Although the safety and

efficacy have not been established, rifampin has been administered in

conjunction with isoniazid in the alleviation of signs associated with

paratuberculosis (Mycobacterium paratuberculosis infection or Johne’s

disease){R-23; 43}. The addition of an aminoglycoside to the regimen

has also been used in the initial weeks of severe infection{R-23; 44}. The

use of rifampin is based on in vitro culture and sensitivity results{R-43}

and on case reports of clinical improvement for extended periods of

time{R-23; 44}; however, internal lesions and fecal shedding of the

organism are rarely controlled. It should be noted that semen from

bulls with paratuberculosis have been found to contain M. paratuber-

culosis even after freezing and processing. Placental infection of a fetus

also can occur in infected cows.{R-23} It is not known if rifampin and

isoniazid therapy can prevent transmission in semen or transplacen-

tally. The cost of rifampin therapy, as well as the inability to

completely clear infection and prevent spread of disease, limits

treatment only to valuable quarantined animals{R-23; 44}.

[Potomac horse fever (treatment)]1—Horses: Although the efficacy is

not established, rifampin is used in combination with erythromycin

in the treatment of Potomac horse fever (equine ehrlichial coli-

tis){R-56}. It is as effective as oxytetracycline in the resolution of

clinical signs, with the exception that rifampin and erythromycin will

not reduce fever as quickly as oxytetracycline, taking up to 12 hours

longer to return the body temperature to normal{R-56}. Rifampin and

erythromycin have the advantage of being available in oral dosage

forms.

UNACCEPTED[Mycobacterial infections (treatment)]1—Current therapeutic regimens

for mycobacterial infections cannot guarantee that an animal is no

longer contagious during treatment. Treatment of Mycobacterium

tuberculosis, Mycobacterium bovis, and other mycobacterial species

transmissible to human beings is nearly always considered inappro-

priate{R-45; 47}. The treatment of tuberculosis in cattle is not permitted

in Canada or the U.S.{R-64}. The treatment of mycobacterial infections

that do not cause human tuberculosis, such as atypical mycobacterial

infections in cats, may be acceptable{R-45–48} although there is

insufficient evidence of efficacy at this time.


Rifampin is not labeled in the United States or Canada for use in

animals, including food-producing animals. There are no established

withdrawal times.

The treatment of tuberculosis in cattle is not permitted in Canada or

the U.S.{R-64}

CHEMISTRYSource: Semisynthetic derivative of rifamycin B{R-2}, a natural

fermentation product of Nocardia (Streptomyces) mediterranei{R-4; 6}.

Chemical group: Macrocyclic antibiotic{R-13}.

Chemical name: Rifamycin,3-[[(4-methyl-1-piperazinyl)imino]methyl]-{R-1}.

Molecular formula: C43H58N4O12{R-1}.


Description: Rifampin USP—Red-brown, crystalline powder{R-3}.

pKa: 7.9{R-22}.

Solubility: Rifampin USP—Very slightly soluble in water; freely soluble

in chloroform; soluble in ethyl acetate and in methanol{R-3}.


Mechanism of action/effect: Rifampin inhibits DNA-dependent RNA

polymerase; however, at therapeutic doses, it inhibits the enzyme in

bacteria, while not affecting mammalian polymerase{R-2; 4}. Rifampin

is bactericidal and is active against extracellular organisms as well as

against susceptible intracellular organisms{R-2; 49}, including intra-

leukocytic organisms{R-20}. Rifampin can enter neutrophils and mac-

rophages to kill intracellular bacteria{R-4; 20}, while not interfering

with phagocytosis{R-20}.

Rifampin appears to penetrate the outer membrane of gram-positive

bacteria more easily than that of gram-negative bacteria{R-4}. This is

reflected in the significantly lower minimum inhibitory concentrations

(MIC) required for gram-positive bacteria (0.01 mcg per mL of serum)

compared with gram-negative bacteria (8 to 32 mcg per mL){R-4}.

Absorption: Rifampin is rapidly absorbed after oral administration to

people, calves, dogs, and horses{R-4; 19}, although bioavailability is not

high in horses and sheep. Administration with food can prolong the

time to peak serum concentration in adult horses and people{R-4; 14}.

Adult sheep appear to have prolonged absorption, possibly because of

prolonged movement through the rumen{R-4; 20}.

Bioavailability—

Oral:

Horses—

48.8%, with a single dose of 10 mg per kg of body weight

(mg/kg){R-6}.

39.5%, with a single dose of 10 mg/kg, administered in the feed{R-13}.

Note: An unpublished study of horses receiving a dose of 5 mg/kg

found a bioavailability of 68% when rifampin was administered

1 hour before feeding and 26% when it was administered 1 hour

after feeding{R-15}. Because rifampin is most often administered

with feed, recommended dosages compensate for the decreased

absorption.

Sheep—

36.6 ± 3.2%, with a dose of 10 mg/kg, as an oral drench{R-19}.

3 to 32%, with a dose of 20 mg/kg, in a gel capsule{R-21}.

14 to 122%, with a dose of 50 mg/kg, in a gel capsule{R-21}.

Note: The study performed using gel capsules of rifampin in sheep

found that absorption was incomplete and still continuing by the

end of the study, producing extremely variable results{R-21}.

Absorption was also relatively low and variable with the oral

192 RIFAMPIN Veterinary—Systemic


drench but not to the same extent as with gel capsules; the

medication may have been administered directly into the aboma-

sum and would therefore have been rapidly and consistently

absorbed{R-21}.

Intramuscular—Horses: 59.8 ± 3.2%, with a dose of 10 mg/kg{R-13}.

Distribution: Rifampin is highly lipid-soluble and is widely distributed

in tissues{R-4; 6}. Antimicrobial concentrations are approached in all

tissue compartments throughout the body, including milk{R-22},

bone{R-54}, cerebrospinal fluid{R-18}, exudates, ascitic fluid, and soft

tissues{R-4}. Rifampin crosses the blood-brain barrier{R-6; 18} and, in

rabbits, the cerebrospinal fluid to plasma concentration ratio ranged

from 0.52 to 1.17, from 30 minutes to 12 hours after an oral dose

of 10 mg/kg{R-18}. Rifampin can penetrate phagocytic cells to kill

susceptible intracellular bacteria{R-6; 7; 20}. In many species, as has

been documented in dogs and human beings, feces, saliva, sweat,

tears, and urine may be discolored red-orange by rifampin and its

metabolites{R-4}.


Horses:

Area—0.93 ± 0.29 liter per kg (L/kg){R-7}; 0.63 ± 0.06 L/kg{R-13}.

Steady state—0.76 L/kg{R-6}.

Sheep: Steady state—0.45 ± 0.06 L/kg{R-21}.

Protein binding:

Horses—High (78%), with serum concentrations of 2 to 20 micrograms

per milliliter (mcg/mL){R-6}.

Human beings—High (80%){R-4}.

Sheep—High (84%){R-22}.

Biotransformation:

The biotransformation and elimination of rifampin in animals is not well

defined. Induction of hepatic enzymes occurs in response to admin-

istration of rifampin in many species{R-17; 25; 26}, but major metab-

olites of the parent drug in most animals have not yet been traced{R-6;

21}. In human studies, it was found that the primary metabolite of

rifampin is 25-desacetylrifampin, which is bioactive{R-4}. Human

desacetylrifampin is more profusely secreted in the bile compared with

rifampin, but is less concentrated in the serum than the parent drug{R-4}.

And while rifampin undergoes extensive human enterohepatic

recycling, desacetylrifampin is poorly absorbed and therefore is not

recycled{R-6}.

Horses—Desacetylrifampin was not detected in serum samples after

an intravenous dose of 10 mg/kg or oral doses of 10 mg/kg every

12 hours for seven doses{R-6}. The metabolite was measured in

urine, but the parent compound was much more predominant{R-6};

however, only 6.82% of the total dose was recovered in the urine as

either rifampin or desacetylrifampin{R-6}.

Rats—Desacetylrifampin is formed in extremely low quantities in

rats{R-25}.

Sheep—Desacetylrifampin was not found in serum samples from sheep

administered either intravenous or oral rifampin{R-21}. Rifampin and

metabolites have not been measured in sheep urine.

Rifampin can induce hepatic enzymes, including increasing its own

hepatic biotransformation with multiple doses{R-17; 25}. Induction has

been shown to occur in many species, including dogs{R-27}, horses{R-

17}, pigs{R-30}, and rabbits{R-28; 29}. The dose needed to induce an

increase in hepatic enzymes varies among species. Rats administered

50 mg/kg intraperitoneally every 12 hours for 6 days did not show

induction of liver microsomal enzyme activity against substances

tested{R-26}, but mice administered the same dose showed significant

induction of the hepatic mixed-function oxidase system and enzymatic

activity{R-26}. In horses, enzyme induction has generally not been seen

with less than 5 days of therapy, but once there is an increase in

hepatic enzyme activity, the increase may last for more than 2 weeks

after discontinuation of treatment{R-17}. However; several factors may

modify the therapeutic levels of rifampin, such as the variability in its

absorption in horses when given alone, and the possible change in

pharmacokinetics due to interactions with other medications that

often are administered with rifampin; data are insufficient for

determining whether the increased elimination of rifampin due to

hepatic enzyme induction during prolonged dosing may be corrected

for by a dose modification.

Half-life:

Absorption—

Intramuscular administration: Horses—6.7 ± 1.5 hours, with a dose of

10 mg/kg{R-13}.

Oral, with food: Horses—

4.2 ± 1.2 hours, with a dose of 10 mg/kg{R-13}.

2.6 ± 1.3 hours, with a dose of 25 mg/kg{R-13}.

Distribution—Intravenous: Horses—13.8 ± 5.2 minutes, with a dose of

10 mg/kg{R-13}.

Elimination—

Intravenous:

Horses—8.1 hours{R-6}; 7.3 hours{R-7}; 6 hours{R-13}.

Sheep—

Nonlactating: 2.9 hours{R-19}; 4.56 hours{R-21}.

Lactating: 3.3 hours{R-22}.

Intramuscular (terminal elimination)—

Horses: 7.3 hours, with a dose of 10 mg/kg{R-13}.

Sheep: 11 hours, with a dose of 20 mg/kg{R-22}.

Oral (terminal elimination)—

Single dose:

Dogs—8 hours, with a dose of 10 mg/kg{R-4; 65}.

Foals—

1 week of age: 25.4 ± 1.2 hours, with a dose of 10 mg/

kg{R-14}.

10 weeks of age: 7.9 ± 1.5 hours, with a dose of 10 mg/

kg{R-14}.

Horses—13.3 hours, with a dose of 10 mg/kg{R-6}.

Sheep—6.42 hours, with a dose of 20 mg/kg{R-21}.

Multiple doses: Horses—7.99 hours, after the seventh dose of 10 mg/

kg, administered every 12 hours{R-6}.

Note: Multiple doses result in lower peak serum concentrations and a

decreased half-life, because of autoinduction of hepatic enzymes{R-4}.

Concentrations:

Time to peak concentration—



Sheep—3 hours, with a dose of 20 mg/kg{R-22}.

Oral:

Calves, 2 to 3 weeks of age—4 to 8 hours, with a dose of 10 mg/kg{R-

19}.



Dogs—2 to 4 hours, with a dose of 10 mg/kg{R-4; 65}.

Foals, 6 to 8 weeks of age—4 hours, with a dose of 10 mg/kg{R-16}.

Horses—

3 hours{R-6}; 1.6 ± 0.5 hours{R-14}, with a single dose of 10 mg/kg.

3.7 ± 1.2 hours{R-13}; 3.5 ± 1.7 hours{R-14}, with a single dose of

10 mg/kg, administered with food{R-13}.

2.5 hours, with an intragastric dose of 20 mg/kg of oral

suspension{R-7}.

3.5 hours, with a dose of 25 mg/kg, administered with food{R-13}.

Sheep—4 to 8 hours{R-19}; 8 to 24 hours{R-21}.

Peak serum concentration—Autoinduction of hepatic enzymes can cause

multiple doses of rifampin to result in lower peak serum concentrations

than expected, if based on single dose measurements{R-4; 19}.

Intramuscular:

Horses—4 ± 0.3 mcg/mL, with a dose of 10 mg/kg{R-13}.

Sheep—Approximately 8 mcg/mL (from graph), with a dose of

20 mg/kg{R-22}.

Oral:

Calves, 2 to 3 weeks of age—11.7 to 24.6 mcg/mL, with a dose of 10

mg/kg{R-19}.

Dogs—40 mcg/mL, with a dose of 10 mg/kg{R-4; 65}.

Foals, 6 to 8 weeks of age—6.7 mcg/mL, with a dose of 10 mg/

kg{R-16}.

Horses—

3.9 mcg/mL{R-6}; 4.5 ± 1.1 mcg/mL{R-14}, with a dose of 10 mg/kg.

2.9 ± 0.4 mcg/mL{R-13}; 3.3 ± 2.9 mcg/mL{R-14}, with a dose of 10

mg/kg, administered with food.

13.3 ± 2.7 mcg/mL, with intragastric administration of 20 mg/kg

of oral suspension{R-7}.

9.8 ± 1.9 mcg/mL, with a dose of 25 mg/kg, administered with

food{R-13}.

Sheep—

0.6 to 2.4 mcg/mL, with a dose of 10 mg/kg{R-19}.

3.27 ± 1.43, with a dose of 20 mg/kg{R-21}.

Other concentrations—

Cerebrospinal fluid: Rabbits—1.3 to 1.6 mcg/mL from 30 minutes to

12 hours after an oral dose of 10 mg/kg{R-18}.

Serum:

Dogs—9 to 10 mcg/mL, 24 hours after an oral dose of 10 mg/

kg{R-65}.

Horses—

6.86 ± 1.69 mcg/mL, 12 hours after an intragastric dose of 20 mg/

kg of oral suspension{R-7}.

3.83 ± 0.87 mcg/mL, 24 hours after an intragastric dose of 20 mg/

kg of oral suspension{R-7}.

Rabbits—Ranged from 1.8 to 2.5 mcg/mL from 30 minutes to 12

hours after an oral dose of 10 mg/kg{R-18}.

Sheep—0.97 ± 0.61 mcg/mL, 24 hours after an oral dose of 20 mg/

kg in a gelatin capsule{R-21}.

Duration of action: The National Committee for Clinical Laboratory

Standards (NCCLS) in the United States lists minimum inhibitory

concentration (MIC) breakpoints for animal isolates and rifampin as

£ 1 mcg/mL for susceptible organisms and ‡ 4 mcg/mL for resistant

organisms{R-8}.

Dogs: Serum concentration was 9 to 10 mcg/mL 24 hours after a single

oral dose of 10 mg/kg{R-65}.

Horses: Serum concentrations greater than 2 mcg/mL were reached 45

minutes after intragastric rifampin administration of 20 mg/kg and

concentrations were maintained at greater than 3 mcg/mL for at least

24 hours.

Elimination: Horses: Only 6.82% of the intravenous dose of 10 mg/kg

was recovered in the urine as rifampin or desacetylrifampin, an active

metabolite{R-6}. It is not known if the rifampin not recovered is pre-

dominately sequestered in the tissue or perhaps excreted in bile pri-

marily as desacetylrifampin, a more polar and more easily bile-excreted

compound{R-6}.

Total clearance—

Horses: 1.14 mL/min/kg{R-6}; 1.34 mL/min/kg{R-13}.

Sheep: 1.16 ± 0.21 mL/min/kg{R-21}; 5.17 mL/min/kg{R-19}.


SPECIES SENSITIVITYDogs: There is very little information about the effects of rifampin in small

animals; however, there is anecdotal information warning that up to

20% or more of dogs receiving 5 to 10 mg per kg of body weight

(mg/kg) a day will develop increases in hepatic enzymes that may lead

to clinical hepatitis{R-4}. Because one study found peak serum

concentrations in dogs that were four times that of horses after a

standard dose of 10 mg/kg, it has been suggested that the incidence of

side effects in dogs may be due to overdosage{R-4; 65}. Some clinicians

have noted lethargy, bilirubinemia, and bilirubinuria in dogs admin-

istered rifampin, but there is no information on incidence of adverse

effects, dosage administered, pretreatment liver evaluation, or other

factors{R-57}.

TUMORGENICITYStudies in female mice of a strain known to be particularly susceptible to

the spontaneous development of hepatomas have shown that rifampin,

given in doses of 2 to 10 times the maximum human dose (20 mg per

kg of body weight, up to 600 mg every 12 hours) for 1 year, causes a

significant increase in the development of hepatomas. However,

studies in male mice of the same strain, in other strains of male or

female mice, and in rats have not shown that rifampin is tumori-

genic{R-2}.

PREGNANCY/REPRODUCTIONMice and rats: Oral doses of 150 to 250 mg/kg during pregnancy

produced dose-dependent teratogenic effects in offspring, including

cleft palate in the mouse and spina bifida in the rat{R-2}.

Human information: Rifampin has caused postnatal hemorrhage in

the mother and infant when administered during the last

weeks of pregnancy{R-2}. Treatment with vitamin K may be

indicated{R-2}.

LACTATIONSheep: Rifampin is well-distributed into milk, with a milk to serum

concentration ratio of 0.9 to 1.28 in sheep given an intramuscular










medication.

Drugs metabolized by hepatic microsomal enzymes, including:

Ciprofloxacin{R-29} or

Corticosteroids{R-4} or

Digitalis glycosides{R-4} or

Itraconazole{R-30} or

Ketoconazole{R-4} or

Phenobarbital{R-5} or

Phenylbutazone{R-17} or

Warfarin{R-4; 31}

(rifampin causes induction of hepatic enzymes in dogs{R-27},

mice{R-26}, horses{R-5; 17}, pigs{R-30}, and rabbits{R-28; 29}, poten-

tially increasing metabolism{R-5} and thereby decreasing serum

concentrations{R-4} of the above medications; there is some

selectivity in enzyme induction so that not every drug that is

oxidized by the system is affected{R-29}; in guinea pigs and rats,

hepatic metabolism does not appear to be significantly induced by

commonly administered dosages of rifampin{R-26; 27} but can be

by extremely high doses{R-25}; phenobarbital will also increase the

metabolism of rifampin by enzyme induction{R-17})




included in the human monograph Rifampin (Systemic) in USP DI


purposes only and may or may not be applicable to the use of rifampin

in the treatment of animals:

Aminophylline or

Oxtriphylline or

Theophylline

(rifampin may increase metabolism of theophylline, oxtriphylline,

and aminophylline by induction of hepatic microsomal enzymes,

resulting in increased theophylline clearance)

Anesthetics, hydrocarbon inhalation, except isoflurane

(chronic use of hepatic enzyme–inducing agents prior to anesthe-

sia, except isoflurane, may increase anesthetic metabolism, leading

to increased risk of hepatotoxicity)

Anticoagulants, coumarin- or indandione-derivative

(concurrent use with rifampin may enhance the metabolism of

these anticoagulants by induction of hepatic microsomal enzymes,

resulting in a considerable decrease in the activity and effective-

ness of the anticoagulants; prothrombin time determinations may

be required as frequently as once a day; dosage adjustments of

anticoagulants may be required before and after rifampin therapy)

Azole antifungals

(concurrent use may increase the metabolism of the azole

antifungals, lowering their plasma concentrations; depending on

the clinical situation, the dose of an azole antifungal may need to

be increased during concurrent use with rifampin)

Barbiturates


hexobarbital by induction of hepatic microsomal enzymes, result-

ing in lower serum concentrations; there are conflicting data on

rifampin’s effect on phenobarbital; dosage adjustment may be

required)

Beta-adrenergic blocking agents, systemic

(concurrent use of metoprolol or propranolol with rifampin has

resulted in reduced plasma concentrations of these two beta-

adrenergic blocking agents due to enhanced metabolism of hepatic

microsomal enzymes by rifampin; although not documented, other

beta-adrenergic blocking agents may also interact with rifampin)


(concurrent use of bone marrow depressants with rifampin may

increase the leukopenic and/or thrombocytopenic effects; if con-

current use is required, close observation for myelotoxic effects

should be considered)

Chloramphenicol


chloramphenicol by induction of hepatic microsomal enzymes,

resulting in significantly lower serum chloramphenicol concen-

trations; dosage adjustment may be necessary)

Clofazimine

(concurrent use with rifampin has resulted in reduced absorption

of rifampin, delaying its time to peak concentration, and increas-

ing its half-life)

Corticosteroids, glucocorticoid and mineralocorticoid


corticosteroids by induction of hepatic microsomal enzymes,

resulting in a considerable decrease in corticosteroid plasma

concentrations; dosage adjustment may be required; rifampin has

also counteracted endogenous cortisol and produced acute adrenal

insufficiency in patients with Addison’s disease)

Cyclosporine

(rifampin may enhance metabolism of cyclosporine by induction of

hepatic microsomal enzymes and intestinal cytochrome P450

enzymes; dosage adjustment may be required)

Dapsone

(concurrent use with rifampin may decrease the effect of dapsone

because of increased metabolism resulting from stimulation of

hepatic microsomal enzyme activity; dapsone concentrations may

be decreased by half; dapsone dosage adjustments are not required

during concurrent therapy with rifampin for leprosy)

Diazepam

(concurrent use with rifampin may enhance the elimination of

diazepam, resulting in decreased plasma concentrations; whether

this effect applies to other benzodiazepines has not been deter-

mined; dosage adjustment may be necessary)

Disopyramide or

Mexiletine or

Propafenone or

Quinidine or

Tocainide


these antiarrhythmics by induction of hepatic microsomal

enzymes, resulting in significantly lower serum antiarrhythmic

concentrations; serum antiarrhythmic concentrations should be

monitored and dosage adjustment may be necessary)



Estramustine or

Estrogens

(concurrent use of estramustine or estrogens with rifampin may

result in significantly reduced estrogenic effect because of stimu-

lation of estrogen metabolism or reduction in enterohepatic

circulation of estrogens)


(concurrent use of rifampin and other hepatotoxic medications

may increase the potential for hepatotoxicity; patients should be

monitored closely for signs of hepatotoxicity)

Human immunodeficiency virus (HIV) protease inhibitors, such as

Amprenavir or

Indinavir or

Nelfinavir or

Ritonavir or

Saquinavir

(rifampin accelerates the metabolism of protease inhibitors

through induction of hepatic P450 cytochrome oxidases, resulting

in subtherapeutic levels of the protease inhibitors; in addition,

protease inhibitors retard the metabolism of rifampin, resulting in

increased serum levels of rifampin and the likelihood of increased

drug toxicity; concurrent use of HIV protease inhibitors with

rifampin is only recommended under specific circumstances as

outlined by the Centers for Disease Control and Prevention [CDC])

Isoniazid

(concurrent use of isoniazid with rifampin may increase the risk of

hepatotoxicity, especially in patients with preexisting hepatic

function impairment and/or in fast acetylators of isoniazid;

patients should be monitored closely for signs of hepatotoxicity

during the first 3 months of therapy)

Phenytoin

(concurrent use with rifampin may stimulate the hepatic metab-

olism of phenytoin, increasing its elimination and thus counter-

acting its anticonvulsant effects; careful monitoring of serum

hydantoin concentrations and dosage adjustments may be neces-

sary before and after rifampin therapy)

Probenecid

(may compete with rifampin for hepatic uptake when used

concurrently, resulting in increased and more prolonged rifampin

serum concentrations and/or toxicity; however, the effect on

rifampin serum concentrations is inconsistent, and concurrent use

of probenecid to increase rifampin serum concentrations is not

recommended)

Trimethoprim

(concurrent use with rifampin may significantly increase the

elimination and shorten the elimination half-life of trimethoprim)

Verapamil, oral

(rifampin has been found to accelerate the metabolism of oral

doses of verapamil, resulting in a significant decrease in serum

verapamil concentration, and thereby reversing its cardiovascular

effects; concurrent use of intravenous verapamil with rifampin

was found to have only minor effects on verapamil’s clearance and

no significant effect on cardiovascular effects)





Indocyanine green and

Sulfobromophthalein sodium excretion test (BSP)

(in rats, plasma clearances of indocyanine green and sulfobromoph-

thalein sodium were increasingly and significantly delayed after 200

mg per kg of body weight a day was administered for 1 to 7 days{R-25};

the impact of recommended doses, such as 20 mg/kg a day, on these

excretion tests has not been measured)


Alkaline phosphatase{R-57}

(in the dog, mild increases in serum alkaline phosphatase levels are

common and are not considered significant unless accompanied by

elevations in other hepatic enzymes{R-4; 54})



humans, and are included in the human monograph Rifampin

(Systemic) in the USP DI Volume I; these laboratory value alterations


applicable to the use of rifampin in the treatment of animals:


Coombs’ (antiglobulin) tests, direct (may become positive rarely

during rifampin therapy)

Dexamethasone suppression test

(rifampin may prevent the inhibitory action of a standard

dexamethasone dose administered for the overnight suppression

test, rendering the test abnormal; it is recommended that rifampin

therapy be discontinued 15 days before administering the dexa-

methasone suppression test)

Folate determinations, serum and

Vitamin B12 determinations, serum

(therapeutic concentrations of rifampin may interfere with stan-

dard microbiological assays for serum folate and vitamin B12;

alternate methods must be considered when determining serum

folate and vitamin B12 concentrations in patients taking rifampin)

Sulfobromophthalein (BSP) uptake and excretion

(hepatic uptake and excretion of BSP in liver function tests may be

delayed by rifampin, resulting in BSP retention; the BSP test

should be performed prior to the daily dose of rifampin to avoid

false-positive test results)

Urinalyses based on spectrometry or color reaction

(rifampin may interfere with urinalyses that are based on

spectrometry or color reaction due to rifampin’s reddish-orange

to reddish-brown discoloration of urine)








Uric acid, serum









problem exists:


(in dogs, hepatic function impairment may predispose to major side

effects, and the risk should be carefully considered{R-4}; in any species,

dosage adjustments may be necessary with hepatic dysfunction and

avoiding use of rifampin should be considered{R-4; 6})




Hepatic enzyme tests

(particularly in dogs, hepatic enzymes should be monitored during

rifampin therapy)





Foals

Diarrhea, self-limiting{R-34}—often occurs in the first week of

therapy and resolves without treatment{R-34}

Incidence unknown

Dogs

Hepatotoxicity{R-4}

Horses

With intravenous administration (dimethylsulfoxide vehicle)

Allergic reactions, specifically anaphylactoid reactions{R-17};

central nervous system depression, generalized{R-13}; decreased

appetite{R-13}; signs of distress (apprehension, pawing with forefeet,

shifting of weight-bearing from one side to another){R-14}; sudden

defecation{R-14}; weakness or unsteadiness{R-14}

Note: Hemolysis was seen grossly in blood samples of some horses

administered intravenous rifampin at a dose of 10 mg/kg{R-13}.

The signs listed above have been reported with administration of

rifampin in a dimethylsulfoxide vehicle; therefore, it is unclear

whether some effects, such as allergic-like reactions or hemolysis,

were caused by the vehicle or by rifampin{R-78}.


Horses

Sweating, mild to moderate—may occur with parenteral adminis-

tration, more prominent with intravenous administration{R-13; 14}.




included in the human monograph Rifampin (Systemic) in USP DI


purposes only and may or may not be applicable to the use of rifampin

in the treatment of animals:


Gastrointestinal disturbances; reddish-orange to reddish-

brown discoloration of urine, feces, saliva, sputum, sweat,

and tears


Flu-like syndrome (chills; difficult breathing; dizziness; fever; head-

ache; muscle and bone pain; shivering); fungal overgrowth; hyper-

sensitivity

Incidence rare

Blood dyscrasias; hepatitis; hepatitis prodromal symptoms;

interstitial nephritis

Note: Intermittent use of rifampin may increase the chance of a patient

developing the flu-like syndrome, as well as acute hemolysis or renal

failure. These reactions are thought to be immunologically medi-

ated, and intermittent use of the medication should be limited to

those conditions in which its safety and efficacy have been

established.

OVERDOSEFor more information in the case of overdose or unintentional ingestion,




and/or the manufacturer.

The lethal dose for 50% of test animals (LD50) is approximately 885 mg

per kg of body weight (mg/kg) in the mouse, 1720 mg/kg in the rat,

and 2120 mg/kg in the rabbit{R-2}.

CLINICAL EFFECTS OF OVERDOSEIn human beings, overdose can cause mental changes, nausea and

vomiting, angioedema, generalized pruritus, and red-orange discolor-

ation of the mucous membranes, sclera, and skin{R-63}. Signs of

overdose specific to animals are not known.

TREATMENT OF OVERDOSEFrom the human therapeutic literature{R-2; 63}:

To decrease absorption—

Evacuating stomach contents using ipecac syrup or gastric lavage.

Administering an activated charcoal slurry to help adsorb residual

rifampin in the gastrointestinal tract.

Supportive therapy.

CLIENT CONSULTATIONNotify your veterinarian of any medications your animal is already

receiving before treatment or any medications that may be initiated

during treatment with rifampin because drug interactions can occur{R-4}.

It is important to be sure that the animal receives the full course of

treatment prescribed. However, if new signs occur, such as decreased

appetite, depression, diarrhea, or jaundice{R-13; 14; 34}, contact your

veterinarian.

Reddish-orange to reddish-brown discoloration of urine, stools, saliva,

sputum, sweat, and tears may occur as a typical effect of the

medication, but is not harmful{R-63; 64}.



VETERINARY DOSING INFORMATIONThe National Committee for Clinical Laboratory Standards (NCCLS) in

the United States lists minimum inhibitory concentration (MIC)

breakpoints of animal isolates for rifampin as £ 1 mcg/mL for

susceptible organisms and ‡ 4 mcg/mL for resistant organisms{R-8}.

Organisms testing between these values are considered intermediate

and may or may not be inhibited{R-8}.

Specifically for Rhodococcus equi, one study of nine strains found minimum

inhibitory concentrations (MICs) for rifampin to be 0.0078 to 0.0625

mcg/mL{R-10}. In another study, aMIC of less than or equal to 0.25mcg/

mL was found for 18 Rhodococcus equi isolates{R-7}; 83% of these isolates

had an MIC of 0.0625 or less{R-7}.

Other equine organisms have also been found to have MICs of less than

0.25 mcg/mL, including coagulase-positive Staphylococcus species (MIC

of 0.0625 or less), Streptococcus zooepidemicus (MIC of 0.0625 or less),

S. equi (MIC of 0.0625 or less), S. equisimilis (MIC of 0.125 or less), and

Corynebacterium pseudotuberculosis (MIC of 0.0156 or less){R-7}. Gram-

negative organisms have been found to be variably susceptible or

resistant{R-7}. The MICs of 19 Actinobacillus isolates from horses ranged

from 1 to 4 mcg/mL{R-7}.

The possibility of mixed infections involving both gram-positive and

gram-negative organisms should be considered in some situations,

such as young horses with respiratory tract infections{R-7; 36}.

Because nonenteric gram-negative organisms can have variable

susceptibility, susceptibility data should be used to determine the

appropriate therapy{R-7}. The possibility of mixed infections and

the rapid rise of resistance to rifampin make combination therapy

the most logical recourse in many cases{R-7}. Rifampin has been

shown in in vitro tests to have synergistic activity with erythromycin

or trimethoprim and to have an additive effect with ampicillin or

penicillin G{R-7; 9; 10}. However, rifampin’s activity in in vitro tests

can be antagonistic to those of other antimicrobials, such as

gentamicin{R-10}; it is not certain how this interaction might affect

in vivo activity.

FOR ORAL DOSAGE FORMS ONLYAdministration with food reduces the rate of absorption and prolongs the

time to peak concentration in adult horses{R-4}.

ORAL DOSAGE FORMSNote: In other USP DI monographs, bracketed uses in the Dosage Forms




labeling. However, since rifampin is not specifically approved for


indications.

RIFAMPIN CAPSULES USPUsual dose:

[Pneumonia, Rhodococcus equi]1 ; or

[Extrapulmonary infection, Rhodococcus equi]1—Foals: Oral, 5 mg per kg

of body weight every twelve hours in combination with 25 mg of

erythromycin estolate or erythromycin ethylsuccinate per kg of body

weight every six to eight hours{R-34; 36}. Therapy may be continued for

four to nine weeks or until radiographs and complete blood counts are

normal{R-66}.

[Potomac horse fever]1—Horses: Oral, 10 mg per kg of body weight every

twelve hours in combination with 25 mg of erythromycin estolate or

erythromycin ethylsuccinate per kg of body weight every twelve

hours{R-56}.

Note: [Horses]1—Although the safety and efficacy of rifampin have not

been established, an oral dose of 10 mg rifampin per kg of body weight

every twelve hours{R-6; 7} has been used in the treatment of susceptible

bacterial infections, such as staphylococcal infections in horses, based on

pharmacokinetic data. It is usually administered in combination with

another antimicrobial, such as erythromycin or penicillin{R-6; 7}.

[Cattle]1, [goats]1, and [sheep]1—For use in animals not to be used in

food production: Although the safety and efficacy of rifampin have not

been established, an oral dose of 20 mg per kg of body weight every

twenty-four hours has been used in the treatment of susceptible

bacterial infections in cattle{R-23} and sheep{R-19; 20}, based on

pharmacokinetic data. For the treatment of paratuberculosis in cattle,

goats, and sheep, an oral dose of 20 mg per kg of body weight every

twenty-four hours, administered in conjunction with 20 mg of oral

isoniazid per kg of body weight every twenty-four hours, has been used

to control signs, based on case reports{R-23} and the pharmacokinetics

known{R-19; 21}; however, clinical improvement only occurs for a short

period of time and does not prevent spread of the infection to other

animals{R-23; 44}.

[Dogs]1—If rifampin is administered to dogs, dosing of rifampin should

generally be kept below 10 mg per kg of body weight a day, based on

limited pharmacokinetic data and reports of hepatic toxicity in dogs{R-4}.

A single oral dose of 10 mg per kg appears to produce much higher

serum concentrations than the same dose administered to other

species{R-4; 65}, with a possibly increased risk of toxicity. The best dose

for maximum safety and efficacy has not been established.


U.S.—




150 mg (Rx) [Rifadin{R-2}].

300 mg (Rx) [Rifadin{R-2}; Rimactane{R-24}; generic].

Canada—




150 mg (Rx) [Rifadin; Rimactane; Rofact].

300 mg (Rx) [Rifadin; Rimactane; Rofact].

Withdrawal times:

U.S. and Canada—The use of rifampin in food-producing animals has not

been approved by the Food and Drug Administration or the Canadian

Health Protection Branch; therefore, there are no established with-

drawal times.

The issue of whether rifampin should be used in food animals is

complicated by its link to hepatic tumors in one strain of femalemice (see

Tumorgenicity under Precautions in this monograph). The significance of

this link is not known, but any residue of a known carcinogen in animal

products for human consumption is considered a violation of the Food,

Drug, and Cosmetic Act. As such, the USPVeterinaryMedicine Advisory

Panel has concluded that rifampin should not be administered to

animals intended for production of products for human consumption.



Packaging and storage: Store below 40 �C (104 �F), in a tight

container, unless otherwise specified by the manufacturer{R-2; 3}.

Protect from light{R-3}.

Preparation of dosage form: Human product labeling suggests the

preparation of an extemporaneous oral 1% w/v suspension with

preprepared syrups when necessary{R-2}.

USP requirements: Preserve in tight, light-resistant containers, pro-

tected from excessive heat. Contain the labeled amount, within ±10%.

Meet the requirements for Identification, Dissolution (75% in 45 min-

utes in 0.1 N hydrochloric acid in Apparatus 1 at 100 rpm), Uniformity

of dosage units, and Loss on drying (not more than 3.0%){R-3}.

PARENTERAL DOSAGE FORMSNote: In other USP DI monographs, bracketed uses in the Dosage Forms

section refer to categories of use and/or indications that are not included

in U.S. product labeling, and superscript 1 refers to categories of use

and/or indications that are not included in Canadian product labeling.

However, since rifampin is not specifically approved for veterinary use,

there is no product labeling identifying approved indications.

RIFAMPIN FOR INJECTION USPNote: Although parenteral pharmacokinetic studies have been performed

in horses{R-6; 7; 13} and sheep{R-19; 21; 22}, rifampin is generally

administered by the oral route in animals.

See Rifampin Capsules USP; however, also note that oral dosing for

horses is adjusted for poor bioavailability. Use of oral dosing for

parenteral administration of rifampin could result in overdosage.

Parenteral rifampin should be administered only by the intravenous

route, not intramuscularly or subcutaneously.


U.S.—




600 mg (Rx) [Rifadin IV]{R-2}.

Canada—





Withdrawal times:

U.S. and Canada—The use of rifampin in food-producing animals has not

been approved by the Food and Drug Administration or the Canadian

Health Protection Branch; therefore, there are no established with-

drawal times.



otherwise specified by the manufacturer. Protect from light{R-2}.

Preparation of dosage form: Human product labeling recommends

that 600 mg of rifampin powder be reconstituted with 10 mL of sterile

water for injection to produce a 60 mg per mL (mg/mL) solution{R-2}.

Prior to intravenous infusion, the amount calculated for administration

is added to 500 mL or, in some cases, 100 mL of infusion medium and

mixed well before administration{R-3}. Dextrose 5% for Injection is

recommended for infusion medium, but sterile saline may also be used

with a slight reduction in stability{R-2}.

Stability: The reconstituted 60 mg/mL solution is stable for 24 hours at

room temperature{R-2}. Once mixed with infusion medium to produce a

100 mL or 500 mL solution, the product should be administered within

4 hours; precipitation of rifampin may occur after this time{R-2}.


the labeled amount, within –10% to +15%. Meets the requirements for

Identification, Bacterial endotoxins, Sterility, pH (7.8–8.8, in a solution

containing 60 mg of rifampin per mL), Water (not more than 1.0%),

and Particulate matter{R-3}.

Developed: 11/05/99


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2. Rifadin and Rifadin I.V. package insert (Hoechst Marion Roussel, Inc—US),

Rev 2/96, Rec 2/4/97.


(January 1, 2003). NF 21st ed (January 1, 2003). Rockville, Maryland: The

United States Pharmacopeial Convention, Inc.; 2002. p. 1640–2, 2579.

4. Frank LA. Clinical pharmacology of rifampin. J Am Vet Med Assoc 1990 Jul 1;

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5. Burrows GE, MacAllister CG, Tripp P, et al. Interactions between chloram-

phenicol, acepromazine, phenylbutazone, rifampin, and thiamylal in the horse.

Equine Vet J 1989; 21(1): 34–8.

6. Kohn CW, Sams R, Kowalske JJ, et al. Pharmacokinetics of single intravenous

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9. Kerry DW, Hamilton-Miller JMT, Brumfitt W. Trimethoprim and rifampicin:

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1975; 1: 417–27.

10. Prescott JF, Nicholson VM. The effects of combinations of selected antibiotics

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14. Burrows GE, MacAllister CG, Ewing P, et al. Rifampin disposition in the horse:

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17. Burrows GE, MacAllister CG, Ewing P, et al. Rifampin disposition in the horse:

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50. Guitierrez CB, Piriz S, Vadillo S, et al. In vitro susceptibility of Actinobacillus

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28: 463–7.






SPECTINOMYCIN Veterinary—Systemic


Adspec Sterile Solution; AmTech Spectam Scour-Halt; Bovispec Sterile

Solution; Spectam; Spectam Injectable; Spectam Oral Solution; Spectam

Scour-Halt; Spectam Soluble Powder; and Spectam Water Soluble.



CATEGORY:Antimicrobial (systemic).

INDICATIONS:Note: Bracketed information in the Indications section refers to uses that



GENERAL CONSIDERATIONSSpectinomycin is an antibiotic that is active against a variety of

aerobic gram-negative and gram-positive organisms{R-3; 4} as well

as Mycoplasma species{R-7}. Spectinomycin is used clinically,

primarily for its activity against gram-negative organisms; some

gram-positive organisms may also be susceptible to this agent. It

has in vitro and in vivo activity against Mannheimia (Pasteurella)

haemolytica, Pasteurella multocida, and Haemophilus somnus{R-25}.

Anaerobic organisms are generally resistant{R-7}. Spectinomycin is

usually bacteriostatic at therapeutic doses{R-5}. As an aminocyclitol

antibiotic, spectinomycin is structurally and functionally similar to

the aminoglycoside antibiotics, which are also aminocyclitols.

Spectinomycin lacks the toxic effects of the aminoglycoside antibi-

otics; however, its use is limited by the ready development of

bacterial resistance{R-5}.

ACCEPTEDAir sacculitis (treatment)1—Turkey poults, 1- to 3-day-old: Spectinomycin

hydrochloride injection is indicated to aid in the control of air sacculitis

associated with Mycoplasma meleagridis sensitive to spectinomycin{R-17}.

Chronic respiratory disease (CRD) (prophylaxis)—Chickens, broiler:

Spectinomycin powder for oral solution is indicated to aid in the

prevention of mortality due to CRD associated with susceptible

Mycoplasma gallisepticum{R-2; 18}.

Chronic respiratory disease (CRD) (treatment)—

Turkey poults, 1- to 3-day-old1: Spectinomycin hydrochloride injection

is indicated to aid in the control of CRD associated with Escherichia

coli{R-17}.

Chickens, broiler: Spectinomycin powder for oral solution is indicated to

aid in the control of mortality due to CRD associated with susceptible

Mycoplasma gallisepticum{R-2; 18}.

Colibacillosis (treatment)1—Chicks, newly hatched: Spectinomycin

hydrochloride injection is indicated in the control of mortality and to

lessen severity of infections caused by E. coli{R-17}.

Enteritis, bacterial (treatment)—Piglets: Spectinomycin oral solution is

indicated in the treatment of bacterial enteritis (white scours)

associated with E. coli in piglets younger than 4 weeks of age{R-3; 4}.

Paratyphoid (treatment)1—Chicks, newly hatched: Spectinomycin hydro-

chloride injection is indicated in the control of mortality and to lessen

severity of infections caused by Salmonella typhimurium{R-17}.

Pneumonia, bacterial (treatment)—Cattle: Spectinomycin sulfate injec-

tion is indicated in the treatment of pneumonia (bovine respiratory

disease) associated with M. haemolytica, P. multocida, and H. somnus in

cattle{R-21; 25}.

Salmonella infantis infection (treatment)1—Chicks, newly hatched: Spec-

tinomycin hydrochloride injection is indicated in the control of

mortality and to lessen severity of infections caused by S. infantis{R-17};

however, S. infantis is not considered to be a major pathogen in the

poultry industry.

Synovitis (prophylaxis)—Chickens, broiler: Spectinomycin powder for oral

solution is indicated to aid in the prevention of mortality associated

with infectious synovitis due to susceptible Mycoplasma synoviae{R-2;

18}.

Synovitis (treatment)—

Chickens, broiler1: Spectinomycin powder for oral solution is indicated

to aid in the control of mortality associated with infectious synovitis

due to susceptible M. synoviae{R-18}.

Chicks, newly hatched1: Spectinomycin hydrochloride injection is

indicated in the control of mortality and to lessen severity of

infections caused by susceptible M. synoviae{R-17}.

[Fowl cholera (treatment)]—Turkeys: Spectinomycin hydrochloride injec-

tion is indicated to reduce mortality due to fowl cholera caused by

sensitive strains of Pasteurella multocida{R-1}.

ACCEPTANCE NOT ESTABLISHEDColibacillosis (treatment)1—[Ducklings]: There are insufficient data to

establish the safety and efficacy of spectinomycin in the treatment of

colibacillosis in ducklings; however, in one study, subcutaneous admin-

istration of spectinomycin reduced the mortality and improved weight

gain in 1-day-old ducklings experimentally infected with E. coli{R-10}.

Infections, bacterial (treatment), including

Respiratory tract infections (treatment)—[Pigs]1: There are insufficient

data to establish the safety and efficacy of spectinomycin injection in

the treatment of respiratory infections and systemic infections due to

susceptible organisms in pigs; however, the parenteral administra-

tion of spectinomycin to pigs has been used in clinical practice to

treat these infections{R-5}.


Spectinomycin oral solution is labeled for use in piglets younger than 4

weeks of age or weighing < 6.8 kg{R-3; 4}.

Spectinomycin injection is labeled for use only in newly hatched chicks

and in 1- to 3-day-old turkey poults{R-17}.

Spectinomycin is not labeled for use in birds producing eggs for human

consumption{R-18}.

Withdrawal times have been established for the use of spectinomy-

cin in newly hatched chicks{R-17}, broiler chickens{R-18}, 1- to



202 SPECTINOMYCIN Veterinary—Systemic


3-day-old turkey poults{R-17}, and piglets{R-4}(see the Dosage Forms

section).

Canada—

Spectinomycin is not labeled for use in birds producing eggs for human

consumption{R-1}.

Spectinomycin injection is not labeled for use in turkeys weighing

< 0.5 kg{R-1}.

Withdrawal times have been established for the use of spectinomycin

in broiler chickens{R-2}, piglets{R-3}, and turkeys{R-1}(see the Dosage

Forms section).

CHEMISTRYSource: Spectinomycin is a product of Streptomyces spectabilis{R-5; 25}.

Chemical group: Aminocyclitol{R-5}.

Chemical name:

Spectinomycin hydrochloride—4H-Pyrano[2,3-b][1,4]benzodioxin-4-one,

decahydro-4a,7,9-trihydroxy-2-methyl-6,8-bis(methylamino)-, dihy-

drochloride, pentahydrate{R-6}.

Spectinomycin sulfate tetrahydrate—Decahydro-4a,7,9-trihydroxy-

2-methyl-6,8-bis(methylamino)-4H-pyrano[2,3-b][1,4]benzodioxin-

4-one sulfate, tetrahydrate{R-25}.

Molecular formula: Spectinomycin hydrochloride—C14H24N2O7 Æ

2HCl Æ 5H2O{R-6}.

Molecular weight: Spectinomycin hydrochloride—495.35{R-6}.

Description: Spectinomycin Hydrochloride USP—White to pale-buff

crystalline powder{R-16}.

pKa: 6.95 and 8.70{R-23}.

Solubility: Spectinomycin Hydrochloride USP—Freely soluble in

water; practically insoluble in alcohol, in chloroform, and in

ether{R-16}.

PHARMACOLOGY/PHARMACOKINETICSNote: Unless otherwise noted, pharmacokinetic data in this section are

based on a single intravenous injection of spectinomycin.

The pharmacokinetics and detection of spectinomycin do not appear to

be influenced by administration in combination with lincomycin{R-7};

some of the pharmacokinetic data in this section are derived from

studies in which lincomycin and spectinomycin were administered

concomitantly{R-7}.

Mechanism of action/effect: Spectinomycin binds to the 30S ribo-

somal subunit of the microorganism and inhibits protein synthesis by

preventing elongation of the polypeptide chain at the translocation

step{R-5}.

Absorption: Spectinomycin is only slightly absorbed from the gas-

trointestinal tract{R-7}; however, it is rapidly absorbed following

intramuscular administration{R-7}. In cattle, spectinomycin is com-

pletely bioavailable following intramuscular administration{R-7}.

Repeated administration in cattle does not appear to result in tis-

sue concentrations higher than those achieved with a single

dose{R-7}.

Distribution: Twelve hours following intramuscular administration

and 24 hours following oral administration, concentrations of specti-

nomycin are found in the following swine tissues in decreasing con-

centrations: kidney, liver, lung, muscle, and fat{R-7}. An identical

profile is seen in cattle 24 and 72 hours following intramuscular

administration of spectinomycin{R-7}. Tissue/serum ratios of spectino-

mycin usually do not exceed 0.25 to 0.5 and are much lower in brain,

aqueous humor, and bone{R-22}.

Volume of distribution (VolD):

Cows—0.295 Liter per kg (L/kg){R-13}.

Ewes—0.307 L/kg{R-13}.

Protein binding: Cows—Low (approximately 10%){R-13}.

Biotransformation: Spectinomycin does not appear to undergo any

significant metabolism. In swine, it is excreted unchanged in the urine

following intramuscular administration{R-7}.


Cows: 1.01{R-13} to 1.2 hours{R-7}.

Ewes: 1.01 hours{R-13}.

Pigs: 0.98 hour{R-7}.

Peak serum concentration/Time to peak serum concentration:

Calves, preruminating—20 mcg/mL between 0.33 and 0.67 hours

following an intramuscular dose of 10 mg/mL{R-7}.

Cows—Approximately 55 micrograms per mL (mcg/mL) at 1 hour

following an intramuscular dose of 20 mg per kg of body weight

(mg/kg){R-13}.

Dogs—

Intramuscular: 78 mcg/mL 40 minutes following an intramuscular

dose of 40 mg/kg.

Oral{R-7}:

22 mcg/mL approximately 4 hours following a dose of

100 mg/kg.

80 mcg/mL approximately 4 hours following a dose of 500 mg/kg.

Ewes—Approximately 53 mcg/mL at 1 hour following an intramuscular


Elimination:

Following intramuscular administration—Spectinomycin is rapidly

absorbed, then quickly eliminated from plasma and tissues

through renal excretion{R-7}. Because of this rapid excretion, drug

accumulation is not observed following repeated administra-

tion{R-7}. Renal impairment may cause accumulation of the active

drug{R-22}.

Following oral administration—Because spectinomycin is poorly

absorbed from the gastrointestinal tract, it is excreted mostly in the

feces{R-7}.


LACTATIONCows: In one experimental study, the milk-to-serum ratio of spectino-

mycin concentrations ranged from 0.44 to 1.12 in mastitic cows

receiving one intramuscular dose of 20 mg per kg of body weight (mg/

kg), followed by three intramuscular doses of 10 mg/kg at hourly

intervals{R-13}. Spectinomycin levels in milk from dairy cows receiving

an intramuscular dose of 20 mg/kg two times a day for 3 consecutive

days were below 0.2 mcg/mL at the fifth milking after the last

injection{R-7}. No residues of spectinomycin were detectable at the

seventh milking{R-7}.

SPECTINOMYCIN Veterinary—Systemic 203





inclusive:


All species

Anaphylactic reactions{R-25}; neuromuscular blockade{R-5}

THOSE INDICATING NEED FOR MEDICAL ATTENTIONONLY IF THEY CONTINUE OR ARE BOTHERSOMEIncidence unknown

Cattle

Discoloration of tissue at the injection site;{R-25} swelling at the

injection site, mild{R-25}




included in the human monograph Spectinomycin (Systemic) in USP DI



spectinomycin in the treatment of animals:

Incidence rare

Dizziness; gastrointestinal disturbance; hypersensitivity; pain

at site of injection






Cattle: When cattle were administered 150 mg per kg a day (10 times

the labeled dose) for 5 days, the effects seen at the end of the

treatment period included increased relative kidney weights{R-25}.

Urinalysis was performed only on steers. Urinary pH was decreased

and squamous and transitional cells were found in the urine{R-25}

CLINICAL EFFECTS OF OVERDOSENote: The following effects have been selected on the basis of their


appropriate)—not necessarily inclusive (» = major clinical signifi-

cance):

Acute effects—

Turkey poults{R-1}

Ataxia{R-1}; coma{R-1}

Note: Clinical signs of ataxia and coma following a single, subcuta-

neous dose of 90 mg per poult were transient, resolving after 4

hours{R-1}; a single, subcutaneous injection of up to 50 mg per

poult caused no detectable ill effects{R-1}.


SAFETY CONSIDERATIONSSome individuals who handle spectinomycin develop serious reactions

involving skin, nails, and eyes{R-1; 9}. Individuals who have experi-

enced a rash or other evidence of allergic reaction should avoid further

contact with spectinomycin{R-2}.


expressed in terms of spectinomycin base (not the hydrochloride salt).

SPECTINOMYCIN HYDROCHLORIDE ORAL SOLUTIONUsual dose: Enteritis, bacterial—Piglets, younger than 4 weeks of age:

For piglets weighing < 4.5 kg—Oral, 50 mg (base) as a total dose per

animal two times a day for three to five days{R-3; 4}.

For piglets weighing 4.5 kg to 6.8 kg—Oral, 100 mg (base) as a total

dose per animal two times a day for three to five days{R-3; 4}.

Note: If improvement is not seen within forty-eight hours of initiating

treatment, the diagnosis or choice of therapy should be reconsidered{R-

3; 4}.


U.S.—

For veterinary-labeled product(s):

50 mg (base) per mL (OTC) [AmTech Spectam Scour-Halt; Spectam

Scour-Halt].

Canada—

For veterinary-labeled product(s):

50 mg (base) per mL (OTC) [SpectamOral Solution; Spectam Scour-Halt].

Withdrawal times:

U.S. and Canada{R-3; 4; 19}—

Withdrawal time

Species Meat (days)

Pigs 21

Note: The above withdrawal time applies when medication is administered

at a total dose of 50 mg (base) two times a day for piglets weighing less

than 4.5 kg or 100 mg (base) two times a day for piglets weighing 4.5 kg

to 6.8 kg, for a maximum duration of five days{R-3; 4}.

Packaging and storage: Store below 23 �C (73 �F). Do not freeze{R-3; 4}.

Auxiliary labeling: When not in use, the plastic doser should be

removed and the original cap replaced on bottle{R-3; 4}. The plastic

doser should be rinsed with water after each use.


SPECTINOMYCIN HYDROCHLORIDE POWDER FORORAL SOLUTION

Usual dose:

Chronic respiratory disease (prophylaxis and treatment)—Chickens,

broiler: Oral, administered as the sole source of drinking water at a



concentration of 0.5 mg (base) per mL (2 grams [base] per gallon) of

water for the first three days of life and for one day following each

vaccination{R-2; 18; 24}.

Synovitis (prophylaxis and treatment1)—Chickens, broiler: Oral, admin-

istered as the sole source of drinking water at a concentration of 0.26

mg (base) per mL (1 gram [base] per gallon) of water for the first three

to five days of life{R-18; 24}.

Note: Canadian labeling lists a dose of 0.5 mg (base) per mL (2 grams

[base] per gallon) of water for this indication{R-2}.


U.S.—


500 mg (base) per gram of water-soluble powder (OTC) [Spectam

Water Soluble].

Canada—


500 mg (base) per gram of water-soluble powder (OTC) [Spectam

Soluble Powder].

Withdrawal times:

U.S. and Canada{R-2; 18; 24}—

Withdrawal time

Species Meat (days)

Chickens 5

Note: The above withdrawal time applies when medication is adminis-

tered in the drinking water up to a maximum concentration of 0.5 mg

(base) per mL for up to a maximum duration of 5 days{R-2; 18}.

Products are not labeled for use in poultry laying eggs for human

consumption{R-24}.



manufacturer.

Preparation of dosage form: Water-soluble powder should be mixed

with drinking water according to the manufacturer’s directions.






in terms of spectinomycin base (not the hydrochloride or sulfate salt).

SPECTINOMYCIN HYDROCHLORIDE INJECTIONUsual dose:

Air sacculitis (treatment)1—Turkey poults, 1- to 3-day-old: Subcuta-

neous in cervical area, 10 mg (base) as a single, total dose per

poult{R-17}.

Chronic respiratory disease (treatment)1—Turkey poults, 1- to 3-day-

old: Subcutaneous in cervical area, 5 mg (base) as a single, total dose

per poult{R-17}. Dilution with sterile physiologic saline is recom-

mended to facilitate accurate dosing{R-17}.

Colibacillosis (treatment)1;

Paratyphoid (treatment)1;

Salmonella infantis infection (treatment)1; or

Synovitis (treatment)1—Chicks, newly hatched: Subcutaneous in

cervical area, 2.5 to 5 mg (base) as a single, total dose per chick{R-17}.

Dilution with sterile physiologic saline is recommended so that the total

volume administered is 0.2 mL{R-17}.

[Fowl cholera (treatment)]—Turkeys: Subcutaneous in dorsal cervical

area, 11 to 22 mg (base) per kg of body weight as a single injection.

The entire flock should be treated as soon as symptoms of fowl

cholera are observed{R-1}. Treatment must not be repeated within

five days of the initial treatment{R-1}.

Note: [Ducklings]1—For use in animals not to be used in food production:

Although there are insufficient data to establish safety and efficacy, a

single, subcutaneous, total dose of 5 mg (base) per duckling has been

shown to reduce mortality and improve weight gain in one-day-old

ducklings experimentally infected with E. coli{R-10}.

[Pigs]1—Although there are insufficient data to establish safety and

efficacy, the intramuscular administration of spectinomycin to pigs,

at doses ranging from 6.6 to 22 mg (base) per kg of body weight

every twelve to twenty-four hours{R-11}, has been used in clinical

practice to treat respiratory infections and systemic infections caused by

organisms sensitive to spectinomycin{R-5}.


U.S.—


100 mg (base) per mL (OTC) [GENERIC]{R-17}.

Canada—


100 mg (base) per mL (OTC) [Spectam; Spectam Injectable]{R-1}.

Withdrawal times:

Note: Pigs—Because injectable spectinomycin is not labeled for use in pigs,

there are no established withdrawal times in the U.S. or Canada. If

spectinomycin is administered intramuscularly at a dose of 20 mg per kg

of body weight, evidence has been compiled by the Food Animal Residue

Avoidance Databank (FARAD) that suggests a meat withdrawal time of

thirty days would be sufficient to avoid violative residues{R-7; 14}.

U.S.{R-17}—

Withdrawal time

Species Meat (days)

Chicks, newly hatched 0

Turkey poults, 1- to 3-day-old 0


tered up to a maximum dose of 5 mg per animal in chicks and 10 mg

per animal in turkey poults as a single injection{R-17}.

Canada{R-1}—

Withdrawal time

Species Meat (days)

Turkeys 5



SPECTINOMYCIN Veterinary—Systemic 205



tered up to a maximum dose of 22 mg per kg of body weight as a single

injection.{R-1}


Dilution with sterile physiologic saline according to product labeling is

recommended when administering total doses <5 mg and is appropri-

ate when large flocks are being treated{R-17}. Aseptic technique must be

employed and unused diluted solution should be discarded{R-17}.



manufacturer. Protect from freezing{R-17}.

Auxiliary labeling: Injection site should be disinfected prior to injection

and precautions should be taken to prevent contamination of the

contents of the bottle{R-1; 17}.


SPECTINOMYCIN SULFATE INJECTIONUsual dose: Pneumonia—Cattle:Subcutaneous, 10 to 15 mg (base) per kg

of body weight every twenty-four hours for three to five days{R-25}.

Note: It is recommended that this medication be administered

subcutaneously in the neck and that not more than 50 mL be given

per site{R-25}.

Strength(s) usually available{R-21; 22; 25}:

U.S.—


100 mg (base) per mL (Rx) [Adspec Sterile Solution; Bovispec Sterile

Solution].

Canada—


100 mg (base) per mL (Rx) [Adspec Sterile Solution].

Withdrawal times:

U.S.—

Withdrawal time

Species Meat (days)

Cattle 11

Note: Product labeling listing the above withdrawal time states that

withdrawal times have not been established for preruminating calves

or for lactating dairy cattle and that it should not be used in female

dairy cattle 20 months of age or older or in calves to be procesed for

veal{R-25}.

Discoloration of tissue at the injection site may last more than 11 days,

making it necessary to trim the site and surrounding tissue at

slaughter{R-25}.

Canada{R-21}—

Withdrawal time

Species Meat(days)

Cattle 11


applies to a dosage of 10 mg per kg of body weight every twenty-four

hours for three to five days.

Package and storage: Store at 20 to 25 �C (68 to 77 �F), unless

otherwise specified by the manufacturer{R-25}. Protect from freezing.


Developed: 07/08/98

Interim revision: 10/15/99; 09/30/02; 04/05/03

REFERENCES1. Spectam Injectable package insert (Vetoquinol—Canada). In: Arrioja-Dechert

A, editor. Compendium of veterinary products, CD ed. Port Huron, MI: North


2. Spectam Soluble Powder package insert (Vetoquinol—Canada). In: Arrioja-

Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI:

North American Compendiums, Inc. 2002.

3. Spectam Scour-Halt package insert (Vetoquinol—Canada). In: Arrioja-Dechert



4. Spectam Scour Halt package labeling (Agrilabs/Durvet—US). In: Arrioja-

Dechert A, editor. Compendium of veterinary products, CD ed. Port Huron, MI:

North American Compendiums, Inc. 2002.


Ames, IA: Iowa State University Press; 1993. p. 174–8.

6. USP Dictionary of USAN and international drug names, 2002 ed. Rockville,

MD: The United States Pharmacopeial Convention, Inc; 2002.

7. Cuerpo L, Livingston RC. Spectinomycin. In: Residues of some veterinary drugs

in animals and foods. Monographs prepared by the forty-second meeting of the

joint FAO/WHO expert committee on food additives. FAO Food Nutr Pap 1994;

41(6): 1–86.

8. Genetzky R, Zeman D, Miskimins D, et al. Intravenous spectinomycin-

associated deaths in feedlot cattle. J Vet Diagn Invest 1994; 5: 266–9.

9. Monte AD, Laffi G, Mancini G. Occupational contact dermatitis due to

spectinomycin. Contact Dermatitis 1994; 31: 204–5.

10. Freed M, Clarke JP, Bowersock TL, et al. Effect of spectinomycin on Escherichia

coli infection in 1-day-old ducklings. Avian Dis 1993; 37: 763–6.

11. Panel comment, Rec 2/97.

12. Hjerpe CA. The bovine respiratory disease complex. In: Howard JL, editor.

Current veterinary therapy 3: food animal practice. Philadelphia: WB

Saunders; 1993. p. 653–64.

13. Ziv G, Sulman FG. Serum and milk concentrations of spectinomycin and

tylosin in cows and ewes. Am J Vet Res 1973; 34: 329–33.

14. Food Animal Residue Avoidance Databank recommendations. Personal

communications, J. E. Riviere, Prof Vet Pharmacol, N.C. State Univ. School

of Vet. Med., 6/12/96.





States Pharmacopeial Convention, Inc; 2002.

17. Spectinomycin Injectable package labeling (Durvet—US). In: Arrioja-Dechert



18. Spectam Water Soluble Concentrate package labeling (Rhone Merieux—US),

Rec 6/20/96.

19. Spectam Scour-Halt package labeling (Rhone Merieux—US), Rec 6/20/96.

20. Jenkins WL. Clinical pharmacology of antibacterials used in bacterial

bronchopneumonia in cattle. Mod Vet Pract 1985; 66: 264–8.

21. Adspec Sterile Solution product information (Pharmacia Animal Health—

Canada). Downloaded from www.pharmaciaah.ca on 2/19/03.



23. O’Neil MJ, editor. The Merck index. An encyclopedia of chemicals, drugs, and

biologicals. 13th ed. Whitehouse Station, NJ: Merck & Co., Inc; 2001. p. 1558.

24. Spectinomycin Water Soluble (Bimeda—US). In: Arrioja-Dechert A, editor.

Compendium of veterinary products, CD ed. Port Huron, MI: North American

Compendiums, Inc. 2002.

25. Adspec Sterile Solution package insert (Pharmacia Animal Health—US), Rev

8/00. Downloaded from www.pharmaciaah.com on 8/13/02.





SULFONAMIDES Veterinary—Systemic

This monograph includes information on the following:

Sulfachlorpyridazine�, Sulfadimethoxine, Sulfamethazine, Sulfanil-

amide*, Sulfaquinoxaline, Sulfathiazole*.



CATEGORY:Antibacterial (systemic); antiprotozoal.




GENERAL CONSIDERATIONSSulfonamides are broad-spectrum antimicrobials inhibiting both gram-

positive and gram-negative bacteria, as well as some protozoa, such

as coccidia.{R-17; 18} They are considered ineffective against most

obligate anaerobes{R-86; 90; 93} and should not be used to treat

serious anaerobic infections. However, they may affect aerobic

organisms that contribute to the lowered oxygen tension in the

microenvironment and, as such, they may be useful in certain

diseases involving Fusobacteria, although the organism itself is often

resistant. The activity of sulfonamides is very sensitive to environ-

ment, and this limitation affects the activity of sulfonamides in

particular fluids and tissues, such as purulent material, as well as the

ability of laboratories to standardize minimum inhibitory concentra-

tions (MIC) of sulfonamides necessary in vivo to inhibit specific

cultured bacteria.{R-17}

Resistance of animal pathogens to sulfonamides is widespread as a result

of more than 50 years of therapeutic use{R-17; 19} and this limits their

effectiveness; however, sulfonamides are still widely used in combina-

tion with other medications, as in the case of the potentiated

sulfonamides. They are also utilized in herd management of disease

and some individual animal applications. Cross-resistance between

sulfonamides is considered complete.{R-17}

ACCEPTEDCoccidiosis (treatment)—Resistance to sulfonamides by coccidia has been

reported in several species, including cattle, chickens{R-22}, and

sheep{R-106}. It also should be noted that sulfonamides aid in reducing

the number of oocysts shed, but they may not alter the clinical course

of a susceptible coccidial infection{R-106}.

Calves and cattle: Sulfamethazine extended-release tablets{R-11} are

indicated in the treatment of Eimeria bovis and Eimeria zuernii.

Sulfaquinoxaline1{R-14} is indicated in the control and treatment of

susceptible E. bovis and E. zuernii.

Chickens: Sulfadimethoxine oral solution1{R-2} and powder for oral

solution1{R-4} are indicated in the treatment of outbreaks of

coccidiosis caused by susceptible coccidia. Sulfamethazine oral

solution{R-12} and powder for oral solution1{R-9} are indicated in

the control of susceptible Eimeria necatrix and Eimeria tenella.

Sulfaquinoxaline{R-14} is indicated in the control of outbreaks of

coccidiosis caused by susceptible Eimeria acervulina, Eimeria brunetti,

Eimeria maxima, E. necatrix, and E. tenella.

Dogs: Sulfadimethoxine injection{R-3}, oral suspension, and tablets{R-6}

are indicated in the treatment of enteritis associated with coccidiosis


Turkeys: Sulfadimethoxine oral solution1{R-2} and powder for oral

solution1{R-4} are indicated in the treatment of outbreaks of

coccidiosis caused by susceptible coccidia. Sulfamethazine oral

solution{R-12} and powder for oral solution1{R-9} are indicated in

the control of susceptible Eimeria adenoeides and Eimeria melea-

grimitis. Sulfaquinoxaline{R-14} is indicated in the control of

outbreaks of susceptible E. adenoeides and E. meleagrimitis.{R-14}

Coryza, infectious (treatment)—Chickens: Sulfadimethoxine oral solu-

tion1{R-2} and powder for oral solution1{R-4} are indicated in the

treatment of outbreaks of infectious coryza caused by susceptible

Haemophilus gallinarum. Sulfamethazine oral solution{R-12} and powder

for oral solution1{R-9} are indicated in the control of infectious coryza

caused by susceptible H. gallinarum.

Albon Boluses [Sulfadimethoxine] Sulfa-Max III Calf Bolus [Sulfamethazine]

Albon 12.5% Concentrated Solution

[Sulfadimethoxine]

Sulfa-Max III Cattle Bolus

[Sulfamethazine]

Albon Injection 40% [Sulfadimethoxine] 2 Sulfamed [Sulfamethazine and

Sulfathiazole]

Albon Oral Suspension 5%

[Sulfadimethoxine]

Sulfa-MT [Sulfamethazine and

Sulfathiazole]

Albon SR [Sulfadimethoxine] Sulfa-Q 20% [Sulfaquinoxaline]

Albon Tablets [Sulfadimethoxine] Sulfasol [Sulfadimethoxine]

AmTech Sulfadimethoxine Injection-40%

[Sulfadimethoxine]

Sulfa 2 Soluble Powder

[Sulfamethazine and Sulfathiazole]

AmTech Sulfadimethoxine 12.5%

Oral Solution [Sulfadimethoxine]

Sulfasure SR Calf Bolus

[Sulfamethazine]

AmTech Sulfadimethoxine Soluble

Powder [Sulfadimethoxine]

Sulfasure SR Calf Tablets

[Sulfamethazine]

Calfspan [Sulfamethazine] Sulfasure SR Cattle Bolus

[Sulfamethazine]

Di-Methox Injection-40%

[Sulfadimethoxine]

Sulforal [Sulfadimethoxine]

Di-Methox 12.5% Oral Solution

[Sulfadimethoxine]

Sulmet Drinking Water Solution 12.5%

[Sulfamethazine]

Di-Methox Soluble Powder

[Sulfadimethoxine]

Sulmet Oblets [Sulfamethazine]

Optimed [Sulfaquinoxaline] Sulmet Soluble Powder [Sulfamethazine]

Powder 21 [Sulfamethazine

and Sulfathiazole]

31.92% Sul-Q-Nox [Sulfaquinoxaline]

S-125 [Sulfadimethoxine] Suprasulfa III Calf Bolus [Sulfamethazine]

S-250 [Sulfadimethoxine] Suprasulfa III Cattle Bolus

[Sulfamethazine]

SDM Injection [Sulfadimethoxine] Sustain III [Sulfamethazine]

SDM Powder [Sulfadimethoxine] Sustain III Calf Bolus [Sulfamethazine]

SDM Solution [Sulfadimethoxine] Sustain III Cattle Bolus [Sulfamethazine]

S-M-T [Sulfamethazine

and Sulfathiazole]

Triple Sulfa Bolus [Sulfamethazine,

Sulfanilamide, and Sulfathiazole]

Sulfa ‘‘25’’ [Sulfamethazine] Vetisulid Boluses [Sulfachlorpyridazine]

Sulfa 25% [Sulfamethazine] Vetisulid Injection [Sulfachlorpyridazine]

Sulfalean Powder [Sulfamethazine

and Sulfathiazole]

Vetisulid Powder [Sulfachlorpyridazine]

*Not commercially available in the U.S.


SULFONAMIDES Veterinary—Systemic 207


Cystitis, bacterial (treatment)—Cats and dogs: Sulfadimethoxine injec-

tion1, oral suspension1, and tablets{R-3; 6} are indicated in the

treatment of cystitis caused by susceptible organisms; however, the

potentiated sulfonamides and other antimicrobials have generally

replaced sulfonamides administered alone.

Diphtheria (treatment)—Cattle: Sulfonamides are not directly effective

against most obligate anaerobes{R-86; 90; 93}, but may affect aerobic

organisms that create the microenvironment in which Fusobacteria

thrive; therefore, sulfonamides may be useful in the treatment of

diphtheria but are not recommended in advanced or serious infections.

Sulfadimethoxine tablets1{R-1}, oral solution1{R-2}, injection1{R-3},

powder for oral solution1{R-4}, and extended-release tablets1{R-5}; and

sulfamethazine tablets, oral solution, powder for oral solution1, and

extended-release tablets{R-7; 9; 10; 12; 13} are indicated in the

treatment of calf diphtheria caused by susceptible Fusobacterium

necrophorum. [Sulfamethazine, sulfanilamide, and sulfathiazole

combination is indicated as an aid in the treatment of diphtheria in

calves{R-97}.]

Enteritis, bacterial (treatment)—The primary treatment for enteritis in

many cases, including those involving colibacillosis in calves, is

aggressive fluid replacement. Treatment of enteritis with antimicrobi-

als should rely on a specific diagnosis and knowledge of pathogen

susceptibility.

Calves, less than 1 month of age1: Sulfachlorpyridazine injection and

tablets are indicated in the treatment of diarrhea caused or

complicated by Escherichia coli{R-89}.

Calves and cattle: Sulfamethazine tablets, oral solution, powder for oral

solution1, and extended-release tablets;{R-7; 9; 10; 12; 13} and

[sulfamethazine and sulfathiazole combination{R-15}] are indicated

in the treatment of enteritis (colibacillosis, scours) caused by

susceptible E. coli. [Sulfamethazine, sulfanilamide, and sulfathiazole

combination{R-97} is indicated as an aid in the treatment of enteritis

caused by susceptible organisms.]

Dogs: Sulfadimethoxine injection1{R-3}, oral suspension1, and tablets{R-6}

are indicated in the treatment of enteritis caused by susceptible

Salmonella species.

Foals: Sulfamethazine tablets are indicated in the treatment of enteritis

caused by susceptible E. coli.{R-13}

Pigs: Sulfachlorpyridazine powder for oral solution1{R-89}, and sulfa-

methazine oral solution{R-12} and powder for oral solution1{R-9} are

indicated in the treatment of enteritis caused by susceptible E. coli.

[Sulfamethazine and sulfathiazole combination is indicated to aid in

the treatment of enteritis.{R-15}]

[Sheep]: Sulfamethazine oral solution{R-16} is indicated in the treatment

of enteritis caused by susceptible organisms.

Fowl cholera (treatment)—

Chickens: Sulfadimethoxine oral solution1{R-2} and powder for oral

solution1{R-4} are indicated in the treatment of acute fowl cholera

caused by susceptible Pasteurella multocida. Sulfamethazine oral

solution{R-12} and powder for oral solution1{R-9}, and sulfaquinox-

aline{R-14} are indicated in the control of acute fowl cholera caused

by susceptible P. multocida.

Turkeys: Sulfadimethoxine oral solution1{R-2} and powder for oral

solution1{R-4} are indicated in the treatment of acute fowl cholera

caused by susceptible P. multocida. Sulfaquinoxaline{R-14} is indicated

in the control of acute fowl cholera caused by susceptible

P. multocida.

Fowl typhoid (treatment)—Chickens and turkeys: Sulfaquinoxaline is

indicated in the control of acute fowl typhoid caused by susceptible

Salmonella gallinarum.{R-14}


Calves: Sulfamethazine tablets{R-13} and extended-release tablets{R-7;

10; 11} are indicated in the treatment of pneumonia and bovine

respiratory disease complex caused by susceptible Pasteurella species.

However, in vitro studies have shown high levels of resistance to

sulfamethazine by Mannheimia (Pasteurella) haemolytica and

P. multocida{R-23}; therefore, sulfamethazine generally has been

replaced by antimicrobials known to be effective against the specific

pathogens involved.

Cats and dogs: Sulfadimethoxine injection1{R-3}, oral suspension1, and

tablets{R-6} are indicated in the treatment of bacterial pneumonia

caused by susceptible organisms; however, sulfadimethoxine gener-

ally has been replaced by antimicrobials known to be effective

against the specific pathogens involved.

Cattle: Sulfamethazine oral solution{R-12}, powder for oral solution1{R-9},

and extended-release tablets{R-10}; and sulfadimethoxine tab-

lets1{R-1}, oral solution1{R-2}, injection1{R-3}, powder for oral solu-

tion1{R-4}, and extended-release tablets1{R-5}; and [sulfamethazine

and sulfathiazole combination{R-15; 96}] are indicated in the treat-

ment of bacterial pneumonia and bovine respiratory disease complex

caused by susceptible organisms. [Sulfamethazine, sulfanilamide,

and sulfathiazole combination is indicated as an aid in the treatment

of pneumonia{R-97}.] However, in vitro studies have shown high

levels of resistance to sulfamethazine by M. haemolytica and

P. multocida{R-23}, and the sulfonamides generally have been


pathogens involved.

Foals: Sulfamethazine tablets{R-13} are indicated in the treatment of

pneumonia caused by susceptible Pasteurella species; however,

sulfamethazine generally has been replaced by antimicrobials known

to be effective against the specific pathogens involved.

Pigs: Sulfamethazine oral solution{R-12} and powder for oral solu-

tion1{R-9} are indicated in the treatment of pneumonia caused by

susceptible organisms; however, sulfamethazine generally has been


pathogens involved.

Pododermatitis, necrotic (treatment)—Cattle: Sulfonamides are not

directly effective against most obligate anaerobes{R-86; 90; 93}, but

may affect aerobic organisms that create the microenvironment in

which Fusobacteria thrive; therefore, they may be useful in the

treatment of pododermatitis but are not recommended in advanced

or serious infections. Sulfadimethoxine tablets1{R-1}, oral solu-

tion1{R-2}, injection1{R-3}, powder for oral solution1{R-4}, and

extended-release tablets1{R-5}; and sulfamethazine oral solu-

tion{R-12}, powder for oral solution1{R-9}, and extended-release

tablets{R-10} are indicated in the treatment of pododermatitis

caused by susceptible Fusobacterium necrophorum. [Sulfamethazine

and sulfathiazole combination{R-15; 96} and sulfamethazine, sulfa-

nilamide, and sulfathiazole combination{R-97} are indicated as aids

in the treatment of necrotic pododermatitis caused by susceptible

F. necrophorum.]

Pullorum disease (treatment)—Chickens: Sulfamethazine oral solution{R-

12} and powder for oral solution1{R-9} are indicated in the control of

susceptible Salmonella pullorum.

208 SULFONAMIDES Veterinary—Systemic


Respiratory infections, bacterial (treatment)—

Cats and dogs: Sulfadimethoxine injection{R-3}, oral suspension, and

tablets{R-6} are indicated in the treatment of respiratory infections,

such as bronchitis, caused by susceptible organisms.

[Pigs]: Sulfamethazine and sulfathiazole combination is indicated as an

aid in the treatment of respiratory infections caused by susceptible

organisms.{R-15}

[Sheep]: Sulfamethazine oral solution is indicated in the treatment

of acute respiratory infections caused by susceptible organ-

isms{R-16}.

Skin and soft tissue infections (treatment)—Cats and dogs: Sulfadime-

thoxine injection1, oral suspension1, and tablets{R-3; 6} are indicated in

the treatment of skin and soft tissue infections; however, sulfonamides

are not effective in infections associated with purulent debris, such as

abscesses.

ACCEPTANCE NOT ESTABLISHEDCats, cattle, dogs, and sheep: Although product labeling in the U.S. and

Canada includes the use of sulfonamides in the treatment of metritis in

cats, dogs, and cattle, and pyometra{R-3; 6; 9; 10; 15; 16} in cats and dogs,

and Canadian labeling also includes the treatment of metritis in sheep,

the efficacy of these uses is not established based on current

knowledge. Sulfonamides are poorly distributed into the uterus and

their activity may be decreased in the presence of purulent debris;

sulfonamides therefore rarely are recommended in the treatment of

metritis{R-103}.

Cattle and sheep: Although product labeling in the U.S. and Canada for

cattle and in Canada for sheep includes use of sulfonamides in the

treatment of mastitis{R-3; 6; 9; 10; 12; 13; 15; 16; 97}, the efficacy of this

use is not established based on current knowledge. Many sulfona-

mides, including most of those labeled for treatment of mastitis, are

poorly distributed into milk. Considering also the high incidence of

pathogen resistance reported, sulfonamides rarely are recommended in

the treatment of mastitis{R-103}.

Horses: Although product labeling in the U.S. and Canada includes the

use of sulfonamides in the treatment of equine strangles (Streptococcus

equi infection), the efficacy of this use is not established based on

current knowledge. The activity of sulfonamides may be decreased in

the presence of purulent debris; therefore, they rarely are recom-

mended in the treatment of strangles{R-103; 107}.


The presence of sulfonamide residues in food for human consumption

has been a concern in recent years. After a variety of efforts to

control residues, the incidence of violative sulfonamide residues

recently was reported to be as low as 1% in the U.S.{R-24}; however,

because of a study linking moderate to high doses of sulfamethazine,

directly or by a secondary mechanism, to the production of thyroid

tumors in mice, concern about residues continues.{R-24; 51}

The use of sulfonamides in lactating dairy cattle, other than those

medications specifically approved for use, has been specified by the

Food and Drug Administration as a high priority for regulatory

attention{R-104}.

Withdrawal times have been established for sulfachlorpyridazine, sul-

fadimethoxine, sulfamethazine, and sulfaquinoxaline. See the Dosage

Forms section.

Federal law restricts the use of some forms of sulfadimethoxine and

sulfamethazine to use by or on the order of a licensed veterinarian.

See the Dosage Forms section.

Canada—

Withdrawal times have been established for sulfamethazine; sulfa-

methazine and sulfathiazole combination; and sulfamethazine,

sulfanilamide, and sulfathiazole combination. See the Dosage Forms

section.

CHEMISTRYChemical name:

Sulfachlorpyridazine—N1-(6-Chloro-3-pyridazinyl)sulfanilamide{R-36}.

Sulfadimethoxine—Benzenesulfonamide, 4-amino-N-(2,6-dimethoxy-4-

pyrimidinyl)-{R-36}.

Sulfamethazine—Benzenesulfonamide, 4-amino-N-(4,6-dimethyl-2-pyri-

midinyl)-{R-36}.

Sulfanilamide—p-Aminobenzenesulfonamide{R-36}.

Sulfaquinoxaline—N1-2-Quinoxalinylsulfanilamide{R-36}.

Sulfathiazole—Benzenesulfonamide, 4-amino-N-2-thiazolyl-{R-36}.

Molecular formula:

Sulfachlorpyridazine—C10H9ClNO2S{R-36}.

Sulfadimethoxine—C12H14N4O4S{R-36}.

Sulfamethazine—C12H14N4O2S{R-36}.

Sulfanilamide—C6H8N2O2S{R-36}.

Sulfaquinoxaline—C14H12N4O2S{R-36}.

Sulfathiazole—C9H9N3O2S2{R-36}.

Molecular weight:

Sulfachlorpyridazine—284.72{R-36}.

Sulfadimethoxine—310.34{R-36}.

Sulfamethazine—278.33{R-36}.

Sulfanilamide—172.21{R-36}.

Sulfaquinoxaline—300.34{R-36}.

Sulfathiazole—255.32{R-36}.

Description:

Sulfadimethoxine USP—Practically white, crystalline powder{R-56}.

Sulfamethazine USP—White to yellowish white powder, which may

darken on exposure to light. Practically odorless.{R-56}

Sulfanilamide—White, odorless, crystalline powder{R-98}.

Sulfaquinoxaline—Yellow, odorless powder{R-94}.

Sulfathiazole USP—Fine, white or faintly yellowish white, practically

odorless powder{R-56}.

pKa:

Sulfadimethoxine—6.15{R-33; 35}.

Sulfamethazine—2.65, 7.4{R-19}.

Sulfanilamide—10.5{R-19; 35}.

Sulfaquinoxaline—5.5{R-19; 46}.

Sulfathiazole—7.1{R-19}.

Solubility:

Sulfadimethoxine USP—Soluble in 2 N sodium hydroxide; sparingly

soluble in 2 N hydrochloric acid; slightly soluble in alcohol, in ether, in

chloroform, and in hexane; practically insoluble in water{R-56}.

Sulfamethazine USP—Very slightly soluble in water and in ether; soluble

in acetone; slightly soluble in alcohol{R-56}.

Sulfanilamide—Slightly soluble in water, in alcohol, in acetone, in

glycerin, in propylene glycol, in hydrochloric acid, and in solutions of





potassium and sodium hydroxide; practically insoluble in chloroform,

in ether, and in petroleum ether{R-98}.

Sulfaquinoxaline—Practically insoluble in water; very slightly soluble in

alcohol; practically insoluble in ether; freely soluble in aqueous

solutions of alkalis{R-94}.

Sulfathiazole USP—Very slightly soluble in water; soluble in acetone, in

dilute mineral acids, in solutions of alkali hydroxides, and in 6 N

ammonium hydroxide; slightly soluble in alcohol{R-56}.

PHARMACOLOGY/PHARMACOKINETICSNote: Unless otherwise noted, pharmacokinetic values are based on a

single intravenous administration of medication.

Mechanism of action: Bacteriostatic. Sulfonamides interfere with the

biosynthesis of folic acid in bacterial cells; they compete with para-

aminobenzoic acid (PABA) for incorporation in the folic acid molecule.

By replacing the PABA molecule and preventing the folic acid for-

mation required for DNA synthesis, the sulfonamides prevent multi-

plication of the bacterial cell. Susceptible organisms must synthesize

their own folic acid; mammalian cells use preformed folic acid and,

therefore, are not susceptible. Cells that produce excess PABA or

environments with PABA, such as necrotic tissues, allow for resistance

by competition with the sulfonamide{R-17; 18}.

Absorption: Most sulfonamides are well absorbed orally with the

exception of the enteric sulfonamides, such as sulfaquinoxaline, which

are minimally absorbed{R-19}. Delays in absorption may occur in adult

ruminants or when sulfonamides are administered with food to

monogastric animals{R-17; 20}.

Bioavailability: Oral—

Sulfadimethoxine:

Cattle—59% (107 mg per kg of body weight [mg/kg] dose){R-44}.

Dogs—48.8% (55 mg/kg dose){R-41}.

Sulfamethazine:

Pigs—86% (50 mg/kg dose){R-66}.

Ponies—84% (160 mg/kg dose){R-57}.

Distribution: Sulfonamides are widely distributed throughout the body.

They cross the placenta, and a few penetrate into the cerebrospinal

fluid{R-20}. Sulfonamides may be distributed into milk; however, they

vary greatly in their ability to do so. The process depends on several

factors, including protein binding and pKa values{R-102}.


Sulfadimethoxine:

Goats—Area: 0.49 ± 0.095 L/kg{R-35}.

Pigs—Area:

Suckling (1 to 2 weeks)—0.483 ± 0.078 L/kg{R-45}.

Growing (11 to 12 weeks)—0.345 ± 0.016 L/kg{R-45}.

Rabbits—Steady state: 0.213 ± 0.007 L/kg{R-40}.

Sulfamethazine:

Buffalo—Area: 0.44 ± 0.17 L/kg{R-55}.

Cattle—Extrapolated: 0.35 L/kg{R-82}.

Goats—Area: 0.28 to 0.39 L/kg; 0.44 L/kg{R-35}.

Horses—Steady state: 0.63 ± 0.074 L/kg{R-57}.

Lambs—Area: 0.334 ± 0.031 L/kg{R-61}.

Pigs—Area: 0.5{R-66; 67}; 0.77 ± 0.06 L/kg{R-70}.

Administered in conjunction with sulfathiazole: Area—1.01 ±

0.12 L/kg{R-70}.

Sheep—Area: 0.4 L/kg{R-62; 63}; 0.6 L/kg{R-58}.

Sulfanilamide: Goats—Area: 1.3 ± 0.13 L/kg{R-35}.

Sulfathiazole: Pigs—Area: 1.16 ± 0.16 L/kg{R-70}.

Protein binding: Binding can vary depending on serum concentra-

tion{R-43} and other factors.

Sulfachlorpyridazine—Cows: High (80 to 85%){R-34}.

Sulfadimethoxine—

Cats: High (87.5%){R-42}.

Chickens: Moderate (40%){R-43}.

Dogs: High (>75%){R-39}.

Goats: High (94%){R-35}.

Sulfamethazine—

Cows:

When plasma concentration is less than 50 mcg per mL

(mcg/mL)—High (79%){R-79}.

When plasma concentration is more than 50 mcg/mL—

Moderate (51%){R-79}.

Goats: High (86%){R-35}.

Horses: High (70%){R-37}.

Sheep: High (77%){R-58}.

Sulfanilamide—Cows: Low (<20%){R-34}.

Sulfathiazole—Cows: High (65 to 76%){R-34}.

Biotransformation: Sulfonamides are primarily metabolized in the liver

but metabolism also occurs in other tissues. Biotransformation occurs

mainly by acetylation, glucuronide conjugation, and aromatic hydrox-

ylation in many species{R-17}. The types of metabolites formed and the

amount of each varies depending on the specific sulfonamide adminis-

tered; the species, age, diet, and environment of the animal; the presence

of disease; and, with the exception of pigs and ruminants, even the sex of

the animal{R-53; 54; 71; 79}. Dogs are considered to be unable to acetylate

sulfonamides to any significant degree{R-108}.

N4-acetyl metabolites have no antimicrobial activity and hydroxymetab-

olites have 2.5 to 39.5% of the activity of the parent compound{R-37}.

Metabolites may compete with the parent drug for involvement in folic

acid synthesis but have little detrimental effect on the bacterial cell, and

so could lower the activity of the remaining parent drug.{R-37}

In pigs, sulfamethazine is metabolized into N4-acetylsulfamethazine,

desaminosulfamethazine and the N4-glucose conjugate of sulfameth-

azine{R-72}. In general, metabolites of sulfonamides are cleared more

quickly than the parent drug{R-78}; however, the desaminosulfameth-

azine half-life of elimination can vary from 1 to 9 days, while

sulfamethazine and other metabolites have a shorter half-life of 10 to

20 hours{R-73}. It has been theorized that diets containing nitrate,

which is then reduced by bacteria to nitrite, will greatly increase the

amount of sulfamethazine biotransformed to the desaminosulfameth-

azine metabolite and prolong tissue residues of metabolite{R-71}, but

there is no conclusive evidence.

Half-life:

Absorption—Sulfadimethoxine: Dogs—Oral dose of 55 mg/kg: 1.9

hours{R-39}.

Elimination—

Sulfachlorpyridazine: Cows—1.2 hours{R-34}.



Sulfadimethoxine:

Cats—10.2 hours{R-42}.

Cattle—12.5 hours{R-38}.

Dogs—13.1 hours{R-39}.

Goats—8.6 hours{R-34}.

Pigs—

Single dose:

Suckling pig (1 to 2 weeks of age)—16.2 hours{R-45}.

Growing pig (11 to 12 weeks of age)—9.4 hours{R-45}.

After 5 days of once-daily intravenous dosing: 9.2 hours{R-40}.

Rabbits—After 6 days of once-daily intravenous dosing: 5.2 hours{R-40}.

Sulfamethazine:

Buffalo—5.5 hours{R-55}.

Calves, 2 to 3 months of age—5.2 to 5.7 hours{R-78; 79}.

Cattle—5 to 11.3 hours{R-34; 78; 79; 82}.

Goats—2.4 to 4.1 hours{R-35}; 8.5 to 9.6 hours{R-35; 82}.

Horses—5.4 hours{R-37}; 11.4 hours{R-57}.

Lambs—7.2 hours{R-61}.

Pigs—9.8 hours{R-70}; 16.9 hours{R-66; 67}.

Sheep—4.5 hours{R-58}; 9.5 to 10.8 hours{R-62; 63}.

Sulfanilamide:

Cows—6.2 hours{R-34}.

Goats—7.7 hours{R-34}.

Sulfathiazole:

Cows—1.5 hours{R-34}.

Pigs—9 hours{R-70}.

Sheep—1.3 hours{R-84}.

Peak serum concentration:

Sulfadimethoxine—Oral:

Chickens—106.3 mcg/mL at 12 hours (100 mg/kg dose).{R-43}

Cattle—114 ± 10 mcg/mL at 10 hours (107 mg/kg dose).{R-44}

Dogs—67 ± 16 mcg/mL of serum at 3.75 hours (55 mg/kg dose).{R-39}

Sulfamethazine—Oral: Ponies—301.4 mcg/mL of serum at 0.83 hour

(160 mg/kg dose).{R-57}

Duration of action:

The sulfonamides have been loosely categorized according to their

duration of action:{R-19}

Short-acting—Sulfathiazole.

Intermediate-acting—Sulfachlorpyridazine, sulfamethazine.

Intermediate- to long-acting—Sulfadimethoxine.

Note: Duration of action may be estimated by the length of time target

serum concentrations are maintained. Target concentrations are

generally based on minimum inhibitory concentrations for each

organism. Many sources use 50 mcg sulfonamide per mL (5 mg per

decaliter) of blood as the minimum effective concentration for

sulfonamides in animals.{R-64; 76; 80}

Sulfadimethoxine—Oral: Chickens—A single dose of 100 mg per kg of

body weight (mg/kg) maintained plasma concentration of greater

than or equal to 50 mcg/mL for 36 hours.{R-43}

Sulfamethazine—

Intravenous: Lambs—An intravenous dose of 107.3 mg/kg main-

tained a plasma concentration of greater than 50 mcg/mL for 18

to 24 hours.{R-64}

Oral (powder for oral solution): Calves, 8 months of age—{R-76}

Oral dose of 214.3 mg/kg a day (1848 mg/L of water) administered

in the only source of drinking water maintained a serum

concentration of at least 50 mcg/mL from 18 hours to at least

120 hours after start of treatment.{R-76}

Oral dose of 142.9 mg/kg a day (1028 mg/L of water) administered

in the only source of drinking water maintained a serum

concentration of at least 50 mcg/mL from 24 to 180 hours after

the start of treatment.{R-76}

Oral dose of 71.4 mg/kg a day (572 mg/L of water) administered in

the only source of drinking water maintained a serum concentra-

tion of at least 50 mcg/mL from only 72 to 96 hours after the start

of treatment.{R-76}

Oral (extended-release tablets):

Calves, 3 to 5 days of age: An oral dose of 396 mg/kg, administered

as a single extended-release tablet, maintained a serum concen-

tration of at least 50 mcg/mL from 4 to 96 hours post-


Calves and cattle: An oral dose of 264 mg/kg maintained a serum

concentration greater than 50 mcg/mL from 12 to 48 or 72 hours

post-administration.{R-81}

Elimination: Renal excretion is the primary route of elimination for

most nonenteric sulfonamides and it occurs by glomerular filtration

of parent drug, tubular excretion of unchanged drug and metabolites,

and passive reabsorption of nonionized drug.{R-17; 20} Alkalization of

the urine increases the fraction of the dose that is eliminated in the

urine.{R-20} In general, the metabolites of the parent drug are more

quickly eliminated by the kidney than the original sulfonamide

is{R-78}, but the proportions of metabolites formed can vary,

depending on many factors.

Sulfonamides are also distributed in relatively small amounts into milk,

saliva, and into the gastrointestinal tract.{R-77; 79}

Sulfadimethoxine—Cattle: 17.9% of an intravenous dose of 107 mg

per kg of sulfadimethoxine is excreted into the urine unchanged and

at least 58.4% is excreted as metabolites into urine.{R-44} Only 6.3%

of an oral dose of 107 mg of sulfadimethoxine per kg is excreted

unchanged in the urine and 37.7% as metabolites in the

urine.{R-44}

Total clearance:

Cats—0.31 mL per minute per kg (mL/min/kg).{R-42}

Dogs—0.36 mL/min/kg.{R-39}

Goats—0.65 mL/min/kg.{R-35}

Pigs—

Suckling pig (1 to 2 weeks): 0.35 mL/min/kg.{R-45}

Growing pig (11 to 12 weeks): 0.44 mL/min/kg.{R-45}

Sulfamethazine—

Cattle: 11 to 37% of a dose of sulfamethazine is excreted into the urine

as parent drug.{R-78; 82}

Horses: Only 43% of the administered dose is eliminated in the urine

and only 7.8% of it is in the form of parent drug.{R-37}

Pigs: 24.5% of a sulfamethazine dose is excreted in the urine as

unchanged drug and 52.1% as measured metabolites.{R-67}

Sheep: 18% of a sulfamethazine dose is excreted into the urine as

parent compound and 53% as metabolites.{R-64}

Total clearance:

Buffalo—0.93 mL/min/kg{R-55}.

Calves, 5 days of age—0.33 mL/min/kg{R-79}.

Calves, 2 to 3 months of age—0.57 mL/min/kg{R-79}.

Cows—0.73 mL/min/kg{R-79}.

Goats—0.55 to 0.65 mL/min/kg; 1.13 to 1.4 mL/min/kg{R-35}.



Horses—0.92 mL/min/kg{R-37}.

Pigs—0.35 mL/min/kg{R-66}.

Ponies—0.7 mL/min/kg{R-57}.

Sheep—1.6 mL/min/kg{R-58}.

Sulfathiazole—Total clearance: Pigs—1.5 mL/min/kg{R-70}.


SPECIES SENSITIVITYDogs: An idiosyncratic sulfonamide toxicosis can occur in any breed of

dog, but has been reported more frequently in the Doberman

Pinscher than in other breeds. This specific type of drug reaction

includes blood dyscrasias, nonseptic polyarthritis, and skin rash.{R-

26; 27} Dogs given sulfonamides may also develop cutaneous

eruptions, hepatitis, or keratitis sicca.{R-17; 27} Dogs are reported

to develop a hemorrhagic syndrome when doses of sulfaquinoxaline

that are tolerated by many chickens are administered in their

drinking water.{R-47–50}

CROSS-SENSITIVITY AND/OR RELATED PROBLEMSPatients allergic to one sulfonamide may be allergic to other sulfona-

mides also.

CARCINOGENICITYFor sulfamethazine—High doses have been shown to induce follicular

cell hyperplasia of the thyroid gland and splenic changes in specific–

pathogen-free mice. When the highest doses (4800 parts per million

in the diet) were fed for 24 months, 26 to 33% of the mice

developed thyroid gland adenomas.{R-51} The applicability of these

results to other species with recommended doses is unclear at this

time.

PREGNANCY/REPRODUCTIONSulfonamides cross the placenta in pregnant animals.{R-20; 60} Some

teratogenic effects have been seen when very high doses were given to

pregnant mice and rats.{R-20}

LACTATIONSulfonamides are distributed into milk; however, the sulfonamides that

are clinically relevant to food-producing animals are distributed into

milk in concentrations too low to be therapeutic but high enough to

produce residues{R-103; 105}. Sulfadiazine and sulfanilamide are more

efficiently distributed into milk than most sulfonamides, but are not

used in dairy cattle{R-103}. For many sulfonamides, 0.5 to 2% of the

total dose is found in the milk.{R-31; 32} Distribution into milk varies

depending on the amount of non–protein-bound sulfonamide present

in the blood and the amount of the nonionized and therefore

liposoluble form of the medication present. Sulfonamides with higher

pKa values produce a higher proportion of drug in the blood that is

non-ionized{R-31}, and if other factors, such as the rate of biotransfor-

mation, also support it, may be distributed more easily into milk. For

lactating dairy cattle, concentration of the active parent compound of

sulfamethazine, measured at a specific time in milk, is about 20% of

the concentration in the blood.{R-77}





Note: Drug interactions relating specifically to the use of sulfonamides in

animals are rarely reported in veterinary literature. Human drug

interactions have been reported and are included in the following

section.


The following drug interactions have been reported in humans, and are

included in the human monograph Sulfonamides (Systemic) in USP DI



sulfonamides in the treatment of animals:



medication.


Anticonvulsants, hydantoin, or

Antidiabetic agents, oral

(these medications may be displaced from protein binding sites and/

or their metabolism may be inhibited by some sulfonamides, result-

ing in increased or prolonged effects and/or toxicity; dosage adjust-

ments may be necessary during and after sulfonamide therapy)


(concurrent use of bone marrow depressants with sulfonamides

may increase the leukopenic and/or thrombocytopenic effects; if

concurrent use is required, close observation for myelotoxic effects

should be considered)

Cyclosporine

(concurrent use with sulfonamides may increase the metabolism

of cyclosporine, resulting in decreased plasma concentrations and

potential transplant rejection, and additive nephrotoxicity; plasma

cyclosporine concentrations and renal function should be moni-

tored)

Hemolytics, other

(concurrent use with sulfonamides may increase the potential for

toxic side effects)


(concurrent use with sulfonamides may result in an increased

incidence of hepatotoxicity; patients, especially those on prolonged

administration or those with a history of liver disease, should be

carefully monitored)

Methenamine

(in acid urine, methenamine breaks down into formaldehyde,

which may form an insoluble precipitate with certain sulfonamides,

especially those that are less soluble in urine, and may also increase

the danger of crystalluria; concurrent use is not recommended)

Methotrexate or

Phenylbutazone

(the effects of methotrexate may be potentiated during concurrent

use with sulfonamides because of displacement from plasma

protein binding sites; phenylbutazone may displace sulfonamides

from plasma protein binding sites, increasing sulfonamide con-

centrations)



Penicillins

(since bacteriostatic drugs may interfere with the bactericidal effect

of penicillins in the treatment of meningitis or in other situations

where a rapid bactericidal effect is necessary, it is best to avoid

concurrent therapy)




Note: Laboratory value alterations relating specifically to the use of

sulfonamides in animals are rarely reported in veterinary literature.

Human laboratory value alterations have been reported and are

included in the following section.



humans, and are included in the human monograph Sulfonamides



applicable to the use of sulfonamides in the treatment of animals:


Benedict’s test

(sulfonamides may produce a false-positive Benedict’s test for urine

glucose)

Jaffe alkaline picrate reaction assay

(sulfamethoxazole may interfere with the Jaffe alkaline picrate

reaction assay for creatinine, resulting in overestimations of

approximately 10% in the normal values for creatinine)

Sulfosalicylic acid test

(sulfonamides may produce a false-positive sulfosalicylic acid test

for urine protein)

Urine urobilinogen test strip (e.g., Urobilistix)

(sulfonamides may interfere with the urine urobilinogen [Urobi-

listix] test for urinary urobilinogen)



Aspartate aminotransferase (AST [SGOT]), serum, and

Bilirubin, serum



Creatinine, serum







used when the following medical problem exists:

» Hypersensitivity to sulfonamides

(animals that have had a previous reaction to sulfonamides may be

much more likely to react on subsequent administration)


problems exist:

Hepatic function impairment

(systemically absorbed sulfonamides are metabolized by the liver;

delayed biotransformation may increase the risk of adverse effects)

Renal function impairment

(systemically absorbed sulfonamides are renally excreted; delayed

elimination could cause accumulation of sulfonamide and metabo-

lites, increasing the risk of adverse effects)







prior to sulfonamide administration to determine pathogen suscep-

tibility)





All species

Crystallization in the urinary tract

Note: Crystallization of sulfonamides can occur in the kidneys or urine

with high doses of sulfonamide or when an animal is dehydrated.

Solubility in the urine is dependent on the concentration of drug in the

urine, urinary pH (less soluble in an acidic pH), the patient’s hydration,

and the amount of drug in the acetylated form. Because dogs do not

produce acetylated metabolites, they may be less susceptible to this

adverse effect{R-85}. It can be minimized in susceptible animals by

maintaining a high urine flow and, if necessary, alkalinizing the urine.

Dogs

Cutaneous drug eruption{R-27}; hepatitis; hypothyroidism{R-100;

101}; idiosyncratic toxicosis{R-26; 27} (blood dyscrasias, including

anemia, leukopenia or thrombocytopenia; fever; focal retinitis; lymph-

adenopathy; nonseptic polyarthritis; polymyositis; skin rash); kerato-

conjunctivitis sicca{R-28–30}

Note: Iatrogenic hypothyroidism may occur and thyroid function test

values may be lowered in dogs administered sulfonamides{R-100;

101}. Although studies have looked at this reaction with potentiated

sulfonamides{R-100; 101}, sulfonamides administered alone have been

reported to impair thyroid function{R-100}. With administration of

sulfamethoxazole and trimethoprim combination at high doses or of

ormetoprim and sulfadimethoxine, thyrotropin stimulation test

values and serum thyroxine values have been significantly

reduced{R-100}. Sulfadiazine and trimethoprim combination, admin-

istered at labeled doses (25 mg of sulfadiazine and 5 mg of

trimethoprim per kg every 24 hours), has not affected thyroid test

values in studies performed.

Idiosyncratic toxicosis can occur 8 to 20 days after initiation of

treatment and is believed to be caused either by an immune-

mediated syndrome or by an idiosyncratic reaction in dogs, perhaps

due to toxic metabolites of the sulfonamide. Of 22 reported cases



compiled in one study, 7 involved Doberman Pinschers, and it has

been theorized that they are more susceptible to this toxicosis{R-26}.

A large majority of the animals in which idiosyncratic toxicosis

occurs have had a previous exposure to a sulfonamide. Most cases

involve a trimethoprim and sulfonamide combination{R-27}. When

sulfonamide therapy is discontinued, recovery generally occurs

within 2 to 5 days.{R-27}

Keratoconjunctivitis sicca is considered a possible side/adverse effect in

any dog on sulfonamide therapy for more than a month; however, it can

occur at any time after therapy is initiated. Reports conflict over whether

this is a dose-related or idiosyncratic reaction{R-108}. The most frequent

reports have been with sulfasalazine or trimethoprim and sulfonamide

combination{R-28–30}, perhaps because these medications are most

commonly used for long-term therapy in dogs. Lacrimation may not

return to normal after discontinuation of sulfonamide treatment.

For sulfaquinoxaline

Chickens and dogs

Hemorrhagic syndrome (anorexia, epistaxis, hemoptysis, lethargy,

pale mucous membranes, possibly death){R-46–50}

Note: Hemorrhagic syndrome has been reported in chickens and dogs

but may occur in other species. It is most often reported with the

addition of sulfaquinoxaline to feed for chickens, but in dogs has been

reported to follow administration in the water supply of products

labeled for poultry.{R-47–50} Sulfaquinoxaline is a vitamin K antag-

onist that inhibits vitamin K eposide and vitamin K quinone

reductase and causes an effect similar to that of coumarin antico-

agulants.{R-46} Rapid hypoprothrombinemia occurs in dogs, and

sulfaquinoxaline may have an additional adverse effect on specific

cell types; this may explain why supplementation of chicken feeds

with vitamin K has not always prevented the syndrome in

chickens.{R-46–47} Rapid discontinuation of medication and initiation

of therapy with vitamin K1 may reverse the effects.




included in the human monograph Sulfonamides (Systemic) in USP DI



sulfonamides in the treatment of animals:


Central nervous system effects; gastrointestinal disturbances;

hypersensitivity; photosensitivity


Blood dyscrasias; hepatitis; Lyell’s syndrome (difficulty in swal-

lowing; redness, blistering, peeling, or loosening of skin); Stevens-

Johnson syndrome (aching joints and muscles; redness, blistering,

peeling, or loosening of skin; unusual tiredness or weakness)

Incidence rare

Central nervous system toxicity; Clostridium difficile colitis;

crystalluria or hematuria; goiter or thyroid function distur-

bance; interstitial nephritis or tubular necrosis

Note: C. difficile colitis may occur up to several weeks after


Fatalities have occurred, although rarely, due to severe reactions

such as Stevens-Johnson syndrome, toxic epidermal necrolysis,

fulminant hepatic necrosis, agranulocytosis, aplastic anemia,

and other blood dyscrasias. Therapy should be discontinued at

the first appearance of skin rash or any serious side/adverse

effects.

The multiorgan toxicity of sulfonamides is thought to be the result

of the way sulfonamides are metabolized in certain patients. It is

probably due to the inability of the body to detoxify reactive

metabolites. Sulfonamides are metabolized primarily by acetyla-

tion. Patients can be divided into slow and fast acetylators. Slow

acetylation of sulfonamides makes more of the medication

available for metabolism by the oxidative pathways of the

cytochrome P450 system. These pathways produce reactive toxic

metabolites, such as hydroxylamine and nitroso compounds. The

metabolites are normally detoxified by scavengers, such as

glutathione. However, some populations, such as human immu-

nodeficiency virus (HIV)–infected patients, have low concentra-

tions of glutathione and these metabolites accumulate, producing

toxicity. Patients who are slow acetylators have a higher incidence

of sulfonamide hypersensitivity reactions, although severe toxicity

has also been seen in fast acetylators. Acetylation status alone

cannot fully explain sulfonamide toxicity since approximately 50%

of North American blacks and whites are slow acetylators and

severe reactions occur in less than 1% of patients treated with

sulfonamides. However, decreased acetylation may increase the

amount of sulfonamide metabolized to toxic metabolites.






Toxicities secondary to acute overdose of sulfonamides are not typically

reported. Side effects may be more likely to occur with high doses and

long-term administration, but are seen at recommended doses as well.

CLIENT CONSULTATIONDosage and length of treatment recommendations should be followed;

high doses or long-term use can increase the risk of side effects.

Animals should have a good water supply and should be monitored to

ensure adequate water consumption during treatment.

VETERINARY DOSING INFORMATIONResidue avoidance: Management practices can affect depletion of residues

in pigs. When pigs have environmental access to urine and manure

from pigs treated with sulfamethazine, the residues are easily recycled

and can cause these animals to have positive urine tests for

sulfonamide and violative tissue residues. Hot or cold environmental

temperatures do not appear to inactivate sulfamethazine in the

environment.{R-70; 74}

FOR ORAL DOSAGE FORMS ONLYIntestinal parasites, among other factors, can affect the pharmacokinetics

of sulfamethazine in lambs and probably in other species also. In

parasitized lambs given a single dose of 99 mg per kg of body weight

(mg/kg), sulfamethazine’s half-life of elimination and time to peak

concentration were doubled.{R-65}




For anaphylaxis



SULFACHLORPYRIDAZINE

SUMMARY OF DIFFERENCESPharmacology/pharmacokinetics: Intermediate duration of action.{R-19}

ORAL DOSAGE FORMS

SULFACHLORPYRIDAZINE POWDER FOR ORALSOLUTIONUsual dose: Enteritis (diarrhea associated with E. coli)1—

Calves, less than 1 month of age: Oral, 33 to 49.5 mg per kg of body


Pigs: Oral, 22 to 38.5 mg per kg of body weight, administered as a

drench every twelve hours or 44 to 77 mg per kg of body weight a

day administered in the only source of drinking water.{R-89}


U.S.—


50 grams per bottle (OTC) [Vetisulid Powder].{R-89}

Canada—




U.S.—

Withdrawal time

Species Meat (days)

Calves 7

Pigs 4

Packaging and storage: Store below 40 �C (104 �F), preferably bet-

ween 15 and 30 �C (59 and 86 �F), unless otherwise specified by

manufacturer.

Additional information: Animals should maintain an adequate water

intake during the treatment period.


SULFACHLORPYRIDAZINE TABLETSUsual dose: Enteritis (diarrhea associated with Escherichia coli)1—Calves,

less than 1 month of age: Oral, 33 to 49.5 mg per kg of body weight

every twelve hours.{R-88}


U.S.—


2 grams (OTC) [Vetisulid Boluses].

Canada—




U.S.—

Withdrawal time

Species Meat (days)

Calves, ruminating 7


applies when medication is administered for a maximum of five days.

No withdrawal times have been established for use in preruminating

calves.{R-88}



manufacturer. Avoid excessive heat.{R-88}





SULFACHLORPYRIDAZINE INJECTIONUsual dose: Enteritis (diarrhea associated with E. coli)1—Calves, less

than 1 month of age: Intravenous, 33 to 49.5 mg per kg of body



U.S.—


200 mg per mL (OTC) [Vetisulid Injection].

Canada—



Withdrawal times:

U.S.—

Withdrawal time

Species Meat (days)

Calves, ruminating 5


applies when medication is administered for a maximum of five days. No

withdrawal times have been established for use in preruminating calves.


between 15 and 30 �C (59 and 86�F), unless otherwise specified by

manufacturer. Protect from light. Protect from freezing{R-87}.










SULFADIMETHOXINE

SUMMARY OF DIFFERENCESPharmacology/pharmacokinetics: Intermediate to long duration of

action{R-19}.

ORAL DOSAGE FORMS

SULFADIMETHOXINE ORAL SOLUTIONUsual dose:

Calf diphtheria1;

Pneumonia, bacterial1; or

Necrotic pododermatitis1—Calves and cattle: Oral, 55 mg per kg of body

weight (2.4 to 3.75 grams per gallon of water) as an initial dose,

followed by 27.5 mg per kg of body weight (1.2 to 1.8 grams per

gallon of water) a day for four days.{R-2}

Coccidiosis1; or

Fowl cholera1—

Chickens, broiler and replacement: Oral, 1875 mg per gallon of water

(0.05% solution), administered as the only source of drinking

water for six days{R-2}.

Turkeys: Oral, 938 mg per gallon of water (0.025% solution),

administered as the only source of drinking water for six

days{R-2}.

Infectious coryza outbreaks1—Chickens, broiler and replacement: Oral,

1875 mg per gallon of water (0.05% solution), administered as the

only source of drinking water for six days{R-2}.

Note: Administration of sulfadimethoxine for longer than the recom-

mended time can result in slowed growth rates and other adverse

effects.{R-83}


U.S.—


125 mg per mL (OTC) [Albon 12.5% Concentrated Solution; AmTech

Sulfadimethoxine 12.5% Oral Solution; Di-Methox 12.5% Oral

Solution; SDM Solution; Sulforal; generic].

Canada—



Withdrawal times:

U.S.—

Withdrawal time

Species Meat (days)

Cattle 7

Chickens, turkeys 5


are not labeled for use in chickens older than 16 weeks of age, turkeys

older than 24 weeks of age, preruminating calves, or lactating dairy

cattle.{R-2}



manufacturer. Protect from light.{R-2}

Stability: Freezing or discoloration does not affect stability. Medication

should be thawed before using.{R-2}

Preparation of dosage form: Prepare fresh drinking water daily.




SULFADIMETHOXINE ORAL SUSPENSION USPUsual dose:

Bacterial pneumonia and other respiratory infections1;

Cystitis1; or

Skin and soft tissue infections1—Cats and dogs: Oral, 55 mg per kg of

body weight as an initial dose, followed by 27.5 mg per kg of body

weight every twenty-four hours.{R-6}

Enteritis associated with coccidiosis or Salmonella1—Dogs: Oral, 55 mg

per kg of body weight as an initial dose, followed by 27.5 mg per kg

of body weight every twenty-four hours.{R-6}


U.S.—


50 mg per mL (Rx) [Albon Oral Suspension 5%].

Canada—





manufacturer.



USP requirements: Preserve in tight, light-resistant containers, and

store at controlled room temperature. Label it to indicate that it is for


the requirements for Identification and pH (5.0–7.0){R-56}.

SULFADIMETHOXINE SOLUBLE POWDER USPUsual dose:

Bacterial pneumonia1;

Calf diphtheria1; or

Necrotic pododermatitis1—Calves and cattle: Oral, 55 mg per kg of

body weight (2.4 to 3.3 grams per gallon) as an initial dose, followed

by 27.5 mg per kg of body weight (1.2 grams per gallon) every

twenty-four hours for four days.{R-4}

Coccidiosis1; or

Fowl cholera1—

Chickens, broiler and replacement: Oral, 1892 mg per gallon of water

(0.05% solution), administered as the only source of drinking

water for six days{R-4}.

Turkeys: Oral, 946 mg per gallon of water (0.025% solution),

administered as the only source of drinking water for six days{R-4}.



Infectious coryza outbreaks1—Chickens, broiler and replacement: Oral,

1892 mg per gallon of water (0.05% solution), administered as the

only source of drinking water for six days{R-4}.


U.S.—


28.3 grams per ounce of powder (OTC) [AmTech Sulfadimethoxine Sol-

uble Powder; Di-Methox Soluble Powder; SDM Powder; Sulfasol; generic].

Canada—



Withdrawal times:

U.S.—

Withdrawal time

Species Meat (days)

Cattle 7

Chickens, turkeys 5


are not labeled for use in preruminating calves, lactating dairy cattle,

chickens older than 16 weeks of age, or turkeys older than 24 weeks of

age.






store at controlled room temperature. Label it to indicate that it is for


the requirements for Identification, Minimum fill, and pH (7.0–8.0, in

a solution [1 in 20]){R-56}.

SULFADIMETHOXINE TABLETS USPUsual dose:

Bacterial pneumonia and other respiratory infections;

Cystitis; or

Skin and soft tissue infections—Cats and dogs: Oral, 55 mg per kg of



Calf diphtheria1;


Pododermatitis1—Cattle: Oral, 55 mg per kg of body weight as the

initial dose, followed by 27.5 mg per kg of body weight every twenty-

four hours for five days{R-1}.

Enteritis associated with coccidiosis or Salmonella—Dogs: Oral, 55 mg

per kg of body weight as an initial dose, followed by 27.5 mg per kg

of body weight every twenty-four hours.{R-6}


U.S.—


125 mg (Rx) [Albon Tablets].



5000 mg (5 grams) (OTC) [Albon Boluses].

15,000 mg (15 grams) (OTC) [Albon Boluses].

Note: The 125-mg, 250-mg, and 500-mg tablets listed above are

labeled for use only in cats and dogs, while the 5-gram and 15-gram

tablets are labeled for use only in cattle.

Canada{R-19}—


125 mg (OTC) [S-125].

250 mg (OTC) [S-250].


U.S.—

Withdrawal time


Cattle 7 60


are not labeled for use in preruminating calves.


intake during the treatment period{R-1}.




store at controlled room temperature. Label the Tablets to indicate that

they are for veterinary use only. Contains the labeled amount, within

±10%. Meets the requirements for Identification, Disintegration (30

minutes), and Uniformity of dosage units{R-56}.

SULFADIMETHOXINE EXTENDED-RELEASE TABLETSUsual dose:

Bacterial pneumonia1;


Pododermatitis1—Cattle: Oral, 137.5 mg per kg of body weight as a

single dose.{R-5}

Note: To maintain sustained release of medication, tablets should not

be divided; it is recommended that animals should receive a tablet for

the nearest 91 kg (200 pounds) of body weight.{R-5}


U.S.—


12.5 grams (Rx) [Albon SR].

Canada—



Withdrawal times:

U.S.—

Withdrawal time

Species Meat (days)

Cattle 21

Note: Product labeling listing the above withdrawal time states that they

are not labeled for use in lactating dairy cattle or preruminating

calves.{R-5}





manufacturer.





SULFADIMETHOXINE INJECTIONUsual dose:

Bacterial respiratory infections1;

Cystitis1; or

Skin and soft tissue infections1—Cats and dogs: Intravenous or subcu-

taneous, 55 mg per kg of body weight as an initial dose, followed by

27.5 mg per kg of body weight every twenty-four hours.{R-3}

Calf diphtheria1;


Necrotic pododermatitis1—Cattle: Intravenous, 55 mg per kg of body

weight as an initial dose, followed by 27.5 mg per kg of body weight

every twenty-four hours.{R-3}

Enteritis associated with coccidiosis or Salmonella1—Dogs: Intravenous

or subcutaneous, 55 mg per kg of body weight as an initial dose,

followed by 27.5 mg per kg of body weight every twenty-four

hours.{R-3}

Note: Intramuscular injection can cause local pain and inflammation

and result in lower serum concentrations of sulfadimethoxine.{R-3}


U.S.—


400 mg per mL (Rx) [Albon Injection 40%; AmTech Sulfadime-

thoxine Injection-40%; Di-Methox Injection-40%; SDM Injection;

generic].

Canada—



Withdrawal times:

U.S.—{R-3}

Withdrawal time


Cattle 5 60


withdrawal times have not been established for use in preruminating

calves.



Stability: Crystallization does not change the potency of sulfadime-

thoxine injection.{R-3}



manufacturer. Protect from light.


SULFAMETHAZINE

SUMMARY OF DIFFERENCESPharmacology/pharmacokinetics: Intermediate duration of action{R-19}.




SULFAMETHAZINE ORAL SOLUTIONUsual dose:

Calf diphtheria; or

Necrotic pododermatitis—Calves and cattle: Oral, 247.5 mg per kg of


weight every twenty-four hours for three days, administered in the

only source of drinking water{R-12}.

Coccidiosis—

Chickens: Oral, 134 to 196 mg per kg of body weight a day for two

days, followed by 67 to 98 mg per kg of body weight for four days,

administered in the only source of drinking water{R-12}.

Turkeys: Oral, 117 to 286 mg per kg of body weight a day for two

days, followed by 58.5 to 143 mg per kg of body weight for four

days, administered in the only source of drinking water{R-12}.

Enteritis, bacterial—

Calves, cattle, and pigs: Oral, 247.5 mg per kg of body weight as an

initial dose, followed by 123.8 mg per kg of body weight every

twenty-four hours for three days, administered in the only source

of drinking water{R-12}.

[Sheep]: Oral, 225 mg per kg of body weight the first day, followed by

112.5 mg per kg of body weight for three days, administered in the

only source of drinking water{R-16}.

Fowl cholera, acute; or

Pullorum disease—Chickens: Oral, 134 to 196 mg per kg of body

weight a day for six days, administered in the only source of drinking

water{R-12}.

Infectious coryza—Chickens: Oral, 134 to 196 mg per kg of body

weight a day for two days, administered in the only source of

drinking water{R-12}.

Pneumonia, bacterial—Calves, cattle, and pigs: Oral, 247.5 mg per kg

of body weight as an initial dose, followed by 123.8 mg per kg of

body weight every twenty-four hours for three days, administered in

the only source of drinking water{R-12}.

Respiratory infections, bacterial—[Sheep]: Oral, 225 mg per kg of body

weight the first day, followed by 112.5 mg per kg of body weight for

three days, administered in the only source of drinking water{R-16}.


U.S.—


125 mg per mL (OTC) [Sulmet Drinking Water Solution 12.5%].







Canada—


125 mg per mL (OTC) [generic].

250 mg per mL (OTC) [Sulfa ‘‘25’’; Sulfa 25%; generic].

Withdrawal times:

U.S.—

Withdrawal time

Species Meat (days)

Cattle, chickens, turkeys 10

Pigs 15


they apply when administered for a maximum of five days in cattle

or pigs. Products are not labeled for use in chickens and turkeys

producing eggs for human consumption, calves less than 1 month

of age or fed an all-milk diet, or dairy cows 20 months of age or

older.

Canada—

Withdrawal time


Cattle 10 or 12, depending on product 96

Calves, pigs, sheep 10 or 12, depending on product

Chickens, turkeys 12


are not labeled for use in laying birds or for use in swine feeds.







SULFAMETHAZINE POWDER FOR ORAL SOLUTIONUsual dose:


Necrotic pododermatitis1—Cattle: Oral, 237.6 mg per kg of body weight

as an initial dose, followed by 118.8 mg per kg of body weight every

twenty-four hours for three days, administered as an individual

animal drench or in the only source of drinking water{R-9}.

Coccidiosis1—

Chickens: Oral, 128 to 187 mg per kg of body weight a day for two

days, followed by 64 to 93.5 mg per kg of body weight for four days,

administered in the only source of drinking water{R-9}.

Turkeys: Oral, 110 to 273 mg per kg of body weight a day for two

days, followed by 55 to 136.5 mg per kg of body weight for four

days, administered in the only source of drinking water{R-9}.

Enteritis, bacterial1; or

Pneumonia, bacterial1—Cattle and pigs: Oral, 237.6 mg per kg of body

weight as an initial dose, followed by 118.8 mg per kg of body weight

every twenty-four hours for three days, administered as an individ-

ual animal drench or in the only source of drinking water{R-9}.

Fowl cholera, acute1; or

Pullorum disease1—Chickens: Oral, 128 to 187 mg per kg of body

weight a day for six days, administered in the only source of drinking

water{R-9}.

Infectious coryza1—Chickens: Oral, 128 to 187 mg per kg of body

weight a day for two days, administered in the only source of

drinking water{R-9}.


U.S.—


453.5 grams of sulfamethazine powder per packet (OTC) [Sulmet

Soluble Powder].

Canada—



Withdrawal times:

U.S.{R-9}—

Withdrawal time

Species Meat (days)

Calves, cattle, chickens, turkeys 10

Pigs 15


they apply when administered for a maximum of five days in cattle

or pigs. Products are not labeled for use in chickens and turkeys

producing eggs for human consumption, calves less than 1 month

of age or fed all-milk diets, or dairy cows 20 months of age or

older.



manufacturer.

Preparation of dosage form: Fresh solutions should be prepared

daily.{R-12}




SULFAMETHAZINE TABLETSUsual dose:

Calf diphtheria—Calves: Oral, 220 mg per kg of body weight as an

initial dose, followed by 110 mg per kg of body weight every twenty-

four hours{R-13}.

Enteritis associated with Escherichia coli—Calves and foals: Oral, 220

mg per kg of body weight as an initial dose, followed by 110 mg per


Pneumonia, bacterial—Calves and foals: Oral, 220 mg per kg of body

weight as an initial dose, followed by 110 mg per kg of body weight





U.S.—


2.5 grams (OTC) [Sulmet Oblets].

5 grams (OTC) [Sulmet Oblets].

Canada—


15 grams (OTC) [generic].

15.6 grams (OTC) [generic].

Withdrawal times:

U.S.—

Withdrawal time

Species Meat (days)

Calves, cattle 10


applies to a maximum of five days treatment. Products are not labeled for

use in calves less than 1 month of age or those fed an all-milk diet, female

dairy cattle 20 months of age or older, or horses intended for food.

Canada—

Withdrawal time


Calves, cattle{R-8} 10 96


apply to a maximum of five days treatment. Products are not labeled

for use in calves less than 1 month of age or those fed an all-milk diet,

or horses intended for food.



manufacturer.




SULFAMETHAZINE EXTENDED-RELEASE TABLETSUsual dose:

Calf diphtheria;

Coccidiosis;

Enteritis, bacterial; or


Calves, 1 month of age or older: Oral, 350 to 400 mg per kg of body

weight, administered as a single dose{R-7; 11}. The dose may be

repeated in three days, if necessary{R-7; 11}.

Cattle: Oral, 330 to 350 mg per kg of body weight as a single dose{R-10}.

The dose may be repeated in three days, if necessary{R-11}.

Necrotic pododermatitis—Cattle: Oral, 330 to 350 mg per kg of body

weight as a single dose{R-10}. The dose may be repeated in three days,

if necessary{R-11}.

Note: Tablets can be broken at the score line, but should not be

crushed.


U.S.{R-7; 10; 11}—


8 grams (OTC) [Sulfa-Max III Calf Bolus; Sustain III Calf Bolus].

8.25 grams (OTC) [Sulfasure SR Calf Bolus; Suprasulfa III Calf Bolus].

30 grams (OTC) [Sulfasure SR Cattle Bolus; Suprasulfa III Cattle Bolus].

32.1 grams (OTC) [Sulfa-Max III Cattle Bolus; Sustain III Cattle Bolus]

Canada—


8 grams (OTC) [Calfspan].

8.25 grams (OTC) [Sulfasure SR Calf Tablets].

32.1 grams (OTC [Sustain III].

Withdrawal times:

U.S.{R-7; 10}—

Withdrawal time

Species Meat (days)

Calves, ruminating and cattle 8 or 12, depending on product


apply to animals given a maximum of two doses. Products are not

labeled for use in calves less than 1 month of age, calves fed an all-milk

diet, or dairy cattle 20 months of age or older.

Canada—

Withdrawal time

Species Meat (days)

Cattle 8, 12, or 28, depending on

product


are not labeled for use in lactating dairy cattle.



manufacturer.




SULFAMETHAZINE, SULFANILAMIDE, ANDSULFATHIAZOLE




SULFAMETHAZINE, SULFANILAMIDE,AND SULFATHIAZOLE TABLETSUsual dose:

[Bacterial enteritis];

[Bacterial pneumonia];

[Calf diphtheria]; or





[Necrotic pododermatitis]—Cattle: Oral, 48.8 mg sulfamethazine, 73

mg sulfanilamide, and 73 mg sulfathiazole per kg of body weight as

an initial dose, followed by 24.4 mg sulfamethazine, 36.5 mg

sulfanilamide, and 36.5 mg sulfathiazole per kg of body weight,

administered twelve hours later.{R-97}


U.S.—



Canada—{R-97}


3.9 grams sulfamethazine, 5.85 grams sulfanilamide, and 5.85

grams sulfathiazole (OTC) [Triple Sulfa Bolus].

Withdrawal times:

Canada—

Withdrawal time


Cattle 10 96



manufacturer. Protect from moisture.




SULFAMETHAZINE AND SULFATHIAZOLE




SULFAMETHAZINE AND SULFATHIAZOLE POWDERFOR ORAL SOLUTIONUsual dose:

[Enteritis]—Cattle and pigs: Oral, 144 mg of sulfamethazine and 72 mg

of sulfathiazole per kg of body weight as an initial dose, followed by

72 mg of sulfamethazine and 36 mg of sulfathiazole per kg of body

weight a day for three days, administered as an individual animal

drench or in the only source of drinking water{R-15}.

[Pneumonia, bacterial]; or

[Pododermatitis]—Cattle: Oral, 144 mg of sulfamethazine and 72 mg

of sulfathiazole per kg of body weight as an initial dose, followed by

72 mg of sulfamethazine and 36 mg of sulfathiazole per kg of body

weight a day for three days, administered as an individual animal

drench or in the only source of drinking water{R-15}.

[Respiratory infections, bacterial]—Pigs: Oral, 144 mg of sulfameth-

azine and 72 mg of sulfathiazole per kg of body weight as an initial

dose, followed by 72 mg of sulfamethazine and 36 mg of sulfathiazole

per kg of body weight a day for three days, administered as an

individual animal drench or in the only source of drinking

water{R-15}.


U.S.—



Canada—


630 mg sulfamethazine and 315 mg of sulfathiazole per gram of

powder (OTC) [2 Sulfamed; S-M-T; Sulfa-MT].

641 mg sulfamethazine and 320 mg of sulfathiazole per gram of

powder (OTC) [Sulfalean Powder].

667 mg of sulfamethazine and 333 mg of sulfathiazole per gram of

powder (OTC) [Powder 21; Sulfa 2 Soluble Powder].

Withdrawal times:

Canada—

Withdrawal time


Cattle 10 96

Pigs 10

Note: Some products are not labeled for use in lactating dairy cattle.



manufacturer. Protect from moisture.{R-15}


intake during the treatment period. These products should not be

administered in animal feeds.


SULFAQUINOXALINE

SUMMARY OF DIFFERENCESPharmacology/pharmacokinetics: Sulfaquinoxaline is minimally absorbed

systemically and is referred to as an enteric sulfonamide.{R-19}

Side/adverse effects: Clotting disorders similar to those resulting from

coumarin anticoagulants have been reported in chickens and

dogs.{R-46–50}

ORAL DOSAGE FORMS

SULFAQUINOXALINE ORAL SOLUTION USPUsual dose:

Acute fowl cholera; or

Acute fowl typhoid—Chickens and turkeys: Oral, a 0.04% solution,

administered in the only source of drinking water for two to three

days{R-14}.

Coccidiosis—

Calves1 and cattle1: Oral, 13.2 mg per kg of body weight a day,

administered in the only source of drinking water as a 0.015%

solution for three to five days{R-14}.

Chickens: Oral, a 0.04% solution, administered in the only source of

drinking water for two to three days{R-14}. Treatment should be

stopped for three days, then the medication readministered as a



0.025% solution for two to four more days. The schedule may be

repeated, if necessary{R-14}.

Turkeys: Oral, a 0.025% solution of sulfaquinoxaline, administered as

the only source of drinking water for two days. Treatment should

be stopped for three days, then the medication readministered as a

0.025% solution for two days; treatment is then stopped for three

days, then medication is readministered as the 0.025% solution for

two final days. The complete schedule may be repeated, if

necessary{R-14}.

Note: For treatment of coccidiosis in chickens and turkeys, it is

recommended that litter not be changed until absolutely necessary.


U.S.—


200 mg per mL (OTC) [Sulfa-Q 20%; generic].

319.2 mg per mL (OTC) [Optimed; 31.92% Sul-Q-Nox].

Canada—


192 mg per mL (OTC) [generic].

Withdrawal times:

U.S.—

Withdrawal time

Species Meat (days)

Calves, cattle, chickens, turkeys 10

Note: Products are not labeled for use in chickens and turkeys laying

eggs for human consumption, preruminant calves, or lactating dairy

cattle.

Canada—

Withdrawal time

Species Meat (days)

Chickens, turkeys 12

Note: Products are not labeled for use in chickens and turkeys laying eggs


Preparation of dosage form: Fresh solutions should be prepared

daily. To help avoid toxic reactions, the medication should be evenly

mixed in drinking water.

Caution: People who handle this medication should avoid contact with

eyes, skin, or clothing to prevent eye and skin burns. In case of con-

tact, the areas affected should be flushed for at least fifteen minutes;

medical attention should be sought for eye exposure.{R-14} Keep out of

the reach of children.{R-14}



manufacturer. Protect from moisture.{R-15}



Chickens: Prolonged administration of sulfaquinoxaline may result in

deposition of crystals in the kidney or interference with normal blood

clotting.{R-14; 95} Sulfaquinoxaline levels of greater than 0.012% in

drinking water for more than twenty-four to thirty-six hours may

result in reduced growth rate from decreased feed or water consump-

tion.{R-14; 95}

USP requirements: Preserve in tight, light-resistant containers. Label

it to indicate that it is for veterinary use only. Contains the equivalent

of the labeled concentration of sulfaquinoxaline, within ±10%. Meets

the requirements for Identification, Deliverable volume and pH (not

less than 12){R-56}.

Developed: 07/01/97


REFERENCES1. Sulfadimethoxine package insert (Albon bolus, Roche—US), Rec 1/16/96.

2. Sulfadimethoxine product information (Albon 12.5% Drinking Water Solu-

tion, SmithKline Beecham—US), Rev 9/93, Rec 11/27/95.

3. Sulfadimethoxine product information (Albon Injection 40%, SmithKline


4. Sulfadimethoxine product information (Albon Soluble Powder, SmithKline


5. Sulfadimethoxine package label (Albon SR, Roche—US), Rec 1/16/96.

6. Sulfadimethoxine product information (Albon Tablets and Oral Suspension,

SmithKline Beecham—US), Rev 9/93, Rec 11/27/95.

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8. Sulfamethazine product information (Sulfamethazine bolus, PVL—Canada),

Rec 12/1/95.

9. Sulfamethazine package insert (Sodium Sulfamethazine Soluble Powder,

Durvet—US), Rec 10/19/95.

10. Sulfamethazine package insert (Sustain III, Durvet—US), Rec 10/19/95.

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58. Srivastava AK, Rampal S. Disposition kinetics and dosage regimen of

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65. Righter HF, Showalter DH, Teske RH. Comparative plasma kinetics of orally

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67. Duffee NE, Bevill RF, Thurman JC, et al. Pharmacokinetics of sulfamethazine

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68. Ashworth RB, Epstein RL, Thomas MH, et al. Sulfamethazine blood/tissue

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70. Van Poucke LSG, Van Peteghem CH. Pharmacokinetic and tissue residues of

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77. Paulson GD, Feil VJ, Zaylskie RG, et al. Depletion of residues from milk and

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95.

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3/95.

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21, PVL—Canada), Rev 9/94, Rec 12/1/95.

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63.






TETRACYCLINES Veterinary—Systemic

This monograph includes information on the following: Chlortetracy-

cline; Doxycycline; Oxytetracycline; Tetracycline.



Agrimycin 100 [Oxytetracycline] Oxytet-250 Concentrate [Oxytetracycline]

Agrimycin 200 [Oxytetracycline] Oxytetra-A [Oxytetracycline]

Agrimycin-343 [Oxytetracycline] Oxytetracycline 50 [Oxytetracycline]

Alamycin LA [Oxytetracycline] Oxytetracycline 100 [Oxytetracycline]

AmTech Chlortetracycline HCL

Soluble Powder [Chlortetracycline]

Oxytetracycline 200 [Oxytetracycline]

AmTech Maxim-100 [Oxytetracycline] Oxytetracycline 100LP [Oxytetracycline]

AmTech Maxim-200 [Oxytetracycline] Oxy Tetra Forte [Oxytetracycline]

Oxytetramycin 100 [Oxytetracycline]

AmTech Oxytetracycline HCL

Soluble Powder [Oxytetracycline]

Oxytet-25-S [Oxytetracycline]

AmTech Oxytetracycline HCL

Soluble Powder-343 [Oxytetracycline]

Oxytet Soluble [Oxytetracycline]

AmTech Tetracycline Hydrochloride

Soluble Powder-324 [Tetracycline]

Oxytet-SP [Oxytetracycline]

Aureomycin 110G [Chlortetracycline] Oxytet-343 Water Soluble Powder

[Oxytetracycline]

Aureomycin 220G [Chlortetracycline] Oxyvet 200 LA [Oxytetracycline]

Aureomycin 50 Granular

[Chlortetracycline]

Oxyvet 100 LP [Oxytetracycline]


[Chlortetracycline]

Panmycin Aquadrops [Tetracycline]


[Chlortetracycline]

Pennchlor 50ÆG [Chlortetracycline]

Aureomycin Soluble Powder

[Chlortetracycline]

Pennchlor 90ÆG [Chlortetracycline]

Aureomycin Soluble Powder

Concentrate [Chlortetracycline]

Pennchlor 100 Hi-Flo Meal

[Chlortetracycline]

Aureomycin Uterine Oblets

[Chlortetracycline]

Pennchlor 50 Meal [Chlortetracycline]

Biomycin 200 [Oxytetracycline] Pennchlor 70 Meal [Chlortetracycline]

Calf Scour Bolus Antibiotic

[Tetracycline]

Pennchlor 100 MR [Chlortetracycline]

Chlor 50 [Chlortetracycline] Pennchlor 64 Soluble Powder

[Chlortetracycline]

Chlor 100 [Chlortetracycline] Pennox 100 Hi-Flo Meal

[Oxytetracycline]

ChlorMax 50 [Chlortetracycline] Pennox 200 Hi-Flo Meal [Oxytetracycline]

Chlorosol-50 [Chlortetracycline] Pennox 200 Injectable [Oxytetracycline]

CLTC 100 MR [Chlortetracycline] Pennox 50 Meal [Oxytetracycline]

CTC 50 [Chlortetracycline] Pennox 100-MR [Oxytetracycline]

CTC Soluble Powder Concentrate

[Chlortetracycline]

Pennox 343 Soluble Powder

[Oxytetracycline]

Duramycin 10 [Tetracycline] PolyOtic Soluble Powder [Tetracycline]

Duramycin 72-200 [Oxytetracycline] Promycin 100 [Oxytetracycline]

Duramycin 100 [Oxytetracycline] Solu-Tet [Tetracycline]

Duramycin-324 [Tetracycline] Solu-Tet 324 [Tetracycline]

Foul Brood Mix [Oxytetracycline] Terramycin 50 [Oxytetracycline]

Geomycin 200 [Oxytetracycline] Terramycin 100 [Oxytetracycline]

Kelamycin [Oxytetracycline] Terramycin 200 [Oxytetracycline]

Liquamycin LA-200 [Oxytetracycline] Terramycin-50 [Oxytetracycline]

Maxim-200 [Oxytetracycline] Terramycin-100 [Oxytetracycline]

Onycin 62.5 [Tetracycline] Terramycin-200 [Oxytetracycline]

Onycin 250 [Tetracycline] Terramycin-Aqua [Oxytetracycline]

Onycin 1000 [Tetracycline] Terramycin 100 For Fish

[Oxytetracycline]

OT 200 [Oxytetracycline] Terramycin Scours Tablets

[Oxytetracycline]

OTC 50 [Oxytetracycline] Terramycin Soluble Powder

[Oxytetracycline]

OXTC 50 [Oxytetracycline] Terramycin-343 Soluble Powder

[Oxytetracycline]

OXTC 100 [Oxytetracycline] Terra-Vet 100 [Oxytetracycline]

OXTC 200 [Oxytetracycline] Terra-Vet Soluble Powder

[Oxytetracycline]

Oxy-110 [Oxytetracycline] Terra-Vet Soluble Powder 343

[Oxytetracycline]

Oxy-220 [Oxytetracycline] Tet-324 [Tetracycline]

Oxy 250 [Oxytetracycline] Tetra 55 [Tetracycline]

Oxy-440 [Oxytetracycline] Tetra 250 [Tetracycline]

Oxy 1000 [Oxytetracycline] Tetra 1000 [Tetracycline]

Oxybiotic-100 [Oxytetracycline] Tetra 4000 [Tetracycline]

Oxybiotic-200 [Oxytetracycline] Tetra Bac 324 [Tetracycline]

Oxy 500 Calf Bolus [Oxytetracycline] Tetrabol [Tetracycline]

Oxy 1000 Calf Bolus [Oxytetracycline] Tetracycline 250 [Tetracycline]

Oxycure 100 [Oxytetracycline] Tetracycline 1000 [Tetracycline]

Oxycure 200 [Oxytetracycline] Tetracycline 250 Concentrate

Soluble Powder [Tetracycline]

Oxy LA [Oxytetracycline] Tetracycline 62.5 Soluble Powder

[Tetracycline]

Oxy LP [Oxytetracycline] Tetradure LA 300 [Oxytetracycline]

Oxy-Mycin 100 [Oxytetracycline] Tetraject LA [Oxytetracycline]

Oxy-Mycin 200 [Oxytetracycline] Tetraject LP [Oxytetracycline]

Oxymycine LA [Oxytetracycline] Tetramed 250 [Tetracycline]

Oxymycine LP [Oxytetracycline] Tetramed 1000 [Tetracycline]

Oxyshot LA [Oxytetracycline] Tetrasol Soluble Powder [Tetracycline]

Oxysol-62.5 [Oxytetracycline] Tetravet-CA [Oxytetracycline]

Oxysol-110 [Oxytetracycline] Tet-Sol 10 [Tetracycline]

Oxysol-220 [Oxytetracycline] Tet-Sol 324 [Tetracycline]

Oxysol-250 [Oxytetracycline] Tetroxy-100 [Oxytetracycline]

Oxysol-440 [Oxytetracycline] Tetroxy HCA Soluble Powder

[Oxytetracycline]

Oxysol-1000 [Oxytetracycline] 5-Way Calf Scour Bolus [Tetracycline]

For human-labeled products—

Achromycin V [Tetracycline] Novo-Doxylin [Doxycycline]

Alti-Doxycycline [Doxycycline] Novo-Tetra [Tetracycline]

Apo-Doxy [Doxycycline] Nu-Doxycycline [Doxycycline]

Apo-Doxy-Tabs [Doxycycline] Nu-Tetra [Tetracycline]

Apo-Tetra [Tetracycline] Vibramycin [Doxycycline]

Doryx [Doxycycline] Vibra-Tabs [Doxycycline]

Doxycin [Doxycycline] Vibra-Tabs C-Pak [Doxycycline]

Doxytec [Doxycycline]



CATEGORY:Antibacterial (systemic); antiprotozoal; antirickettsial.




GENERAL CONSIDERATIONSThe tetracyclines are broad-spectrum antibiotics with activity against

gram-positive and gram-negative bacteria, including some anaerobes.

They are also active against chlamydia, mycoplasmas, some proto-

zoa{R-28; 133}, and several rickettsiae, including Anaplasma, Ehrlichia,

and Haemobartonella. The activity range of the tetracyclines also

includes Escherichia coli, Klebsiella species, Pasteurella species, Salmo-

nella species, Staphylococcus species, and Streptococcus species{R-4}.

Susceptibility testing has demonstrated that some coliforms, myco-

plasma, streptococci, and staphylococci have developed resistance to

tetracyclines{R-21; 150}. However, the breakpoints used to classify these

organisms as susceptible or resistant are not validated for animal

indications. Susceptibility testing should not be the sole basis for

selecting tetracyclines for therapy{R-65}.

TETRACYCLINES Veterinary—Systemic 225


ACCEPTEDAbortion, vibrionic (prophylaxis)1—Sheep: Chlortetracycline for medi-

cated feed{R-16; 152} is indicated to aid in reduction of the incidence of

vibrionic abortion caused by susceptible Campylobacter fetus.

Abscesses, cervical (prophylaxis)1—Pigs: Chlortetracycline for medicated

feed{R-152} is indicated for reduction of the incidence of cervical

abscesses caused by susceptible organisms.

Abscesses, hepatic (prophylaxis)1—Cattle: Chlortetracycline for medi-

cated feed{R-16; 152} is indicated as an aid in the prevention of hepatic

abscesses in cattle.

Actinobacillosis (treatment)1—Cattle: Oxytetracycline injection{R-45} is

indicated in the treatment of actinobacillosis (wooden tongue) caused

by susceptible Actinobacillus lignieresii.

Anaplasmosis (treatment)1—Cattle: Chlortetracycline for medicated

feed{R-16; 152} is indicated in the control of active infection caused

by susceptible Anaplasma marginale.

Diphtheria (treatment)1—Cattle: Oxytetracycline injection{R-24; 45} is

indicated in the treatment of diphtheria (necrotic laryngitis, necrotic

necrophorus stomatitis) caused by susceptible Fusobacterium necropho-

rum.

Enteritis, bacterial (treatment)—The treatment of enteritis should be

dependent on a specific diagnosis and knowledge of pathogen

susceptibility to tetracyclines. Some pathogens associated with enter-

itis, such as Escherichia coli, are found to be resistant to the

tetracyclines.

Calves: Chlortetracycline soluble powder1, oxytetracycline tablets{R-

60}, and tetracycline boluses and soluble powder{R-1} are indicated

in the control of bacterial enteritis (scours) caused by suscep-

tible E. coli. Chlortetracycline for medicated feed{R-16; 152} and

soluble powder; oxytetracycline for medicated feed{R-117}, injection,

soluble powder, and tablets1{R-23; 24; 60; 61}; and tetracycline

bolus and soluble powder{R-1; 18} are indicated in the treatment of

bacterial enteritis caused by susceptible E. coli and Salmonella

species.

Cattle: Chlortetracycline for medicated feed1{R-16; 152} and oxy-

tetracycline for medicated feed1{R-117}, injection1{R-45}, and soluble

powder{R-61} are indicated in the treatment of bacterial enteritis

caused by susceptible E. coli and Salmonella{R-11}.

Pigs: Chlortetracycline soluble powder1{R-17}, oxytetracycline soluble

powder{R-11; 54}, and tetracycline powder for oral solution{R-18} are

indicated in the control and treatment of bacterial enteritis caused

by susceptible E. coli. Chlortetracycline for medicated feed{R-16; 152}

and oxytetracycline injection{R-24; 45} and for medicated feed{R-117}

are indicated in the treatment of bacterial enteritis (scours) caused

by susceptible E. coli and Salmonella.

Sheep: Oxytetracycline for medicated feed1{R-117} and soluble pow-

der{R-54; 61} and [tetracycline soluble powder]{R-18} are indicated in

the treatment of enteritis caused by susceptible organisms.

Turkeys, growing: Chlortetracycline soluble powder1{R-17} and oxytet-

racycline soluble powder{R-11; 54} are indicated in the control of

susceptible organisms involved in the development of enteritis

(bluecomb).

Turkeys: Chlortetracycline for medicated feed{R-16; 152} and [powder for

oral solution]{R-17} and tetracycline soluble powder{R-18; 19} are

indicated in the control and treatment of enteritis caused by

susceptible organisms. Oxytetracycline for medicated feed{R-117} is

indicated in the treatment of susceptible E. coli involved in the

development of enteritis (bluecomb).

[Chickens]: Oxytetracycline soluble powder{R-54} and chlortetracycline

for medicated feed are indicated in the treatment of susceptible E. coli

involved in the development of enteritis.

[Lambs]: Oxytetracycline for medicated feed{R-26} is indicated in

the reduction of bacterial enteritis in creep-fed suckling lambs.

Escherichia coli infections (treatment)1—Chickens: Chlortetracycline for

medicated feed{R-16; 115; 152} is indicated as an aid in reducing

mortality due to E. coli infections.

Feed efficiency, improved; or

Weight gain, increased rate—Calves1, cattle1, chickens, pigs, sheep1, and

turkeys: Chlortetracycline for medicated feed{R-16; 152} and oxy-

tetracyline for medicated feed1{R-117} are indicated for growth promo-

tion and feed efficiency.

Foul brood (treatment)—Bees: Oxytetracycline for medicated feed{R-117}

and soluble powder{R-61; 117} are indicated in the treatment of

American and European foul brood caused by susceptible organisms.

Fowl cholera (prophylaxis)—Chickens: Oxytetracycline for medicated

feed{R-122} and soluble powder1{R-61; 122} are indicated in the

prevention of fowl cholera caused by susceptible organisms.

Fowl cholera (treatment)—

Chickens: Chlortetracycline soluble powder1 and oxytetracycline for

medicated feed1{R-117} and soluble powder{R-11} are indicated in the

control of mortality from fowl cholera caused by susceptible

Pasteurella multocida{R-80}. [Tetracycline soluble powder{R-18} is

indicated in the treatment of fowl cholera caused by susceptible

organisms.]

Ducks1: Chlortetracycline for medicated feed{R-152} is indicated as an

aid in the control and treatment of fowl cholera caused by susceptible

Pasteurella multocida.

Furunculosis (treatment)—Salmonids (salmon and trout): Oxytetracy-

cline for medicated feed{R-62; 124} is indicated in the control of

furunculosis caused by susceptible Aeromonas salmonicida.

Gaffkemia (treatment)—Lobsters: Oxytetracycline for medicated feed{R-27;

124} is indicated in the treatment of gaffkemia caused by susceptible

Aerococcus viridans.

Gastroenteritis (treatment)1—Cats and dogs: Tetracycline oral suspen-

sion{R-4} is indicated in the treatment of bacterial gastroenteritis, but

use should be reserved for treatment of organisms known to be

susceptible.

Hemorrhagic septicemia, bacterial (treatment)1—Catfish and salmonids:

Oxytetracycline for medicated feed{R-62; 124} is indicated in the control

of hemorrhagic septicemia caused by susceptible Aeromonas hydrophila,

A. sobia, and Pseudomonas species{R-173}.

Hexamitiasis (treatment)—Turkeys: Chlortetracycline for medicated

feed1{R-16; 152} and oxytetracycline for medicated feed1{R-117} are

indicated in the control of hexamitiasis, and oxytetracycline soluble

powder1{R-11; 61} and [tetracycline soluble powder]{R-18} are indicated

in the treatment of hexamitiasis caused by susceptible Hexamita

meleagridis.

Keratoconjuntivitis, infectious (treatment)—Cattle: Long-acting oxytet-

racycline injection{R-45} is indicated in the treatment of keratocon-

junctivitis caused by susceptible Moraxella bovis.

Leptospirosis (treatment)—

Pigs: Chlortetracycline for medicated feed1{R-16; 152} and oxytetracy-

cline for medicated feed{R-122} are indicated to aid in reducing the

shedding of leptospirosis and the incidence of abortion. Oxytetracy-

cline for medicated feed is indicated as an aid in the reduction of

abortion and urinary shedding of leptospirosis, production of

226 TETRACYCLINES Veterinary—Systemic


healthier newborn pigs, and maintenance of weight gains in the

presense of leptospirosis{R-122}. Oxytetracycline injection{R-24; 45}

and soluble powder{R-11} are indicated in the treatment of leptospi-

rosis caused by susceptible Leptospira pomona. Oxytetracycline can

reduce the incidence of abortions and shedding of leptospira;{R-11}

however, it can be ineffective in eliminating the organism{R-113}.

Cattle: Oxytetracycline injection{R-24; 45} is indicated in the treatment

of leptospirosis caused by susceptible Leptospira pomona.

Paratyphoid (treatment)1—Turkeys, less than 4 weeks of age: Chlortet-

racycline for medicated feed{R-16; 152} is indicated as an aid in reducing

mortality from paratyphoid infection caused by susceptible Salmonella

typhimurium.

Pneumonia, bacterial (prophylaxis)—Cattle: Oxytetracycline for medi-

cated feed1{R-117; 122} is indicated in the prevention of pneumonia and

as an aid in the reduction of losses due to bovine respiratory disease

complex.


Calves:Chlortetracycline soluble powder1, oxytetracycline tablets1{R-60},

and tetracycline boluses{R-1} are indicated in the control of

pneumonia and bovine respiratory disease complex caused by

susceptible organisms, including Pasteurella species. Chlortetracy-

cline soluble powder; oxytetracycline injection, soluble powder, and

tablets1{R-60; 61}; and tetracycline boluses and soluble powder{R-1;

18} are indicated in the treatment of pneumonia caused by

susceptible organisms, including Pasteurella species. However, due

to resistance{R-51; 171; 180} by pathogens, the tetracyclines may no

longer be effective in the treatment of some types of bacterial

pneumonia.

Cattle: Chlortetracycline for medicated feed{R-152} is indicated in the

control1 and treatment of pneumonia caused by susceptible organ-

isms. Oxytetracycline{R-24; 45; 61} is indicated in the treatment of

pneumonia and shipping fever complex caused by susceptible

Pasteurella and Haemophilus species. Increasing resistance to tetra-

cyclines by strains of organisms involved in bovine pneumonia is

reported{R-51; 171; 180}.

Pigs: Chlortetracycline soluble powder1{R-17} is indicated in the control

of pneumonia caused by susceptible Actinobacillus pleuropneumoniae

(Haemophilus species), Pasteurella species, and Klebsiella species.

Chlortetracycline for medicated feed1{R-152} and oxytetracycline

soluble powder are indicated in the treatment of pneumonia caused

by susceptible Pasteurella multocida. Chlortetracycline soluble pow-

der{R-17}, oxytetracycline injection{R-24; 45}, and tetracycline soluble

powder{R-1; 18} are indicated in the treatment of pneumonia caused

by susceptible Actinobacillus pleuropneumonia (Haemophilus species),

Klebsiella, and Pasteurella species. Increasing resistance to tetracy-

cline by strains of organisms involved in porcine pneumonia is

reported{R-50}.

Sheep: Oxytetracycline for medicated feed1{R-117}, [injection]{R-24; 121},

and soluble powder{R-6; 13}, and [tetracycline soluble powder]{R-18}

are indicated in the treatment of pneumonia caused by susceptible

organisms.

Pododermatitis (treatment)—Cattle: Long-acting oxytetracycline injec-

tion{R-24; 45} is indicated in the treatment of pododermatitis (‘foot rot’)

caused by susceptible Fusobacterium necrophorum. Signs may not be

completely resolved by oxytetracycline alone and other treatment or

surgery may be required.

Pseudomonas disease (treatment)1—Catfish and salmonids: Oxytetracy-

cline for medicated feed{R-62} is indicated in the control of pseudomo-

nas disease caused by susceptible organisms.

Psittacosis (treatment)1—Cockatoos, macaws, and parrots: Chlortetracy-

cline for medicated feed{R-152} is indicated in the treatment of

psittacosis caused by susceptible Chlamydia psittaci.

Respiratory disease, bacterial, chronic (prophylaxis)—Chickens: Oxytet-

racycline for medicated feed{R-122} is indicated in the prevention of

chronic respiratory disease caused by susceptible organisms.

Respiratory disease, bacterial, chronic (treatment)—Chickens: Chlortet-

racycline for medicated feed and soluble powder1{R-16; 17; 152},

oxytetracycline for medicated feed1 and soluble powder{R-11; 22}, and

tetracycline soluble powder{R-18; 127} are indicated in the control of

respiratory disease, including air sac disease, caused by susceptible

Mycoplasma gallisepticum and E. coli. Chlortetracycline for medicated

feed{R-16; 115} and powder for oral solution{R-17} are indicated in the

treatment of chronic respiratory disease caused by susceptible organ-

isms.

Skeletal tissue marking1—Salmon, Pacific: Oxytetracycline for medicated

feed{R-117} is indicated to mark skeletal tissue in Pacific salmon.

Skin and soft tissue infections (treatment)1—Cattle:{R-45} Oxytetracycline

injection is indicated in the treatment of wounds infected by

susceptible Staphylococcus species or Streptococcus species.

Synovitis, infectious (treatment)—Chickens and turkeys: Chlortetracycline

for medicated feed1{R-16; 152} and soluble powder1{R-17}, oxytetracy-

cline for medicated feed{R-117} and soluble powder{R-11}, and tetracy-

cline soluble powder{R-3} are indicated in the control of infectious

synovitis caused by susceptible Mycoplasma synoviae. Chlortetracycline

powder for oral solution{R-17} is indicated in the treatment of infectious

synovitis caused by susceptible M. synoviae.

Ulcer disease (treatment)—Salmonids (salmon, trout): Oxytetracycline for

medicated feed{R-62; 124} is indicated in the control of ulcer disease

caused by susceptible Haemophilus piscium.

Urinary tract infections (treatment)1—Cats and dogs: Tetracycline oral

suspension{R-4} is indicated in the treatment of urinary tract infections

caused by susceptible Staphylococcus species and E. coli. Also, concen-

trations of tetracycline in urine are high enough to be effective against

Pseudomonas species{R-150}.

Uterine infections, acute (treatment)—

Cattle: Oxytetracycline injection{R-24; 45} is indicated in the treatment

of acute metritis caused by susceptible strains of Staphylococcus and

Streptococcus species.

[Pigs]: Oxytetracycline injection{R-24} is indicated in the treatment of

acute metritis caused by susceptible organisms.

[Sheep]: Oxytetracycline injection{R-24; 121} is indicated in the treat-

ment of uterine infections.

[Arthritis, bacterial (treatment)]—Cattle and sheep: Oxytetracycline

injection{R-24; 25} is indicated in the treatment of septic arthritis (joint

ill) caused by susceptible organisms.

[Atrophic rhinitis (treatment)]—Pigs: Oxytetracycline for medicated

feed{R-122} is indicated for use as an aid in maintaining weight gain

in pigs infected with atrophic rhinitis.

[Blackleg (treatment)]; or

[Malignant edema (treatment)]—Cattle: Oxytetracycline injection{R-24;

25; 121} is indicated in the treatment of infections caused by susceptible

Clostridia species.



[Bloat]—Cattle: Oxytetracycline for medicated feed{R-26} is indicated as an

aid in reducing the incidence of bloat in young cattle on pasture and in

feedlots.

[Cold water disease (treatment)]—Salmonids:{R-124} Oxytetracycline for

medicated feed is indicated in the treatment of cold water disease

caused by susceptible Cytophaga psychrophilia.

[Columnaris disease (treatment)]—Salmonids: Oxytetracycline for medi-

cated feed{R-124} is indicated in the treatment of columnaris disease

caused by susceptible Chondrococcus (Flexibacter) columnaris.

[Egg production, increased]; or

[Egg hatchability, increased]—Chickens and turkeys: Chlortetracycline for

medicated feed is indicated for use in increasing egg production or egg

hatchability.

[Ehrlichiosis, equine (treatment)]1—Horses: Oxytetracycline is used in the

treatment of ehrlichiosis caused by susceptible Ehrlichia equi{R-46; 138}.

[Enteric redmouth disease (treatment)]—Salmonids: Oxytetracycline for

medicated feed{R-124} is indicated in the treatment of enteric red-

mouth disease caused by susceptible Yersinis ruckeri.

[Enterotoxemia (treatment)]—Lambs: Chlortetracycline for medicated

feed and oxytetracycline for medicated feed{R-26} are indicated in the

reduction of losses due to enterotoxemia in feedlot lambs.

[Erysipelas (treatment)]—Pigs: Oxytetracycline injection{R-24; 25; 121} is

indicated in the treatment of erysipelas caused by susceptible organ-

isms.

[Mastitis (treatment)]—Cattle, pigs, and sheep: Oxytetracycline injec-

tion{R-24; 25} is indicated in the treatment of mastitis caused by

susceptible organisms. Oxytetracycline, administered at the dosage

recommended in product labeling, does not appear to be effective

for the cure of Staphylococcus aureus infections in the dry

cow{R-103}.

[Omphalophlebitis (treatment)]—Cattle: Oxytetracycline injection{R-24;

25} is indicated in the treatment of omphalophlebitis (navel ill) caused


[Peritonitis (treatment)]—Cattle: Oxytetracycline injection{R-25; 121} is

indicated in the treatment of peritonitis caused by susceptible

organisms.

[Pododermatitis (prophylaxis)]—Cattle: Chlortetracycline for medicated

feed is indicated as an aid in the prevention of pododermatitis{R-116}.

[Potomac horse fever (treatment)]1—Horses: Oxytetracycline is used in

the treatment of Potomac horse fever (equine ehrlichial colitis) caused

by susceptible Ehrlichia risticii{R-47; 48}. Treatment of exposed animals

to prevent development of disease is not recommended; the incubation

period will be increased but the disease is not prevented{R-48}.

[Rocky Mountain spotted fever (treatment)]1—Dogs: Tetracycline or dox-

ycycline{R-151} is used in the treatment of Rocky Mountain spotted

fever caused by susceptible Rickettsia rickettsii{R-140; 141}.

[Sinusitis, infectious (prophylaxis)]—Turkeys: Chlortetracycline for med-

icated feed is indicated in the prevention of sinusitis caused by

susceptible organisms.

[Sinusitis, infectious (treatment)]—Turkeys: Oxytetracycline for medi-

cated feed{R-26; 122} and tetracycline soluble powder are indicated in

the control of sinusitis caused by susceptible organisms, such as

susceptible Mycoplasma gallisepticum.

ACCEPTANCE NOT ESTABLISHED[Brucellosis (treatment)]1—Dogs: There are insufficient data to establish

the efficacy of tetracycline administered concurrently with strepto-

mycin in the treatment of brucellosis in dogs; however, studies suggest

that specific dosage regimens may be successful in treating the

infection{R-160}. No controlled studies are available.

[Chlamydial infection (treatment)]1; or

[Respiratory tract infections, bacterial (treatment)]1—Cats: There are

insufficient data to establish the safety and efficacy of doxycycline in

the treatment of chlamydial infections or bacterial respiratory infec-

tions in cats; however, it is used in the treatment of infections caused

by susceptible organisms{R-151; 177}.

[Ehrlichiosis (treatment)]1—Dogs: There are insufficient data to establish

the efficacy of doxycycline in the treatment of ehrlichiosis in dogs.

Clinical signs are often resolved by administration of doxycycline or

tetracycline{R-40; 41; 43; 139}, but it is uncertain whether the organism

is cleared from dogs treated{R-40; 139}. Serum Ehrlichia canis antibody

titers can remain increased in some dogs for over 2 years after the

resolution of clinical signs during treatment with tetracycline{R-139};

also, in some dogs, blood and tissue cultures have tested positive for

Ehrlichia canis 2 months after treatment with doxycycline{R-40}.

[Flexural limb deformities (treatment)]1—Foals: There are insufficient

data to establish the efficacy of oxytetracycline in the treatment of

flexural limb deformities in foals; however, studies show that oxytet-

racycline can cause a short-term moderate improvement in meta-

carpophalangeal joint angle and an increase in range of joint motion

in newborn foals as compared to untreated foals{R-157; 158}. The

available studies were performed in healthy foals rather than foals with

deformities and both the ideal dose and actual short- and long-term

benefits and risks of this treatment are unknown.

[Haemobartonella felis infection (treatment)]1—Cats: There are insufficient

data to establish the safety and efficacy of doxycycline in the treatment

of feline infectious anemia, caused by susceptible Haemobartonella felis;

however, it is used in the treatment of acute infections{R-147}. If

considered clinically necessary, corticosteroids{R-149} and blood trans-

fusions are used concurrently with doxycycline in the treatment of this

infection{R-147}. Acutely infected cats may clinically recover without

treatment{R-147; 159}, although it is believed that the organism is not

cleared from these animals; there is also some question about the

efficacy of doxycycline or other tetracyclines in completely clearing the

organism from infected cats{R-148}. Controlled clinical efficacy trials

have not been conducted for any medication; however, a tetracycline

is usually administered when a cat is diagnosed and doxycycline is

considered the tetracycline of choice{R-147} because of an expectation

of fewer side effects. Cats with serious underlying viral infections, such

as feline leukemia virus, are not expected to respond well to therapy.

[Leptospirosis (treatment)]1—Dogs: Although doxycyline is proposed in

some veterinary references for use in the clearance of the leptospirosis

carrier state in dogs, there are insufficient data showing clearance or

prevention of a potential carrier state to support this use as an

established indication.

[Lyme disease (treatment)]1—Dogs: There are insufficient data to

establish the efficacy of tetracyclines in the treatment of Lyme

borreliosis. Doxycycline has been effective in the resolution of early

Borrelia burgdorferi infection in people{R-163}; therefore, doxycycline

and tetracycline are used to treat the infection in dogs{R-164; 165};

however, it is uncertain whether this is the best medication to produce

long-term resolution of the infection{R-163}.

[Thromboembolic meningoencephalitis (treatment)]1—Cattle: There are

insufficient data to establish the efficacy of oxytetracycline in the

treatment of thromboembolic meningoencephalitis; however, if cattle

are diagnosed in the early stages of the disease, before recumbency,



treatment can be effective against susceptible Haemophilus som-

nus{R-161; 166}.

[Uterine infections, bacterial (treatment)]—Cattle, horses, pigs, and sheep:

Although Canadian product labeling includes the use of intrauterine

chlortetracycline, oxytetracycline, and tetracycline in the treatment of

uterine infections, there are insufficient available data concerning the

efficacy and safety of this use. Intrauterine tetracycline treatment can

reduce the incidence of putrefaction of retained fetal membranes and

fever associated with infection in cattle, but because it is believed to

penetrate only into the endometrium from infusion into the

uterus{R-104; 130}, parenteral antibiotics are recommended for those

animals that have evidence of infection or develop signs of septice-

mia{R-144}. The intrauterine administration of tetracyclines for the

treatment of uterine infections such as endometritis or treatment of

infection associated with retained placentas in cattle is not effective in

shortening the interval from parturition to conception, increasing

pregnancy rates, or reducing culling rates{R-144–146}. Considering

costs, risks of residues{R-129}, and a lack of significant change in long-

term fertility in cattle, there is no evidence to support the routine use of

intrauterine tetracyclines in cattle, horses, pigs, and sheep.


Withdrawal times have been established for chlortetracycline for

medicated feed and soluble powder; oxytetracycline soluble powder,

for medicated feed, tablets, and injection; and tetracycline soluble

powder and boluses. See the Dosage Forms section.

Canada—

Withdrawal times have been established for chlortetracycline for

medicated feed, and uterine tablets; oxytetracycline soluble powder,

for medicated feed, uterine infusion, and injection; and tetracycline

soluble powder, boluses, and uterine tablets. See the Dosage Forms

section.

CHEMISTRYSource:

Chlortetracycline—Isolated from the fungus Streptomyces aureofac-

iens{R-22}.

Doxycycline—Produced semisynthetically.{R-22}

Oxytetracycline—Isolated from the fungus Streptomyces rimosus{R-22}.

Tetracycline—Produced by some streptomyces strains; however, it is

manufactured by hydrogenolysis of chlortetracycline{R-113}.

Chemical name:

Chlortetracycline hydrochloride—2-Naphthacenecarboxamide, 7-chloro-

4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-

pentahydroxy-6-methyl-1,11-dioxo-, monohydrochloride [4S-(4 alpha,

4a alpha,5a alpha,6 beta,12a alpha)]-{R-114}.

Doxycycline—2-Naphthacenecarboxamide, 4-(dimethylamino) - 1,4,4a,

5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-

1,11-dioxo-, [4S-(4 alpha,4a alpha,5 alpha,5a alpha,6 alpha,12a

alpha)]-, monohydrate{R-114}.

Doxycycline hyclate—2-Naphthacenecarboxamide, 4-(dimethylamino)-

1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-

1,11-dioxo-, monohydrochloride, compd. with ethanol (2:1), mono-

hydrate, [4S-(4 alpha, 4a alpha, 5 alpha, 5a alpha, 6 alpha, 12a

alpha)]-{R-114}.

Oxytetracycline—2-Naphthacenecarboxamide, 4-(dimethylamino)-1,4,-

4a,5,5a,6,11,12a-octahydro-3,5,6,10,12,12a-hexahydroxy-6-methyl-

1,11-dioxo-, [4S-(4 alpha,4a alpha,5 alpha,5a alpha,6 beta,12a

alpha)]-, dihydrate{R-114}.

Oxytetracycline hydrochloride—2-Naphthacenecarboxamide, 4-(dimeth-

ylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,6,10,12,12a-hexa-

hydroxy-6-methyl-1,11-dioxo-, monohydrochloride, [4S-(4 alpha,4a

alpha,5 alpha,5a alpha,6 beta,12a alpha)]-{R-114}.

Tetracycline—2-Naphthacenecarboxamide, 4-(dimethylamino)-1,4,4a,

5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-

dioxo-, [4S-(4 alpha,4a alpha,5a alpha,6 beta,12a alpha)]-{R-114}.

Tetracycline hydrochloride—2-Naphthacenecarboxamide, 4-(dimethyla-

mino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-

6-methyl-1,11-dioxo-, monohydrochloride, [4S-(4 alpha,4a alpha,5a

alpha,6 beta,12a alpha)]-{R-114}.

Molecular formula:

Chlortetracycline hydrochloride—C22H23ClN2O83 Æ HCl{R-114}.

Doxycycline—C22H24N2O8 Æ H2O{R-114}.

Doxycycline hyclate—(C22H24N2O8ÆHCl)2 Æ C2H6O Æ H2O{R-114}.

Oxytetracycline—C22H24N2O9 Æ 2H2O{R-114}.

Oxytetracycline hydrochloride—C22H24N2O9 Æ HCl{R-114}.

Tetracycline—C22H24N2O8{R-114}.

Tetracycline hydrochloride—C22H24N2O8 Æ HCl{R-114}.

Molecular weight:

Chlortetracycline hydrochloride—515.34{R-114}.

Doxycycline—462.45{R-114}.

Doxycycline hyclate—1025.87{R-114}.

Oxytetracycline—496.46{R-114}.

Oxytetracycline hydrochloride—496.89{R-114}.

Tetracycline—444.43{R-114}.

Tetracycline hydrochloride—480.90{R-114}.

Description:

Chlortetracycline Hydrochloride USP—Yellow, crystalline powder. Is

odorless. Is stable in air, but is slowly affected by light{R-128}.

Doxycycline USP—Yellow, crystalline powder{R-128}.

Doxycycline Hyclate USP—Yellow, crystalline powder{R-128}.

Oxytetracycline USP—Pale yellow to tan, odorless, crystalline powder. Is

stable in air, but exposure to strong sunlight causes it to darken. It

loses potency in solutions of pH below 2, and is rapidly destroyed by

alkali hydroxide solutions{R-128}.

Oxytetracycline Hydrochloride USP—Yellow, odorless, crystalline pow-

der. Is hygroscopic. Decomposes at a temperature exceeding 180 �C,

and exposure to strong sunlight or to temperatures exceeding 90 �C in

moist air causes it to darken. Its potency is diminished in solutions

having a pH below 2, and is rapidly destroyed by alkali hydroxide

solutions{R-128}.

Tetracycline USP—Yellow, odorless, crystalline powder. Is stable in air,

but exposure to strong sunlight causes it to darken. It loses potency in

solutions of pH below 2, and is rapidly destroyed by alkali hydroxide

solutions{R-128}.

Tetracycline Hydrochloride USP—Yellow, odorless, crystalline powder. Is

moderately hygroscopic. Is stable in air, but exposure to strong

sunlight in moist air causes it to darken. It loses potency in solution

at a pH below 2, and is rapidly destroyed by alkali hydroxide

solutions{R-128}.





pKa:

Chlortetracycline: 3.3, 7.4, 9.3{R-133}.

Oxytetracycline: 3.3, 3.7, 9.1{R-156}.

Tetracycline: 8.3, 10.2{R-133}.

Solubility:

Chlortetracycline Hydrochloride USP—Sparingly soluble in water; solu-

ble in solutions of alkali hydroxides and carbonates; slightly soluble in

alcohol; practically insoluble in acetone, in chloroform, in dioxane,

and in ether{R-128}.

Doxycycline USP—Very slightly soluble in water; freely soluble in dilute

acid and in alkali hydroxide solutions; sparingly soluble in alcohol;

practically insoluble in chloroform and in ether{R-128}.

Doxycycline Hyclate USP—Soluble in water and in solutions of alkali

hydroxides and carbonates; slightly soluble in alcohol; practically

insoluble in chloroform and in ether{R-128}.

Oxytetracycline USP—Very slightly soluble in water; freely soluble in 3 N

hydrochloric acid and in alkaline solutions; sparingly soluble in

alcohol{R-128}.

Oxytetracycline Hydrochloride USP—Freely soluble in water, but crystals

of oxytetracycline base separate as a result of partial hydrolysis of the

hydrochloride. Sparingly soluble in alcohol and in methanol, and even

less soluble in dehydrated alcohol; insoluble in chloroform and in

ether{R-128}.

Tetracycline USP—Very slightly soluble in water; freely soluble in dilute

acid and in alkali hydroxide solutions; sparingly soluble in alcohol;

practically insoluble in chloroform and in ether{R-128}.

Tetracycline Hydrochloride USP—Soluble in water and in solutions of

alkali hydroxides and carbonates; slightly soluble in alcohol; practi-

cally insoluble in chloroform and in ether{R-128}.

PHARMACOLOGY/PHARMACOKINETICSNote: Unless otherwise noted, pharmacokinetic values are based on a

single intravenous dose of medication.


Tetracyclines are broad-spectrum bacteriostatic agents that inhibit

protein synthesis by binding reversibly to receptors of the 30 S

ribosomal subunit of susceptible microorganisms. The binding of a

tetracycline to the subunit blocks the binding of the aminoacyl-tRNA

to the acceptor site on the mRNA-ribosomal complex and prevents the

addition of new amino acids to the peptide chain, inhibiting protein

synthesis.{R-22}

Tetracyclines must enter the target cell to be effective. Uptake appears

to depend on passive diffusion and active transport, with the

exception of doxycycline, which enters the cell by passive diffu-

sion{R-28}. Susceptible cells concentrate the antibiotic; resistant

strains appear to carry an R-factor that inhibits uptake of

drug.{R-22}

Absorption:

Oral—Doxycycline: Generally is more completely absorbed from the

gastrointestinal tract than are the tetracyclines developed less

recently{R-40; 64; 74}, which can be poorly and variably absorbed.

Human studies have shown that the absorption of oxytetracycline or

tetracycline is decreased when either is administered with food; the

effect of food on doxycycline absorption is insignificant. Doxycycline is

also less likely than the older tetracyclines to form chelation complexes

with divalent and trivalent metals and, therefore, there is less

interference with oral absorption by calcium or other substances{R-

133}. See the Drug interactions section.

Parenteral—Oxytetracycline: As with other parenteral medications, the

absorption and bioavailability of intramuscularly administered oxytet-

racycline can vary depending on the site of administration. Oxytetra-

cycline is more bioavailable when administered intramuscularly into

the shoulder of calves than when administered intramuscularly into

the neck or particularly into the buttock.{R-94}

The absorption of the long-acting formulations of oxytetracycline (with

2-pyrrolidone excipient) administered intramuscularly has been

described as having a rapid phase of 48 minutes for 14% of the dose

and a slow phase of 18 hours for 38% of the dose in cattle administered

a 20 mg/kg dose{R-99}. With a 10 mg/kg dose, the rapid phase is 16

minutes and the slow phase is 11 hours.{R-100}

Bioavailability:

Oral—

Chlortetracycline:

Chickens—1% (25 mg per kg of body weight [mg/kg] dose).{R-78; 79}

Pigs—Fasted or fed: 18 to 19%{R-77}.

Turkeys—6% (15 mg/kg dose).{R-78; 80}

Doxycycline:

Chickens—41.3% (20 mg/kg dose).{R-64}

Human value—90 to 95%{R-169}.

Oxytetracycline:

Pigs—4.8% (50 mg/kg dose).{R-109}

Piglets, weaned, 10 weeks of age—

By drench: 9% (20 mg/kg dose).{R-82}

In medicated feed for 3 days: 3.7% (400 parts per million [ppm] of

feed).{R-82}

Trout, rainbow (Oncorhynchus mykiss)—5.6% (75 mg/kg dose).{R-89}

Turkeys—

Fasted: 47.6% (10 mg/kg dose).{R-85}

Fed: 9.4% (10 mg/kg dose).{R-85}

Tetracycline: Pigs, fasted—23% (22 mg/kg dose).{R-74}

Intramuscular—

Oxytetracycline, conventional formulation:

Buffalo—63.2% (22 mg/kg dose).{R-87}

Calves, 17 days of age—61% (20 mg/kg dose){R-99}.

Calves, 3 months of age—76 hours postinjection of 18 mg/kg dose:

Buttock administration—83.1%.{R-94}

Neck administration—93.3%.{R-94}

Shoulder administration—99.4%.{R-94}

Catfish, African, and trout, rainbow—85% (60 mg/kg dose).{R-90}

Cows—80.8% (8 mg/kg dose){R-95}; 95% (20 mg/kg dose){R-174}.

Goats—65.5% (20 mg/kg dose).{R-81}

Oxytetracycline, long-acting formulation:

Camels—93.7% (10 mg/kg dose).{R-88}

Cattle—51%; 78.5%; 95% (20 mg/kg dose).{R-98; 99; 174}

Goats—79.4% (20 mg/kg dose).{R-81}

Distribution: Tetracyclines are lipid soluble and are well distributed to

most tissues. Doxycycline is the most lipid soluble and shows the

greatest degree of tissue penetration.{R-28; 71}


Chlortetracycline:

Calves, ruminating—Area volume of distribution: 1.93 ± 0.15 liters

per kg (L/kg).{R-76}



Pigs—Steady state volume of distribution:

Fasted—0.97 ± 0.21 L/kg.{R-77}

Fed—1.39 ± 0.31 L/kg.{R-77}

Turkeys—Area: 0.23 ± 0.05 L/kg.{R-78}

Doxycycline:

Calves—Steady state:

Preruminating—1.81 ± 0.24 L/kg.{R-68}

Ruminating—1.31 ± 0.11 L/kg.{R-68}

Cats—Steady state: 0.34 ± 0.03 L/kg.{R-70}

Dogs—Steady state: 0.93 ± 0.14 L/kg.{R-70}

Pigs—Steady state: 0.53 ± 0.04 L/kg.{R-69}

Oxytetracycline:

Buffalo—Area: 0.28 to 0.45 L/kg.{R-87}

Calves, newborn to 8 months—Area: 1.67 L/kg.{R-93; 100}

Camels—Steady state: 0.71 L/kg.{R-88}

Cows—Area: 0.80 ± 0.03 L/kg.{R-95}

Dogs—Area: 2.10 ± 0.42 L/kg.{R-84}

Donkeys—

Area: 0.78 L/kg{R-92}.

Steady state: 0.65 L/kg{R-92}.

Foals—

Area: 2.19 L/kg.{R-154}

Steady state: 2.17 L/kg.{R-154}

Goats—Area: 1.44 L/kg.{R-81}

Horses—

Apparent: 1.35 L/kg.{R-96}

Area: 0.67 L/kg.{R-92}


Pigs—Area:

Adult—1.8 L/kg.{R-83}

Adult with pneumonia—1.53 L/kg.{R-83}

Ponies—

Area: 1.05 L/kg.{R-92}


Rabbits—0.86 L/kg.{R-86}

Rats—Area: 0.79 L/kg.{R-91}

Tetracycline:

Chickens—Steady state: 0.17 L/kg.{R-73}

Pigs—Area: 4.5 ± 1.1 L/kg.{R-74}

Rabbits—Area: 1.05 ± .88 L/kg.{R-72}

Protein binding:

Chlortetracycline—

Cows: Moderate (47 to 51%).{R-67}

Sheep: Moderate (46 to 50%).{R-67}

Doxycycline—

Calves: Very high (92%).{R-68}

Cats: Very high (98%);{R-70} albumin binding—76%.{R-70}

Dogs: Very high (91%);{R-70} albumin binding—54%.{R-70}

Pigs: Very high (93%).{R-69}

Sheep: High (84 to 90%).{R-67}

Oxytetracycline—

Buffalo: Moderate (42%).{R-87}

Cows: Low (18 to 22%){R-67}.

Horses and cows: Combined results—Moderate (50%).{R-96}

Pigs, weaned, 10 weeks of age: High (75.5%).{R-82}

Sheep: Low (21 to 25%).{R-67}

Trout, rainbow: Moderate (55%).{R-89}

Tetracycline—

Cows: Low to moderate (31 to 41%).{R-67}

Sheep: Low (28 to 32%).{R-67}

Biotransformation: All species—The tetracyclines are not known to be

biotransformed to any significant extent before elimination.{R-28; 68–70}


Chlorotetracycline:

Calves, ruminant—8.3 hours.{R-76}

Turkeys—0.88 hour.{R-78}

Doxycycline:

Calves—

Preruminant: 9.8 hours.{R-68}

Ruminant: 14.2 hours.{R-68}

Cats—4.6 hours.{R-70}

Chickens—4.8 hours.{R-64}

Dogs—7 to 10.4 hours.{R-63; 70}

Horses—Oral administration (apparent half-life): 8.7 ± 1.6

hours{R-131}.

Pigs—3.9 hours.{R-69}

Oxytetracycline:

Buffalo—2.8 to 3.6 hours.{R-87}

Calves—

Newborn: 11.2 hours.{R-93}

6 weeks of age: 3.5 to 7.2 hours.{R-93; 100; 106}

6 weeks of age with induced Mannheimia (Pasteurella) haemolytica

pneumonia: 2.5 hours.{R-106}

8 months of age: 6.3 hours.{R-93}

Camels—7.7 hours.{R-88}

Catfish, African—80.3 hours.{R-90}

Cows—10 hours.{R-95}

Dogs—6 hours.{R-84}

Donkeys—6.5 hours.{R-92}

Foals—6.7 to 7.3 hours.{R-154}

Goats—6.5 hours.{R-81}

Horses—13 hours{R-92}; 15.7 hours{R-175}.

Pigs—

10 weeks of age, weaned: 11.6 to 17.2 hours.{R-82}

Adult: 3.8 to 6.7 hours.{R-77; 83}

Adult, with pneumonia: 5.1 to 5.2 hours.{R-83}

Ponies—15 hours.{R-92}

Rabbits—1.3 hours.{R-86}

Trout, rainbow—

Oncorhynchus mykiss: 60.3 hours.{R-89}

Salmo gairdneri: 89.5 hours.{R-90}

Turkeys—0.73 hour.{R-85}

Tetracycline:

Cats—2.5 hours.{R-75}

Chickens—2.8 hours.{R-73}

Dogs—1.6 to 2 hours.{R-75}

Pigs—16 hours.{R-74}

Rabbits—2 hours.{R-72}

Time to peak concentation/Peak serum concentration:

Chlortetracycline—Oral:

Calves (22 mg/kg dose)—



Milk fed: 15.7 ± 0.33 hours to a peak serum concentration of 1.86 ±

0.54 mcg per mL (mcg/mL).{R-76}

Ruminant: 13.3 ± 2.67 hours to a peak serum concentration of 0.67

± 0.24 mcg/mL.{R-76}

Turkeys—2.5 hours to a peak serum concentration of 0.6 mcg/mL (15

mg/kg dose).{R-80}

Doxycycline—Oral:

Single dose—

Chickens—0.35 ± 0.02 hour to a peak serum concentration of 54.6

± 2.4 mcg/mL (20 mg/kg dose).{R-64}

Horses—

1 hour to a peak serum concentration of 0.22 mcg/mL (3 mg/kg

dose){R-131}.

1 hour to a peak serum concentration of 0.32 mcg/mL (dose of 10

mg/kg){R-131}.

Multiple dosing: Horses—2 hours postadministration to a serum

concentration of 0.42 mcg/mL at 2 hours after the fifth dose (five

intragastric doses of 10 mg/kg administered at twelve hour

intervals){R-131}.

Note: The MIC90 of doxycycline has been reported as £1 mcg/mL for

Streptococcus zooepidemicus and 0.25 mcg/mL for Staphylococcus

aureus in horses{R-131}.

Oxytetracycline—

Oral: Pigs, weaned, 10 weeks of age—

30 hours after start of administration to a peak serum concentration

of 0.2 ± 0.06 mcg/mL (dose of 400 parts per million in feed for 3

days).{R-82}

1 to 5 hours to a peak serum concentration of 1.18 to 1.41 mcg/mL

(20 mg per kg single dose).

Intramuscular:

Conventional formulation—

Calves, 14 weeks of age: 6 hours to a peak serum concentration of

5.5 ± 1.25 mcg/mL (dose of 18 mg/kg in the neck).{R-95}

Catfish, African: 7 hours to a peak serum concentration of 43.4

mcg/mL (60 mg/kg dose).{R-90}

Cows: 6.7 hours to a peak serum concentration of 5.7 ± 2.39 mcg/

mL (dose of 8 mg/kg in the neck).{R-95}

Pigs: 1.5 hours to a peak serum concentration of 6.7 ± 3.4 (dose of

20 mg/kg in the hindquarter).{R-107}

Trout, rainbow: 4 hours to a peak serum concentration of 56.9 mcg/

mL (60 mg/kg dose).{R-90}

Long-acting formulation—

Calves, nonruminating, 5 weeks of age: 1 to 1.5 hours to a peak

serum concentration of 4 mcg/mL (dose of 20 mg/kg in the gluteal

muscles).{R-99}

Calves, nonruminating, 6 weeks of age: 4.01 ± 2.84 hours to a peak

serum concentration of 3.01 ± 0.72 mcg/mL (dose of 10 mg/kg in

the hindquarter).{R-100}

Calves, ruminating: 7.6 ± 4 hours to a peak serum concentration of

9.6 ± 2.6 mcg/mL (dose of 40 mg/kg in the hindquarter).{R-101}

Camels: 7.3 ± 3.5 hours to a peak serum concentration of 3.49 ±

0.44 mcg/mL (10 mg/kg dose).{R-88}

Cows: 5 to 10 hours to a peak serum concentration of 4.5 to 6.8

mcg/mL (dose of 10 mg/kg in the neck).{R-97}

Pigs: 0.5 hour to a peak serum concentration of 6 ± 2.2 mcg/mL

(dose of 20 mg/kg in the hindquarters).{R-107}

Steers: 8 hours to a peak serum concentration of 3.13 mcg/mL

(dose of 20 mg/kg in the hindquarters).{R-98}

Tetracycline—Oral: Pigs—72 hours to a peak serum concentration of 0.6

mcg/mL (dose of 0.55 gram per kg of feed).{R-74}

Duration of action:

Note: Duration of action may be estimated by the time target serum

concentrations are maintained. Target concentrations are generally

based on minimum inhibitory concentrations (MIC) for each organ-

ism. While 0.5 mcg/mL has been considered the MIC of oxytetracy-

cline for many pathogens in the past and research studies were based

on that target, there are now many pathogens with MICs of 4 to 16

mcg/mL. Duration of action may be minimal or nonexistent for these

isolates.

Chlortetracycline—

Pigs: When administered 110 mg chlortetracycline per kg of feed, fed

as the only ration, therapeutic plasma or tissue concentrations were

not produced{R-155}.

Turkeys: A single oral dose of 15 mg/kg produces serum concentrations

above 0.4 mcg/mL for 8 to 10 hours.{R-80}

Doxycycline—Dogs: An intravenous dose of 5 mg/kg produces serum

concentrations above 2 mcg/mL for 8 hours.{R-63}

Oxytetracycline—

Oral:

Pigs—A single oral 50 mg/kg dose produces >0.5 mcg/mL serum

concentrations for at least 8 hours.{R-109}

Pigs, after challenge with Actinobacillus pleuropneumonia—A single

oral 50 mg/kg dose produces >0.5 mcg/mL serum concentrations

for at least 24 hours.{R-109}

Pigs—When administered 550 mg of oxytetracycline per kg of feed,

fed as the only diet, plasma concentrations peaked at 0.4 mcg/

mL{R-107}.

Note: These results may vary by size of pig and amount of feed

intake.

Intramuscular:

Conventional formulation—

Calves: A single dose of 18 mg/kg maintains serum concentrations

> 1 mcg/mL for at least 32 hours.{R-94}

Cows: A single dose of 20 mg/kg in the hindquarters maintains

serum concentrations of > 0.5 mcg/mL for 52 hours{R-98}.

Pigs: A single dose of 20 mg/kg maintains serum concentrations

> 0.5 mcg/mL for 28 to 36 hours.{R-107; 174}

Long-acting formulation—

Calves, milk fed: A single dose of 10 mg/kg maintains serum

concentrations > 0.5 mcg/mL for 12 to 24 hours.{R-100}

Calves, ruminating: A single dose of 40 mg/kg maintains serum

concentrations > 2 mcg/mL for 48 hours;{R-101} also lung

concentrations produced are 2 mcg/mL at 48 hours.{R-101}

Camels: A single dose of 10 mg/kg maintains serum concentrations

> 0.5 mcg/mL for 72 hours.{R-88}

Cows:

A single dose of 10 mg/kg in the neck maintains > 0.5 mcg/mL

serum concentrations for 48 to 70 hours and milk concentrations

for 33 to 49 hours.{R-97}

A single dose of 20 mg/kg in the hindquarters maintains serum

concentrations of > 0.5 mcg/mL for 86 hours.{R-98}

A single dose of 20 mg/kg in the gluteal muscles maintains serum

concentrations > 4 mcg/mL for 12 hours; also lung concentra-

tions are > 0.5 mcg/mL for 65 hours.{R-99}



Pigs: A single dose of 20 mg/kg produces serum concentrations > 0.5

mcg/mL for 35 to 48 hours{R-107; 174}; however, the use of the

long-acting formulation does not produce significantly different

plasma oxytetracycline concentrations from those produced by the

conventional formulation{R-107}.

Tetracycline—Pigs: A ration containing 0.55 gram of tetracycline

hydrochloride per kg of feed, fed as the only ration, produces 0.3 to

0.4 mcg/mL serum concentrations for the 96 hours that it is fed.{R-74}

Note: These results may vary by size of pig and amount of feed intake.

Elimination:

Chlortetracycline—Total clearance:

Calves, ruminating—2.70 ± 0.17 mL per minute per kg (mL/min/

kg).{R-76}

Pigs, fasted—2.75 ± 0.92 mL/min/kg.{R-77}

Pigs, fed—5.12 ± 0.88 mL/min/kg.{R-77}

Turkeys—3.77 ± 0.77 mL/min/kg.{R-78}

Doxycycline—Doxycycline differs from the other tetracyclines in that a large

percentage is excreted into the intestines and is inactive there.{R-133}

Dogs: 90% of a single intravenous dose is eliminated within 48 hours

in nonmetabolized form. Of the 90%, 16% is eliminated in urine,

<5% in the bile, and the remainder in the intestines.{R-63}

Total clearance:

Calves—

Preruminant: 2.20 mL/min/kg.{R-68}

Ruminant: 1.07 mL/min/kg.{R-68}

Cats—1.09 ± 0.21 mL/min/kg.{R-70}

Dogs—1.7 mL/min/kg{R-63; 70}.

Pigs—1.67 ± 0.18 mL/min/kg.{R-69}

Oxytetracycline—Calves, cows, dogs, pigs, and turkeys: The conventional

formulation of oxytetracycline is eliminated primarily by glomerular

filtration; only a small amount (1 to 2% in pigs and turkeys) is

eliminated in the bile.{R-63; 82; 85; 93; 97}

Total clearance:

Oxytetracycline—

Buffalo: 1.02 to 1.45 mL/min/kg.{R-87}

Calves, 6 to 8 weeks of age: 1.66 to 1.88{R-93}; 2.67 to 4.67 mL/

min/kg.{R-100}

Camels: 1.26 mL/min/kg{R-88}.

Dogs: 4.23 ± 1.29 mL/min/kg.{R-84}

Donkeys: 1.52 mL/min/kg.{R-92}

Foals, 4 to 5 days of age: 3.17 mL/min/kg{R-154}.

Goats: 2.67 mL/min/kg.{R-81}

Horses: 0.66 mL/min/kg.{R-92}

Pigs, 10 weeks of age: 4.17 mL/min/kg.{R-82}

Pigs, adult: 3.5 mL/min/kg.{R-83}

Ponies: 1.01 mL/min/kg.{R-92}

Rabbits: 7.23 mL/min/kg.{R-86}

Rats: 2.79 mL/min/kg.{R-91}

Tetracycline—Total clearance:

Chickens—1.63 ± 0.18 mL/min/kg.{R-73}

Pigs—3.08 ± 0.4 mL/min/kg.{R-74}

Rabbits—6.1 ± 0.6 mL/min/kg.{R-72}


SPECIES SENSITIVITYAll species: Rapid intravenous administration of tetracyclines can result in

cardiovascular dysfunction and collapse in any species{R-33–35; 169}.

Some studies have linked the cardiovascular effects of intravenous

administration in calves to the propylene glycol vehicle in some

preparations{R-33; 170}; however, adverse cardiovascular effects and

collapse have been shown to occur after intravenous administration of

tetracycline without propylene glycol vehicle{R-34}; the electrocardio-

graphic abnormalities may be due to chelation of free calcium ions{R-34}.

Tetracyclines ideally should be diluted in fluids and administered

slowly if given by the intravenous route{R-176}. If this is not possible,

intravenous injections should be made as a slow push, with the dose

administered over 1 to 2 minutes.

Horses: While rapid intravenous administration of tetracyclines causes

reactions in many species, doxycycline in particular can lead to severe

cardiovascular dysfunction and death when administered intrave-

nously at any rate to horses.{R-35}

Administration of tetracyclines can also lead to severe diarrhea in some

horses. However, oral, multiple-dose administration of doxycycline

to horses without observed side effects has been reported{R-131}.

PREGNANCY/REPRODUCTIONTetracyclines have been shown to cross the placenta{R-22} and may affect

fetal bone formation.{R-135}

LACTATIONTetracyclines are distributed into milk.

PEDIATRICSUse of tetracyclines during tooth development (the last 2 to 3 weeks of

pregnancy to 1 month of age){R-22} may cause discoloration of the

bones and teeth.{R-4} In neonates that have not yet developed full renal

function, excretion of chlortetracycline, oxytetracycline, and tetracy-

cline may occur more slowly than in a mature animal. One exception

is that 4-day-old foals have a faster elimination half-life and more rapid

clearance of oxytetracycline compared to adults{R-154}.





Note: Although methoxyflurane has been suspected of increasing the

potential for tetracycline-induced nephrotoxicity in people, this has not

been shown to be true in dogs.{R-137}

Combinations containing any of the following medications, depending

on the amount present, may also interact with this medication.

» Antacids or

» Calcium supplements, such as calcium carbonate, or

» Iron supplements or

» Magnesium-containing laxatives or

Sodium bicarbonate

(concurrent use with tetracyclines may result in formation of non-

absorbable complexes; also, concurrent use within 1 to 3 hours of

antacid or sodium bicarbonate administration may result in decreased

absorption of oral tetracyclines because of increased intragastric pH)

Phenobarbital or

Microsomal enzyme inducers, other



(concurrent use with doxycycline may result in decreased doxycy-

cline serum concentrations due to induction of microsomal enzyme

activity; adjustment of doxycycline dosage or substitution of another

tetracycline may be necessary)

Tereftalic acid

(blood concentrations of chlortetracycline are increased when it is

administered concurrently with tereftalic acid{R-156})




included in the human monograph Tetracyclines (Systemic) in USP DI



tetracyclines in the treatment of animals:

Cholestyramine

(concurrent use with cholestyramine may result in binding of oral

tetracyclines, thus impairing their absorption; an interval of several

hours between administration of cholestyramine and oral tetracy-

clines is recommended)

Vitamin A

(concurrent use with tetracycline has been reported to cause benign

intracranial hypertension)





Urinalysis

(transient hemoglobinuria has been reported in cattle given paren-

teral oxytetracycline){R-38; 45; 56}



humans, and are included in the human monograph Tetracyclines



applicable to the use of tetracyclines in the treatment of animals:


Catecholamine determinations, urine

(may produce false elevations of urinary catecholamines because

of interfering fluorescence)




Amylase and


Bilirubin

(serum concentrations may be increased)

Blood urea nitrogen (BUN)

(antianabolic effect of tetracyclines [except doxycycline] may

increase BUN concentrations; in patients with significantly

impaired renal function, increased serum concentrations of tetra-

cyclines may lead to azotemia, hyperphosphatemia, and acidosis)






problem exists:

Renal function impairment, severe

(chlortetracycline, oxytetracycline, and tetracycline are eliminated

primarily by the kidney and can accumulate in animals with severe

renal dysfunction; doxycycline is only partially eliminated renally

and is much less likely to accumulate{R-71})







prior to administration of tetracyclines to determine pathogen

susceptibility)




THOSE INDICATING NEED FOR MEDICAL ATTENTIONIncidence rare

All species

Hypersensitivity reactions, specifically anaphylaxis{R-32; 45}

(defecation; eruption of skin plaques; frothing from the mouth;

glassy-eyed appearance; labored breathing; muscle trembling; piloe-

rection; prostration; restlessness; swelling of eyelids, ears, muzzle,

anus, vulva or scrotum and sheath){R-45}; photosensitization{R-39}

Cattle, dogs, and horses

Nephrotoxicosis{R-29–31; 112; 168}—with high doses, concurrent

debilitating conditions, or use of outdated tetracyclines

Incidence unknown

All species

Overgrowth of nonsusceptible organisms

Cats, cattle, dogs, horses, monkeys, rabbits, rats, and sheep{R-33–35}

Cardiovascular dysfunction, including atrioventricular block,

atrial tachycardia, ventricular bradycardia, hypotension (in

order of appearance—agitation or nervousness, dyspnea, muscle

fasciculations, urination, defecation, collapse, death)—a dose-depen-

dent effect{R-34} with rapid intravenous administration; cardiovascu-

lar dysfunction, including hypertension, arterial{R-35}—in horses

given doxycycline

Note: Although the propylene glycol vehicle of some oxytetracycline

preparations has been shown to have some cardiovascular effects

when administered intravenously{R-33}, the calcium-binding nature

of the tetracyclines has been implicated in cardiovascular dysfunction

and sudden collapse in cattle and sheep after intravenous admin-

istration of tetracyclines.{R-34; 35} Although pretreatment with

calcium borogluconate has been considered before intravenous



administration{R-34}, specific postreaction therapy for possible

hypocalcemia has not been recommended.

In horses, doses of doxycycline as low as 0.2 to 0.4 mg per kg of

body weight administered intravenously have caused cardiovascular

dysfunction, collapse, and death. Instead of hypotension, hyper-

tension is reported in horses given intravenous doxycycline and

is associated with the other signs of cardiovascular dysfunction

seen with rapid intravenous tetracycline administration in other

species.

Cats

Fever (anorexia, sometimes diarrhea)—usually resolves within 48

hours of discontinuing oxytetracycline or tetracycline{R-39}

Cattle

Hemoglobinuria, transient{R-38; 45; 56} (brownish-red urine)—with

parenteral administration of oxytetracycline; hepatitis with fatty

degeneration and/or bile stasis{R-168}—with repeated high doses or

concurrent debilitating conditions

Horses

Colitis; diarrhea, severe

Psittacine birds (cockatoos, macaws, and parrots)

Aspergillosis, increased risk of—may occur with prolonged chlor-

tetracycline treatment{R-152}

Rabbits

Anorexia; diarrhea—with doses administered that are two times the

recommended dose{R-86}


All species

Discoloration of teeth in young animals (yellow, brown, or grey

discoloration)—when administered during late pregnancy or during

period of tooth development{R-39}; local tissue irritation at site of

injection—with intramuscular administration{R-37; 101}

Cats and dogs

Nausea or vomiting—with oral administration{R-39}, in particular,

with doxycycline on an empty stomach{R-156}




included in the human monograph Tetracyclines (Systemic) in USP DI



tetracyclines in the treatment of animals:


Central nervous system toxicity; staining of infants’ or

children’s teeth; gastrointestinal disturbances; photosensitivity


Fungal overgrowth; hypertrophy of the papillae; nephrogenic

diabetes insipidus; pigmentation of skin and mucous mem-

branes

Incidence rare

Benign intracranial hypertension; hepatotoxicity; pancreatitis

Note: Tetracycline-induced hepatotoxicity is usually seen as a fatty

degeneration of the liver. It is more likely to occur in pregnant

women, in patients receiving high-dose intravenous therapy, and

in patients with renal function impairment. However, hepatotox-

icity has also occurred in patients without these predisposing

conditions. Tetracycline-induced pancreatitis has also been de-

scribed in association with hepatotoxicity, and without associated

liver disease.






Overdose of tetracyclines in animals is unusual because very high doses are

often tolerated; however, effects that have been associated with overdose

in animals include nephrotoxicosis and possible hepatotoxicity.

Acute toxicity of intravenously-administered tetracyclines{R-33; 34} in

many species is most often seen with rapid administration; however,

intravenous doxycycline administration in horses has caused collapse

even when administered over a 3- to 7-minute period. This reaction to

intravenous tetracyclines is dose-dependent, but is not only associated

with high doses.

Administration of repeated high doses of intravenous or intramuscular

oxytetracycline to calves or cattle can result in renal cortical tubular

nephrosis. While a single intramuscular dose of 40 mg of an

oxytetracycline per kg (in a 2-pyrrolidine formulation) administered

to healthy calves produced no significant toxicity{R-101}, studies have

shown that 33 to 44 mg of oxytetracycline per kg of body weight a day

administered intravenously or intramuscularly for 2 or more days can

produce renal protein casts, tubular necrosis, and death in calves with

respiratory disease{R-30; 168}. A similar dose of 33 mg oxytetracycline

per kg of body weight administered intravenously for 3 days produces

a rise in blood urea nitrogen and the appearance of renal casts in the

urine of normal heifers{R-167}. The vehicles used in formulations, such

as propylene glycol, have been linked to reduced renal blood flow and

have been suspected of exacerbating adverse effects{R-29; 33}. Tetra-

cycline and its degradation products have been reported to also cause

nephrotoxicity in cattle and foals{R-29; 112}. Serious toxicity can be

expected to be more likely in animals that are already compromised by

disease or dehydration.

Hepatotoxicity has been reported as a human side effect of tetracyclines

and may be more common in pregnant women{R-167}. Hepatic fatty

degeneration has been observed in people and has been induced in

mice and rats given extremely high doses (100 to 300 mg of

tetracycline per kg of body weight); however, fatty infiltration of the

liver was also observed in calves that had respiratory disease and

that developed renal tubular necrosis after administration of two

doses of 33 mg of oxytetracycline per kg of body weight 24 hours

apart{R-168}.


FOR ORAL DOSAGE FORMS ONLYFor some tetracyclines, serum concentrations from animal to animal

vary more widely when administered in drinking water than when

administered in feed.{R-59}

Unlike other tetracyclines, doxycycline can be used without dosage

adjustment in animals with renal function impairment.



FOR PARENTERAL DOSAGE FORMS ONLYCare should be taken to administer intravenous tetracyclines slowly and/

or dilute them in fluids to avoid cardiovascular side effects.{R-33–35}

Intramuscular injection of oxytetracycline will affect the quality of meat

for a prolonged period. Whenever possible, subcutaneous administra-

tion should be chosen{R-65}.

DIET/NUTRITIONOral tetracyclines are absorbed more efficiently when administered

without food, particularly without foods containing divalent or

trivalent metals, such as milk or milk replacer. Doxycycline absorption

appears to be less affected than other tetracyclines.


For anaphylaxis



FOR TREATMENT OF ACUTE REACTIONS TOINTRAVENOUS ADMINISTRATIONRecommended treatment consists of the following:

• Intravenous fluids.


Note: Because the specific causes of acute reactions may be difficult to

immediately determine, an electrocardiogram should be monitored

when possible to identify cardiac arrythmias and direct the course of

therapy.

CHLORTETRACYCLINE

ADDITIONAL DOSING INFORMATIONWhen possible, oral chlortetracycline should be administered 1 hour

before or 2 hours after milk replacer.{R-1}

MUCOSAL DOSAGE FORMSNote: Bracketed information in the Dosage Forms section refers to uses



CHLORTETRACYCLINE UTERINE TABLETSUsual dose:

Note: [Cattle]—Although the efficacy and safety are not currently

established, an intrauterine dose of 500 to 1000 mg administered as a

single dose after parturition{R-118} for the treatment of acute uterine

infections is included in Canadian product labeling.

[Ewes] and [sows]—Although the efficacy and safety are not currently

established, an intrauterine dose of 250 to 500 mg administered as a

single dose after parturition{R-118} for the treatment of acute uterine

infections is included in Canadian product labeling.


U.S.—



Canada—


500 mg (OTC) [Aureomycin Uterine Oblets].

Withdrawal times:

Canada—

Withdrawal time

Species Meat (days)

Cattle, pigs, sheep 0



manufacturer.





CHLORTETRACYCLINE HYDROCHLORIDE SOLUBLEPOWDER USPUsual dose:

Calves1 and pigs1—

Bacterial enteritis; or

Bacterial pneumonia: Oral, 22 mg per kg of body weight a day,

administered in the only source of drinking water.{R-17}

Chickens1—

Chronic respiratory disease: Oral, 400 to 800 mg per gallon of

water{R-17} (approximately 22 to 59 mg per kg of body weight a

day{R-143}), administered in the only source of drinking

water.{R-17}

Fowl cholera: Oral, 1000 mg (1 gram) per gallon of water,

administered in the only source of drinking water.

Synovitis: Oral, 200 to 400 mg per gallon of water (approximately

11 to 29.5 mg per kg of body weight a day), administered in the

only source of drinking water.{R-17; 143}

Turkeys, growing1—

Enteritis: Oral, 55 mg per kg of body weight a day, administered in

the only source of drinking water.{R-17}

Infectious synovitis: Oral, 400 mg per gallon of water

(approximately 7 to 37 mg per kg of body weight a day),

administered in the only source of drinking water.{R-143}

Note: Environmental and health conditions may affect the intake of

water and the amount of medication consumed.{R-17}

Administration of medication in food or water to animals with

pneumonia or other infections can be affected by reduced feed and

water intake{R-109}.


U.S.—{R-17}


25 grams per pound of powder (OTC) [Aureomycin Soluble Powder].

64 grams per pound of powder (OTC) [AmTech Chlortetracycline HCL

Soluble Powder; Aureomycin Soluble Powder Concentrate; CTC Soluble

Powder Concentrate; Pennchlor 64 Soluble Powder].



Canada—



Withdrawal times:

Note: With chlortetracycline soluble powder, withdrawal times vary

greatly from product to product and may differ from those listed below.

See also individual manufacturer’s labeling.

U.S.—{R-17; 58}

Withdrawal time

Species Meat (days)

Calves, chickens, and turkeys 1


Note: Product labeling with the above withdrawal time listed for poultry

states that it applies when the medication is mixed at 1000 mg of

chlortetracycline per gallon of drinking water.

Product labeling with the above withdrawal times states that they

apply when cattle and pigs are treated for a maximum of five days and

chickens and turkeys are treated for a maximum of fourteen days.

Not labeled for use in laying hens, preruminating calves, or lactating

dairy cattle.



otherwise specified by manufacturer. Protect from light.

Preparation of dosage form: Fresh solutions should be prepared every

24 hours. When administered in a galvanized waterer, fresh solutions

should be prepared every 12 hours.

Incompatibilities: Administration 1 hour before or 2 hours after giving

milk or milk replacers is recommended. Chlortetracycline hydrochlo-

ride soluble powder should not be mixed with milk replacers.

USP requirements: Preserve in tight containers, protected from

light. Label it to indicate that it is intended for oral veterinary

use only. Contains the labeled amount, within –10% to +25%.

Meets the requirement for Loss on drying (not more than

2.0%).{R-128}

CHLORTETRACYCLINE FOR MEDICATED FEEDUsual dose:

Calves—

Improved feed efficiency and increased weight gain for calves

weighing up to 250 pounds1: Oral, 0.22 mg per kg of body

weight a day administered in the feed, fed as the only ration.{R-16;

152}

Improved feed efficiency and increased weight gain for calves

weighing 250 to 400 pounds1: Oral, 25 to 70 mg per animal a

day administered in the feed, fed as the only ration.{R-16; 152}

Enteritis: Oral, 22 mg per kg of body weight a day, administered in

the feed and fed as the only ration{R-152}.

Note: Products made to add to calf milk replacer are indicated for

treatment of bacterial enteritis and for improved feed efficiency and

increased weight gain only.

Cattle—

Anaplasmosis (treatment)1:

Cattle weighing < 700 pounds—Oral, 350 mg per animal a day,

administered in the feed and fed as the only ration{R-16; 152}.

Cattle weighing ‡ 700 pounds—Oral 1.1 mg per kg of body

weight a day, administered in the feed and fed as the only

ration{R-152}.

Bacterial enteritis1; or bacterial pneumonia (treatment)1: Oral, 22

mg per kg of body weight a day, administered in the feed and fed as

the only ration{R-152}.

Bacterial pneumonia (control)1: Oral, 350 mg per animal a day

administered in the feed, fed as the only ration.{R-16; 152}

Improved feed efficiency and increased rate of weight gain1; or

hepatic abscesses (prophylaxis)1: Oral, 70 mg a day per animal


[Pododermatitis (prophylaxis)]: Oral, 0.22 mg per kg of body weight

a day or 70 mg per animal a day, administered in the feed and fed

as the only ration{R-116}.

Chickens—

Chronic respiratory disease: Oral, 200 to 400 grams per ton of feed,

fed as the only ration.{R-16; 152}

Escherichia coli infections1: Oral, 500 grams per ton of feed, fed as the

only ration.{R-16; 115}

Improved feed efficiency and increased rate of weight gain: Oral, 10

to 50 grams per ton of feed, fed as the only ration.{R-152}

Synovitis1: Oral, 100 to 200 grams per ton of feed, fed as the only

ration{R-152}.

[Enteritis; or increased egg production or hatchability]: Oral, 100 to

200 grams per ton of feed (110 to 220 grams per metric ton [1000

kg] of feed), fed as the only ration.

Note: Canadian product labeling also lists the above dose for feed

efficiency.

Cockatoos, macaws, and parrots—Psittacosis1: Oral, 10 mg per gram of

mash or feed, administered continuously for 45 days as the only

ration{R-152}.

Ducks1—Fowl cholera: Oral, 200 to 400 grams per ton of feed

(approximately 17.6 to 61.6 mg per kg of body weight a day)


Pigs—

Cervical abscesses (prophylaxis)1: Oral, 50 to 100 grams per ton of

feed, fed as the only ration.{R-115}

Bacterial enteritis; or bacterial pneumonia1: Oral, 22 mg per kg of

body weight a day, administered in the only ration{R-152}.

Improved feed efficiency and increased rate of weight gain: Oral, 10

to 50 grams per ton of feed, fed as the only ration.{R-152}

For reducing the shedding of leptospirosis and the incidence of

associated abortion1: Oral, 400 grams per ton of feed, fed as the

only ration for fourteen days.{R-152}

Note: Canadian product labeling lists a dose in the treatment of

enteritis and for increasing feed efficiency and improving weight

gain of 50 to 100 grams per ton of feed (55 to 110 grams per

metric ton [1000 kg] of feed), fed as the only ration{R-116}.

Sheep—Vibrionic abortion (prophylaxis)1: Oral, 80 mg per animal a

day administered in the feed, fed as the only ration continuously

during pregnancy.{R-16; 152}

Sheep, growing1—Improved feed efficiency and increased rate of

weight gain1: Oral, 20 to 50 grams per ton of feed, fed as the only

ration.{R-16}



Turkeys—

Bacterial enteritis: Oral, 55 mg per kg of body weight a day,

administered in the only ration{R-16; 152}.

Note: Canadian product labeling lists a dose in the treatment of

enteritis of 100 to 200 grams per ton of feed (110 to 220 grams per

metric ton [1000 kg] of feed), fed as the only ration{R-116}.

Hexamitiasis1: Oral, 400 grams per ton of feed, fed as the only

ration{R-16; 152}.

Synovitis1: Oral, 200 grams per ton of feed, fed as the only

ration{R-16; 152}.

[Increased egg production; or sinusitis (prophylaxis)]: Oral, 100 to

200 grams per ton of feed (110 to 220 grams per metric ton [1000

kg] of feed), fed as the only ration.

Turkeys, growing, less than 4 weeks of age—Paratyphoid1: Oral, 400

grams per ton of feed, fed as the only ration.{R-115}

Turkeys, growing—Improved efficiency or; increased rate of weight

gain: Oral 10 to 50 grams per ton of feed, fed as the only ration{R-16;

152}.

[Lambs]—Enterotoxemia: Oral, 20 grams per ton of feed (22 grams per

metric ton [1000 kg] of feed), fed as the only ration.


water and the amount of medication consumed.{R-17}

Administration of medication in food or water to animals with

pneumonia or other infections can be affected by reduced feed and

water intake{R-109}.


U.S.—


110 grams per kg of premix (OTC) [Aureomycin 50 Granular;

ChlorMax 50; CTC 50; Pennchlor 50ÆG; Pennchlor 50 Meal].

154 grams per kg of premix (OTC) [Pennchlor 70 Meal].

198 grams per kg of premix (OTC) [Aureomycin 90 Granular;

Pennchlor 90ÆG].

220 grams per kg of premix (OTC) [Aureomycin 100 Granular; CLTC

100 MR; Pennchlor 100 Hi-Flo Meal; Pennchlor 100MR].

Canada—


110 grams per kg of premix (OTC) [Aureomycin 110G; Chlor 50;

Chlorosol-50].

220 grams per kg of premix (OTC) [Aureomycin 220G; Chlor 100].


Note: With chlortetracycline oral premix, withdrawal times vary greatly

from product to product and may differ from those listed below.

See also individual manufacturer’s labeling.

U.S.—{R-123}

Withdrawal time

Species Meat (days) Eggs (hours)

Calves, cattle 0, 1, or 2, depending

on product and dose

Chickens 0 or 1, depending on

product and dose

0 for some products

Pigs, sheep, turkeys 0


apply when product is fed to calves at a dose of up to 70 mg per animal

a day, and to cattle at a dose of 350 mg per animal a day or 1.1 mg per

kg of body weight a day in feed, to chickens at 500 grams or more per

ton of feed for a maximum of five days, to pigs at 400 grams or less per

ton of feed or 22 mg per kg of body weight a day for up to fourteen

days, and to sheep when fed 80 mg per animal a day or 20 to 50

grams per ton of feed.

Not labeled for use in preruminating calves, lactating dairy cows, or

horses to be used for food.{R-16}

Some products are not labeled for use in chickens, ducks, or turkeys

producing eggs for human consumption.{R-152}

When fed at 22 mg per kg of body weight a day:

Withdrawal time

Species Meat (days)

Calves, cattle 0 or 10, depending on product

Note: Not labeled for use in lactating dairy cows.{R-16}

Canada—

Withdrawal time

Species Meat (days)

Calves, cattle 5

Chickens, pigs, turkeys 7

Lambs 4


apply when the product is fed to chickens and turkeys at 55 to 220 mg

per kg of feed, to pigs at 55 to 110 mg per kg of feed, to calves at 55 mg

per kg of feed, to lambs at 22 mg per kg of feed, and to cattle at 0.22

mg per kg of body weight or 70 mg per animal.

Not labeled for use in lactating diary cows.



manufacturer.


DOXYCYCLINE

SUMMARY OF DIFFERENCESPharmacology/pharmacokinetics: More completely absorbed from the

gastrointestinal tract than the tetracyclines developed earlier and

absorption is less likely to be affected by food or calcium or other

divalent or trivalent metals. Doxycycline is also more lipid-soluble than

other tetracyclines. In dogs, doxycycline is eliminated primarily

through intestinal excretion.{R-63}

Precautions: Medical considerations—Doxycycline is only partially

eliminated renally and is less likely to accumulate in animals with

renal function impairment; it can be used without dosage adjustment.

Side/adverse effects: Horses—Intravenous administration can lead to

cardiovascular dysfunction and death.{R-34}









in terms of doxycycline base.

DOXYCYCLINE FOR ORAL SUSPENSION USPUsual dose: [Rocky Mountain spotted fever]1—Dogs: Oral, 5 mg per kg

of body weight every twelve hours{R-151} for fourteen days.

Note: [Cats]1—Although the efficacy has not been established, an oral

dose of 5 mg per kg of body weight every twelve hours for twenty-one

days has been used in the treatment of feline infectious anemia{R-147;

151}. For chlamydial infections or respiratory infections in cats, a dose of 5

mg per kg of body weight every twelve hours or 10 mg per kg of body

weight every twenty-four hours has been used{R-151}.

[Dogs]1—Although the efficacy has not been established, an oral dose

of 10 mg per kg of body weight every twelve hours for two to three

weeks has been used for the treatment of ehrlichiosis; this regimen is

based on a clinical trial that found, however, that only two out of five

dogs treated with the above dose and a twenty-four-hour dosing

interval for one week were cleared of Ehrlichia canis, as shown by

negative blood and tissue cultures{R-40}. A dose of 5 mg per kg of

body weight every twelve hours for six to eight weeks has been used in

the treatment of ehrlichiosis to decrease the risk of side effects{R-176};

however, the efficacy of this regimen has not been confirmed. Retesting

serum immunoflourescent antibody for E. canis two months posttreat-

ment is recommended, and retreatment should be started if values

have not dropped significantly.{R-40}


U.S.—



Human-labeled products:

5 mg (base) per mL, when reconstituted according to manufacturer’s

instructions (Rx) [Vibramycin].

Canada—





Packaging and storage: Prior to reconstitution, store below 40 �C (104

�F), preferably between 15 and 30 �C (59 and 86 �F), unless otherwise

specified by manufacturer. Store in a tight, light-resistant container.

Stability: After reconstitution, suspensions retain their potency for 14

days at room temperature.

Auxiliary labeling:

• Shake well.


tains one or more suitable buffers, colors, diluents, flavors, and pre-

servatives. Contains the labeled amount, within –10% to +25% when

constituted as directed. Meets the requirements for Identification,

Uniformity of dosage units (single-unit containers), Deliverable

volume, pH (5.0–6.5, in the suspension constituted as directed in the

labeling), and Water (not more than 3.0%).{R-128}

DOXYCYCLINE CALCIUM ORAL SUSPENSION USPUsual dose: See Doxycycline for Oral Suspension USP.


U.S.—




10 mg (base) per mL (Rx) [Vibramycin].

Canada—






15 and 30 �C (59 and 86 �F), unless otherwise specified by manufac-

turer. Store in a tight, light-resistant container. Protect from freezing.

Auxiliary labeling:

• Shake well.

USP requirements: Preserve in tight, light-resistant containers. Pre-

pared from Doxycycline Hyclate, and contains one or more suitable

buffers, colors, diluents, flavors, and preservatives. Contains an

amount of doxycycline calcium equivalent to the labeled amount of

doxycycline, within –10% to +25%. Meets the requirements for

Identification, Uniformity of dosage units (single-unit containers),

Deliverable volume, and pH (6.5–8.0).{R-128}

DOXYCYCLINE HYCLATE CAPSULES USPUsual dose: See Doxycycline for Oral Suspension USP.


U.S.—{R-135}




50 mg (base) (Rx) [Vibramycin; generic].

100 mg (base) (Rx) [Vibramycin; generic].

Canada—




100 mg (base) (Rx) [Alti-Doxycycline; Apo-Doxy; Doxycin; Doxytec

(lactose); Novo-Doxylin; Nu-Doxycycline; Vibramycin].





tain an amount of doxycycline hyclate equivalent to the labeled

amount of doxycycline, within –10% to +20%. Meet the require-

ments for Identification, Dissolution (80% in 30 minutes in water in



Apparatus 2 at 75 rpm), Uniformity of dosage units, and Water (not

more than 8.5%).{R-128}

DOXYCYCLINE HYCLATE DELAYED-RELEASECAPSULES USPNote: Delayed-release capsules must be swallowed whole and, in general,

absorption of delayed-release dosage forms is unpredictable in animals.

Doxycycline Hyclate Delayed-release Capsules USP are not recom-

mended for use in animals.


U.S.—




100 mg (base) (Rx) [Doryx (lactose)].

Canada—








USP requirements: Preserve in tight, light-resistant containers. The

label indicates that the contents of the Capsules are enteric-coated.

Contain an amount of doxycycline hyclate equivalent to the labeled

amount of doxycycline, within –10% to +20%. Meet the requirements

for Identification, Drug release (Acid stage: 50% [Level 1 and Level 2]

in 20 minutes in 0.06 N hydrochloric acid in Apparatus 1 at 50 rpm;

Buffer stage: 85% in 30 minutes in neutralized phthalate buffer [pH

5.5] in Apparatus 1 at 50 rpm), Uniformity of dosage units, and Water

(not more than 5.0%).{R-128}

DOXYCYCLINE HYCLATE TABLETS USPUsual dose: See Doxycycline for Oral Suspension USP.


U.S.—{R-135}




100 mg (base) (Rx) [Vibra-Tabs; generic].

Canada—




100 mg (base) (Rx) [Alti-Doxycycline; Apo-Doxy-Tabs; Doxycin; Novo-

Doxylin; Nu-Doxycycline; Vibra-Tabs; Vibra-Tabs C-Pak].





tain an amount of doxycycline hyclate equivalent to the labeled

amount of doxycycline, within –10% to +20%. Meet the requirements

for Identification, Dissolution (85% in 90 minutes in water in Appa-

ratus 2 at 75 rpm), Uniformity of dosage units, and Water (not more

than 5.0%).{R-128}





in terms of doxycycline base (not the hyclate salt).

DOXYCYCLINE FOR INJECTION USPUsual dose:

Note: [Dogs]1—Although the efficacy has not been established, an

intravenous dose of 3 to 5 mg (base) per kg of body weight every


infections.{R-70}

This dose is based on pharmacokinetic studies.


U.S.—




100 mg (base) (Rx) [Vibramycin].

200 mg (base) (Rx) [Vibramycin].

Canada—







otherwise specified by manufacturer. Protect from light.

Preparation of dosage form: To prepare initial dilution for intrave-

nous use, 10 mL of sterile water for injection or other suitable diluent

(see manufacturer’s package insert) should be added to each 100-mg

vial or 20 mL of diluent should be added to each 200-mg vial. The

resulting solution containing the equivalent of 100 to 200 mg of

doxycycline may be further diluted in 100 to 1000 mL or in 200 to

2000 mL of suitable diluent, respectively.

Stability:

After reconstitution, intravenous infusions of doxycycline hyclate retain

their potency for twelve hours at room temperature or for seventy-two

hours if refrigerated at concentrations of 100 mcg (0.1 mg) to 1 mg

per mL in suitable fluids (see manufacturer’s package insert). Intra-

venous infusions of doxycycline hyclate retain their potency for six





hours at room temperature at concentrations of 100 mcg (0.1 mg) to 1

mg per mL in lactated Ringer’s injection or 5% dextrose and lactated

Ringer’s injection. Infusions must be protected from direct sunlight

during administration.

If frozen immediately after reconstitution with sterile water for injection,

solutions at concentrations of 10 mg per mL retain their potency for up

to eight weeks at –20 �C (–4 �F). Once thawed, solutions should not be

refrozen.


Concentrations of less than 100 mcg (0.1 mg) per mL or greater than

1 mg per mL are not recommended.

Infusions may be administered over a one- to four-hour period. Rapid

administration should be avoided.

Intramuscular or subcutaneous administration is not recommended.

USP requirements: Preserve in Containers for Sterile Solids, protected

from light. Contains an amount of doxycycline hyclate equivalent to

the labeled amount of doxycycline, within –10% to +20%. Meets the

requirements for Constituted solution, Identification, Bacterial endo-

toxins, Sterility, pH (1.8–3.3, in the solution constituted as directed in

the labeling), Loss on drying (not more than 4.0%), and Particulate

matter.{R-128}

OXYTETRACYCLINE

ADDITIONAL DOSING INFORMATIONWhen possible, oral oxytetracycline should be administered 1 hour before

or 2 hours after milk replacer.{R-1}




OXYTETRACYCLINE HYDROCHLORIDE UTERINESUSPENSIONUsual dose:

Note: [Cows]—Although the efficacy and safety are not currently

established, an intrauterine dose of 3.9 to 4.4 mg per kg of body

weight, administered as a single dose{R-12}, is included in Canadian

product labeling for the treatment of uterine infections.


U.S.—



Canada—{R-12}


50 mg per mL (Rx) [Kelamycin].

Withdrawal times:

Canada—

Withdrawal time


Cows 18 24



manufacturer.

Preparation of dosage form: Warm to body temperature to ease


Stability: Preparation may darken on standing, but the potency

remains unaffected.{R-12}





OXYTETRACYCLINE HYDROCHLORIDESOLUBLE POWDER USPUsual dose:

Bees—American and European foul brood: Oral, 200 mg per colony

once every four to five days for three treatments in the spring

and/or fall. Powder is dusted on the outer parts of the frames or

mixed as a syrup and fed in feeder pails or in the combs.{R-6; 61;

134}

Note: Honey from infected colonies should not be used for the

preparation of medicated syrup.

Calves and cattle—

Bacterial enteritis: Oral, 22 mg per kg of body weight every twenty-

four hours, administered in the only source of drinking water or as

a drench.{R-61}

Bacterial pneumonia1: Oral, 22 mg per kg of body weight every

twenty-four hours, administered in the only source of drinking

water or as a drench.{R-61}

Chickens—

Chronic respiratory disease; or fowl cholera: Oral, 400 to 800 mg per

gallon of water (approximately 22 to 59 mg per kg of body weight

a day), administered as the only source of drinking water.{R-11}

Synovitis1: Oral, 200 to 400 mg per gallon of water, administered as

the only source of drinking water.{R-11; 13; 61}

[Bacterial enteritis]: Oral, 200 to 400 mg per gallon of water,

administered as the only source of drinking water.

Pigs—

Bacterial enteritis: Oral, 22 mg per kg of body weight, administered

in the only source of drinking water.{R-11; 13; 61}

Bacterial pneumonia: Oral, 22 mg per kg of body weight, admin-

istered in the only source of drinking water{R-6; 13}.





Leptospirosis1: Oral, 22 mg per kg of body weight, administered in

the only source of drinking water{R-6; 13}.

Sheep—

Bacterial enteritis: Oral, 22 mg per kg of body weight every


water.{R-61}

Bacterial pneumonia1: Oral, 22 mg per kg of body weight every


water{R-13}.

Turkeys, growing—Bacterial enteritis: Oral, 55 mg per kg of body

weight a day for seven to fourteen days.{R-7; 11; 13}

Turkeys—

Hexamitiasis1: Oral, 200 to 400 mg per gallon of water (approxi-

mately 3.5 to 37 mg per kg of body weight a day), administered as

the only source of drinking water.{R-11}

Synovitis1: Oral, 400 mg per gallon of water (7 to 37 mg per kg of

body weight a day), administered as the only source of drinking

water.{R-7; 11; 13}


water and the amount of medication consumed.{R-17} Administra-

tion of medication by food or water to animals with pneumonia or

other infections can be affected by reduced feed and water

intake{R-109}.


U.S.—


25 grams per pound of powder (OTC) [AmTech Oxytetracycline HCL

Soluble Powder; Terramycin Soluble Powder; Terra-Vet Soluble

Powder].

166 grams per pound of powder (OTC) [Oxytet Soluble; Tetravet-CA;

Tetroxy HCA Soluble Powder].

343 grams per pound of powder (OTC) [Agrimycin-343; AmTech

Oxytetracycline HCL Soluble Powder-343; Oxytet-343 Water Soluble

Powder; Pennox 343 Soluble Powder; Terramycin-343 Soluble

Powder; Terra-Vet Soluble Powder 343; generic].

Canada—


11 mg per gram of powder (OTC) [Foul Brood Mix].

55 mg per gram of powder (OTC) [Oxytetra-A; Oxytet-25-S].

62.5 mg per gram of powder (OTC) [Oxysol-62.5; Oxytet-SP].

220 mg per gram of powder (OTC) [Oxy Tetra Forte].

250 mg per gram of powder (OTC) [Oxy 250; Oxysol-250; Oxytet-

250 Concentrate].

1 gram per gram of powder (OTC) [Oxy 1000; Oxysol-1000].


Note: With oxytetracycline soluble powder, withdrawal times vary

greatly from product to product and may differ from those listed below.

See also individual manufacturer labeling.

Bees: To avoid contamination of honey, oxytetracycline hydrochloride

soluble powder should be fed early in the spring or fall before the main

honey flow begins. Honey stored during treatment should be

removed following last medication and cannot be used for human

food.{R-61}

Withdrawal time

Species Meat (days)

Calves, cattle, sheep 5

Chickens 0

Pigs 0, 5, or 13, depending on product

Turkeys 0 or 5, depending on product


treatment of calves, cattle, pigs, and sheep should be for a maximum of

five days and chickens and turkeys for a maximum of fourteen days.

Not labeled for use in lactating dairy cattle, preruminating calves, or

birds producing eggs for human consumption.

Canada—{R-54}

Withdrawal time

Species Meat (days)

Calves, pigs, sheep 10

Chickens, turkeys 7


apply to doses of 5 to 10 mg per kg of body weight every twelve hours

for three to five days for calves, 10 mg per kg of body weight every

twelve hours for three or four days for pigs, 50 mg per L of drinking

water for three or four days for chickens and turkeys, and 5 mg per kg

of body weight every twelve hours for three or four days for sheep.

These products are not labeled for use in lactating dairy cattle or birds

producing eggs for human consumption{R-54}.

Withdrawal time

Species Meat (days) Milk (hours) Eggs (hours)

Cattle 10 60 or 96,

depending

on product

Chickens,

turkeys

7 60 or 120,

depending

on product

Pigs, sheep 10

Note: Some products are not labeled for use in lactating cattle and some

are not labeled for use in poultry laying eggs for human consumption.

Product labeling listing the above withdrawal times states that they

apply to doses of 22 mg per kg of body weight a day for five days for

calves and cattle, 33 mg per kg of body weight a day for pigs, and 111

mg per L of water for chickens and turkeys.



manufacturer.


Oxytetracycline soluble powder can be mixed with water and adminis-

tered as a drench. Fresh drinking water and drench solutions should be

prepared daily as recommended by the manufacturer.{R-11}

For bees, medication is mixed with powdered sugar and dusted on the

frames or mixed with sugar and water to form a paste or syrup and

applied as recommended by manufacturer.{R-54}

Stability: Stable for twenty-four hours.{R-11}



Incompatibilities: Milk replacer—Oxytetracycline is bound to milk

replacer at a rate of 63%; this is a binding that is not readily revers-

ible.{R-111} Administration of oral oxytetracycline in milk replacer will

result in lower bioavailability.{R-111}

USP requirements: Preserve in well-closed containers. A mixture of

Oxytetracycline Hydrochloride and one or more suitable excipients.

Label it to indicate that it is for oral veterinary use only. Contains

the labeled amount, within ±10%. Meets the requirements for

Identification, pH (1.5–3.0, in the solution obtained as directed in

the labeling), Loss on drying (not more than 3.0%, and Minimum

fill.{R-128}

OXYTETRACYCLINE FOR MEDICATED FEEDUsual dose:

Bees, honey—Foul brood: Oral, 200 mg per colony of bees every four to

five days in the spring and/or fall{R-117}. Powder is dusted on the

outer parts of the frames or mixed as a syrup and fed in feeder pails or

in the combs{R-117}.

Note: Honey from infected colonies should not be used for the

preparation of medicated syrup{R-117}.

Calves—

Bacterial enteritis: Oral, 22 mg per kg of body weight a day{R-117}.

Note: Canadian labeling lists a dose of 50 grams per ton (55 grams

per metric ton [1000 kg]) in the treatment of bacterial

enteritis{R-26}.

Improved feed efficiency1; or increased weight gain1 in calves

weighing less than 113.6 kg (250 pounds): Oral 0.11 to 0.22 mg

per kg of body weight a day, administered in the feed and fed as the

only ration{R-117}.

Improved feed efficiency1; or increased weight gain1 in calves

weighing 113 to 181 kg (250 to 400 pounds): Oral, 25 mg

per animal a day, administered in the feed and fed as the only

ration{R-117}.

Note: According to product labeling, when administered in milk

replacer, the 22 mg per kg of body weight dose is indicated in the

treatment of bacterial enteritis only{R-117}.

Catfish1—Hemorrhagic septicemia; or pseudomonas disease: Oral 55 to

82.5 mg per kg of body weight a day for a maximum of ten days,

administered in the feed and fed as the only ration{R-27}.

Cattle—

Bacterial enteritis1: Oral, 22 mg per kg of body weight a day{R-117}.

Bacterial pneumonia, acute (prophylaxis and treatment)1: Oral, 500

to 2000 mg (2 grams) per animal a day, administered in the feed

and fed as the only ration for three to five days prior to shipping

and three to five days after shipping{R-122; 117}.

Bacterial pneumonia (treatment)1: Oral, 22 mg per kg of body weight

a day, administered in feed and fed as the only ration for seven to

fourteen days{R-117}.

Improved feed efficiency1; or increased weight gain1, in growing

cattle weighing over 400 pounds: Oral, 75 mg per animal a day,


[Bloat]—Oral, 75 mg per animal a day, administered in the feed and


Chickens—

Chronic respiratory disease, specifically air sacculitis, reduction in

associated mortality1: Oral, 500 grams per ton of feed, fed as the

only ration{R-117}.

Chronic respiratory disease (control): Oral, 400 grams per ton of

feed, fed as the only ration{R-117}.

Note: Canadian labeling lists a dose of 100 grams per ton (110

grams per metric ton [1000 kg]) in the treatment of chronic

respiratory disease{R-26}.

Fowl cholera1; or synovitis: Oral, 100 to 200 grams per ton of feed,


Improved feed efficiency1 and increased weight gain1: Oral, 10 to 50

grams per ton of feed, fed as the only ration{R-117}.

Lobsters—Gaffkemia: Oral, 2.2 grams per kg of feed, fed as the only

ration{R-27; 124}.

Pigs—

Bacterial enteritis: Oral, 22 mg per kg of body weight a day,



grams per metric ton [1000 kg]) in the treatment of bacterial

enteritis{R-26}.

For reducing the shedding of leptospirosis and reducing the incidence

of associated abortions: Oral, 22 mg per kg of body weight per

animal a day, administered in the feed and fed as the only ration{R-

117}.


grams per metric ton [1000 kg]) in the treatment of leptospi-

rosis{R-26}.

Improved feed efficiency and increased weight gain1: Oral, 10 to 50


[Atrophic rhinitis]: Oral, 50 grams per ton (55 grams per metric ton

[1000 kg]) of feed, fed as the only ration{R-26}.

Note: Different feeding regimens will result in differences in actual mg

of oxytetracycline per kg of body weight consumed by individual

pigs{R-110}.

Therapeutic serum concentrations of > 0.5 mcg/mL were not

produced when 550 mg of oxytetracycline per kg of feed was

administered to 30-kg pigs in one study{R-107}.

An oral dose of 54 to 108 mg per kg of body weight a day

(concentrations of 1600 and 2400 mg of oxytetracycline per kg of

feed) was reported to be required to produce 1 mcg per mL serum

concentrations in pigs{R-110}.

Salmon, Pacific1—Marking of skeletal tissue: Oral, 250 mg per kg of

body weight a day{R-27}.

Salmonids—[Cold water disease]; [columnaris disease]; [enteric red-

mouth disease]; furunculosis; hemorrhagic septicemia1; pseudo-

monas disease1; or ulcer disease: Oral, 55 to 82.5 mg per kg of

body weight a day, administered in the feed and fed as the only

ration{R-27; 124}.

Sheep1—

Bacterial enteritis; or bacterial pneumonia: Oral 22 mg per kg of

body weight per animal a day, administered in the feed and fed as

the only ration{R-117}.

Improved feed efficacy and increased weight gain: Oral, 10 to 20


Turkeys—

Bacterial enteritis (bluecomb): Oral, 55 mg per kg of body weight

a day, administered in the feed and fed as the only ration{R-117}.

Note: Canadian labeling lists a dose of 100 grams per ton (110 grams

per metric ton [1000 kg]) of feed, fed as the only ration{R-26}.

Hexamitiasis1: Oral, 100 grams per ton of feed, fed as the only

ration{R-117}.



Improved feed efficiency1 and increased weight gain1: Oral, 10 to 50


Synovitis: Oral, 200 grams per ton of feed, fed as the only

ration{R-26}.

[Sinusitis]: Oral, 100 grams per ton (110 grams per metric ton [1000

kg]) of feed, fed as the only ration{R-26}.

[Lambs]—

Bacterial enteritis: Oral, 100 grams per ton (110 grams per metric

ton [1000 kg]) of feed, fed as the only ration{R-26}.

Enterotoxemia: Oral, 20 grams per ton (22 grams per metric ton

[1000 kg]) of feed, fed as the only ration{R-26}.

Note: Environmental and health conditions may affect the intake of water

and the amount of medication consumed.{R-17} Administration of

medication by food or water to animals with pneumonia or other

infections can be affected by reduced feed and water intake{R-109}.


U.S.—{R-62; 122}


110 grams per kg of premix (OTC) [OTC 50; OXTC 50; Pennox 50

Meal; Terramycin 50].

220 grams per kg of premix (OTC) [OXTC 100; Pennox 100 Hi-Flo

Meal; Pennox 100-MR; Terramycin 100; Terramycin 100 For Fish].

440 grams per kg of premix (OTC) [OXTC 200; Pennox 200 Hi-Flo

Meal; Terramycin 200].

Canada—{R-26; 55}


110 grams per kg of premix (OTC) [Oxy-110; Oxysol-110; Oxytet-

racycline 50; Terramycin-50].


racycline 100; Terramycin-100].


racycline 200; Terramycin-200; Terramycin-Aqua].


Note: Bees—To avoid contamination of honey, oxytetracycline hydro-

chloride soluble powder should be fed early in the spring or fall before

the main honey flow begins. Honey stored during therapy should be

removed following the last medication and should not be used for

human food{R-117}.

U.S.—{R-27; 186}

When fed 500 grams per ton of feed:

Withdrawal time

Species Meat (days)

Chickens 1

If fed low-calcium feed 3

Note: Not labeled for chickens producing eggs for human consumption{R-

117}.

When fed up to 400 grams per ton of feed:

Withdrawal time

Species Meat (days)

Chickens 0

If fed low-calcium feed 3

Note: Not labeled for chickens producing eggs for human consump-

tion{R-117}.

When fed up to 200 grams per ton of feed:

Withdrawal time

Species Meat (days)

Turkeys 0

Note: Not labeled for turkeys producing eggs for human consump-

tion{R-117}.

When fed to turkeys at 200 grams or more per ton of feed, and to cattle,

pigs, and sheep at 22 mg/kg:

Withdrawal time

Species Meat (days)

Bees 42 (honey)

Catfish 21

Calves (some products),

cattle, sheep, turkeys

5

Lobsters 30

Pacific salmon 7


Salmonids 21

Note: Not labeled for poultry producing eggs for human consump-

tion{R-117}. A withdrawal time has not been established for prerumi-

nating calves for some products{R-117}.

Canada{R-26; 55}—

Note: Bees—Withdraw medication 4 weeks prior to honey flow.

Withdrawal time

Species Meat (days)

Bees 28 (honey)

Calves, cattle 5

Chickens, pigs, turkeys 7

Lambs 4

Lobsters 30

Salmonids, 10 �C or warmer 40

Salmonids, below 10 �C 80

Note: Not labeled for chickens producing eggs for human consumption{R-

117}. Withdrawal time has not been established for preruminating

calves{R-117}.



manufacturer.

Preparation of dosage form: For use in dry feeds only, as indi-

cated on manufacturer’s labeling. Should not be used without

diluting.{R-122}

Incompatibilities: Salmonid and lobster feeds having a high ash con-

tent (calcium, copper, iron, or zinc) may bind oxytetracycline and

prevent absorption. Oxytetracycline also should not be administered

with feeds containing bentonite.{R-124}

Additional information: U.S.—For fish, this medication should not be

used when water temperature is below 16.7 �C (62 �F) for catfish or

below 9 �C (48.2 �F) for salmonids.{R-62}




OXYTETRACYCLINE TABLETS USPUsual dose:

Bacterial enteritis1; or

Bacterial pneumonia1—Calves:

Control—Oral, 5.5 mg per kg of body weight every twelve hours.{R-2;

60}

Treatment—Oral, 11 mg per kg of body weight every twelve hours for

up to four days.{R-2; 60}


U.S.—{R-2; 60}


250 mg (OTC) [Terramycin Scours Tablets].

500 mg (OTC) [Oxy 500 Calf Bolus].

1000 mg (OTC) [Oxy 1000 Calf Bolus].

Canada—



Withdrawal times:

U.S.—{R-60}

Withdrawal time

Species Meat (days)

Calves 0 or 7, depending on product

Note: Product labeling with the above withdrawal time states that it

applies when calves are treated for up to four days.

Products are not labeled for use in preruminating calves{R-58}.

USP requirements: Preserve in tight, light-resistant containers. Contain

the labeled amount, within –10% to +20%. Meet the requirements for

Identification, Dissolution (75% in 45 minutes in 0.1 N hydrochloric acid

in Apparatus 1 at 100 rpm), Uniformity of dosage units, and Water (not

more than 7.5%).{R-128}




OXYTETRACYCLINE INJECTION USPUsual dose:

Cattle—Actinobacillosis1; [bacterial arthritis]; bacterial enteritis; [black-

leg/malignant edema]; diphtheria1; [leptospirosis]; [mastitis]; [ompha-

lophlebitis]; [peritonitis]; pneumonia and bovine respiratory disease

complex; pododermatitis; skin and soft tissue infections1; or uterine

infections: Intramuscular or intravenous, 6.6 to 11 mg per kg of body

weight every twenty-four hours.{R-24; 121}

Note: For uterine infections in cattle, an [intravenous dose of 11 mg per

kg of body weight every eight to twelve hours]1 has been

recommended, based on distribution studies{R-104}. The shortened

dosing interval will require an extended withdrawal time{R-14}.

For pneumonia caused by Pasteurella, an [intravenous dose of 11 mg

per kg of body weight every twelve hours]1 has been recommended,

based on pharmacokinetic changes in calves with induced pneumo-

nia{R-106}; however, this regimen is usually reserved for serious

cases. The shortened dosing interval will require an extended

withdrawal time{R-14}.

For [thromboembolic meningoencephalitis]1, a dose of 11 mg per kg of

body weight every twenty-four hours has been recommended;

however, there are no specific research data to support the efficacy

of this use{R-178; 179}.

[Pigs]—Bacterial enteritis; bacterial pneumonia; erysipelas; lepto-

spirosis; mastitis; or uterine infections: Intramuscular or intra-

venous, 6.6 to 11 mg per kg of body weight every twenty-four

hours.{R-10}

Note: No more than 10 mL should be injected per site in adult cattle and

no more than 5 mL per site in pigs. Less mature animals should have

decreasing volumes injected per site (but not total mg per kg of body

weight) so that small animals receive 0.5 to 2 mL per injection site.

Intravenously administered oxytetracycline should be injected slow-

ly.{R-21} Intramuscularly administered oxytetracycline causes a nota-

ble tissue reaction (see note on slaughter trim below under Withdrawal

times).

[Horses]1—Ehrlichiosis (Ehrlichiosis equi); or Potomac horse fever (Ehr-

lichiosis risticii): Intravenous, 10 mg per kg of body weight every

twenty-four hours.{R-46–48; 92; 138}

Note: Gastrointestinal side effects are possible following oxytetracycline

administration to horses.

The above dose is based on clinical trials and retrospective dose-

response studies.


a single intravenous dose of 44 mg of oxytetracycline per kg of body

weight has been used in the treatment of flexural limb deformities in

newborn foals, based on controlled studies in healthy foals{R-157;

158}. The dose is most often administered as a single intravenous dose

of 2 to 3 grams per foal{R-158} or as an intravenous dose of 1.5 grams

per foal, repeated in twenty-four hours. In some cases, clinicians

have repeated an initial 2- to 3-gram dose twenty-four hours

following the initial dose{R-20; 157}.

Studies have demonstrated the safety, including lack of renal

toxicity, of doses of up to 54.5 to 75 mg per kg of body weight,

administered two times, twenty-four hours apart, to twenty

newborn foals{R-20; 158}; however, because high doses of oxytet-

racyclines have been associated with renal toxicity in many

species{R-15}, some clinicians prefer to test renal function before

treatment. It is recommended that this high dose of oxytetracy-

cline not be administered to foals with any systemic illness or

disorder predisposing to renal compromise, including dehydration

or endotoxemia.

[Sheep]—Bacterial arthritis; bacterial pneumonia; mastitis; or uterine

infections: Intramuscular or intravenous, 6.6 mg per kg of body



U.S.—


100 mg per mL (OTC) [Agrimycin 100; AmTech Maxim-100;

Duramycin 100; Oxybiotic-100; Oxycure 100; Oxy-Mycin 100;

Promycin 100; Terra-Vet 100; Tetroxy-100].





Canada—


100 mg per mL (OTC) [Oxy LP; Oxymycine LP; Oxytetracycline

100LP; Oxytetramycin 100; Oxyvet 100 LP; Tetraject LP].


U.S.—{R-21; 56}

Withdrawal time

Species Meat (days)

Cattle 18, 19, 20, or 22, depending

on product


apply to a dose of 6.6 to 11 mg per kg of body weight a day in cattle for

a maximum of four days.

Not labeled for use in lactating cattle or preruminating calves.

Cattle slaughtered within 20 days of intramuscular administration of

oxytetracycline may require trimming of the injection sites and

surrounding tissues during dressing procedure.

Canada—{R-24}

Withdrawal time


Cattle 18 60 or 72, depending

on product

Pigs, sheep 18

Note: The above withdrawal times are based on Canadian labeling that

lists a dose of 6.6 mg per kg of body weight a day for a maximum of

two to three days.{R-24}



manufacturer. Protect from light. Protect from freezing.

Preparation of dosage form: For intravenous administration, dilution

in water for injection or physiological saline is recommended. Doses of

up to 2500 mg (50 mL) can be diluted in 250 mL of diluent, and larger

doses in 500 mL of diluent.

Stability: Diluted medication should be used or discarded immediately

after mixing.{R-21} Solution may darken on standing but this color

change does not affect the potency of the medication.


tainers, protected from light. A sterile solution of Oxytetracycline with

or without one or more suitable anesthetics, antioxidants, buffers,

complexing agents, preservatives, and solvents. Contains the labeled

amount, within –10% to +20%. Meets the requirements for Identifi-

cation, Bacterial endotoxins, Sterility, and pH (8.0–9.0).{R-128}

OXYTETRACYCLINE INJECTION USP (LONG-ACTING)Note: The formulations listed below have a viscosity excipient intended to

prolong therapeutic serum antibiotic concentrations. These products

are believed to differ from other oxytetracycline injection products

only in the rate of absorption from intramuscular injection; moreover,

some studies using oxytetracycline products with 2-pyrrolidone

viscosity excipient have failed to show that the duration of action is

significantly prolonged over that of the conventional formulation after

intramuscular injection, when they are administered at the same

dose.{R-107; 162}. As such, use of the long-acting formulations at

standard doses of 6 to 11 mg per kg of body weight may not result in a

prolonged duration of action. Also, there is no difference in duration of

action between conventional and long-acting formulations when they

are administered intravenously{R-99; 151}.

Usual dose:

Cattle—Actinobacillosis1; bacterial enteritis1; bacterial pneumonia and

bovine respiratory disease complex; diphtheria1; keratoconjunctivi-

tis; leptospirosis; metritis, acute1; pododermatitis; or skin and soft

tissue infections1: Intramuscular, intravenous, or, when labeled,

subcutaneous, 6.6 to 11 mg per kg of body weight every twenty-four

hours for four days{R-3; 45}.

Note: When it is impractical to give cattle more than a single dose for

the treatment of keratoconjunctivitis or pneumonia, an intramus-

cular or, when labeled, subcutaneous dose of 20 mg per kg of body

weight administered as a single dose is recommended.{R-45}

In calves, [40 mg per kg of body weight as a single dose]1 has been

used in the treatment of bacterial pneumonia that is unresponsive to

20 mg per kg of body weight, based on pharmacokinetic and

toxicity data{R-95; 101}; however, the clinical efficacy was not

established in this study. This higher dose should not be repeated

because of the risk of adverse effects{R-30; 167; 168}.

For [thromboembolic meningoencephalitis]1 in cattle, a dose of 11 mg

per kg of body weight every twenty-four hours has been

recommended; however, there are no specific research data to

support the efficacy of this use{R-178; 179}.

Pigs—Bacterial enteritis1; bacterial pneumonia; or leptospirosis: Intra-

muscular, 6.6 to 11 mg per kg of body weight every twenty-four

hours for four days.{R-45}

Note: When it is impractical to give pigs more than a single dose for the

treatment of pneumonia, an intramuscular dose of 20 mg per kg of

body weight administered as a single dose is recommended.{R-45}

Sows—Bacterial enteritis in suckling pigs: Intramuscular, 6.6 mg per

kg of body weight, administered once eight hours before farrowing or

immediately after farrowing.{R-45}

Note: No more than 10 mL should be administered intramuscularly at

any one site in adult cattle. No more than 5 mL should be injected

intramuscularly at any one site in adult pigs.{R-45} Injections should be

administered deep into the fleshy part of the muscle.{R-25} Less mature

animals should have size-dependent decreasing volumes injected per

site so that small calves receive only 1 to 2 mL per injection site.


U.S.—{R-3; 45}


200 mg per mL (OTC) [Agrimycin 200; AmTech Maxim-200;

Biomycin 200; Duramycin 72-200; Geomycin 200; Liquamycin

LA-200; Maxim-200; OT 200; OxyBiotic-200; Oxycure 200; Oxy-

Mycin 200; Oxyshot LA; Pennox 200 Injectable].

Note: The above products contain the following viscosity excipients:

Biomycin 200 contains polyethylene glycol; Duramycin 72-200,

Liquamycin LA-200, Maxim-200; and Pennox 200 contain 2-

pyrrolidone; and Oxyshot LA contains N-methylpyrrolidone.

Canada—{R-25; 120}


200 mg per mL (OTC) [Alamycin LA; Biomycin 200; Liquamycin LA-

200; Oxy LA; Oxymycine LA; Oxyvet 200 LA; Tetraject LA].

300 mg per mL (OTC) [Tetradure LA 300].




U.S.—{R-3; 5; 45; 153}

Note: If oxytetracycline injection is administered to calves as a single

intramusuclar dose of 40 mg per kg of body weight, there is some

evidence to suggest that a withdrawal time of 49 days would be

sufficient to avoid residues, based on tissue depletion studies of the

parent drug{R-101}.

Withdrawal time

Species Meat (days)

Cattle 28


Note: Some products are not labeled for use in lactating dairy cattle and

list the above withdrawal times.

Product labeling listing the above withdrawal times states that they

apply to a dose of 6.6 to 11 mg per kg of body weight a day for a

maximum of four days or 20 mg per kg of body weight administered as a

single dose.

Withdrawal time


Cattle 28 96

Pigs 28


apply to a dose of 6.6 to 11 mg per kg of body weight a day for a

maximum of four days or 20 mg per kg of body weight administered as

a single dose.

Canada—{R-25; 120}

Withdrawal time

Species Meat (days)

Cattle and pigs

Intramuscular injection 21 or 28, depending on product

Cattle



apply to a dose of 20 mg per kg of body weight administered once. Not

labeled for use in lactating dairy cattle.

One product recommends a 42-day withdrawal to avoid excess trim at

the injection site{R-58}.

Packaging and storage: Store between 15 and 30� C (59 and 86 �F),

unless otherwise specified by manufacturer. Protect from light. Protect

from freezing.{R-45}

Preparation of dosage form: Warm to room temperature before

administration.


tainers, protected from light. A sterile solution of Oxytetracycline with

or without one or more suitable anesthetics, antioxidants, buffers,

complexing agents, preservatives, and solvents. Contains the labeled


cation, Bacterial endotoxins, Sterility, and pH (8.0–9.0).{R-128}

TETRACYCLINE

ADDITIONAL DOSING INFORMATIONWhen possible, oral tetracycline should be administered 1 hour before or

2 hours after milk replacer.{R-1}




TETRACYCLINE UTERINE TABLETSUsual dose:

Note: [Cows] and [mares]—Although the efficacy and safety are not

currently established, the use of a 4-gram bolus administered as a

single intrauterine dose is included in Canadian product labeling{R-9}

for the treatment of uterine infections. The dose may be repeated in

two days if necessary.{R-9}


U.S.—



Canada—{R-9}


4 grams (OTC) [Tetra 4000; Tetrabol].

Withdrawal times:

Canada—{R-9}

Withdrawal time


Cows 18 72


tween 15 and 30 �C (59 and 86 �F), in a tight container, unless


Auxiliary labeling: Protect from excessive moisture.{R-9}





TETRACYCLINE BOLUSES USPUsual dose: Bacterial enteritis; or bacterial pneumonia—Calves: Oral,

11 mg per kg of body weight every twelve hours for five days.{R-1}


U.S.—{R-1}


500 mg (OTC) [Calf Scour Bolus Antibiotic; 5-Way Calf Scour Bolus].

Canada—{R-9}


4 grams (OTC) [Tetra 4000; Tetrabol].






U.S.—{R-1}

Withdrawal time

Species Meat (days)

Calves 12, 14 or 24, depending on

product

Canada—{R-9}

Withdrawal time

Species Meat (days)

Calves 5

Cattle 18

Note: Product labeling with the above withdrawal times state that they

apply to a dose of 20 mg per kg of body weight a day for three to five

days.




Auxiliary labeling:

• Protect from excessive moisture.{R-9}

USP requirements: Preserve in tight containers. Label Boluses to

indicate that they are intended for veterinary use only. Contain the

equivalent of the labeled amount of tetracycline hydrochloride, within

–10% to +20%. Meet the requirements for Identification, Uniformity of

dosage units, and Loss on drying (not more than 3.0%; or for Boluses

greater than 15 mm in diameter, not more than 6.0%).{R-128}

TETRACYCLINE HYDROCHLORIDE CAPSULES USPUsual dose: [Rocky Mountain spotted fever]1—Dogs: Oral, 22 mg per

kg of body weight every eight hours for fourteen days.{R-140; 141}

Note: [Dogs]1—The above dose is based on clinical trials and

retrospective dose-response studies. The same dosage regimen has

also been used in the treatment of ehrlichiosis in dogs{R-43; 139},

although the efficacy of this treatment has not been confirmed.

A dose of 22 mg per kg of body weight every six to eight hours has

also been used in the treatment of other susceptible bacterial

infections in dogs.

Dosing trials suggest that 30 mg of oral tetracycline per kg of body

weight every twelve hours for twenty-eight days, administered in

conjunction with 20 mg of intramuscular streptomycin every

twenty-four hours for the first fourteen days, may be successful in

resolving brucellosis in dogs. It has been recommended that all dogs

be treated in a population in which some have tested positive for

brucellosis; good management practices are recommended and

repeated follow-up testing is needed for several months to confirm

that all dogs remain seronegative{R-160}.

See also Tetracycline Oral Suspension USP.


U.S.—




250 mg (Rx) [Achromycin V; generic].

500 mg (Rx) [Achromycin V; generic].

Canada—




250 mg (Rx) [Apo-Tetra; Novo-Tetra; Nu-Tetra].





tain the labeled amount, within )10% to +25%. Meet the require-

ments for Identification, Dissolution (80% in 60 minutes, 90 minutes

for 500-mg capsules, in water in Apparatus 2 at 75 rpm), Uniformity

of dosage units, Loss on drying (not more than 4.0%), and Limit of

4-epianhydrotetracycline (not more than 3.0%).{R-128}

TETRACYCLINE HYDROCHLORIDE SOLUBLEPOWDER USPUsual dose:

Calves and pigs—Bacterial enteritis; or bacterial pneumonia: Oral, 11

mg per kg of body weight every twelve hours, administered in the

only source of drinking water for three to five days.{R-19}

Chickens—Chronic respiratory disease; or infectious synovitis: Oral,

27.5 mg per kg of body weight every twelve hours, administered in

the only source of drinking water for seven to fourteen days.{R-19}

Turkeys—Infectious synovitis; or bacterial enteritis: Oral, 27.5 mg per

kg of body weight every twelve hours, administered in the only

source of drinking water for seven to fourteen days.{R-19}

[Sheep]—Bacterial enteritis; or respiratory tract diseases: Oral, 40 mg

per kg of body weight every twelve hours for four to five days{R-18}.

Note: Environmental and health conditions may affect the intake of water

and the amount of medication consumed.{R-17} Administration of

medication by food or water to animals with pneumonia or other

infections can be affected by reduced feed and water intake{R-109}.


U.S.—{R-8; 19}


25 grams per pound of powder (OTC) [Duramycin 10; PolyOtic Soluble

Powder; Solu-Tet; Tet-Sol 10].

324 grams per pound of powder (OTC) [AmTech Tetracycline Hydro-

chloride Soluble Powder-324; Duramycin-324; Solu-Tet 324; Tet-324;

Tetra Bac 324; Tetrasol Soluble Powder; Tet-Sol 324; generic].

Canada—{R-18}


55 mg per gram of powder (OTC) [Tetra 55; generic].

62.5 mg per gram of powder (OTC) [Onycin 62.5; Tetracycline 62.5

Soluble Powder].

250 mg per gram of powder (OTC) [Onycin 250; Tetra 250;

Tetracycline 250; Tetracycline 250 Concentrate Soluble Powder;

Tetramed 250].

1000 mg per gram of powder (OTC) [Onycin 1000; Tetra 1000;

Tetracycline 1000; Tetramed 1000].



Withdrawal times:

U.S.—{R-8; 19}

Withdrawal time

Species Meat (days)

Calves 4 or 5, depending on product

Chickens, pigs, turkeys 4 or 7, depending on product

Note: Products are not labeled for use in preruminating calves or poultry

producing eggs for human consumption{R-58}.

Canada—{R-18}

Withdrawal time

Species Meat (days)

Calves, chickens, pigs,

sheep, turkeys

5

Note: Product labeling with the above withdrawal time states that it applies

to a dose of 20 to 40 mg per kg of body weight every twelve hours for a

maximum of five days for calves, pigs, and sheep and a dose of 200 mg

per liter of water for three to five days for chickens and turkeys.

Although a milk withdrawal time is included on one product label,

these products are not specifically labeled for use in lactating

dairy cows in Canada. Products are not labeled for use in laying

hens{R-18; 58}.




Preparation of dosage form: Fresh solutions should be prepared every

24 hours when administered in plastic or stainless steel waterers and

every 12 hours when administered in galvanized waterers.

Stability: Solutions are stable for 24 hours.{R-8}

USP requirements: Preserve in tight containers. Label it to indicate

that it is intended for veterinary use only. Contains the labeled


cation and Loss on drying (not more than 2.0%).{R-128}

TETRACYCLINE ORAL SUSPENSION USPUsual dose: Bacterial gastroenteritis1 or urinary tract infections1—Cats

and dogs: Oral, 14 to 22 mg per kg of body weight every six to eight

hours.{R-177}

See also Tetracycline Hydrochloride Capsules USP.


U.S.—{R-4}


100 mg per mL (Rx) [Panmycin Aquadrops].

Canada—{R-126}




in a tight container, unless otherwise specified by manufacturer.

Protect from light.

Auxiliary labeling:

• Shake well before each dose{R-4}.

USP requirements: Preserve in tight, light-resistant containers. It is

Tetracycline with or without one or more suitable buffers, preser-

vatives, stabilizers, and suspending agents. Contains the equivalent of

the labeled amount of tetracycline hydrochloride, within –10% to

+25%. Meets the requirements for Identification, Uniformity of dos-

age units (single-unit containers), Deliverable volume, pH (3.5–6.0),

and Limit of 4-epianhydrotetracycline (not more than 5.0%).{R-128}

Developed: 07/17/96

Revised: 7/14/98; 10/12/99; 6/30/02; 04/05/03

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178. Panel comment, Rec 5/21/ 96.





Indications Index

Note: Both labeled and extra-labeled indications are included in this index

without differentiation. Please consult the individual monograph

Indications section for US and Canadian product labeling status for

each species and for more information on when use is appropriate.

This reference does not include every antimicrobial product available;

therefore, it should not be assumed that all medications appropriate for

a given indication are listed or that those not listed are inappropriate.

Because clinical variables play an important role in choice of

antimicrobial treatment, it cannot be assumed that the agents listed

for any indication are interchangeable in a particular situation.

Indications may be found under more than one Indications subheading

(Accepted, Acceptance not established, Unaccepted) when recommended

for more than one species or medication within a monograph.

Indications below can be found under the Accepted subheading of the

listed monograph’s Indications section for at least one species unless

‘‘Not estab’’ is stated. ‘‘Not estab’’ signifies a drug monograph in which

the indication is listed under the Acceptance not established subheading.

Unaccepted uses have not been indexed. Listing as Accepted, Acceptance

not established, or Unaccepted in a monograph is not meant to signify

label versus extra-label status.

Abortion, vibrionic (prophylaxis)

Tetracyclines, 226

Abscesses, cervical (prophylaxis)

Tetracyclines, 226

Abscesses, hepatic (prophylaxis)

Macrolides, 119

Tetracyclines, 226

Abscesses, laryngeal (treatment)

Lincosamides, Not estab, 110

Actinobacillosis (treatment)

Tetracyclines, 226

Actinomycosis (treatment)

Penicillin G, 151

Air sacculitis (treatment)

Spectinomycin, 202

Amebiasis, intestinal (treatment)

Metronidazole, Not estab, 144

Anaplasmosis (treatment)

Tetracyclines, 226

Arthritis, bacterial (treatment)


Macrolides, 119

Penicillin G, 151

Potentiated Sulfonamides, 165

Tetracyclines, 227

Atrophic rhinitis (treatment)

Macrolides, 119

Tetracyclines, 227

Bacteremia (treatment)

Aminoglycosides, 2

Balantidiasis, intestinal (treatment)


Bartonella infections (treatment)

Fluoroquinolones, Not estab, 88

Blackleg (treatment)

Penicillin G, 151

Tetracyclines, 227

Bloat

Tetracyclines, 228

Bone and joint infections (treatment)

Aminoglycosides, 2

Bovine respiratory disease (treatment)—See Pneumonia and Respiratory

tract infections

Bowel disease, inflammatory (treatment)


Brucellosis (treatment)


Tetracyclines, Not estab, 228

Chlamydial infections (treatment)


Macrolides, Not estab, 121

Rifampin, Not estab, 192


Chronic respiratory disease (CRD) (prophylaxis)

Macrolides, 120

Spectinomycin, 202

Chronic respiratory disease (CRD) (treatment)

Macrolides, 120

Spectinomycin, 202

Tetracyclines, 227

Coccidiosis (prophylaxis)


Coccidiosis (treatment)


Potentiated Sulfonamides, Not estab, 166

Sulfonamides, 207

Cold water disease (treatment)

Tetracyclines, 228

Colibacillosis (prophylaxis)


Colibacillosis (treatment)

Fluoroquinolones, 87


Spectinomycin, 202

Spectinomycin, Not estab, 202

Colitis, antibiotic-associated (treatment)


Colitis, chronic (treatment)


Colitis, clostridial (treatment)


Columnaris disease (treatment)

Tetracyclines, 228

Coryza, infectious (prophylaxis)

Macrolides, 119

Coryza, infectious (treatment)

Macrolides, 119

Sulfonamides, 207

Cryptosporidiosis (treatment)


Indications Index 253


Cystitis (treatment)


Sulfonamides, 208

Dermatitis, bacterial (treatment)

Aminopenicillins, 36

Diphtheria (treatment)

Macrolides, 120

Sulfonamides, 208

Tetracyclines, 226

Distemper, canine (treatment)

Aminoglycosides, Not estab 3


Dysentery, swine (prophylaxis)

Macrolides, 120

Dysentery, swine (treatment)

Lincosamides, 109

Macrolides, 120

Egg hatchability, increased

Tetracyclines, 228

Egg production, increased

Tetracyclines, 228

Ehrlichiosis, canine (treatment)


Ehrlichiosis, equine (treatment)

Tetracyclines, 228

Encephalopathy, hepatic (treatment)


Endometritis (treatment)


Endophthlalmitits, bacterial (treatment)


Enteric redmouth disease (treatment)

Tetracyclines, 228

Enteric septicemia (treatment)


Enteritis, bacterial (treatment)

Aminoglycosides, 2

Macrolides, 120


Spectinomycin, 202

Sulfonamides, 208

Tetracyclines, 226

Enteritis, Campylobacter (treatment)

Macrolides, 121

Enteritis, necrotic (treatment)

Lincosamides, 109

Enterotoxemia (prophylaxis)

Macrolides, 120

Enterotoxemia (treatment)

Tetracyclines, 228

Equine infectious arthritis (treatment)


Equine protozoal myeloencephalitis (treatment)


Pyrimethamine, 185

Erysipelas (treatment)

Macrolides, 120

Penicillin G, 151

Tetracyclines, 228

Escherichia coli infection (treatment)

Aminoglycosides, 2

Cephalosporins, 51

Tetracyclines, 226

Feed efficiency, improved

Macrolides, 120

Tetracyclines, 226

Flexural limb deformities (treatment)


Foul brood (treatment)

Tetracyclines, 226

Fowl cholera (prophylaxis)


Tetracyclines, 226

Fowl cholera (treatment)



Spectinomycin, 202

Sulfonamides, 208

Tetracyclines, 226

Fowl typhoid (treatment)

Sulfonamides, 208

Furunculosis (treatment)

Florfenicol, 81


Tetracyclines, 226

Gaffkemia (treatment)

Tetracyclines, 226

Gastroenteritis/Gastrointestinal infections, bacterial (treatment)

Aminoglycosides, Not estab, 3



Tetracyclines, 226

Genitourinary tract infections, bacterial (treatment)


Giardiasis (treatment)

Metronidazole, 144

Growth promotion and feed efficiency, increased

Lincosamides, 109

Haemobartonella felis infection (treatment)



Helicobacter species infections (treatment)


Hemorrhagic septicemia, bacterial (treatment)

Tetracyclines, 226

Hexamitiasis (treatment)

Tetracyclines, 226

Infections, bacterial (treatment)


Aminopenicillins, Not estab, 36

Cephalosporins, Not estab, 52





Spectinomycin, Not estab, 202



Infectious coryza (prophylaxis)


Joint infections (treatment)

Lincosamides, 109

Keratoconjunctivitis (treatment)

Florfenicol, 81

Tetracyclines, 226

Leptospirosis (treatment)


Aminopenicillins, Not estab, 36

Macrolides, 120

Penicillin G, 151

Tetracyclines, 226

Lyme disease (treatment)


Malignant edema (treatment)

Penicillin G, 151

Tetracyclines, 227

Mastitis (treatment)


Aminopenicillins (Intramammary), 33

Cephapirin (Intramammary), 71

Erythromycin (Intramammary), 79



Penicillin G (Intramammary), 149

Pirlimycin (Intramammary), 161


Tetracyclines, 228

Meningitis, bacterial (treatment)



Metritis (treatment)

Cephalosporins, 51

Lincosamides, 109

Macrolides, 120

Penicillin G, 151


Mycobacterial infections (treatment)


Mycoplasmal infections (treatment)


Neospora caninum infection (treatment)

Pyrimethamine, Not estab, 185

New duck disease (treatment)


Nocardiosis (treatment)


Omphalophlebitis (treatment)

Tetracyclines, 228

Osteomyelitis (treatment)

Amoxicillin and Clavulanate, Not estab, 46

Lincosamides, 109

Otitis media (treatment)


Pancreatitis (treatment)


Panleukopenia (treatment)


Paracolon (treatment)

Aminoglycosides, 2

Paratuberculosis (treatment)


Paratyphoid (treatment)

Spectinomycin, 202

Tetracyclines, 227

Pasteurellosis (treatment)


Periodontal infections (treatment)

Amoxicillin and Clavulanate, 46

Lincosamides, 109


Perioperative infections (prophylaxis)

Cephalosporins, 52


Peritonitis (treatment)

Tetracyclines, 228

Pharyngitis (treatment)

Penicillin G, 151

Pneumonia, bacterial (prophylaxis)

Tetracyclines, 227

Pneumonia, bacterial (treatment)


Florfenicol, 81


Lincosamides, 109

Macrolides, 120

Penicillin G, 151



Spectinomycin, 202

Sulfonamides, 208

Tetracyclines, 227

Pneumonia, Rhodococcus equi (treatment)

Macrolides, 120


Rifampin, 191

Pneumonitis (treatment)


Pododermatitis (prophylaxis)

Tetracyclines, 228

Pododermatitis (treatment)


Cephalosporins, 51

Florfenicol, 81

Macrolides, 120


Sulfonamides, 208

Tetracyclines, 227

Potomac horse fever (treatment)


Tetracyclines, 228

Proliferative enteropathy, porcine (prophylaxis and treatment)

Lincosamides, 109

Macrolides, 120

Prostate infection (treatment)

Indications Index 255



Protozoal infections (treatment)


Pseudomonas aeruginosa infection (treatment)

Aminoglycosides, 2

Pseudomonas disease (treatment)

Tetracyclines, 227

Psittacosis (treatment)

Tetracyclines, 227

Pullorum disease (treatment)

Sulfonamides, 208

Pyelonephritis (treatment)

Penicillin G, 151

Pyoderma (treatment)

Macrolides, 121

Respiratory disease, bacterial, chronic (prophylaxis)

Tetracyclines, 227

Respiratory tract infections, bacterial (treatment)

Aminoglycosides, 3

Cephalosporins, 51


Lincosamides, 109

Macrolides, 120


Sulfonamides, 209


Rhinitis (treatment)

Penicillin G, 151

Rocky Mountain spotted fever


Tetracyclines, 228

Salmonella infantis infection (treatment)

Spectinomycin, 202

Salmonella typhimurium infection (treatment)

Aminoglycosides, 2

Septicemia (treatment)

Aminoglycosides, 2


Sinusitis, infectious (prophylaxis)

Tetracyclines, 228

Sinusitis, infectious (treatment)

Macrolides, 121

Tetracyclines, 228

Skeletal tissue marking

Tetracyclines, 227

Skin and soft tissue infections (treatment)

Aminoglycosides, 3



Cephalosporins, 52


Lincosamides, 109

Penicillin G, 151


Sulfonamides, 209

Tetracyclines, 227

Strangles (treatment)


Penicillin G, 151


Swine dysentery (treatment)

Aminoglycosides, 3

Synovitis, infectious (prophylaxis)

Macrolides, 121

Spectinomycin, 202

Synovitis, infectious (treatment)

Spectinomycin, 202

Tetracyclines, 227

Tetanus (treatment)

Penicillin G, 151

Thromboembolic meningoencephalitis (treatment)


Tonsillitis, bacterial (treatment)


Toxoplasmosis (treatment)


Pyrimethamine, Not estab, 185

Tracheobronchitis, bacterial (treatment)


Trichomoniasis, intestinal (treatment)


Ulcer disease (treatment)

Tetracyclines, 227

Upper respiratory tract infections (treatment)


Urinary tract infections, bacterial (treatment)

Aminoglycosides, 3


Cephalosporins, 52


Tetracyclines, 227

Urogenital tract infections (treatment)


Uterine infections, bacterial (treatment)

Aminoglycosides, 3

Tetracyclines, 227


Vibrio anguillarum infection


Weight gain, increased rate

Macrolides, 120

Tetracyclines, 226



Dosing Index

Note: Both labeled and extra-labeled dosage recommendations are included in

this index without differentiation. Please consult the individual mono-

graph for US and Canadian product labeling status for each species and

for more information on when use is appropriate.

Amikacin—Included in Aminoglycosides (Veterinary—Systemic), 1

Cats, dogs, calves, donkeys, foals, goats, guinea pigs, hawks, parrots, ponies,

pythons, snakes, tortoises

Amikacin Sulfate Injection, 14

Horses


Amikacin Sulfate Uterine Solution, 13

Amoxicillin—

Included in Aminopenicillins (Veterinary—Intramammary-Local),

33

Cows

Amoxicillin Intramammary Infusion, 34

Included in Aminopenicillins (Veterinary—Systemic), 36

Calves

Amoxicillin Tablets, 40

Cats, dogs

Amoxicillin For Injectable Suspension, 41

Amoxicillin For Oral Suspension, 40


Cattle

Amoxicillin For Injectable Suspension, 41

Amoxicillin and Clavulanate—Included in Amoxicillin and Clavu-

lanate (Veterinary—Systemic), 46

Cats, dogs

Amoxicillin and Clavulanate Potassium For Oral Suspension, 48

Amoxicillin and Clavulanate Potassium Tablets, 49

Ampicillin—Included in Aminopenicillins (Veterinary—Systemic),

36

Calves, cattle

Ampicillin For Injectable Suspension, 42

Cats, dogs

Ampicillin Capsules, 42

Ampicillin For Injectable Suspension, 42

Ampicillin For Injection, 43

Horses

Ampicillin For Injection, 43

Apramycin—Included in Aminoglycosides (Veterinary—Systemic),

1

Pigs

Apramycin Sulfate Powder For Oral Solution, 15

Azithromycin—Included in Macrolides (Veterinary—Systemic),

119

Cats, dogs, foals

Azithromycin For Oral Suspension, 128

Azithromycin Tablets, 128

Cefaclor—Included in Cephalosporins (Veterinary—Systemic), 51

Dogs

Cefaclor Capsules, 56

Cefaclor For Oral Suspension, 57

Cefadroxil—Included in Cephalosporins (Veterinary—Systemic),

51

Cats, dogs

Cefadroxil For Oral Suspension, 57

Cefadroxil Tablets, 57

Cefazolin—Included in Cephalosporins (Veterinary—Systemic), 51

Dogs

Cefazolin For Injection, 58

Cefazolin Injection, 58

Cefixime—Included in Cephalosporins (Veterinary—Systemic), 51

Dogs

Cefixime For Oral Suspension, 59

Cefixime Tablets, 59

Cefotaxime—Included in Cephalosporins (Veterinary—Systemic),

51

Cats, dogs, foals

Cefotaxime For Injection, 60

Cefotaxime Injection, 60

Cefotetan—Included in Cephalosporins (Veterinary—Systemic), 51

Dogs

Cefotetan For Injection, 60

Cefoxitin—Included in Cephalosporins (Veterinary—Systemic), 51

Dogs, horses

Cefoxitin For Injection, 61

Cefoxitin Injection, 61

Ceftiofur—Included in Cephalosporins (Veterinary—Systemic), 51

Cattle, pigs

Ceftiofur Hydrochloride Injection, 62

Ceftiofur Sodium For Injection, 62

Chicks, dogs, goats, horses, sheep, turkey poults


Cephalexin—Included in Cephalosporins (Veterinary—Systemic),

51

Birds, dogs

Cephalexin Capsules, 63

Cephalexin For Oral Suspension, 64

Cephalexin Hydrochloride Tablets, 64

Cephalexin Tablets, 64

Cephalothin—Included in Cephalosporins (Veterinary—Systemic),

51

Birds, dogs, horses

Cephalothin For Injection, 65

Cephapirin—

Included in Cephalosporins (Veterinary—Systemic), 51

Dogs, horses

Cephapirin For Injection, 66

In Cephapirin (Veterinary—Intramammary-Local), 71

Cows

Cephapirin Benzathine Intramammary Infusion, 72

Cephapirin Sodium Intramammary Infusion, 72

Cephradine—

Included in Cephalosporins (Veterinary—Systemic), 51

Dogs, foals

Cephradine Capsules, 66

Cephradine For Oral Suspension, 66

Chloramphenicol—In Chloramphenicol (Veterinary—Systemic),

74

Dosing Index 257


Cats, dogs

Chloramphenicol Capsules, 76

Chloramphenicol Palmitate Oral Suspension, 76

Chloramphenicol Sodium Succinate For Injection, 77

Chloramphenicol Tablets, 77

Horses

Chloramphenicol Capsules, 76

Chloramphenicol Sodium Succinate For Injection, 77

Chloramphenicol Tablets, 77

Chlortetracycline—Included in Tetracyclines (Veterinary—Syste-

mic), 225

Calves, chickens, pigs, turkeys

Chlortetracycline For Medicated Feed, 237

Chlortetracycline Hydrochloride Soluble Powder, 236

Cattle


Chlortetracycline Uterine Tablets, 236

Cockatoos, ducks, lambs, macaws, parrots, sheep


Ewes, sows

Chlortetracycline Uterine Tablets, 236

Ciprofloxacin—Included in Fluoroquinolones (Veterinary—Syste-

mic), 87

Dogs

Ciprofloxacin For Oral Suspension, 97

Ciprofloxacin Injection, 97

Ciprofloxacin Tablets, 97

Horses



Clarithromycin—Included in Macrolides (Veterinary—Systemic),

119

Dogs

Clarithromycin For Oral Suspension, 129

Clarithromycin Tablets, 129

Clindamycin—Included in Lincosamides (Veterinary—Systemic),

109

Cats

Clindamycin Hydrochloride Oral Solution, 114

Dogs

Clindamycin Hydrochloride Capsules, 114


Difloxacin—Included in Fluoroquinolones (Veterinary—Systemic),

87

Dogs

Difloxacin Hydrochloride Tablets, 98

Dihydrostreptomycin—Included in Aminoglycosides (Veterinary

—Systemic), 1

Cattle, dogs, pigs

Dihydrostreptomycin Injection, 15

Doxycycline—Included in Tetracyclines (Veterinary—Systemic),

225

Cats, dogs

Doxycycline Calcium Oral Suspension, 239

Doxycycline For Oral Suspension, 239

Doxycycline Hyclate Capsules, 239

Doxycycline Hyclate Tablets, 240

Dogs

Doxycycline For Injection, 240

Enrofloxacin—Included in Fluoroquinolones (Veterinary—Syste-

mic), 87

Bustards, cats, dogs, ducks, horses, pacu, parrots, rabbits

Enrofloxacin Injection, 100

Enrofloxacin Tablets, 99

Camels, cattle, emus, llamas, oryx, potbellied and minature pigs, pythons,

sheep

Enrofloxacin Injection, 100

Chickens, turkeys

Enrofloxacin Oral Solution, 99

Foals

Enrofloxacin Tablets, 99

Erythromycin—

Included in Erythromycin (Veterinary—Intramammary-Local), 79

Cows

Erythromycin Intramammary Infusion, 80

Included in Macrolides (Veterinary—Systemic), 119

Dogs

Erythromycin Tablets, 130

Cattle, lambs, pigs, piglets, sheep

Erythromycin Injection, 131

Erythromycin Estolate—Included in Macrolides (Veterinary—Sys-

temic), 119

Foals

Erythromycin Estolate Capsules, 132

Erythromycin Estolate Oral Suspension, 132

Erythromycin Estolate Tablets, 132

Erythromycin Gluceptate—Included in Macrolides (Veterinary—

Systemic), 119

Foals

Sterile Erythromycin Gluceptate, 134

Erythromycin Phosphate—Included in Macrolides (Veterinary—

Systemic), 119

Chickens, turkeys

Erythromycin Phosphate Powder For Oral Solution, 135

Erythromycin Stearate—Included in Macrolides (Veterinary—Sys-

temic), 119

Dogs

Erythromycin Stearate Oral Suspension, 135

Erythromycin Stearate Tablets, 136

Erythromycin Thiocyanate—Included in Macrolides (Veterinary—

Systemic), 119

Chickens, turkeys

Erythromycin Thiocyanate For Medicated Feed, 136

Florfenicol—In Florfenicol (Veterinary—Systemic), 81

Cattle

Florfenicol Injection, 84

Salmon

Florfenicol For Medicated Feed, 84

Gentamicin—Included in Aminoglycosides (Veterinary—Systemic),

1

Cats, chicks, dogs, baboons, buffalo calves, budgerigars, calves, cattle, eagles,

foals, goats, hawks, llamas, owls, pythons, turkey poults

Gentamicin Injection, 17

Horses

258 Dosing Index



Gentamicin Uterine Infusion, 16

Pigs


Gentamicin Oral Solution, 16

Gentamicin Powder For Oral Solution, 17

Hetacillin—Included in Aminopenicillins (Veterinary—Intramam-

mary-Local), 33

Cows

Hetacillin Potassium Intramammary Infusion, 34

Kanamycin—Included in Aminoglycosides (Veterinary—Systemic),

1

Cats, dogs

Kanamycin Injection, 19

Lincomycin—Included in Lincosamides (Veterinary—Systemic),

109

Cats and dogs

Lincomycin Hydrochloride Syrup, 116

Lincomycin Hydrochloride Tablets, 116

Lincomycin Injection, 116

Cattle


Chickens

Lincomycin Hydrochloride For Medicated Feed, 115

Lincomycin Hydrochloride Soluble Powder, 115

Pigs

Lincomycin Hydrochloride For Medicated Feed, 115

Lincomycin Hydrochloride Soluble Powder, 115

Sheep


Marbofloxacin—Included in Fluoroquinolones (Veterinary—Syste-

mic), 87

Cats, dogs

Marbofloxacin Tablets, 101

Metronidazole—In Metronidazole (Veterinary—Systemic), 144

Cats, dogs, horses

Metronidazole Capsules, 146

Metronidazole Injection, 147

Metronidazole Hydrochloride For Injection, 147

Metronidazole Tablets, 146

Neomycin—Included in Aminoglycosides (Veterinary—Systemic), 1

Cattle, goats, pigs, and sheep

Neomycin Sulfate For Medicated Feed, 19

Neomycin Sulfate Oral Solution, 19

Neomycin Sulfate Powder For Oral Solution, 20

Horses



Turkeys


Orbifloxacin—Included in Fluoroquinolones (Veterinary—Syste-

mic), 87

Cats, dogs, horses

Orbifloxacin Tablets, 102

Ormetoprim and Sulfadimethoxine—Included in Potentiated Sul-

fonamides (Veterinary—Systemic), 164

Catfish, chickens, ducks, partridges, salmon, trout, turkeys

Ormetoprim and Sulfadimethoxine For Medicated Feed, 175

Dogs

Ormetoprim and Sulfadimethoxine Tablets, 176

Oxytetracycline—Included in Tetracyclines (Veterinary—Syste-

mic), 225

Bees

Oxytetracycline For Medicated Feed, 243

Oxytetracycline Hydrochloride Soluble Powder, 241

Calves



Oxytetracycline Tablets, 245

Catfish, lobsters, salmon, salmonids


Cattle



Oxytetracycline Hydrochloride Uterine Suspension, 241

Oxytetracycline Injection, 245

Oxytetracycline Injection (Long-Acting), 246

Chickens, turkeys



Horses


Lambs


Pigs





Sheep




Sows



Penicillin G—

Included in Penicillin G (Veterinary—Intramammary-Local), 149

Cows

Penicillin G Procaine Intramammary Infusion, 150

Included in Penicillin G (Veterinary—Systemic), 151

Cats, dogs, horses

Penicillin G Potassium For Injection, 156

Penicillin G Procaine Injectable Suspension, 156

Penicillin G Sodium For Injection, 157

Cattle, pigs, sheep


Turkeys

Penicillin G Potassium For Oral Solution, 154

Pirlimycin—In Pirlimycin (Veterinary—Intramammary-Local),

161

Cows

Pirlimycin Intramammary Infusion, 162

Pyrimethamine—In Pyrimethamine (Veterinary—Systemic), 185

Cats, dogs, horses

Pyrimethamine Tablets, 188

Dosing Index 259


Pyrimethamine and Sulfaquinoxaline—Included in Potentiated

Sulfonamides (Veterinary—Systemic), 164

Chickens, turkeys

Pyrimethamine and Sulfaquinoxaline Oral Solution, 177

Rifampin—In Rifampin (Veterinary—Systemic), 191

Cattle, dogs, foals, goats, horses, sheep

Rifampin Capsules, 198

Spectinomycin—In Spectinomycin (Veterinary—Systemic), 202

Cattle

Spectinomycin Sulfate Injection, 206

Chicks, ducklings, pigs, turkeys, turkey poults

Spectinomycin Hydrochloride Injection, 205

Chickens

Spectinomycin Hydrochloride Powder For Oral Solution, 204

Piglets

Spectinomycin Hydrochloride Oral Solution, 204

Streptomycin—Included in Aminoglycosides (Veterinary—Syste-

mic), 1

Calves, chickens, pigs

Streptomycin Sulfate Oral Solution, 21

Sulfachlorpyridazine—Included in Sulfonamides (Veterinary—Sys-

temic), 207

Calves

Sulfachlorpyridazine Injection, 215

Sulfachlorpyridazine Powder For Oral Solution, 215

Sulfachlorpyridazine Tablets, 215

Pigs

Sulfachlorpyridazine Powder For Oral Solution, 215

Sulfadiazine and Trimethoprim—Included in Potentiated Sulfona-

mides (Veterinary—Systemic), 164

Calves

Sulfadiazine and Trimethoprim Tablets, 178

Cats, dogs

Sulfadiazine and Trimethoprim Injection, 179


Horses

Sulfadiazine and Trimethoprim Injection, 179

Sulfadiazine and Trimethoprim Oral Paste, 177

Sulfadiazine and Trimethoprim Oral Powder, 177

Piglets

Sulfadiazine and Trimethoprim Oral Suspension, 178

Salmon

Sulfadiazine and Trimethoprim Oral Powder, 177

Sulfadimethoxine—Included in Sulfonamides (Veterinary—Syste-

mic), 207

Calves, cattle

Sulfadimethoxine Extended-Release Tablets, 217

Sulfadimethoxine Injection, 218

Sulfadimethoxine Oral Solution, 216

Sulfadimethoxine Soluble Powder, 216

Sulfadimethoxine Tablets, 217

Cats, dogs


Sulfadimethoxine Oral Suspension, 216


Chickens, turkeys



Sulfadoxine and Trimethoprim—Included in Potentiated Sulfona-

mides (Veterinary—Systemic), 164

Cattle, pigs

Sulfadoxine and Trimethoprim Injection, 180

Sulfamethazine—Included in Sulfonamides (Veterinary—Syste-

mic), 207

Calves, cattle

Sulfamethazine Extended-Release Tablets, 220

Sulfamethazine Oral Solution, 218

Sulfamethazine Powder For Oral Solution, 219

Sulfamethazine Tablets, 219

Chickens, turkeys



Foals

Sulfamethazine Tablets, 219

Pigs



Sheep


Sulfamethazine, Sulfanilamide, and Sulfathiazole—Included in


Cattle

Sulfamethazine, Sulfanilamide, and Sulfathiazole Tablets, 220

Sulfamethazine and Sulfathiazole—Included in Sulfonamides

(Veterinary—Systemic), 207

Cattle, pigs

Sulfamethazine and Sulfathiazole Powder For Oral Solution, 221

Sulfamethoxazole and Trimethoprim—Included in Potentiated


Dogs

Sulfamethoxazole and Trimethoprim Oral Suspension, 180

Sulfamethoxazole and Trimethoprim Tablets, 180

Foals

Sulfamethoxazole and Trimethoprim Injection, 181

Horses




Sulfaquinoxaline—Included in Sulfonamides (Veterinary—Syste-

mic), 207

Calves, cattle, chickens, turkeys

Sulfaquinoxaline Oral Solution, 221

Tetracycline—Included in Tetracyclines (Veterinary—Systemic),

225

Calves

Tetracycline Boluses, 247

Tetracycline Hydrochloride Soluble Powder, 248

Cats

Tetracycline Oral Suspension, 249

Chickens, pigs, sheep, turkeys


Cows, mares

Tetracycline Uterine Tablets, 247

Dogs

Tetracycline Hydrochloride Capsules, 248

Tetracycline Oral Suspension, 249

260 Dosing Index


Tilmicosin—Included in Macrolides (Veterinary—Systemic), 119

Calves, cattle, and lambs

Tilmicosin Injection, 137

Pigs

Tilmicosin For Medicated Feed, 137

Tylosin Base—Included in Macrolides (Veterinary—Systemic),

119

Cats, cattle, dogs, pigs

Tylosin Injection, 138

Tylosin Phosphate—Included in Macrolides (Veterinary—Syste-

mic), 119

Cattle, chickens, pigs

Tylosin Granulated, 138

Tylosin Tartrate—Included in Macrolides (Veterinary—Systemic),

119

Chickens, dogs, pigs, turkeys

Tylosin Tartrate Powder For Oral Solution, 139

Withdrawal times, extra-label

Note: Label and extra-label withdrawal recommendations can be found

in the Withdrawal times section for each dosage form.





Spectinomycin Hydrochloride Injection, 205


Dosing Index 261


Veterinary Brand and Generic Name Index

Note: Includes both United States and Canadian products.

Adspec Sterile Solution—Spectinomycin Sulfate Injection, 206

Agri-cillin—Penicillin G Procaine Injectable Suspension, 156

Agrimycin 100—Oxytetracycline Injection, 245

Agrimycin 200—Oxytetracycline Injection (Long-Acting), 246

Agrimycin-343—Oxytetracycline Hydrochloride Soluble Powder, 241

Alamycin LA—Oxytetracycline Injection (Long-Acting), 246

Albon Boluses—Sulfadimethoxine Tablets, 217

Albon 12.5% Concentrated Solution—Sulfadimethoxine Oral Solution, 216

Albon Injection 40%—Sulfadimethoxine Injection, 218

Albon Oral Suspension 5%—Sulfadimethoxine Oral Suspension, 216

Albon SR—Sulfadimethoxine Extended-Release Tablets, 217

Albon Tablets—Sulfadimethoxine Tablets, 217

Ambi-pen—Penicillin G Benzathine and Penicillin G Procaine Injectable

Suspension, 155

Amifuse E—Amikacin Sulfate Uterine Solution, 13

Amiglyde-V—Amikacin Sulfate Uterine Solution, 13

Amiglyde-V Injection—Amikacin Sulfate Injection, 14

Amiglyde-V Intrauterine Solution—Amikacin Sulfate Uterine Solution, 13

Amiject D—Amikacin Sulfate Injection, 14

Amikacin C Injection—Amikacin Sulfate Injection, 14

Amikacin E Solution—Amikacin Sulfate Uterine Solution, 13

Amikacin (Amifuse E; Amiglyde-V; Amiglyde-V Injection; Amiglyde-V

Intrauterine Solution; Amiject D; Amikacin C Injection; Amikacin E

Solution; AmTech AmiMax C Injection; AmTech AmiMax E Solution;

CaniGlide; Equi-Phar EquiGlide)

See Aminoglycosides (Veterinary—Systemic), 1

Injection, 14

Uterine Solution, 13

Amoxicillin (Amoxi-Drop; Amoxi-Inject; Amoxil Tablets; Amoxi-Tabs;

Biomox Oral Suspension; Biomox Tablets; Moxilean-50 Suspension;

Robamox-V Oral Suspension; Robamox-V Tablets)

See Aminopenicillins (Veterinary—Systemic), 36

For Injectable Suspension, 41

For Oral Suspension, 40

Tablets, 40

Amoxicillin, Intramammary (Amoxi-Mast)

See Aminopenicillins (Veterinary—Intramammary-Local), 33

Intramammary Infusion, 34

Amoxicillin and Clavulanate (Clavamox)

See Amoxicillin and Clavulanate (Veterinary—Systemic), 46


Tablets, 49

Amoxi-Drop—Amoxicillin For Oral Suspension, 40

Amoxi-Inject—Amoxicillin For Injectable Suspension, 41

Amoxi-Mast—Amoxicillin Intramammary Infusion, 34

Amoxil Tablets—Amoxicillin Tablets, 40

Amoxi-Tabs—Amoxicillin Tablets, 40

Amphicol Film-coated Tablets—Chloramphenicol Tablets, 77

Ampicillin (Polyflex)


For Injectable Suspension, 42

AmTech


Amikacin Sulfate Uterine Solution, 13

Chlortetracycline Hydrochloride Soluble Powder, 236



Gentamicin Oral Solution, 16

Gentamicin Uterine Infusion, 16





Spectinomycin Hydrochloride Oral Solution, 204





Antirobe—Clindamycin Hydrochloride Capsules, 114

Antirobe Aquadrops—Clindamycin Hydrochloride Oral Solution, 114

Apralan—Apramycin Sulfate Powder For Oral Solution, 15

Apralan Soluble—Apramycin Sulfate Powder For Oral Solution, 15

Apramycin (Apralan; Apralan Soluble)


Powder For Oral Solution, 15

Aquacillin—Penicillin G Procaine Injectable Suspension, 156

Aquaflor—Florfenicol For Medicated Feed, 84

Aureomycin 110G, Aureomycin 220G—Chlortetracycline For Medicated

Feed, 237

Aureomycin 50 Granular, Aureomycin 90 Granular, Aureomycin 100

Granular—Chlortetracycline For Medicated Feed, 237

Aureomycin Soluble Powder—Chlortetracycline Hydrochloride Soluble

Powder, 236

Aureomycin Soluble Powder Concentrate—Chlortetracycline Hydrochloride

Soluble Powder, 236

Aureomycin Uterine Oblets—Chlortetracycline Uterine Tablets, 236

Azramycine S125, Azramycine S250—Chloramphenicol Palmitate Oral

Suspension, 76

Baytril 3.23% Concentrate Solution—Enrofloxacin Oral Solution, 99

Baytril Injectable Solution—Enrofloxacin Injection, 100

Baytril Injectable Solution 2.27%—Enrofloxacin Injection, 100

Baytril 100 Injectable Solution—Enrofloxacin Injection, 100

Baytril Tablets—Enrofloxacin Tablets, 99

Baytril Taste Tabs—Enrofloxacin Tablets, 99

Benzapro—Penicillin G Benzathine and Penicillin G Procaine Injectable

Suspension, 155

Bimotrim—Sulfadoxine and Trimethoprim Injection, 180

Biomox Oral Suspension—Amoxicillin For Oral Suspension, 40

Biomox Tablets—Amoxicillin Tablets, 40

Biomycin 200—Oxytetracycline Injection (Long-Acting), 246

Biosol Liquid—Neomycin Sulfate Oral Solution, 19

Borgal—Sulfadoxine and Trimethoprim Injection, 180

Bovispec Sterile Solution—Spectinomycin Sulfate Injection, 206

Calf Scour Bolus Antibiotic—Tetracycline Boluses, 247

Calfspan—Sulfamethazine Extended-Release Tablets, 220

CaniGlide—Amikacin Sulfate Injection, 14

Cefa-Dri—Cephapirin Benzathine Intramammary Infusion, 72

Cefa-Drops—Cefadroxil For Oral Suspension, 57

Cefadroxil (Cefa-Drops; Cefa-Tabs)



See Cephalosporins (Veterinary—Systemic), 51


Tablets, 57

Cefa-Lak—Cephapirin Sodium Intramammary Infusion, 72

Cefa-Tabs—Cefadroxil Tablets, 57

Ceftiofur (Excenel; Excenel RTU; Naxcel)


Ceftiofur Hydrochloride Injection, 62


Cephapirin (Cefa-Dri; Cefa-Lak; ToDay; ToMorrow)

See Cephapirin (Veterinary—Intramammary-Local), 71

Cephapirin Benzathine Intramammary Infusion, 72

Cephapirin Sodium Intramammary Infusion, 72

Chlor 50, Chlor 100—Chlortetracycline For Medicated Feed, 237

Chlor 100, Chlor 250, Chlor 500, Chlor 1000—Chloramphenicol Tablets,

77

Chloramphenicol (Amphicol Film-Coated Tablets; Azramycine S125;

Azramycine S250; Chlor 100; Chlor 250; Chlor 500; Chlor 1000; Chlor

Palm 125; Chlor Palm 250; Duricol; Karomycin Palmitate 125;

Karomycin Palmitate 250; Viceton)

See Chloramphenicol (Veterinary—Systemic), 74

Capsules, 76

Oral Suspension, 76

Tablets, 76

ChlorMax 50—Chlortetracycline For Medicated Feed, 237

Chlorosol-50—Chlortetracycline For Medicated Feed, 237

Chlor Palm 125, Chlor Palm 250—Chloramphenicol Palmitate Oral

Suspension, 76

Chlortetracycline (AmTech Chlortetracycline HCL Soluble Powder;

Aureomycin 110G; Aureomycin 220G; Aureomycin 50 Granular;

Aureomycin 90 Granular; Aureomycin 100 Granular; Aureomycin Soluble

Powder; Aureomycin Soluble Powder Concentrate; Aureomycin Uterine

Oblets; Chlor 50; Chlor 100; ChlorMax 50; Chlorosol-50; CLTC 100 MR;

CTC 50; CTC Soluble Powder Concentrate; Pennchlor 50ÆG; Pennchlor

90ÆG; Pennchlor 100 Hi-Flo Meal; Pennchlor 50 Meal; Pennchlor 70

Meal; Pennchlor 100 MR; Pennchlor 64 Soluble Powder)

See Tetracyclines (Veterinary—Systemic), 225

For Medicated Feed, 237

Soluble Powder, 236

Uterine Tablets, 236

Clavamox—

Amoxicillin and Clavulanate Potassium For Oral Suspension, 48

Amoxicillin and Clavulanate Potassium Tablets, 49

Clincaps—Clindamycin Hydrochloride Capsules, 114

ClindaCure—Clindamycin Hydrochloride Oral Solution, 114

Clinda-Guard—Clindamycin Hydrochloride Oral Solution, 114

Clindamycin (AmTech; Antirobe; Antirobe Aquadrops; Clincaps; ClindaCure;

Clinda-Guard; Clindrops; nvClindamycin Capsules)

See Lincosamides (Veterinary—Systemic), 109

Capsules, 114

Oral Solution, 114

Clindrops—Clindamycin Hydrochloride Oral Solution114

CLTC 100 MR—Chlortetracycline For Medicated Feed, 237

Combicillin—Penicillin G Benzathine and Penicillin G Procaine Injectable

Suspension, 155

Combicillin AG—Penicillin G Benzathine and Penicillin G Procaine

Injectable Suspension, 155

CTC 50—Chlortetracycline For Medicated Feed, 237

CTC Soluble Powder Concentrate—Chlortetracycline Hydrochloride Soluble

Powder, 236

Depocillin—Penicillin G Procaine Injectable Suspension, 156

Derapen SQ/LA—Penicillin G Procaine Injectable Suspension, 156

Dicural Tablets—Difloxacin Hydrochloride Tablets, 98

Difloxacin (Dicural Tablets)

See Fluoroquinolones (Veterinary—Systemic), 87

Tablets, 98

Dihydrostreptomycin (Ethamycin)—


Injection, 15

Di-Methox Injection-40%—Sulfadimethoxine Injection, 218

Di-Methox 12.5% Oral Solution—Sulfadimethoxine Oral Solution, 216

Di-Methox Soluble Powder—Sulfadimethoxine Soluble Powder, 216

Duo-Pen—Penicillin G Benzathine and Penicillin G Procaine Injectable

Suspension, 155

Duplocillin LA—Penicillin G Benzathine and Penicillin G Procaine

Injectable Suspension, 155

Duramycin 10—Tetracycline Hydrochloride Soluble Powder, 248

Duramycin 72-200—Oxytetracycline Injection (Long-Acting), 246

Duramycin 100—Oxytetracycline Injection, 245

Duramycin-324—Tetracycline Hydrochloride Soluble Powder, 248

Durapen—Penicillin G Benzathine and Penicillin G Procaine Injectable

Suspension, 155

Duricol—Chloramphenicol Capsules, 76

Enrofloxacin (Baytril 3.23% Concentrate Solution; Baytril Injectable

Solution; Baytril Injectable Solution 2.27%; Baytril 100 Injectable

Solution; Baytril Tablets; Baytril Taste Tabs)


Injection, 100

Oral Solution, 99

Tablets, 99

Equi-Phar EquiGlide—Amikacin Sulfate Uterine Solution, 13

Erymycin-100—Erythromycin Thiocyanate For Medicated Feed, 136

Erythro-36—Erythromycin Intramammary Infusion, 80

Erythro-200—Erythromycin Injection, 131

Erythro-Dry Cow—Erythromycin Intramammary Infusion, 80

Erythromycin Base (Erythro-200; Gallimycin-100; Gallimycin-200)

See Macrolides (Veterinary—Systemic), 119

Injection, 131

Erythromycin, Intramammary (Erythro-36; Erythro-Dry Cow; Galli-

mycin-36; Gallimycin-Dry Cow)

See Erythromycin (Veterinary—Intramammary-Local), 79


Erythromycin Phosphate (Gallimycin; Gallimycin PFC; Gallistat)



Erythromycin Thiocyanate (Erymycin-100; Gallimycin-50)



Ethamycin—Dihydrostreptomycin Injection, 15

Excenel—Ceftiofur Sodium For Injection, 62

Excenel RTU—Ceftiofur Hydrochloride Injection, 62

Florfenicol (Aquaflor; NuFlor)

See Florfenicol (Veterinary—Systemic), 81


Injection, 84

Foul Brood Mix—Oxytetracycline Hydrochloride Soluble Powder, 241

Veterinary Brand and Generic Name Index 263


Gallimycin—Erythromycin Phosphate Powder For Oral Solution, 135

Gallimycin-36—Erythromycin Intramammary Infusion, 80

Gallimycin-50—Erythromycin Thiocyanate For Medicated Feed, 136

Gallimycin-100, Gallimycin-200—Erythromycin Injection, 131

Gallimycin-Dry Cow—Erythromycin Intramammary Infusion, 80

Gallimycin PFC—Erythromycin Phosphate Powder For Oral Solution,

135

Gallistat—Erythromycin Phosphate Powder For Oral Solution, 135

Garacin Piglet Injection—Gentamicin Injection, 17

Garacin Pig Pump—Gentamicin Oral Solution, 16

Garacin Soluble Powder—Gentamicin Powder For Oral Solution, 17

Garasol Injection—Gentamicin Injection, 17

Garasol Pig Pump Oral Solution—Gentamicin Oral Solution, 16

Garasol Solution Injectable—Gentamicin Injection, 17

Gentamicin (AmTech GentaMax 100; AmTech Gentamicin Sulfate Pig

Pump Oral Solution; AmTech Gentapoult; Garacin Piglet Injection; Garacin

Pig Pump; Garacin Soluble Powder; Garasol Injection; Garasol Pig Pump

Oral Solution; Garasol Solution Injectable; Gen-Gard; Genta-fuse; Genta-

Max 100; GentaVed 50; GentaVed 100; Gentocin; Gentocin Solution;

Gentocin Solution Injectable; Gentozen; Legacy)


Injection, 17

Oral Solution, 16


Uterine Infusion, 16

Gen-Gard—Gentamicin Powder For Oral Solution, 17

Genta-fuse—Gentamicin Injection, 17

GentaMax 100—Gentamicin Uterine Infusion, 16

GentaVed 50—Gentamicin Injection, 17

GentaVed 100—Gentamicin Uterine Infusion, 16

Gentocin—Gentamicin Injection, 17

Gentocin Solution—Gentamicin Uterine Infusion, 16

Gentocin Solution Injectable—Gentamicin Injection, 17

Gentozen—Gentamicin Uterine Infusion, 16

Geomycin 200—Oxytetracycline Injection (Long-Acting), 246

Go-dry—Penicillin G Procaine Intramammary Infusion, 150

Hetacillin (Hetacillin K Intramammary Infusion)

See Aminopenicillins (Veterinary—Intramammary-Local), 33


Hetacillin K Intramammary Infusion—Hetacillin Potassium Intramam-

mary Infusion, 34

Hi-Pencin 300—Penicillin G Procaine Injectable Suspension, 156

Kanamycin (Kantrim)


Injection, 19

Kantrim—Kanamycin Injection, 19

Karomycin Palmitate 125, Karomycin Palmitate 250—Chloramphenicol

Palmitate Oral Suspension, 76

Kelamycin—Oxytetracycline Hydrochloride Uterine Suspension, 241

Legacy—Gentamicin Uterine Infusion, 16

Lincocin—Lincomycin Hydrochloride Tablets, 116

Lincocin Aquadrops—Lincomycin Hydrochloride Syrup, 116

Lincocin Injectable—Lincomycin Injection, 116

Lincocin Sterile Solution—Lincomycin Injection, 116

Lincomix 20 Feed Medication, Lincomix 50 Feed Medication —Lincomycin

Hydrochloride For Medicated Feed, 115

Lincomix Injectable—Lincomycin Injection, 116

Lincomix Injectable Solution—Lincomycin Injection, 116

Lincomix 44 Premix, Lincomix 110 Premix—Lincomycin Hydrochloride


Lincomix Soluble Powder—Lincomycin Hydrochloride Soluble Powder,

115

Lincomycin (Lincocin, Lincocin Aquadrops, Lincocin Injectable, Lincocin

Sterile Solution, Lincomix 20 Feed Medication, Lincomix 50 Feed

Medication, Lincomix Injectable, Lincomix Injectable Solution, Lincomix

44 Premix, Lincomix 110 Premix, Lincomix Soluble Powder, Lincomycin

44 Premix, Lincomycin 110 Premix, Lincomycin 44G Premix, Lincomycin

110G Premix, Lincosol Soluble Powder, Moorman’s LN 10)

See Lincosamides (Veterinary—Systemic), 109


Injection, 116

Soluble Powder, 115

Syrup, 116

Tablets, 116

Lincomycin 44 Premix, Lincomycin 110 Premix, Lincomycin 44G Premix,

Lincomycin 110G Premix—Lincomycin Hydrochloride For Medicated

Feed, 115

Lincosol Soluble Powder—Lincomycin Hydrochloride Soluble Powder, 115

Liquamycin LA-200—Oxytetracycline Injection (Long-Acting), 246

Longisil—Penicillin G Benzathine and Penicillin G Procaine Injectable

Suspension, 155

Marbofloxacin (Zeniquin Tablets)


Tablets, 101

Masti-Clear—Penicillin G Procaine Intramammary Infusion, 150

Maxim-100—Oxytetracycline Injection, 245

Maxim-200—Oxytetracycline Injection (Long-Acting), 246

Micotil—Tilmicosin Injection, 137

Microcillin—Penicillin G Procaine Injectable Suspension, 156

Moorman’s LN 10—Lincomycin Hydrochloride For Medicated Feed, 115

Moxilean-50 Suspension—Amoxicillin For Oral Suspension, 40

Naxcel—Ceftiofur Sodium For Injection, 62

Neomycin (AmTech; Biosol Liquid; Neo-325; Neomed 325; Neomix 325;

Neomix AG 325; Neomix AG 325 Medicated Premix; Neomix Soluble

Powder; Neomycin 200; Neomycin 325; Neo-Sol 50; Neosol-Oral; Neosol

Soluble Powder; Neoved 200; Neovet 325/100; Neovet Neomycin Oral

Solution)



Oral Solution, 19


Neo-325—Neomycin Sulfate Powder For Oral Solution, 20

Neomed 325—Neomycin Sulfate Powder For Oral Solution, 20

Neomix 325—Neomycin Sulfate Powder For Oral Solution, 20

Neomix AG 325—Neomycin Sulfate Powder For Oral Solution, 20

Neomix AG 325 Medicated Premix—Neomycin Sulfate For Medicated

Feed, 19

Neomix Soluble Powder—Neomycin Sulfate Powder For Oral Solution, 20

Neomycin 200—Neomycin Sulfate Oral Solution, 19

Neomycin 325—Neomycin Sulfate Powder For Oral Solution, 20

Neo-Sol 50—Neomycin Sulfate Powder For Oral Solution, 20

Neosol-Oral—Neomycin Sulfate Oral Solution, 19

Neosol Soluble Powder—Neomycin Sulfate Powder For Oral Solution, 20

Neoved 200—Neomycin Sulfate Oral Solution, 19

Neovet 325/100—Neomycin Sulfate Powder For Oral Solution, 20

Neovet Neomycin Oral Solution—Neomycin Sulfate Oral Solution, 19



NuFlor—Florfenicol Injection, 84

nvClindamycin Capsules—Clindamycin Hydrochloride Capsules, 114

Onycin 62.5, Onycin 250, Onycin 1000—Tetracycline Hydrochloride

Soluble Powder, 248

Optimed—Sulfaquinoxaline Oral Solution, 221

Orbax Tablets—Orbifloxacin Tablets, 102

Orbifloxacin (Orbax Tablets)


Tablets, 102

Ormetoprim and Sulfadimethoxine (Primor 120; Primor 240; Primor

600; Primor 1200; Rofenaid 40; Romet 30; Romet-30)

See Potentiated Sulfonamides (Veterinary—Systemic), 164


Tablets, 176

OT 200—Oxytetracycline Injection (Long-Acting), 246

OTC 50—Oxytetracycline For Medicated Feed, 243

OXTC 50, OXTC 100, OXTC 200—Oxytetracycline For Medicated Feed,

243

Oxy-110, Oxy-220, Oxy-440—Oxytetracycline For Medicated Feed, 243

Oxy 250, Oxy 1000—Oxytetracycline Hydrochloride Soluble Powder,

241

Oxybiotic-100—Oxytetracycline Injection, 245

Oxybiotic-200—Oxytetracycline Injection (Long-Acting), 246

Oxy 500 Calf Bolus, Oxy 1000 Calf Bolus—Oxytetracycline Tablets, 245

Oxycure 100—Oxytetracycline Injection, 245

Oxycure 200—Oxytetracycline Injection (Long-Acting), 246

Oxy LA—Oxytetracycline Injection (Long-Acting), 246

Oxy LP—Oxytetracycline Injection, 245

Oxy-Mycin 100—Oxytetracycline Injection, 245

Oxy-Mycin 200—Oxytetracycline Injection (Long-Acting), 246

Oxymycine LA—Oxytetracycline Injection (Long-Acting), 246

Oxymycine LP—Oxytetracycline Injection, 245

Oxyshot LA—Oxytetracycline Injection (Long-Acting), 246

Oxysol-62.5, Oxysol-250, Oxysol-1000—Oxytetracycline Hydrochloride

Soluble Powder, 241

Oxysol-110, Oxysol-220, Oxysol-440—Oxytetracycline For Medicated

Feed, 243

Oxytet-250 Concentrate—Oxytetracycline Hydrochloride Soluble Powder,

241

Oxytetra-A—Oxytetracycline Hydrochloride Soluble Powder, 241

Oxytetracycline (Agrimycin 100; Agrimycin 200; Agrimycin-343;

Alamycin LA; AmTech Maxim-100; AmTech Maxim-200; AmTech

Oxytetracycline HCL Soluble Powder; AmTech Oxytetracycline HCL Soluble

Powder-343; Biomycin 200; Duramycin 72-200; Duramycin 100; Foul

Brood Mix; Geomycin 200; Kelamycin; Liquamycin LA-200; Maxim-200;

OT 200; OTC 50; OXTC 50; OXTC 100; OXTC 200; Oxy-110; Oxy-220;

Oxy 250; Oxy-440; Oxy 1000; Oxybiotic-100; OxyBiotic-200; Oxy 500

Calf Bolus; Oxy 1000 Calf Bolus; Oxycure 100; Oxycure 200; Oxy LA;

Oxy LP; Oxy-Mycin 100; Oxy-Mycin 200; Oxymycine LA; Oxymycine

LP; Oxyshot LA; Oxysol-62.5; Oxysol-110; Oxysol-220; Oxysol-250;

Oxysol-440; Oxysol-1000; Oxytet-250 Concentrate; Oxytetra-A; Oxyte-

tracycline 50; Oxytetracycline 100; Oxytetracycline 200; Oxytetracycline

100LP; Oxy Tetra Forte; Oxytetramycin 100; Oxytet-25-S; Oxytet

Soluble; Oxytet-SP; Oxytet-343 Water Soluble Powder; Oxyvet 200 LA;

Oxyvet 100LP; Pennox 100 Hi-Flo Meal; Pennox 200 Hi-Flo Meal;

Pennox 200 Injectable; Pennox 50 Meal; Pennox 100-MR; Pennox 343

Soluble Powder; Promycin 100; Terramycin 50; Terramycin-50; Terra-

mycin 100; Terramycin-100; Terramycin 200; Terramycin-200; Terra-

mycin-Aqua; Terramycin 100 For Fish; Terramycin Scours Tablets;

Terramycin Soluble Powder; Terramycin-343 Soluble Powder; Terra-Vet

100; Terra-Vet Soluble Powder; Terra-Vet Soluble Powder 343; Tetradure

LA 300; Tetraject LA; Tetraject LP; Tetravet-CA; Tetroxy-100; Tetroxy

HCA Soluble Powder)



Injection, 245

Injection (Long-Acting), 246

Soluble Powder, 241

Tablets, 245

Uterine Suspension, 241

Oxytetracycline 50, Oxytetracycline 100, Oxytetracycline 200—Oxytetra-

cycline For Medicated Feed, 243

Oxytetracycline 100LP—Oxytetracycline Injection, 245

Oxy Tetra Forte—Oxytetracycline Hydrochloride Soluble Powder, 241

Oxytetramycin 100—Oxytetracycline Injection, 245

Oxytet-25-S—Oxytetracycline Hydrochloride Soluble Powder, 241

Oxytet Soluble—Oxytetracycline Hydrochloride Soluble Powder, 241

Oxytet-SP—Oxytetracycline Hydrochloride Soluble Powder, 241

Oxytet-343 Water Soluble Powder—Oxytetracycline Hydrochloride Solu-

ble Powder, 241

Oxyvet 200 LA—Oxytetracycline Injection (Long-Acting), 246

Oxyvet 100 LP—Oxytetracycline Injection, 245

Panmycin Aquadrops—Tetracycline Oral Suspension, 249

Pen-Aqueous—Penicillin G Procaine Injectable Suspension, 156

Pen G Injection—Penicillin G Procaine Injectable Suspension, 156

Penicillin G (Agri-cillin; Ambi-pen; Aquacillin; Benzapro; Combicillin;

Combicillin AG; Depocillin; Derapen SQ/LA; Duo-Pen; Duplocillin LA;

Durapen; Hi-Pencin 300; Longisil; Microcillin; Pen-Aqueous; Pen G

Injection; Penmed; Penpro; Pot-Pen; Propen LA; R-Pen; Twin-pen; Ultrapen

LA)

See Penicillin G (Veterinary—Systemic), 151

Benzathine and Procaine Injectable Suspension, 155

Potassium For Oral Solution, 154

Procaine Injectable Suspension, 156

Penicillin G, Intramammary (Go-dry; Masti-Clear)

See Penicillin G (Veterinary—Intramammary-Local), 149


Penmed—Penicillin G Procaine Injectable Suspension, 156

Pennchlor 50ÆG, Pennchlor 90ÆG—Chlortetracycline For Medicated Feed,

237

Pennchlor 100 Hi-Flo Meal—Chlortetracycline For Medicated Feed, 237

Pennchlor 50 Meal, Pennchlor 70 Meal—Chlortetracycline For Medicated

Feed, 237

Pennchlor 100 MR—Chlortetracycline For Medicated Feed, 237

Pennchlor 64 Soluble Powder—Chlortetracycline Hydrochloride Soluble

Powder, 236

Pennox 100 Hi-Flo Meal, Pennox 200 Hi-Flo Meal—Oxytetracycline For

Medicated Feed, 243

Pennox 200 Injectable—Oxytetracycline Injection (Long-Acting), 246

Pennox 50 Meal—Oxytetracycline For Medicated Feed, 243

Pennox 100-MR—Oxytetracycline For Medicated Feed, 243

Pennox 343 Soluble Powder—Oxytetracycline Hydrochloride Soluble

Powder, 241

Penpro—Penicillin G Procaine Injectable Suspension, 156

Pirlimycin, Intramammary (Pirsue Aqueous Gel; Pirsue Sterile Solution)

See Pirlimycin (Veterinary—Intramammary-Local), 161




Pirsue Aqueous Gel—Pirlimycin Intramammary Infusion, 162

Pirsue Sterile Solution—Pirlimycin Intramammary Infusion, 162

Polyflex—Ampicillin For Injectable Suspension, 42

PolyOtic Soluble Powder—Tetracycline Hydrochloride Soluble Powder,

248

Potensulf—Sulfadoxine and Trimethoprim Injection, 180

Pot-Pen—Penicillin G Potassium For Oral Solution, 154

Powder 21—Sulfamethazine and Sulfathiazole Powder For Oral Solution,

221

Primor 120, Primor 240, Primor 600, Primor 1200—Ormetoprim and


Promycin 100—Oxytetracycline Injection, 245

Propen LA—Penicillin G Procaine Injectable Suspension, 156

Pulmotil 90—Tilmicosin For Medicated Feed, 137

Pulmotil Premix—Tilmicosin For Medicated Feed, 137

Pyrimethamine and Sulfaquinoxaline (Quinnoxine-S; Sulfaquinoxa-

line-S)


Oral Solution, 177

Quinnoxine-S—Pyrimethamine and Sulfaquinoxaline Oral Solution, 177

Robamox-V Oral Suspension—Amoxicillin For Oral Suspension, 40

Robamox-V Tablets—Amoxicillin Tablets, 40

Rofenaid 40—Ormetoprim and Sulfadimethoxine For Medicated Feed,

175

Romet 30—Ormetoprim and Sulfadimethoxine For Medicated Feed, 175

R-Pen—Penicillin G Potassium For Oral Solution, 154

S-125, S-250—Sulfadimethoxine Tablets, 217

SDM Injection—Sulfadimethoxine Injection, 218

SDM Powder—Sulfadimethoxine Soluble Powder, 216

SDM Solution—Sulfadimethoxine Oral Solution, 216

S-M-T—Sulfamethazine and Sulfathiazole Powder For Oral Solution, 221

Solu-Tet—Tetracycline Hydrochloride Soluble Powder, 248

Solu-Tet 324—Tetracycline Hydrochloride Soluble Powder, 248

Spectam Injectable—Spectinomycin Hydrochloride Injection, 205

Spectam Oral Solution—Spectinomycin Hydrochloride Oral Solution, 204

Spectam Scour-Halt—Spectinomycin Hydrochloride Oral Solution, 204

Spectam Soluble Powder—Spectinomycin Hydrochloride Powder For Oral

Solution, 204

Spectam Water Soluble—Spectinomycin Hydrochloride Powder For Oral

Solution, 204

Spectinomycin (Adspec Sterile Solution; AmTech Spectam Scour-Halt;

Bovispec Sterile Solution; Spectam; Spectam Injectable; Spectam Oral

Solution; Spectam Scour-Halt; Spectam Soluble Powder; Spectam Water

Soluble)

See Spectinomycin (Veterinary—Systemic), 202

Hydrochloride Injection, 205

Hydrochloride Oral Solution, 204

Hydrochloride Powder For Oral Solution, 204

Sulfate Injection, 206

Streptomycin


Oral Solution, 21

Sulfa ‘‘25’’—Sulfamethazine Oral Solution, 218

Sulfa 25%—Sulfamethazine Oral Solution, 218

Sulfachlorpyridazine (Vetisulid Boluses; Vetisulid Injection; Vetisulid

Powder)

See Sulfonamides (Veterinary—Systemic), 207

Injection, 215


Tablets, 215

Sulfadiazine and Trimethoprim (Tribrissen 30; Tribrissen 120;

Tribrissen 480; Tribrissen 960; Tribrissen 24%; Tribrissen 48%; Tribrissen

400 Oral Paste; Tribrissen Piglet Suspension; Tribrissen 40% Powder;

Tucoprim Powder; Uniprim Powder)


Injection, 179

Oral Paste, 177

Oral Powder, 177

Oral Suspension, 178

Tablets, 178

Sulfadimethoxine (Albon 12.5% Concentrated Solution; Albon Injection

40%; Albon Oral Suspension 5%; Albon SR; Albon Tablets; AmTech

Sulfadimethoxine Injection-40%; AmTech Sulfadimethoxine 12.5% Oral

Solution; AmTech Sulfadimethoxine Soluble Powder; Di-Methox Injection-

40%; Di-Methox 12.5% Oral Solution; Di-Methox Soluble Powder; S-125;

S-250; SDM Injection; SDM Powder; SDM Solution; Sulfasol; Sulforal)


Extended-Release Tablets, 217

Injection, 218

Oral Solution, 216


Soluble Powder, 216

Tablets, 217

Sulfadoxine and Trimethoprim (Bimotrim; Borgal; Potensulf; Trimidox;

Trivetrin)


Injection, 180

Sulfalean Powder—Sulfamethazine and Sulfathiazole Powder For Oral

Solution, 221

Sulfa-Max III Calf Bolus—Sulfamethazine Extended-Release Tablets, 220

Sulfa-Max III Cattle Bolus—Sulfamethazine Extended-Release Tablets,

220

2 Sulfamed—Sulfamethazine and Sulfathiazole Powder For Oral Solution,

221

Sulfamethazine (Calfspan; Sulfa ‘‘25’’; Sulfa 25%; Sulfa-Max III Calf

Bolus; Sulfa-Max III Cattle Bolus; Sulfasure SR Calf Bolus; Sulfasure SR

Calf Tablets; Sulfasure SR Cattle Bolus; Sulmet Drinking Water Solution

12.5%; Sulmet Oblets; Sulmet Soluble Powder; Suprasulfa III Calf Bolus;

Suprasulfa III Cattle Bolus; Sustain III; Sustain III Calf Bolus; Sustain III

Cattle Bolus)



Oral Solution, 218


Tablets, 219

Sulfamethazine, Sulfanilamide, and Sulfathiazole (Triple Sulfa Bolus)


Tablets, 220

Sulfamethazine and Sulfathiazole (Powder 21; S-M-T; Sulfalean

Powder; 2 Sulfamed; Sulfa-MT; Sulfa 2 Soluble Powder)



Sulfa-MT—Sulfamethazine and Sulfathiazole Powder For Oral Solution,

221

Sulfa-Q 20%—Sulfaquinoxaline Oral Solution, 221



Sulfaquinoxaline (Optimed; Sulfa-Q 20%; 31.92% Sul-Q-Nox)


Oral Solution, 221

Sulfaquinoxaline-S—Pyrimethamine and Sulfaquinoxaline Oral Solution,

177

Sulfasol—Sulfadimethoxine Soluble Powder, 216

Sulfa 2 Soluble Powder—Sulfamethazine and Sulfathiazole Powder For

Oral Solution, 221

Sulfasure SR Calf Bolus—Sulfamethazine Extended-Release Tablets, 220

Sulfasure SR Calf Tablets—Sulfamethazine Extended-Release Tablets, 220

Sulfasure SR Cattle Bolus—Sulfamethazine Extended-Release Tablets, 220

Sulforal—Sulfadimethoxine Oral Solution, 216

Sulmet Drinking Water Solution 12.5%—Sulfamethazine Oral Solution,

218

Sulmet Oblets—Sulfamethazine Tablets, 219

Sulmet Soluble Powder—Sulfamethazine Powder For Oral Solution, 219

31.92% Sul-Q-Nox—Sulfaquinoxaline Oral Solution, 221

Suprasulfa III Calf Bolus—Sulfamethazine Extended-Release Tablets, 220

Suprasulfa III Cattle Bolus—Sulfamethazine Extended-Release Tablets,

220

Sustain III—Sulfamethazine Extended-Release Tablets, 220

Sustain III Calf Bolus—Sulfamethazine Extended-Release Tablets, 220

Sustain III Cattle Bolus—Sulfamethazine Extended-Release Tablets, 220

Terramycin 50, Terramycin 100, Terramycin 200—Oxytetracycline For

Medicated Feed, 243

Terramycin-Aqua—Oxytetracycline For Medicated Feed, 243

Terramycin 100 For Fish—Oxytetracycline For Medicated Feed, 243

Terramycin Scours Tablets—Oxytetracycline Tablets, 245

Terramycin Soluble Powder—Oxytetracycline Hydrochloride Soluble Pow-

der, 241

Terramycin-343 Soluble Powder—Oxytetracycline Hydrochloride Soluble

Powder, 241

Terra-Vet 100—Oxytetracycline Injection, 245

Terra-Vet Soluble Powder—Oxytetracycline Hydrochloride Soluble Pow-

der, 241

Terra-Vet Soluble Powder 343—Oxytetracycline Hydrochloride Soluble

Powder, 241

Tet-324—Tetracycline Hydrochloride Soluble Powder, 248

Tetra 55, Tetra 250, Tetra 1000—Tetracycline Hydrochloride Soluble

Powder, 248

Tetra 4000—



Tetra Bac 324—Tetracycline Hydrochloride Soluble Powder, 248

Tetrabol—



Tetracycline (AmTech Tetracycline Hydrochloride Soluble Powder-324; Calf

Scour Bolus Antibiotic; Duramycin 10; Duramycin-324; Onycin 62.5;

Onycin 250; Onycin 1000; Panmycin Aquadrops; PolyOtic Soluble

Powder; Solu-Tet; Solu-Tet 324; Tet-324; Tetra 55; Tetra 250; Tetra

1000; Tetra 4000; Tetra Bac 324; Tetrabol; Tetracycline 250;

Tetracycline 1000; Tetracycline 250 Concentrate Soluble Powder; Tetra-

cycline 62.5 Soluble Powder; Tetramed 250; Tetramed 1000; Tetrasol

Soluble Powder; Tet-Sol 10; Tet-Sol 324; 5-Way Calf Scour Bolus)


Boluses, 247


Soluble Powder, 248

Uterine Tablets, 247

Tetracycline 250, Tetracycline 1000—Tetracycline Hydrochloride Soluble

Powder, 248

Tetracycline 250 Concentrate Soluble Powder—Tetracycline Hydrochloride

Soluble Powder, 248

Tetracycline 62.5 Soluble Powder—Tetracycline Hydrochloride Soluble

Powder, 248

Tetradure LA 300—Oxytetracycline Injection (Long-Acting), 246

Tetraject LA—Oxytetracycline Injection (Long-Acting), 246

Tetraject LP—Oxytetracycline Injection, 245

Tetramed 250, Tetramed 1000—Tetracycline Hydrochloride Soluble

Powder, 248

Tetrasol Soluble Powder—Tetracycline Hydrochloride Soluble Powder,

248

Tetravet-CA—Oxytetracycline Hydrochloride Soluble Powder, 241

Tetroxy-100—Oxytetracycline Injection, 245

Tetroxy HCA Soluble Powder—Oxytetracycline Hydrochloride Soluble

Powder, 241

Tet-Sol 10, Tet-Sol 324—Tetracycline Hydrochloride Soluble Powder,

248

Tilmicosin (Micotil; Pulmotil 90; Pulmotil Premix)



Injection, 137

ToDay—Cephapirin Sodium Intramammary Infusion, 72

ToMorrow—Cephapirin Benzathine Intramammary Infusion, 72

Tribrissen 30, Tribrissen 120, Tribrissen 480, Tribrissen 960—Sulfadiazine

and Trimethoprim Tablets, 178

Tribrissen 24%, Tribrissen 48%—Sulfadiazine and Trimethoprim Injec-

tion, 179

Tribrissen 400 Oral Paste—Sulfadiazine and Trimethoprim Oral Paste,

177

Tribrissen Piglet Suspension—Sulfadiazine and Trimethoprim Oral Suspen-

sion, 178

Tribrissen 40% Powder—Sulfadiazine and Trimethoprim Oral Powder,

177

Trimidox—Sulfadoxine and Trimethoprim Injection, 180

Triple Sulfa Bolus—Sulfamethazine, Sulfanilamide, and Sulfathiazole

Tablets, 220

Trivetrin—Sulfadoxine and Trimethoprim Injection, 180

Tucoprim Powder—Sulfadiazine and Trimethoprim Oral Powder, 177

Twin-pen—Penicillin G Benzathine and Penicillin G Procaine Injectable

Suspension, 155

Tylan 10, Tylan 40, Tylan 100—Tylosin Granulated, 138

Tylan 50, Tylan 200—Tylosin Injection, 138

Tylan Soluble—Tylosin Tartrate Powder For Oral Solution, 139

Tylocine 200—Tylosin Injection, 138

Tylosin Base (Tylan 50; Tylan 200; Tylocine 200; Tyloved)


Injection, 138

Tylosin Phosphate (Tylan 10; Tylan 40; Tylan 100; Tylosin 10 Premix;

Tylosin 40 Premix)


Granulated, 138

Tylosin 10 Premix, Tylosin 40 Premix—Tylosin Granulated, 138

Tylosin Tartrate (Tylan Soluble)





Tyloved—Tylosin Injection, 138

Ultrapen LA—Penicillin G Procaine Injectable Suspension, 156

Uniprim Powder—Sulfadiazine and Trimethoprim Oral Powder, 177

Vetisulid Boluses—Sulfachlorpyridazine Tablets, 215

Vetisulid Injection—Sulfachlorpyridazine Injection, 215

Vetisulid Powder—Sulfachlorpyridazine Powder For Oral Solution, 215

Viceton—Chloramphenicol Tablets, 77

5-Way Calf Scour Bolus—Tetracycline Boluses, 247

Zeniquin Tablets—Marbofloxacin Tablets, 101



Human Brand and Generic Name Index

Note: Only human dosage forms considered by USP Veterinary Medicine

Advisory Committees to be appropriate have been included in this

publication.

Includes both United States and Canadian products.

Achromycin V—Tetracycline Hydrochloride Capsules, 248

Alti-Doxycycline—



Ampicillin (Ampicin; Apo-Ampi; Novo-Ampicillin; Nu-Ampi; Omnipen;

Omnipen-N; Penbritin; Polycillin-N; Principen; Totacillin; Totacillin-N)


Capsules, 42

For Injection, 43

Ampicin—Ampicillin For Injection, 43

Ancef—

Cefazolin For Injection, 58

Cefazolin Injection, 58

Apo-Ampi—Ampicillin Capsules, 42

Apo-Cefaclor—



Apo-Cephalex—Cephalexin Tablets, 64

Apo-Doxy—Doxycycline Hyclate Capsules, 239

Apo-Doxy-Tabs—Doxycycline Hyclate Tablets, 240

Apo-Erythro—Erythromycin Tablets, 130

Apo-Erythro E-C—Erythromycin Delayed-Release Capsules, 130

Apo-Erythro-ES—Erythromycin Ethylsuccinate Tablets, 133

Apo-Erythro-S—Erythromycin Stearate Tablets, 136

Apo-Metronidazole—Metronidazole Tablets, 146

Apo-Sulfatrim—



Apo-Sulfatrim DS—Sulfamethoxazole and Trimethoprim

Tablets, 180

Apo-Tetra—Tetracycline Hydrochloride Capsules, 248

Azithromycin (Zithromax)


For Injection, 129


Bactrim—



Bactrim DS—Sulfamethoxazole and Trimethoprim Tablets, 180

Bactrim I.V. —Sulfamethoxazole and Trimethoprim Injection, 181

Bactrim Pediatric—Sulfamethoxazole and Trimethoprim Oral Suspension,

180

Biaxin—

Clarithromycin For Oral Suspension, 129

Clarithromycin Tablets, 129

Biaxin XL—Clarithromycin Extended-Release Tablets, 130

Cefaclor (Apo-Cefaclor; Ceclor)


Capsules, 56


Ceclor—



Cefadyl—Cephapirin For Injection, 66

Cefazolin (Ancef; Kefzol)


For Injection, 58

Injection, 58

Cefixime (Suprax)



Tablets, 59

Cefotan—Cefotetan For Injection, 60

Cefotaxime (Claforan)


For Injection, 60

Injection, 60

Cefotetan (Cefotan)


For Injection. 60

Cefoxitin (Mefoxin)


For Injection, 61

Injection, 61

Cephalexin (Apo-Cephalex; Keflex; Keftab; Novo-Lexin; Nu-Cephalex; PMS-

Cephalexin)


Capsules, 63


Hydrochloride Tablets, 64

Tablets, 64

Cephalothin (Ceporacin; Keflin)


For Injection, 65

Cephapirin (Cefadyl)

See Cephalosporins (Veterinary—Systemic)

For Injection, 66

Cephradine (Velosef)


Capsules, 66


Ceporacin—Cephalothin For Injection, 65

Chloramphenicol (Chloromycetin; Novochlorocap)

See Chlorampheniol (Veterinary—Systemic), 74

Capsules, 76

Sodium Succinate For Injection, 77

Chloromycetin—Chloramphenicol Sodium Succinate For Injection, 77

Cipro—



Ciprofloxacin (Cipro; Cipro I.V.)



Injection, 97

Tablets, 97

Human Brand and Generic Name Index 269


Cipro I.V.—Ciprofloxacin Injection, 97

Claforan—

Cefotaxime For Injection, 60

Cefotaxime Injection, 60

Clarithromycin (Biaxin; Biaxin XL)




Tablets, 129

Cofatrim Forte—Sulfamethoxazole and Trimethoprim Tablets, 180

Cotrim—Sulfamethoxazole and Trimethoprim Tablets, 180

Cotrim DS—Sulfamethoxazole and Trimethoprim Tablets, 180

Cotrim Pediatric—Sulfamethoxazole and Trimethoprim Oral Suspension,

180

Daraprim—Pyrimethamine Tablets, 188

Doryx—Doxycycline Hyclate Delayed-Release Capsules, 240

Doxycin—



Doxycycline (Alti-Doxycycline; Apo-Doxy; Apo-Doxy-Tabs; Doryx; Dox-

ycin; Doxytec; Novo-Doxylin; Nu-Doxycycline; Vibramycin; Vibra-Tabs;

Vibra-Tabs C-Pak)



Calcium Oral Suspension, 239

Capsules, 239

Delayed-Release Capsules, 240

For Injection, 240

Tablets, 240

Doxytec—Doxycycline Hyclate Capsules, 239

E-Base—Erythromycin Delayed-Release Tablets, 130

E.E.S.—

Erythromycin Ethylsuccinate For Oral Suspension, 133

Erythromycin Ethylsuccinate Oral Suspension, 133

Erythromycin Ethylsuccinate Tablets, 133, 134

E-Mycin—Erythromycin Delayed-Release Tablets, 130

Erybid—Erythromycin Delayed-Release Tablets, 130

ERYC, ERYC-250, ERYC-333—Erythromycin Delayed-Release Capsules,

130

EryPed—

Erythromycin Ethylsuccinate For Oral Suspension, 133

Erythromycin Ethylsuccinate Tablets, 133, 134

Ery-Tab—Erythromycin Delayed-Release Tablets, 130

Erythro—

Erythromycin Ethylsuccinate Oral Suspension, 133

Erythromycin Ethylsuccinate Tablets, 134

Erythrocin—

Erythromycin Lactobionate For Injection, 134



Erythrocot—Erythromycin Stearate Tablets, 136

Erythromid—Erythromycin Tablets, 130

Erythromycin Base (Apo-Erythro; Apo-Erythro E-C; E-Base; E-Mycin;

Erybid; ERYC; ERYC-250; ERYC-333; Ery-Tab; Erythromid; Ilotycin;

Novo-rythro Encap; PCE)


Delayed-Release Capsules, 130

Delayed-Release Tablets, 130

Tablets, 130

Erythromycin Estolate (Ilosone; Novo-rythro)


Capsules, 132


Tablets, 132

Erythromycin Ethylsuccinate (Apo-Erythro-ES; E.E.S.; EryPed; Ery-

thro; Novo-Rythro)




Tablets, 133, 134

Erythromycin Gluceptate (Ilotycin)



Erythromycin Lactobionate (Erythrocin)


Erythromycin Lactobionate For Injection, 134

Erythromycin Stearate (Apo-Erythro-S; Erythrocin; Erythrocot; My-E;

Novo-rythro; Wintrocin)




Flagyl—

Metronidazole Capsules, 146

Metronidazole Injection, 147

Metronidazole Tablets, 146

Flagyl I.V.—Metronidazole Hydrochloride For Injection, 147

Flagyl I.V. RTU—Metronidazole Injection, 147

Keflex—




Keflin—Cephalothin For Injection, 65

Keftab—Cephalexin Hydrochloride Tablets, 64

Kefzol—Cefazolin For Injection, 58

Ilosone—



Erythromycin Estolate Tablets, 132

Ilotycin—

Erythromycin Delayed-Release Tablets, 130


Mefoxin—

Cefoxitin For Injection, 61

Cefoxitin Injection, 61

Metric 21—Metronidazole Tablets, 146

Metro I.V. —Metronidazole Injection, 147

Metronidazole (Apo-Metronidazole; Flagyl; Flagyl I.V.; Flagyl I.V. RTU;

Metric 21; Metro I.V.; Novonidazol; Protostat; Trikacide)

See Metronidazole (Veterinary—Systemic), 144

Capsules, 146

Hydrochloride For Injection, 147

Injection, 147

Tablets, 146

My-E—Erythromycin Stearate Tablets, 136

Novo-Ampicillin—Ampicillin Capsules, 42

Novochlorocap—Chloramphenicol Capsules, 76

270 Human Brand and Generic Name Index


Novo-Doxylin—



Novo-Lexin—




Novonidazol—Metronidazole Tablets, 146

Novo-Rythro—Erythromycin Ethylsuccinate For Oral Suspension, 133

Novo-rythro—





Novo-rythro Encap—Erythromycin Delayed-Release Capsules, 130

Novo-Tetra—Tetracycline Hydrochloride Capsules, 248

Novo-Trimel—



Novo-Trimel D.S.—Sulfamethoxazole and Trimethoprim Tablets, 180

Nu-Ampi—

Ampicillin Capsules, 42

Nu-Cephalex—Cephalexin Tablets, 64

Nu-Cotrimox—



Nu-Cotrimox DS—Sulfamethoxazole and Trimethoprim Tablets, 180

Nu-Doxycycline—



Nu-Tetra—Tetracycline Hydrochloride Capsules, 248

Omnipen—Ampicillin Capsules, 42

Omnipen-N—Ampicillin For Injection, 43

PCE—Erythromycin Delayed-Release Tablets, 130

Penbritin—Ampicillin Capsules, 42

Penicillin G (Pfizerpen)

See Penicillin G (Veterinary—Systemic), 151

Potassium For Injection, 156

Sodium For Injection, 157

Pfizerpen—Penicillin G Potassium For Injection, 156

PMS-Cephalexin—



Polycillin-N—Ampicillin For Injection, 43

Principen—Ampicillin Capsules, 42

Pyrimethamine (Daraprim)

See Pyrimethamine (Veterinary—Systemic), 185

Tablets, 188

Protostat—Metronidazole Tablets, 146

Rifadin—Rifampin Capsules, 198

Rifadin IV—Rifampin For Injection, 199

Rifampin (Rifadin; Rifadin IV; Rimactane; Rofact)

See Rifampin (Veterinary—Systemic), 191

Capsules, 198

For Injection, 199

Rimactane—Rifampin Capsules, 198

Rofact—Rifampin Capsules, 198

Roubac—Sulfamethoxazole and Trimethoprim Tablets, 180

Septra—




Septra DS—Sulfamethoxazole and Trimethoprim Tablets, 180

Septra Grape Suspension—Sulfamethoxazole and Trimethoprim Oral

Suspension, 180

Septra I.V.—Sulfamethoxazole and Trimethoprim Injection, 181

Septra Suspension—Sulfamethoxazole and Trimethoprim Oral Suspension,

180

Sulfamethoxazole and Trimethoprim (Apo-Sulfatrim; Apo-Sulfatrim

DS; Bactrim; Bactrim DS; Bactrim I.V.; Bactrim Pediatric; Cofatrim Forte;

Cotrim; Cotrim DS; Cotrim Pediatric; Novo-Trimel; Novo-Trimel D.S.; Nu-

Cotrimox; Nu-Cotrimox DS; Roubac; Septra; Septra DS; Septra Grape

Suspension; Septra I.V.; Septra Suspension; Sulfatrim; Sulfatrim DS;

Sulfatrim Pediatric; Sulfatrim S/S; Sulfatrim Suspension)


Injection, 181


Tablets, 180

Sulfatrim—Sulfamethoxazole and Trimethoprim Tablets, 180

Sulfatrim DS—Sulfamethoxazole and Trimethoprim Tablets, 180

Sulfatrim Pediatric—Sulfamethoxazole and Trimethoprim Oral Suspen-

sion, 180

Sulfatrim S/S—Sulfamethoxazole and Trimethoprim Tablets, 180

Sulfatrim Suspension—Sulfamethoxazole and Trimethoprim Oral Suspen-

sion, 180

Suprax—

Cefixime For Oral Suspension, 59

Cefixime Tablets, 59

Tetracycline (Achromycin V; Apo-Tetra; Novo-Tetra; Nu-Tetra)


Capsules, 248

Trikacide—Metronidazole Capsules, 146

Totacillin—Ampicillin Capsules, 42

Totacillin-N—Ampicillin For Injection, 43

Velosef—

Cephradine Capsules, 66

Cephradine For Oral Suspension, 66

Vibramycin—

Doxycycline Calcium Oral Suspension, 239

Doxycycline For Injection, 240

Doxycycline For Oral Suspension, 239


Vibra-Tabs—Doxycycline Hyclate Tablets, 240

Vibra-Tabs C-Pak—Doxycycline Hyclate Tablets, 240

Wintrocin—Erythromycin Stearate Tablets, 136

Zithromax—

Azithromycin For Injection, 129

Azithromycin For Oral Suspension, 128

Human Brand and Generic Name Index 271


Documents

USP Veterinary Pharmaceutical Information Monographs