PHARMACOLOGICAL ASPECTS OF MACROLIDES AND LINCOSAMIDES

IN ANIMAL THERAPY______________________________________________________________________________

The macrolides (macrocyclic lactones) are a group of closely related bacteriostatic

antibiotics, characterized by a macrocyclic lactone ring (usually containing 14 or 16 atoms) to

which deoxy sugars are attached by glycosidic linkages. .

The macrolide antibiotics typically have a large lactone ring in their structure and are much more

effective against gram-positive than gram-negative bacteria. They are also active against

mycoplasmas and some rickettsiae.

Each macrolide antibiotic is actually a complex mixture of closely related antibiotics that differ

from one another with respect to the chemical substitutions on the various carbon atoms in the

structure, and in the aminosugars and neutral sugars. For example, erythromycin consists of

erythromycin A, B, C, D, and E forms.

Macrolides are mostly obtained from various species of Streptomyces soil borne bacteria; some

are prepared semi synthetically.The macrolide antibiotics are colorless, crystalline substances.,

containing a dimethylamino group, which makes them basic in nature.. Although they are poorly

water soluble, they do dissolve in more polar organic solvents. Macrolides are often inactivated

in basic (pH >10) as well as acidic environments (pH <4 for erythromycin). The multiple

functional groups make it possible for them to undergo a large number of chemical reactions.

They are lipid soluble, but are often used in ester forms to enhance oral bioavailability and to

improve oral tolerance.

More stable ester forms are commonly used in pharmaceutical preparations—eg, acetylates,

estolates, lactobionate, succinates, propionates, and stearates

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Classification

Large 14 member macrolactone ring with one or more deoxy sugars attached

① 14-atom lactone ring macrolides: erythromycin oleandomycin troleandomycin

clarithromycin roxithromycin, dirithromycin

② 15-atom lactone ring macrolides : azithromycin (semisythetic)

③ 16-atomlactone ring macrolides: medecamycin,acetylmedecamycin,kitasamycin,

acetylkitasamycin, josamycin, spiramycin , acetylspiramycin, tylosin rokitamycin

Large 14 member lactone ring with modification of C6 to a methoxy group. Azithromycin has a

15 membered lactone ring

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Mechanism of Action

Macrolides are regarded as being bacteriostatic, but may become bactericidal at high

concentrations. They interfere with protein synthesis by reversibly binding to the 50 S subunit of

the ribosome. They appear to bind at the donor site, thus preventing the translocation necessary

to keep the peptide chain growing.., Macrolides are significantly more active at higher pH ranges

(7.8-8).

The action of macrolide is divided in to two processes.

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1. Passage of macrolides in to bacterial cells: Macrolides are transported in tio cytoplasm of

susceptible organism by an active transport system.The gram positive bacteria

accumulate about 100 times more antibiotics than garm negative organisms. The

nonionised form of the macrocycluic antibiotic is more permeable to bacterial cells., so

the drugs show enhanced activity at alkaline pH.

2. Interactions of macrolide with bacterial ribosome: Macrolide bind to 50s ribosomal sub

unit and block the translocation step, wherein a newly synthesized peptidyl tRNA

molecule moves from the acceptor site(A site) on risbosome to the peptidyl site(P

site).Failure of translocation stops protein synthesis as A site is not available for the next

incoming aminoacyl tRNA and ribosomal complex can not move to the next codon. The

effect is essentially more pronounced in rapidly dividing bacteria and mycoplasmas

Antimicrobial Spectrum

The antimicrobial spectrum is similar to benzyl penicillin but in addition active against

Mycoplasmae, Chlamydiae, Legionellae, gram positive anaerobes etc.

The newer agents like clarithromycin, Azithromycin, Dirithromycin are found to be effective

against pathogens implicated in opportunistic infections associated with Toxoplasmosis,

Cryptosporidiosis etc., and also in the eradication of H.pylori infection and in Lyme disease

caused by B.burgedorferi

Macrolides are active against most aerobic and anaerobic gram-positive bacteria, although there

is considerable variation as to potency and activity. In general, they have a spectrum similar to

that of the penicillins and are often used as penicillin substitutes.

In general, macrolides are not active against gram-negative bacteria, but some strains of

Pasteurella , Haemophilus , and Neisseria spp may be sensitive. An exception is tilmicosin, the

spectrum of which is characterized as broad and includes Mannheimia (Pasteurella) haemolytica

and P multocida . Bacteroides fragilis strains are moderately susceptible to macrolides.

Macrolides are active against atypical mycobacteria, Mycobacterium , Mycoplasma ,

Chlamydia , and Rickettsia spp but not against protozoa or fungi. In vitro synergism is seen with

cefamandole (against Bacteroides fragilis ), ampicillin (against Nocardia asteroides ), and

rifampin (against Rhodococcus equi)

G+ (pneumococci, streptococci, staphylococci, corynebacteria; mycoplasma, legionella,

chlamydia trachomatis, helicobacter, listeria, certain mycobacteria),

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G- (neisseria species, bordetalla pertussis), some rickettsia species, treponema pallidum, and

campylobacter species

Bacterial Resistance

Resistance to macrolides in gram-positive organisms results from alterations in ribosomal

structure and loss of macrolide affinity. The resistance may be intrinsic or plasmid-mediated and

constitutive or inducible; Resistance to antibiotics is usually plasmid-encoded. it may develop

rapidly (erythromycin) or slowly (tylosin). Cross-resistance between macrolides has been

reported. Gram- negative organisms are probably resistant because macrolides cannot penetrate

their cell walls. There are a few exceptions, and gram-negative forms without cell walls are

usually sensitive Three mechanisms have been identified.

a. Reduced permeability of the cell membrane or active efflux;

b. Production (by enterobacteriaceae) of esterases that hydrolyze macrolides;

c. Modification of the ribosomal binding

Pharmacokinetics

Absorption: Macrolides are lipid soluble, that are readily absorbed from the GI tract if not

inactivated by gastric acid. Oral preparations are often enteric-coated, or stable salts or esters

(such as stearate,lactobionate, glucoheptate, propionate, and ethylsuccinate) are used. Plasma

levels peak within 1-2 hr in most cases, although absorption patterns may be erratic due to the

presence of food and may depend on the salt or ester used. Absorption from the ruminoreticulum

is usually delayed and is unreliable. Erythromycin and tylosin may also be administered IV or

IM. Tilmicosin is administered SC. Absorption after injection is rapid, but pain and swelling can

develop at the injection sites

Distribution: Macrolides become widely distributed in tissues, and concentrations are about the

same as in plasma, or even higher in some instances. The plasma half-lives of macrolides usually

are 1-3 hr, and apparent volumes of distribution of 1,000-2,000 mL/kg reflect the extensive

tissue distribution They actually accumulate within many cells, including macrophages, in which

they may be ≥20 times the plasma concentration. This accumulation accounts in part for the long

dosing interval that characterizes some macrolides (eg, tilmicosin). With spiramycin, the tissue

concentrations remain especially high even though plasma concentrations are rather low.

Macrolides tend to concentrate in the spleen, liver, kidneys, and particularly the lungs. They

enter pleural and ascitic fluids but not the CSF (only 2-13% of plasma concentration unless the

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meninges are inflamed). They concentrate in the bile and milk. Up to 75% of the dose is bound

to plasma proteins, and they bind to α1-acid glycoproteins rather than to albumin

Biotransformation: Metabolic inactivation of the macrolides is usually extensive (80% in liver

through microsomal enzyme system), but the relative proportion depends on the route of

administration and the particular antibiotic. After administration PO, 80% of an erythromycin

dose undergoes metabolic inactivation, whereas tylosin appears to be eliminated in an active

form

Excretion: Macrolide antibiotics and their metabolites are excreted mainly in bile (>60%) and

often undergo enterohepatic cycling. Urinary clearance may be slow and variable (often <10%)

but may represent a more significant route of elimination after parenteral administration. The

concentration of macrolides in milk often is several times greater than in plasma, especially in

mastitis. Due to enterohepatic cycling, the effective inhibitory concentrations are usually

maintained fro about 6 hours after oral administration and for 12-24 hours after IM injection.

Dosage frequencies are commonly 2-3 times/day, PO, or 1-2 times/day, parenterally

Clinical use/ Indications

The macrolides are used to treat both systemic and local infections. They are often regarded as

alternatives to penicillins for the treatment of streptococcal and staphylococcal infections.

General indications include upper respiratory tract infections, bronchopneumonia, bacterial

enteritis, metritis, pyodermatitis, urinary tract infections, arthritis, and others. Formulations for

treating mastitis are also available and often have the advantage of a short withholding time for

milk. Tilmicosin is approved for use in the treatment of bovine respiratory diseases associated

with Mannheimia (Pasteurella) haemolytica

Side Effects and Toxicity

Toxicity and side effects are uncommon for most macrolides (except tilmicosin), although pain

and swelling may develop at injection sites.

a. Gastrointestinal disturbances: are the most common adverse effect noticed.

Vomiting, diarrhoea, anorexia, regurgitation and epigastric pain may be observed.Horses

are sensitive to macrolide-induced GI disturbances that can be serious and even fatal.

Some salts: Erythromycin estolate may be hepatotoxic and cause cholestasis; it may also

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induce vomiting and diarrhea, particularly when high doses are administered. However

these GI uosets are less commonly seen in animals than inm humans.

b. Hypersensitivity reactions have occasionally been seen. Clinical signs include

rashes, fever, skin eruptions.

c. Other effects: Pain and swelling at the injection site . In pigs, tylosin may cause

edema of the rectal mucosa, mild anal protrusion with diarrhea, and anal erythema and

pruritus. After 5 mg/kg/day, dogs had a greater tendency to develop ventricular

tachycardia and fibrillation during acute myocardial ischemia. Tylosin and Tilmicosin

have a tendency to produce cardiac toxicity characterized by tachycardia and decreased

contractility. Tilmicosin is contraindicated in swine and should not be used in an extra-

label manner. Cattle have died after IV injection of tilmicosin

d. Transcient auditory (hearing)impairments and super infections in humans are the other

unwanted side effects.

e. They are contraindicated in patients hypersensitive to them and should be used

cautiously in patients with pre existing liver dysfunction . Although they have not

demonstrated teratogenic effect, they should be used during pregnancy only when the

benefits outweigh the risks.

f. Drug withdrawal and milk discard times should be followed carefully to prevent food

residues and consequent public health implications. Tilmicosin is characterized by a 28-

day withdrawal time and should not be used in any species other than adult cattle

Interactions

Macrolide antibiotics should not be used with chloramphenicol or the lincosamides because they

may compete for the same 50 S ribosomal binding site, although the in vivo significance of this

potential interaction is unclear. Activity of macrolides is depressed in acidic environments.

Macrolide preparations for parenteral administration are incompatible with many other

pharmaceutical preparations. Erythromycin and troleandomycin are microsomal enzyme

inhibitors that depress the metabolism of some drugs like warfarin, theophylline, carbamazepine

and methyl prednisolone.

CYP Receptor in the liver - By this effect with the exception of Azithromycin, Dirithromycin

and spiramycin other Macrolides inhibit CYP3A isoenzyme and therefore involved in many

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clinically significant drug interactions and adverse effects. Ex: Interactions with theophylline,

Digoxin,Oral anticoagulants, Terfinadine, Azole antifungals, Cisapride etc

Erythromycin

It is prototype macrolide antibiotic isolated from Streptomyces erythreus. The antimicrobial

spectrum of erythromycin is narrow, including mostly gram positive organisms and a few gram

negative organisms.– Gram positives: pneumococci, viridans streptococci, Group A streptococci,

methicillin sensitive staphylococci; Gram negatives: bordetella, neisseria,campylobacter, ±

hemophilus; Miscellaneous: mycoplasma, legionella, chlamydia,treponemes

It the drug of choice in croynebacterial infections (diphtheria, corynebacterial sepsis,

erythrasma); in respiratory , neonatal ocular inflammation, or genital chlamydial infections; and

in treatment of community-acquired pneumonia because its spectrum of activity includes the

pneumococcus, mycoplasma, and legionella .

Erythromycin is useful as a penicillin substitute in penicillin-allergic individuals with infections

caused by staphylococci (assuming that the isolate is susceptible), streptococci, or pneumococci.

t has been recommended as prophylaxis against endocarditis during dental procedures in

individuals with valvular heart disease, though clindamycin, which is better tolerated, has largely

replaced it

Clinical use

- Small animals: erythromycin is used to treat pyoderma caused by staphylococci,

respiratory infection caused by Mycoplasma, diarrhea caused by Campylobacter

(erythromycin stopped the shedding but not eliminate the Campylobacter)

- Bovine: respiratory disease;

- Pig:- infections caused by Erysipelothrix- respiratory infections caused by Streptococcus

andPasteurella

- Poultry: - respiratory infections caused by MycoplasmaErythromycin is administered in

water for the treatment

- Horses: in foals, erythromycin is used in combination with rifampin (synergistic efect),

for treatment of pneumonia caused by Rhodococcus equi.

Side effects/adverse effects

Gastrointestinal effects

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Anorexia, nausea, vomiting, and diarrhea. Gastrointestinal intolerance, which is due to a

direct stimulation of gut motility, is the most frequent reason for discontinuing erythromycin

and substituting another antibiotic . The prokinetic effect of stimulating the motilin receptors

is responsible for diarrhoea. The diarrhoea is self limiting, except in adult horses it could be

fatal. Rectal oedema and partial anal prolapse is seen in pigs. Erythromycin is not

recommended in adult horses (oral and systemic) and ruminants (oral).

Liver toxicity

Erythromycin, particularly the estolate, can produce acute cholestatic hepatitis (fever,

jaundice, impaired liver function), probably as a hypersensitivity reaction. Most patients

recover from this, but hepatitis recurs if the drug is readministered. Other allergic reactions

include fever, eosinophilia, and rashes.

Drug interactions

Erythromycin metabolites can inhibit cytochrome P450 enzymes and thus ↑the serum

concentrations of numerous drugs, including theophylline, oral anticoagulants, cyclosporine,

and mehtylprednisolone. Erythromycin ↑ serum concentrations of oral digoxin by ↑ its F.

Dose:

Dogs and cats: 2-10mg/kg,PO,tid; cattle: 8-15mg/kg,IM,bid; Foals: 25mg/kg,PO or IM, tid;

Sheep and swine: 2-6mg/kg, IM,sid; Poultry: 25g/100litres drinking water.

Azalides

Their spectrum of activity, similar to erythromycin in addition have increased activity against

hemophilus, Mycobacterium avium intracellulare,toxoplasma. In general, Azithromycin > Gram

negative activity; Clarithromycin > Gram positive activity an dthese are well distributed, with

CNS penetration beinglimited except with inflammation

Clarithromycin

Clarithromycin, semisynthetically derived from erythromycin. is tolerated better than

erythromycin, has a broader spectrum of activity than erythromycin, and, like azithromycin, it

also concentrates in leukocytes.

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It possess better pharmacokinteic and antimicrobial profiles unlike older compounds like

erythromycin. Clarithromycin exhibits even bactericidal activity against some of the pathogens

and even Post Antibiotic Effect (PAE) which is not seen with others.

- It has Good activity against;C.trachomatis C.pneumoniae M.catarhalis , H.influenzae

H.parainfluenzae , L.pneumophiliae Etc., It is very active against agents causing atypical

pneumonia like C.pneumoniae, M.pneumoniae and markedly active against

L.pneumophiliae. With reference to H.influenzae clarithromycin has twice the activity

of erythromycin Clarithromycin has very good activity against agents causing

opportunistic infections in AIDS patients viz., MAC infection, Toxoplasmosis,

Cryptosporidiosis

- Clarithromycin is effective in eradication of H.pylori in patients with peptic ulcer.  It is

also effective against Toxoplasmosis, and Cryptosporidiosis None of the existing

Macrolides are effective against MRSA and Enterococci.

- Clarithromycin improves immune function via its modulatory effects on cytokine

production normalizes and/or improves viscoelastic properties of mucus and sputum and

reduces sputum volume in normal individuals too Clarithromycin is acid stable rapidly

and completely absorbed per orally to the extent of 100% and absolute bioavailability is

55% and is unaffected by food.

- Prolonged high concentrations in - Lungs, Tonsils, nasal tissue, middle ear and WBC

(twice that of plasma). Of particular note is the high concentration in the alveolar

macrophages, Lung tissue and tonsillar tissue show high penetration of the drug into the

respiratory tract cells, a feature that should enhance efficacy against typical and atypical

pathogens which usually cause community acquired pneumonia ( CAP)

- Inhibits the isoenzyme of Cyt P 450 viz., CYP3A family and thereby increase the

concentrations of several drugs administered concurrently resulting in serious clinically

significant drug interactions.

- More acid stability, more active against mycobacterium avium complex, M leprae and

Toxoplasma gondii, lower frequency of GI intolerance.

- It is metabolized in the liver. The major metabolite is 14-hydroxyclarithromycin, which

has antibacterial activity. All of them are eliminated in the urine.

- Dose: Dogs and cats: 5-10mg/kg,PO, bid

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Azithromycin

Azithromycin, is a rather normal macrolide with a desosamine and a cladinose sugar. However,

the insertion of the azo-group into the lactone ring, which therefore becomes 15 membered. The

azo-group leads to a better acid stability and bio-availibility

- Azithromycin is slightly less active than erythromycin against staphylococci and

streptococci and slighyly more active against Haemophilus influenzae. but not against

enteric gram-negative bacteria or Pseudomonas - it has good activity against many

intracellular organism. (Clamydia, Toxoplasma) .It is also active against mycobacteria and

Mycoplasma It is highly active against chlamydia.

- It has advantages like: a) better oral absorption, b) better tolerated c) much longer half-

life d) higher tissue concentration and e) broader spectrum of activity than erythromycin

- It differs from erythromycin mainly in pharmacokinetic properties. F) lesser drug

interactions

- It penetrates into most tissues, (except CSF), and phagocytic cells extremely well, with

tissue concentrations exceeding serum concentrations by 10- to 100-fold. It has an

extraordinary ability to concentrate in tissues, particularly in leukocytes, macrophyges, and

fibroblast.

- The intracellular reservoir of azithromycin apparently produces effective drug

- concentrations in interstitial fluids even after the plasma concentrations have declined

below detectable levels

- Drug is slowly released from tissues to produce an elimination half-life approaching 3

days. It is rapidly absorbed and well tolerated orally.

- It should be administered 1h before or 2h after meals.

- It does not inactivate cytochrome P450 enzymes and is free of the drug interactions that

occur with erythromycin.

- Dose: Dogs : 5-10mg/kg,PO, sid ; cats: 5mg/kg.PO, once daily or every alternate day

Roxithromycin

It is a semisynthetic macrolide, is longer acting and more stable than erythromycin.It is mostly

used as an alternative to erythromycin

Dogs : 15mg/kg,PO, sid

Tilmicosin

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Tilmicosin is a newer macrolide antibiotic, that is closely related to erythromycin. Tilmicosin is

synthesized from tylosin and developed for veterinary use.

It is recommended for treatment and prevention of pneumonia in cattle, sheep and pigs,

associated with Pasteurella haemolytica, P. multocida, Actinobacillus pleuropneumoniae,

mycoplasma species and other microorganisms found sensitive to this compound

- Tilmicosin phosphate has been effective for treating: - bovine respiratory disease (as

effective or more effective than other established treatments: ceftiofur, oxytetracycline,

or florfenicol). The lung concentrations are so high for tilmicosin that they persist for at

least 72 hours after a single dose. Resistance among cattle respiratory pathogens has

been recognised. Tilmicosin also has been used as a prophylactic antibiotic for

administration to calves entering a feed-lot situation

- has in vitro activity against gram-positive organisms and mycoplasma and is active

against certain gram-negative organisms,such as Histophilus somni (Haemophilus

somnus), Mannheimia (Pasteurella) haemolytica, and Pasteurella multocida. However,

M. haemolytica is more sensitive than P. multocida to tilmicosin. Other gram-negative

organisms tested, including Enterobacter aerogenes, Escherichia coli, Klebsiella

pneumoniae, Pseudomonas aeruginosa, Salmonella, and Serratia species, are very

resistant to tilmicosin.

- Injections of tilmicosin to horses, goats, swine, or nonhuman primates can be fatal.

The heart is the target of toxicity, mediated via depletion of cardiac intracellular

calcium, resulting negative inotropic efect. Other results suggested that tilmicosin may

cause oxidative stress in the heart, liver, lung and kidneys, but the adverse effects could

be attenuated by L-carnitine administration.

- Tilmicosin phosphate is administered as a feed additive has been shown to be effective

for controling pneumonia in swine. When injected in swine, tilmicosin has caused toxic

reactions and death due to cardiovascular reaction.

- Dose: Cattle and sheep: 10mg/kg, SC, every 72 hours; Pigs: 200-400g/tonne feed

Tulathromycin : Tulathromycin has a semi-synthetic, 15-membered macrolide ring structure .

Tulathromycin differs from other macrolides since it has three amino groups. It is a member of

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the triamilide subclass of macrolides because it has three polar amine groups, which distinguish

its structure from other macrolides,including the azalides.

It is used in treatment of swine respiratory disease (SRD) and bovine respiratory disease (BRD).

It is formulated for parenteral injection as a single dose to provide a full course of therapy

- Tulathromycin has three ionizable groups (azithromycin has two ionizable groups and

erythromycin has one). At neutral to acidic pH, the high positive charge of the molecule

would decrease lipid solubility, concomitantly reducing the ability of tulathromycin to

diffuse across cell membranes and reach the intracellular target.

- The pH of feces and colonic contents can range generally from 6.3 to 6.9 for swine and

cattle. At these pH values,tulathromycin activity against enteric organisms is markedly

attenuated, lessening its ability to exert selective pressure for organisms in vivo

- Administered as a single injection is characterized by rapid and extensive absorption

followed by high distribution and slow elimination.

- Concentrations in lung are considerably higher than those in plasma.

- Not extensively metabolized and is excreted in the urine andfeces, mainly (>90%) as

unchanged drug

Dose: cattle- 2.5 mg / kg body weight, SC,as a single dose.; Pig: 2.5 mg /kg,IM, single dose

Tylosin

- spectrum of activity similar to that of erythromycin but is more active than

erythromycin against certain mycoplasmas.

- Tylosin is an antibiotic veterinary drug for the treatment ofdisease in food producing

animals, including cattle, swine, and poultry, and for growth promotion in pigs, cattle,

and chickens.

- Therapeutically used to treat: swine dysentery, pleuropneumonia due to Haemophilus

parahemolyticus, colitis in dog, other infections in cats, chickens Mycoplasma canis

and Mycoplasma haemocanis(formerly Haemobartonella canis) infection in dog

Dose: Dogs and cats: 40mg/kg,PO,tid; 4mg/kg,IM,sid; Cattle: 10-20mg/kg,IM,bid; Pig:

10mg/kg, IM, bid,25g/100litres drinking water,100g/tonne feed;Poultry: 10 mg/kg, IM, SID-BID

7-10 mg/kg, PO, TID ; 50g/100litres drinking water

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Kitasamycin (chemical name: Leucomycin)

- similar to erythromycin, and produced by Streptomyces kitasatoensis.

- broad spectrum of antibiotic activity,inhibiting many Gram-positive bacteria (including

C. perfringens). While inactive against the Enterobacteriaceae, it is active against

particular Gram-negative bacteria such asNeisseria spp, Haemophilus spp and Brucella

spp.

- The sensitivity of Mycoplasma species to kitasamycin, the high inclusion level in the

feed of pigs and the likelihood of good systemic availability suggest that kitasamycin

could play an important role in preventing enzootic pneumonia

Josasamycin

- obtained by fermentation of Streptomyces narbonensis is effective in vitro against

Mycoplasma, gram-positive cocci (Staphylococcus, Streptococcus, Diplococcus).

- In veterinary medicine, it is used for the prevention and the treatment of chronic

respiratory diseases, sinuitis, synovitis and arthritis caused by Mycoplasma and gram-

positive germ in chicken.

Spiramycin

- It is available as a spiramycin ebonate for use in animal feed, and as the adipate, a more

solube form for administration by other routes is for the treatment and control of number

of bacterial and mycoplasmal infections in animals.

- well absorbed after oral administration with high levels beeing found in bone. Bone

spiramycin slowly decreased over a 24-day period. Whengiven as the adipate in water to

pigs high levels were noted in the liver, bile and kidney.

- It ia an alternative to Amoxicillin in the Treatment of acute upper respiratory tract

infections.

Polyene Macrolide Antibiotics

A number of polyene antifungal antibiotics has been isolated from various strains of Actinomyces

, but only amphotericin B, nystatin, and pimaricin (natamycin) are used in veterinary medicine.

The polyenes are poorly soluble in water and the common organic solvents. They are reasonably

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soluble in highly polar solvents such as dimethylformamide and dimethyl sulfoxide. In

combination with bile salts, such as sodium deoxycholate, amphotericin B is readily soluble

(micellar suspension) in 5% glucose. This colloidal preparation is used for IV infusion. The

polyenes are quite unstable in aqueous, acidic, or alkaline media but in the dry state, in the

absence of heat and light, they remain stable for indefinite periods. They should be administered

parenterally (diluted in 5% dextrose) as freshly prepared aqueous suspensions (stable for 1 wk if

refrigerated).

LINCOSAMIDES

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These antibiotics are structurally distinct (but share many properties), basic compounds,

characterized by their high lipidsolubility, wide distribution in the body, and capacity to

penetrate cellular barriers, bacteriostatic drug (particularly active against grampositive

bacteria, and mycoplasma, and have good activity against anaerobic bacteria /most aerobic gram-

negative bacteria are resistant/).They have similar pharmacokinetic features, common site of

action (on the 50S ribosome).

Lincomycin, the parent compound, is a fermentation product of Streptomyces lincolnensis var.

Lincolnensis. It is a monoglycoside with amino acid-like side chain Lincomycin has one

derivative, clindamicyn (significantly greater activity than the parent compound)Mechanism of

action: Inhibit protein synthesis (by binding to the 50S ribosomal subunit and inhibiting peptidyl

transferase). The lincosamides are usually considered bacteriostatic, however, whenclindamycin

is present at sufficient concentrations, it may act as a bactericidal antibiotic against sensitive

organisms.

Antimicrobial activity

Lincosamides are moderate spectrum antimicrobial drugs. Clindamicyn is several times more

active (especially against anaerobes and S. aureus)

Lincomycin has been shown to have efficacy against Erysipelothrix insidiosa, Leptospira

pomona, Mycoplasma species, Staphylococcus species, and Streptococcus species (except

Streptococcus faecalis

Clindamycin has a spectrum of activity that includes Mycoplasma species, Staphylococcus

species, and Streptococcus species (except Streptococcus faecalis), aswell as anaerobic

organisms, such as Actinomyces species,Bacteroides species, Clostridium perfringens (but not

necessarily other clostridia), Fusobacterium species, Peptostreptococcus species, and many

Propionibacterium species.The antimycoplasma activity of the lincosamides is similar tothat of

erythromycin but less than that of the other macrolides.

Mode of Action : Lincomycin and clindamycin bind exclusively to the 50 S subunit of

bacterial ribosomes and suppress protein synthesis. Lincosamides, macrolides, and

chloramphenicol, although not structurally related, seem to act at this same site. The

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lincosamides are bacteriostatic or bactericidal depending on the concentration. Activity is

enhanced at an alkaline pH

Bacterial Resistance: Resistance to lincosamides appears slowly, perhaps as a result of

chromosomal mutation. Plasmid-mediated resistance has been found in strains of Bacteroides

fragilis . Resistance appears to be due to an alteration in the 50 S ribosomal subunit. Cross-

resistance with other antibiotics has been shown in vitro but not in vivo with erythromycin

Lincomycin

Lincomycin has a limited spectrum against aerobic pathogens but a fairly broad spectrum against

anaerobes. Clindamycin is a more active analog with somewhat different pharmacokinetic

patterns.

Many gram-positive cocci are inhibited by lincosamides, but most gram-negative organisms are

resistant, as are most mycoplasmas. Bacteroides spp and other anaerobes are usually susceptible.

Clostridium difficile strains appear to be regularly resistant

Oral absorption of the lincosamides is rapid, but orallyadministered lincomycin is less well

absorbed thanclindamycin. Intramuscular absorption: Lincomycinhydrochloride is rapidly

absorbed after intramuscularadministration.

Clindamycin and lincomycin are widely distributed intomost tissues, including respiratory tissue,

soft tissue, bones Lincomycin is incompletely absorbed from the GI tract, especially if

dministered soon after feeding; plasma levels peak within 2-4 hr. Absorption from IM injection

sites is good; plasma levels peak in 1-2 hr. About 90% of an oral dose of clindamycin is

absorbed, and effective plasma concentrations are achieved more rapidly than with lincomycin.

Absorption is not significantly affected by the ingestion of food. Clindamycin palmitate is used

PO, and clindamycin phosphate IM; the latter reaches peak plasma concentration in 1-3 hr

Distribution. Lincosamides are widely distributed in many fluids and tissues, including bone,

but significant concentrations are not attained in the CSF even when the meninges are inflamed.

They diffuse across the placenta in many species. About 90% of clindamycin is bound to plasma

proteins. It also accumulates in polymorphonuclear WBC and alveolar macrophages such that

concentrations exceed those of plasma 50-fold, but the clinical relevance of this phenomenon is

unclear.

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Biotransformation After administration PO, ~50% of a dose of lincomycin and 80-90% of a

dose of clindamycin are metabolically altered in the liver. Metabolites often retain activity. Liver

disease impairs the biotransformation of lincosamides

Elimination:

Parent drug and metabolites are primarily excreted in the urine and the bile. Small amounts are

excreted in intestinal contents and pancreatic and prostatic fluids. Unchanged antibiotic and

several metabolites may be excreted in bile and urine. The proportions depend on the route of

administration.Milk is also an important excretory route

Pharmacokinetics: The elimination half-life of lincosamides is frequently >3 hr, and the

apparent volume of distribution is >1 L/kg. They are usually administered BID. In dogs,

clindamycin has an elimination half-life of 3.9 hr and a volume of distribution of 1.4 L/kg The

lincosamides are indicated for infections caused by susceptible gram-positive organisms,

particularly streptococci and staphylococci, and for those caused by anaerobic pathogens

Side Effects and Toxicity:

- Chinchillas, guinea pigs, hamsters, horses, ponies, and rabbits: 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. 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.

- Ruminants exposed to oral lincomycin have also been reported to have side effects such

as anorexia, ketosis, and sometimes severe diarrhea. No serious organ toxicity has been

reported, but GI disturbances do occur.

- Clindamycin-induced pseudomembranous enterocolitis (caused by toxigenic Clostridium

difficile ) is a serious adverse reaction seen in humans.

- Lincosamides are contraindicated in horses because severe and even fatal colitis may

develop.

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- Skeletal muscle paralysis may be seen at high concentrations. Hypersensitivity reactions

occasionally are seen.

- Lincosamides should not be used in neonates because of their limited ability to

metabolize drugs

Interactions: Lincosamides have additive neuromuscular effects with anesthetic agents and

skeletal muscle relaxants. Antidiarrheals, adsorbent (concurrent use of kaolin- or astringens-

containing antidiarrheals with oral lincomycin may significantly decrease absorption of oral

lincomycin; concurrent use with oral clindamycin may delay absorption; Antidiarrheals,

antiperistaltic (antiperistaltic agents, such as opiates, or loperamide /opioid receptor agonist/ ,

may prolong or worsen pseudomembranous colitis by delaying toxin elimination). Kaolin-pectin

prevents their absorption from the GI tract. They should not be combined with bactericidal

agents or with the macrolides.

Chloramphenicol or Erythromycins (may displace clindamycin or lincomycin from or prevent

their binding to 50S 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 respiratory depression or paralysis [apnea]; caution

and careful monitoring of the patient are recommended

Clindamycin

Like erythromycin, clindamycin inhibits protein synthesis by interfering with the formation of

initiation complexes and with aminoacyl translocation reactions. The binding site for

clindamycin on the 50S subunit of the bacterial ribosome is same as that for erythromycin

Resistance to clindamycin, which generally confers cross-resistance to other macrolides, is due

to ① mutation of the ribosomal receptor site; ② modification of the receptor by a constitutively

expressed methylase; and ③ enzymatic inactivation of clindamycin.

Pharmacokinetics: Well absorbed by orally, or iv, about 90% protein-bound, excretion is mainly

via the liver, bile, and urine. Clindamycin penetrates well into most tissues, it penetrates well

into abscesses and is actively taken up and concentrated by phagocytic cells.

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It is metabolized by the liver, and both active drug and active metabolites are excreted in bile.

The half-life is about 2.5 hours in normal individuals, increasing to 6 hours in patients with

anuria. No dosage adjustment is required for renal failure.

Clinical Indications of Lincosamides:

- Dental infections in cats, dogs: Lincomycin hydrochloride

- swine dysentery Lincomycin hydrochloride for medicated feed, and soluble powder

- necrotic enteritis in chickens: Lincomycin HCl medicated feed and soluble

- Joint infections in Pigs: Lincomycin HCl injection in the treatment of infectious

arthritis caused by susceptible organisms, including susceptible Staphylococcus species,

Streptococcus species, Erysipelothrix rhusiopathiae, and Mycoplasma species.

- Metritis in Dogs: Lincomycin injection, syrup, and tablets are indicated in the treatment

of metritis caused by susceptible organisms.

- Respiratory tract infections in Cats, Dogs

- Skin infections in dogs: Lincomycin injection, syrup, and tablets : in the treatment of

skin infections, such as pustular dermatitis,

- Osteomyelitis in Dogs: Clindamycin capsules, and oral solution are indicated

- Soft tissue infections in cats, dogs: : Clindamycin and lincomycin in the treatment of

soft tissue infections, including abscesses, caused by susceptible organisms.

- The most important indication for clindamycin is the treatment of severe anaerobic

infection caused by bacteroides and other anaerobes that often participate in mixed

infections.

- In combination with an aminoglycoside or cephalosporin clindamycin is used to treat

penetrating wounds of the abdomen and the gut; infections originating in the female

genital tract, such as septic abortion and pelvic abscesses; or aspiration pneumonia.

- Dose: Lincomycin: 10 mg/kg, IM, BID- Cattle,pig,cats; 20 mg/kg, PO, SID- dog.;

Clindamycin: 5-10 mg/kg, PO, BID- Dogs, catsTacrolimus Tacrolimus is a macrolide

antibiotic and an immunosuppressive compound derived from the fermentation of

Streptomyces tsukybaensis that has a similar mechanism of action as cyclosporine to

inhibit T lymphocyte proliferation. Tacrolimus binds macrophilin-12, an immunophilin

known as FK506binding protein and inhibits the proliferation and activation of CD4+ T

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helper cells. it is available in an oral formulation used extensively as an

immunosuppressive in human transplants that has very similar actions to cyclosporine.

Side effects preclude this form the use in dogs and cats. The topical formulation of

tacrolimus is available as a 0.1% ointment. Tacrolimus has topical anti inflammatory

effects without the atrophogenic effects and metabolic effects of topical GC’s. It was

used recently for the treatment of atopic dermatitis in humans and is also beneficial in

psoriasis and possibly alopecia areata. Its mechanism of action is similar to cyclosporine

but 10 to 100 times more potent. It works by calcineurin inhibition, resulting in

suppression of antigen presenting T cells, inhibition of the production of multiple

cytokines from T cells (IL-2, IL-3, IL-4, IFNy, GMCSF, and TNF-alpha), down regulates

cytokine expression in other cells including mast cells, basophils, eosinophils,

keratinocytes and Langerhans cells. It also inhibits mast cell adhesion, inhibits the release

of mediators from mast cells and basophils, and down-regulates the expression of

interleukin-8 receptor and FcγRI on Langerhans’ cells. Tacrolimus and cyclosporine

reduce production of eosinophils, block transcriptional activation of mast cell cytokine

genes, and suppress tumor necrosis factor-alpha production by B cell It has been reported

effective in canine perianal fistula though at a lower rate than systemic cyclosporine,

but has been used once there is significant response to cyclosporine for the final therapy

or maintenance of perianal fistula therapy. It appears to have some efficacy in atopic

diseases and other possible indications with localized lesions associated with discoid

lupus erythematosus, pemphigus erythematosus, pemphigus foliaceous. Anecdotal

reports describe its use for a wide number of veterinary dermatologic diseases.It is used

topically for atopic dermatitis. Similar to cyclosporine, systemic use has side effects

including neurologic and renal problems but they abate when the medication is

discontinued. A major advantage of topical tacrolimus is that it does not cause skin

atrophy and may reverse corticosteroid-induced skin atrophy.Pimecrolimus:

Pimecrolimus (ElidelTM) is an ascomycin macrolactam derivative that acts similarly to

tacrolimus. It is used similarly to tacrolimus topically.It shows similar or lower efficacy

than Tacrolimus.

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