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BETA LACTAM ANTIBIOTICS AND OTHER
CELL WALL SYNTHESIS INHIBITORS
Ma. Shiela Cano-Guiking, M.D.
PENICILLINS I. CLASSIFICATION
A. Penicillinase Resistant ( Antistaphylococcal Penicillins)
1. Methicillin ( Staphcillin)2. Nafcillin (Unipen, Nafcil, Nallpen)3. Isoxazolyl penicillins
a. Oxacillin b. Cloxacillin c. Dicloxacillin d. Flucloxacillin
B. Penicillinase-Susceptible 1. Narrow-Spectrum a. Benzylpenicillin – Penicillin G
b. Phenoxymethyl penicillin – Penicillin V
2. Extended Spectrum
A. Aminopenicillins
a.1 Ampicillina.2 Esters
a.2.1. Bacampicillin a.2.2. Pivampicillin a.2.3. Talampicillin
a.3. Amoxicillin
B. Carboxypenicillins
a.1 Carbenicillin
a.1.1. Indanyl carbenicillin e.g Geopen
a.1.2. Disodium carbenicillin e.g. Pyopen
a.2. Ticarcillina.3. Temocillin
C. Ureido-penicillinsc.1. Mezlocillinc.2. Azlocillinc.3. Piperacillinc.4. Apalcillin
II. GENERAL PROPERTIES
A. Chemical Properties
Penicillins are derivatives of benzylpenicillin, from which
the methyl benzene radical is split
off by amidase producing 6-aminopenicillanic acid, the parent compound of all semisynthetic penicillins
The compound consists of 2 basic structures:
1 Thiazolidine Ring (A)
2.Beta-Lactam Ring (B)
- Site of action of Beta-lactamase
- Site of action of Amidase
- Site of attachment of side chain ®, which determines many of the antibacterial and pharmacologic characteristics of a derivative
( spectrum and penicillin-resistance)
Mechanisms of Action:
Specific:
inhibit the last step in the peptidoglycan synthesis of
the cell wall
Underlying:
1. inhibition of transpeptidase enzymes
2. activation of penicillin binding proteins (PBPs)
3. activation of autolysins (murein hydrolases)
•
C. Mechanisms of Resistance
1. inactivation of antibiotic by Beta lactamases 2. modification of PBPs 3. impaired penetration of drug to target PBPs 4. presence of an efflux pump Kinetics: - absorption vary with the preparation
depending on their acid stability and protein binding
- absorption of most oral penicillins (except amoxicillin) impaired by food and drugs should be given 1-2 hours before or after meal; parenteral – complete and rapid
- cannot penetrate the blood-brain barrier; but 50% of the plasma concentration can pass through in the presence of inflammation:
Probenecid and certain organic acids can inhibit transfer from cerebrospinal fluid (CSF) to blood stream; may lead to increase CSF level.
- Metabolized by the liver to penicillanic/penicillenic acid; penicillamine, penicilloic acid and other penicilloyl derivatives (allergenic metabolites)
- Excreted primarily by the kidneys (90% tubular secretion, 10% glomerular filtration) small amount through bile and feces, sputum and milk; renal excretion inhibited by probenecid
E. Adverse Effects:
1. Hypersensitivity reactions
most common adverse effects - cause the highest incidence of antibiotic allergy
a. major antigenic determinant- penicilloyl metabolite skin testing( penicilloyl polylysine (PPL) )
b. Signs and symptoms: - varied skin rashes and purpuric
reactions - angioedema and anyaphylactic
reactions - fever - eosinophilia - interstitial nephritis
2.Gastrointestinal disturbances after oral administration
3.Convulsions following rapid IV administration
4. Accidental injection into the sciatic nerve – severe pain and nerve
dysfunction persisting for weeks
5. Chronic use may cause: hepatitisovergrowth of minor/atypical organisms following use of broad spectrum preparations
6. Specific toxicities:
a. Procaine Penicillin G after accidental IV injection: pulmonary embolism
acute psychotic reactionsb. Oxacillin and Nafcillin
hepatitisgranulocytopenia, bone marrow depression
c. Disodium Carbenicillin and high dose Penicillin G Na
-hypernatermiad. Penicillin G Potassium
hyperkalemia with high doses
e. Penicillin G Sodium Jarisch_herxheimer reaction with high
doses
in secondary syphilis f. Carbenicillin and Ticarcillin
bleeding diathesis
g. Methicillin interstitial nephritis
h. Ampicillin
associated with pseudomembranous colitis
III. INDIVIDUAL AGENTS
A. Penicillin G
1. Antimicrobial Spectrum- Streptococci, meningococci,
enterococci, pen. susceptible pneumococci, non-B lactamase producing staph, Treponema, spirochetes, B. anthracis, Clostridium, Actinomyces, G(+) rods and non B lactamase producing G (-)anaerobic organisms
2.Kinetics - 1/3 of oral dose absorbed from
intestinal tract rapidly; food impair absorption
- maximal concentration: 30-60 min.
- intravenous a. Aqueous Penicillin G - peak in 15-30 min -T ½ - 0.5-2 hrs.
- intramuscular B. Procaine Penicillin G
peak in 1-3 hrs. T1/2 – 12 hrs.
C. Benzathine Penicillin G
mean duration of antimicrobial activity - 26 days - 60% albumin bound
- widely distributed to the tissues and body fluids - does not readily enter the cerebrospinal fluid when meninges are not inflamed
- probenecid and uremia inhibits active transport secretion into the blood stream
Preparations: “ International Units “ – measure of strength Oral Preparations: Penicillin G Sodium
Penicillin G Potassium Parenteral Preparations 1.short acting
a. aqueous Penicillin G Potassium – 1.7 meq K/1M “u” b. aqueous Penicillin G Sodium – 2.4. meq Na/1M “u”
2. long acting a. Procaine Penicillin G – 300,000 – 600,000 “u” 120 mg procaine/vial b. Benzathine Penicillin G – 600,000 “u” 1.2 M “u”/vial
4. Doses and Therapeutic Uses
a. Aqueous Penicillin G Child: mild infections – 50,000 “u” – 100,000 “u”/kg/day in
equally divided Doses every 4-6 hrs. for 7
days Severe infections – 200,000 “u” – 600,000 “u”/kg/day
in equally divided Doses every 2-6 hrs.
for 14 days.
a. Procaine Penicillin G – 300,000 – 600,000 “u” IM OD or BID for 7 days for Adults b. Benzathine Penicillin G – 1.2 million – 2.4 “u” IM monthly
Syphilis – less than 1 year duration – 2.4 M “u” IM + Probenicid 1 gm/day for 10 days or 2.4 M “u” Benzathine Penicillin G IM
single dose
late latent, complicated – 20 M “u” aqueous Penicillin G/day for 10 days
congenital syphilis – 50,000 “u”/kg/day aqueous Penicillin G for 10 days
Staphylococcal infectionsGram (+) anaerobesMeningococcal infectionsGonococcal infectionsCarrier state diphtheria
Other unusual infections – actinomycosis, Anthrax, rat bite fever, listeria, pasteurella, lyme disease, erysipeloid
Prophylaxis – recurrences of streptococcal, rheumatic fever, gonorrhea, syphilis, bacterial endocarditis
D . Penicillin V
Oral form indicated only in minor infections Relative poor bioavailability; need for
dosing 4x a day
Gram (+) aerobic activities similar to Penicillin G
5-10x less active against gram(-) microbes, esp. Neisseria and certain anaerobes
better absorbed from the gastrointestinal tract because of better acidic stability
D. Ampicillin
1. Microbial SpectrumSomewhat less active than Penicillin G
against gram (+) cocci Enterococcal grp. D and viridans grp. Of streptococci
- Listeria monocytogenes - H. influenza
Effective for Shigellosis
Should not be used for uncomplicated salmonella gastroenteritis – may prolong the carrier state
2. Kinetics: Gastric acid stable and well absorbed
from the gastrointestinal tractOrally absorbed drug peaks in 2 hrs.
Intramuscular administered drug peaks in 1 hour
Mainly excreted by the kidneys; also thru the bile and feces
Undergoes enterohepatic circulation
Other kinetic properties similar to Penicillin G Sodium
3. Adverse Effects: “Ampicillin skin rash” – occurs in 7-8%
others similar to Pen G
4. Preparations a. Oral
Capsules – 250-500 mgSuspension – 125 mg, 250 mg/5
mlDrops – 100 mg/ml
b. parenteral250 mg; 500 mg/ml vial
5. Doses a. mild infections
Newborn – 25-50 mg every 12 hrs. Child – 50-100 mg/kg/d in 4-6 divided
doses Adult – 1-4 gm/day
b. severe infectionsChild – 200-600 mg/kg/dayAdult – 6-12 gm/day
E. Esters of Ampicillin No inherent antimicrobial activity as esters, but
pharmacologically active following hydrolysis to Ampicillin
50% higher blood concentration than Ampicillin and Amoxicillin
F. Amoxicillin
Closely related to Ampicillin in chemical
and pharmacologic properties
More rapidly and completely absorbed
from gastrointestinal tractAttains higher serum levels than
ampicillin
G. CARBOXYPENICILLINS AND UREIDOPENICILLINS
1. Antimicrobial SpectrumGram (-) aerobesPseudomonas aeroginosaBacteroides fragilis; but in higher
amount/dose
Carboxypenicillins – certain indole (-)
ProteusUreidopenicillins – KlebsiellaAzlocillin – 10x more active than
carbenicillin against Pseudomonas
2.Preparations
a. Carbenicillin Disodium salt – contains approximately 5 meq sodium/gm
for parenteral administration
Indanyl esters – 500 mg tablets
b.UreidopenicillinsParenteral preparations
H. Penicillinase-Resistant
1. Methicillin -15-80x more active against penicillinase producing microbes than Penicillin G; only parenterally available; currently many resistant strains of Staph. Aureus have emerged, no longer
used because of nephrotoxicity
2. Nafcillin – slightly more active than Cloxacillin against penicillinase producing Staph. Aureus, available in oral and parenteral preparations: GIT absorption is erratic
3. Isoxazolyl PenicillinsStable in gastric acid and adequately
absorbed after oral administrationDicloxacillin is most active against
penicillinase producing Staph. Aureus
Available in oral and parenteral preparations
CEPHALOSPORINS
I. CLASSIFICATION A. First Generation
1. Cephaloridine-Loridine, Ceporan 2. Cephalothin-Keflin 3. Cephalexin-Keflex, Ceporex 4. Cefazolin-Cefacidal 5. Cephradine-Velosef 6. Cepharpirin-Cefadyl 7. Cephadroxil-Doricef, Cefamox
– B. Second Generation
1. Cefaclor-Ceclor 2. Cefoxitin – Mefoxin 3. Cefuroxime – Zinacef, Zinnat 4. Cefonicid – Monocid 5. Cefotetan - Cefotan 6. Cefamdandole – Mandol 7. Cefprozil – Cefzil 8. Loracarbef – Lorabid 9. Cefmetazole – Zefazone 10. Ceforanide
C. Third Generation 1. Cefotaxime – Claforan 2. Cefoperazone – Cefobid 3. Moxolactam – Moxam 4. Ceftizoxime – Cefizox 5. Ceftriaxone – Rocephin 6. Ceftazidime – Fortum 7. Cefotiam – Ceradolan 8. Cefixime – Suprax 9. Cefetamet – Globocef 10. Cefpodoxime – Vantin 11. Ceftibuten – Cedax 12. Cefdinir –Omnicef 13. Cefditoren
D. Fourth Generation1. Cefepime – Maxipime2. Cefpirome – Cefrom
II. BASIS FOR CLASSIFICATIONA. Antimicrobial SpectrumB. Pharmacokinetic Properties
III. GENERAL PROPERTIES
A. Chemistry
7-amino cephalosporanic acid – parent
compound contains an R2 that makes the compound stable in dilute acid and highly penicillinase resistant
* MW – 400-450 *Soluble to water and relatively stable to
ph and temperature changes
C7 modifications alter antibacterial activity
C3 substitutes change metabolism and kinetic properties
B. MECHANISM OF ACTION AND RESISTANCESimilar to penicillins
C. Antimicrobial SpectrumGenerally broader spectrum than
PenicillinsGenerally more effective than Penicillins
against B- lactamase-producing microbes
(except enterococci, Methicillin-resistant Staph. aureus and Staph. epidermis)
D. SPECIFIC GROUPS/INDIVIDUAL AGENTS
1. FIRST GENERATION Good activity against gram (+) and modest
against gram (-) microbes
Penetration of the cerebrospinal fluid (CSF) is
inadequate
UTI, minor staph lesions, minor polymicrobial
infections – cellulitis, soft tissue abscessNot used in serious systemic infections
2. SECOND GENERATION
Better activity against anaerobes and gram (-) aerobes
Only Cefuroxime can produce sufficient
CSF level
Sinusitis, otitis, LRTI, mixed anaerobic
infections such as peritonitis/diverticulitis
3. THIRD GENERATION
Generally less active than the first generation against gram (+) cocci but most active against gram (-)
including B-lactamase- producing strains
Cefoperazone, Ceftazidime – (more active) against
Pseudomonas
Active against anaerobes – Cefoperazone,
Cefotaxime
Ceftizoxime, Moxolactam – B. fragilis
Cefoperazone & Ceftriaxone -excreted primarily in the bile; Probenecid does not affect
renal excretion
Cross BBB except Cefoperazone, Cefixime, Ceftibuten and Cefpodoxime proxetil
Ceftriaxone, 125 mg inj., Cefixime, single 400 mg oral dose -N. gonorrhea
Cefoperazone –(T1/2 – 2 hrs. ) 25-100 mg/kg/d injected q 8-12 hrs Cefixime 200 mg orally twice a day or 400 mg
ODCefpodoxime proxetil & Ceftibuten –
200 mg 2x/dayMeningitis caused by pneumococci,
meningococci, H. influenza & susceptible enteric gram (-) rods but not by L. monocytogenes; should be used in combination with
aminoglycoside for the treatment of meningitis caused by P. aeruginosa.
4. FOURTH GENERATION
More resistant to hydrolysis by chromosomal
beta lactamases (eg. Those produced by enterobacter)
Good activity against P. aeruginosa, enterobacteriaceae, staph. aureus,
S. pneumoniaeHighly active against Haemophilus &
Neisseria
Penetrates well into CSFCleared by kidneysT1/2 – 2 hrsGood activity against most penicillin
resistant strains of streptococci
Useful in the treatment of enterobacter infections
E. ADVERSE EFFECTS1. Allergy2. Toxicity:3. Renal toxicity – interstitial nephritis and even tubular
necrosis Cephalosporin that contains a methyl thiotetrazole
group ( Cefamandole, Cefmetazole, Cefotetan, Cefoperazone)
– cause disulfiram like reactions, hypoprothrombinemia and bleeding disorders- Antidote: Vit K, 10 mg 2x/week Moxolactam – interferes with platelet function, severe bleeding
4. Superinfection
MONOBACTAMS
Monocyclic beta lactam ringResistant to B-lactamaseActive against gram (-) rods including
Pseudomonas and SerratiaAztreonam – resembles aminoglycosides
in spectrum of activity
Given 1-2 g IV q 8 hrs.; T1/2 – 1-2 hrs
BETA LACTAMASE INHIBITORS ( CLAVULANIC ACID, SULBACTAM & TAZOBACTAM)
Resemble B- lactam moleculesBind to Beta-lactamase, inactivate them and
prevent the destruction Synergistic with other beta-lactams A. Clavulanic Acid – produced by S. Clavuligerul
potentnt inhibitor of beta-lactamases (plasmid encoded)
weak antibacterial action combined with Amoxicillin (Augmentin) or Ticarcillin( Timentin):
the combination widens the antimicrobial spectrum
B. Sulbactam Pivoxil and Ampicillin ( Unasyn)C. Tazobactam and Piperacillin (Tazocin)
CARBAPENEMS - structurally related to Beta lactam
antibiotics 1. Imipenem – gram (-) rods, gram (+) org. &
anaerobes inactivated by dehydropeptidases in renal tubules resulting in low urinary concentration
combined with Cilastatin ( dehydropeptidase
inhibitor ) to reduce inactivation penetrates body tissues and fluids well including
the CSF.25-0.5 g IV q 6-8 hrsAdverse effects include nausea, vomiting,
diarrhea, reactions to infusion site; excessive in renal failure – seizures 2. Meropenem – slightly greater activity
against gram (-) aerobesdoes not require an inhibitorpenetrates CSF 1 g q 8 hrs.
ERTAPENEM
-Less active than meropenem or imipenem
against Pseudomonas aeruginosa and
acinetobacter species
- It is not degraded by renal dehydropeptidase
OTHER CELL WALL SYNTHESIS INHIBITORS
1. VANCOMYCIN
Gram (+) staphWater soluble and quite stable
MOA - Inhibits cell wall synthesis by binding firmly to D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide
Resistance – modification of the D-Ala-D-Ala binding site of the peptidoglycan building block in which the terminal D-Ala is replaced by D-lactate resulting to loss of a critical H bond that facilitates high affinity binding of vancomycin to its target and loss of activity
Synergistic with gentamicin and Streptomycin against E. faecium and E. faecalis strains that do not exhibit high levels of aminoglycoside resistance
Poorly abosorbed from the GITAdministered orally for the treatment of antibiotic associated enterocolitis caused by C. difficile; 0.125 – 0.25 g q 6 hrs
99% excreted by glomerular filtrationT1/2 6-10 days – not removed by dialysis
- Sepsis or endocarditits caused by Methicillin resistant staph
Combined with Cefotaxime, Ceftriaxone or Rifampicin for the treatment of meningitis suspected or known to be caused by a highly penicillin resistant strain of pneumococcus.
- Recommended dosage is 30 mg/kg/day in two
or three divided doses - Adults with normal renal function – 1 g every
12 hrsChildren – 40 mg/kg/d in 3 to 4 divided dose -
Causes phlebitis, chills and fever, ototoxicity, nephrotoxicity, red man or red neck syndrome
2. FOSFOMYCIN
- inhibits a very early stage of bacterial cell
wall synthesis- inhibits cytoplasmic enzyme enol
pyruvate transferase by covalently binding to the cysteine residue of the active site and blocking the phosphoenolpyruvate to UDP-N-acetylglucosamine – 1st step in the formation
of UDP-N- acetylmuramic acid, the
precursor of acetylmuramic acid – found
only in bacterial cell walls.
- Drug is transported into the cell by glycerophosphate or glucose 6 phosphate transport systems
- Resistance is due to inadequate transport of drug into the cell
- Active against both Gram (+) and Gram (-)- In vitro synergism with beta lactams,
aminoglycosides or fluoroquinolones- Available orally ( 2-4 g, single dose
in uncomplicated UTI) and parenterally- Excreted through the kidneys - Safe in pregnancy
4. BACITRACIN- cyclic peptide mixture- active against Gram (+) organisms- inhibits cell wall formation by interfering
with dephosphorylation
- in cycling of the lipid carrier that transfers peptidoclycan subunits to the growing cell wall
nephrotoxic- poorly absorbed; limited to topical use 500 units/g ointment + Polymyxin B or
Neomycin
5. CYCLOSERINE
- water soluble; very unstable at acid ph treat tuberculosis caused by M. tuberculosis resistant to first line agents- structural analogs of D-alanine and inhibits incorporation of D-alanine into peptidoglycan
pentapeptide by inhibiting alanine racemase
which converts L alanine to D alanine and D- alanyl- D-alanine ligase
- widely distributed into tissues- excreted through the urine- 0.5 – 1 g /d in 2 – 3 divided doses- causes dose related CNS toxicity,
headaches, tremors, acute psychocis, convulsions
THANK YOU VERY MUCH
AND
STUDY WELL!
PROTEIN SYNTHESIS INHIBITORS
Ma. Shiela Cano-Guiking, M.D.
The 30 S Inhibitors:
I. AMINOGLYCOSIDES
Older Aminoglycosides:StreptomycinKanamycin
Newer Aminoglycosides:GentamicinTobramycinNeomycinAmikacinNetilmicinSisomicin
Antimicrobial Spectrum:1. Gram (-) Aerobic Bacilli2. Beta-lactamase producers:
Staph. aureus N. gonorrhea
3. Mycobacteria Mechanism of Action:
- interferes with initiation complex of peptide formation
- induces misreading of mRNA causing incorporation of incorrect AA
causes breakup of polysomes into nonfunctional monosomes
- Requires oxygen uptake, therefore ineffective against anaerobes.
- Bactericidal
Microbial Resistance:1. enzyme inactivation2. Cell surface alteration3. receptor protein alteration4. oxygen requirement related
Kinetics:minimally absorbed from the GIT, well absorbed thru
IM, IVpoorly penetrate the BBBnot significantly metabolizedprimarily executed unchanged through GF
Clinical Uses:severe gram (-) rod infectionsMycobacterial infections
Toxicity:Ototoxicity (esp. with loop diuretics)Auditory damage – Neomycin, Kanamycin
and AmikacinVestibular Damage – Streptomycin,
GentamicinNephrotoxicity (esp. with cephalosporins)Neomycin, Tobramycin, Gentamicin- most
nephrotoxic
STREPTOMYCIN - ribosomal resistance to this agent develops readily, limiting its role as a single agent- mainly used as a second line agent for treatment of
tuberculosis- given at 0.5-1 g/d (7.5-15 mg/kg/day for children) IM or IV should be used only in combination with other agents to
prevent emergence of resistance- In plague, tularemia and sometimes brucellosis, 1 g/d
(15 mg/kg/day for children) IM or IV + oral tetracycline +Penicillin; effective for enterococcal endocarditis and 2 week therapy of viridans streptococcal endocarditis- Can cause fever, skin rashes and other allergic reactions, pain at injection site, vestibular dysfunction – most serious toxic
effectIf given during pregnancy, can cause deafness in the newborn
GENTAMICINemployed mainly in severe infections (sepsis and
pneumonia) caused by gram (-) bacteria in combination with a cephalosporin or a penicillin may be life saving
given at 5-6 mg/kg/day IV in three equal doses+ Penicillin G for bactericidal activity in endocarditis
due to viridans streptococci or enterococci and in combination with Nafcillin in selected cases of staphylococcal endocarditis
Serum concentrations and renal function should be monitored if administered for more than a few days
or if renal function is changing (eg. Sepsis; often complicated by acute renal failure)
Gentamicin sulfate 0.1% -0.3% cream, ointment – for the treatment of infected burns, wounds, or skin lesions and the prevention of intravenous catheter infectionsTopical gentamicin is partly inactivated by purulent exudatesTen milligrams can be injected subconjunctivally for treatment of ocular infections.Nephrotoxicity is reversible and usually mild; Irreversible ototoxicity manifested as vestibular dysfunction, hypersensitivity reactions are uncommon
TOBRAMYCIN
Antimicrobial spectrum and pharmacokinetic properties virtually identical to gentamicin
Given at 5-6 mg/kg IM or IV into three equal amounts q 8 hours
Blood levels should be monitored in renal insufficiency
Slightly more active against pseudomonas but not E. faecium
Ototoxic and nephrotoxic
AMIKACIN
semisynthetic derivative of kanamycinresistant to many inactivating enzymesfor tuberculosis; given at 7.5 – 15 mg/kg/d as a once
daily or 2- 3x weeklySerum concentrations should be monitoredNephrotoxic and ototoxic
NETILMICIN
shares many characteristics with gentamicin and tobramycin
dosage and the routes of administration are the same, completely therapeutically interchangeable with gentamicin or tobramycin and has similar toxicities
KANAMYCIN AND NEOMYCIN
Paromomycin is also a member of this group and all have similar properties
Used for bowel preparation for elective surgery
There is complete cross-resistance between kanamycin and neomycin
Not significantly absorbed from the GIT; excretion of any absorbed drug is mainly through GF into the urine
Too toxic for parenteral use, now limited to topical and oral use
Solutions 1-5 mg/ml – used on infected surfaces or injected into joints, pleural cavity, tissue spaces or abscess cavities where
infection is present (15 mg/kg/day)
Ointments (Neomycin-Polymyxin-Bacitracin combination) applied to infected skin lesions or in the nares for suppression of staphylococci
In preparation for elective bowel surgery, 1 g of Neomycin given orally q 6-8 hours + 1 g of erythromycin base;
Paromomycin, 1 g q 6 hours orally for 2 weeks; effective in intestinal amoebiasis
Sudden absorption of postoperatively instilled kanamycin from the peritoneal cavity (3-5 g) has resulted in curare-like
neuromuscular blockade and respiratory arrest (Calcium gluconate and neostigmine can act as antidotes)
Prolonged application to skin and eyes-severe allergic reactions
SPECTINOMYCIN
chemically related to the aminoglycosides
binds at the 30 S subunit (bacteriostatic)
Dispensed as the dihydrochloride pentahydrate for IM
injection
Used almost solely as an alternative treatment for gonorrhea in patients who are allergic to penicillin or whose gonococci are resistant to other drugs
Single dose of 2 g ( 40 mg/kg )
II.TETRACYCLINES: Short Acting: Tetracyline, Oxytetracycline, ChlortetracyclineIntermediate Acting: Demeclocycline, MethacyclineLong Acting: Doxycycline, MinocyclineAntimicrobial Spectrum: Rickettsia, V. cholera, M. pneumonia, Chlamydia, Shigella, H. pylori, P.tularensis, P. pseudomallei, Brucella, Psittacosis, BorreliaMinocycline – carrier state of Meningococcal infections, N. asteroides N. gonorrhea
Mechanism of Action: - enter microorganisms in part by passive diffusion and in part by an energy dependent process of active transport
binds to 30 S and prevents attachment of aminoacyl tRNA, prevents the addition of amino acids to the growing peptide
Bacteriostatic
Resistance:decreased intracellular accumulation due to impaired influx or increased efflux by an active transport protein pumpribosome protection due to production of proteins that interfere with tetracycline binding to the ribosomeenzymatic inactivation
Kinetics:limited CNS penetrationabsorption occurs mainly in the upper small intestine and is impaired by food ( except Doxycycline and
Minocycline) Must not be taken with milk or antacidsCross placenta, excreted in milkCarbamazepine, phenytoin, barbiturates, and chronic alcohol ingestion may shorten the half life of
doxycyclineExcreted mainly in bile and urine ( Doxycycline
fecally eliminated; can be used in renal failure
Clinical Uses:Borrelia burgdorfi (Lyme disease), Chlamydia, Ureaplasma, M. pneumonia, Rickettsia, Acne, Tularemia, Cholera,
Leptospirosis, Protozoal infectionsMinocycline, 200 mg orally daily for 5 days, can eradicate the meningococcal carrier stateDemeclocycline – inhibits the action of ADH in the renal tubule and has
been used in the treatment of inappropriate secretion of ADH or similar peptides by certain tumors
Tetracycline – 250-500 mg 4x/day adults20-40 mg/kg/d – children above 8 y/0
600 mg daily dose for Demeclocycline and Methacycline100 mg 1-2x/d for Doxycycline and Minocycline
Toxicity: Renal toxicity, local tissue toxicity, photosensitization, GI distress, discolors teeth, inhibits bone growth in children, potentially teratogencic, hepatotoxicity, vestibular toxicity
THE 50 S INHIBITORS:
CHLORAMPHENICOL
MACROLIDES
CLINDAMYCIN/LINCOMYCIN
STREPTOGRAMINS
OXAZOLADINONES
I CHLORAMPHENICOL Bactericidal – H. influenzae, N. meningitides, B. fragilis Bacteriostatic – S. epidermidis, S. aureus, , M. pneumonia, L. monocytogenes, diphtheria, L. multocida, Salmonella sp., Shigella sp., E. coli, Rickettsia, Anaerobes,ineffective for chlamydial infections
Mechanism of Action:
attaches at P sites of 50 S subunit of microbial ribosomes and inhibits functional attachment of amino-acyl end of AA-t-RNA to 50 S subunit
inhibits peptidyl transferase step
Spectrum:broad spectrum antibioticmore effective than Tetracyclines against Typhoid Fever and
other Salmonella infections Kinetics:
well absorbed after oral administrationChloramphenicol succinate used for parenteral administration is highly water solubledistributed into total body waterexcellent penetration into CSF, ocular and joint fluidsrapidly excreted in urine, 10% as chloramphenicol; 90% as
glucuronide conjugatesystemic dosage need not be altered in renal insufficiency but
must be reduced markedly in hepatic failureNewborns less than a week old and premature infants also clear Chloramphenicol less well, dosage should be reduced at 25
mg/kg/d
Uses: meningitis, rickettsia, Salmonella and anaerobic infections
ineffective against chlamydial infectionsoccasionally used topically in the treatment of eye
infections for its well penetration to ocular tissues and the aqeous humor
Adverse Effects: GIT, oral or vaginal candidiasis, irreversible aplastic anemia, reversible bone marrow depression, Gray Baby Syndrome
II. MACROLIDES: Old Generation: Erythromycin, Oleandomycin, Troleandomycin, Spiramycin, Josamycin New Generation: Rosaramycin, Roxithromycin, Clarithromycin, Azithromycin, Dirithromycin
Mechanism of Action:binds to the P site of the 50 S bacterial ribosomal subunit.Aminoacyl translocation and formation of initiation complex are blockedInhibitory or bactericidal
RESISTANCE:reduced permeability of the cell membrane or active effluxproduction (by Enterobacteriaceae) of esterases that hydrolyze macrolidesmodification of the ribosomal binding site by chromosomal
mutation
Spectrum: Erythromycin has a narrow Gram (+) spectrum similar to Pen. G.Also active against Chlamydia and Legionella organisms1. Erythromycin:
prototypedistributed into total body waterpoor CSF penetrationfood interferes with absorptionserum half life is app. 1.5 h normally and 5 hours in patients with anurianot removed by dialysismetabolized in the livertraverses the placenta and reaches the fetus
Commercial Preparations:Oral-stearate, ethyl succinate, estolate salts – 250-500 mg q 6 h adults40 mg/kg/d - children
Parenteral- lactobionate, gluceptate – 0.5-1 g q 6 hours for adults 20-40 mg/kg/d for children
Adverse Effects: GIT dysfunction, intrahepatic cholestatic jaundice- Erythromycin metabolites can inhibit cytochrome p450
enzymes and thus increase the serum concentrations of theophylline, oral anticoagulants, cyclosporine and methylprednisolone;also oral digoxin by increasing its bioavailability
2. Clarithromycin- hydroxylated derivative of erythromycin- more active against Gram (+) pathogens, Legionella
and Chlamydia than Erythromycin- lower frequency of GIT effects, less frequent dosing- Half life of 6 hours- given at 250-500 mg twice daily
3.Azithromycin- more active than erythromycin against several Gram (-)
pathogens- maintains high concentrations for prolonged periods into a
number of tissues (lungs, tonsil, cervix)- tissue half life – 2-4 days- long half-life allows once daily oral administration and
shortening of treatment in many cases ( a single 1 g dose of azithromycin is as effective as a 7 day course of doxycycline for chlamydial cervicitis and urethritis)
-Community acquired pneumonia – 500 mg loading dose, followed by a 250 mg
- single daily dose for the next 4 days-Should be administered 1 hour before or 2 hours after meals;
aluminum and magnesium delay absorption and reduce peak serum concentrations
Does not inactivate cytochrome p450 enzymes and free of the drug interactions that occur with erythromycin and clarithromycin
AZITHROMYCIN
KETOLIDES
- semisynthetic 14 membered ring macrolides
Telithromycin – active in vitro against S pyogenes, S.
penumoniae, S. aureus, H. influenzae, Moraxella catarrhalis, mycopasmas, legionella sp, chlamydia sp, Helicobacter pylori, N. gonorrhoaea, B. fragilis, T gondii and nontuberculosis mycobacteria
-Oral bioavailability – 57%- good tissue and intracellular penetration- metabolized in the liver- eliminated by a combination of biliary and urinary routes of excretion- administered as a once daily dose of 800 mg- indicated for treatment of respiratory tract infections, including community acquired bacterial pneumonia, acute exacerbations of chronic bronchitis, sinusitis and streptococcal pharyngitis- a reversible inhibitor of the CYP3A4 enzyme system
TELITHROMYCIN
III. CLINDAMYCIN/LINCOMYCINMechanism of Action: attach to 50
S ribosomal subunit, inhibits protein synthesis by interfering with the formation of initiation complexes and translocation reaction
Spectrum: Narrow Gram (+) spectrum, excellent activity against anaerobic bacteria; strep, pneumococci, staphylococci
Resistance: mutation of the ribosomal receptor
sitemodification of the receptor by a
constitutively expressed methylase enzymatic inactivation
Clindamycin is more clinically used than Lincomycin:excellent absorptiongiven at 150-300 mg q 6 hrs – adults; 10-20 mg/kg/d
for childrenlow concentration in CSFwell bone penetrationexcreted mainly via the liver, bile and urinehalf life is 2.5 hours normally and 6 hours in patients
with anuriamore toxic than erythromycinprophylaxis of endocarditis in patients with valvular
heart disease for dental procedures
most important indication is the treatment of severe anaerobic infection caused by bacteroides and other anaerobes that often participate in mixed infections
+ aminoglycoside or cephalosporin used to treat penetrating wounds of the abdomen and the gut
Septic abortion, pelvic abscesses, aspiration pneumonia
+ primaquine – effective alternative to trimethoprim sulfamethoxazole for moderate to moderately severe Pneumocystis carinii pneumonia in AIDS patients+ Pyrimethamine for AIDS – related toxoplasmosis
of the brain
ADVERSE EFFECTS:
Diarrhea, nausea, skin rashes, impaired liver function and neutropenia; Antibiotic associated colitis caused by toxigenic C. difficile
NEWER AGENTS:
STREPTOGRAMINS:Quinuprisitn-Dalfopristin (Synercid)action is similar to macrolides except bactericidal for staph and most organisms except Enterococcus faeciumprolonged postantibiotic effect up to 10 h for Staph. aureusadministered IV at 7.5 mg/kg q 8-12 heliminated through fecal route, < 20% urineinhibits CYP 3A4, which metabolizes warfarin, diazepam,
astemizole, terfenadine, cisapride, nonnucleoside reverse transcriptase inhibitors and cyclosporine.Clinical Uses: infections caused by Vancomycin resistant strains of E faecium but not E. faecalis, bacteremis or respiratory tract infections caused by methicillin-resistant staphylococci and penicllin susceptibe and resistant strains of S. pheumoniaToxicities: infusion related events, pain at the injection site, arthralgia, myalgia synd
STREPTOGRAMIN A
STREPTOGRAMIN B
OXAZOLADINONES: Linezolid (Zyvox)inhibits protein synthesis by preventing formation of the ribosome complex that initiated protein
synthesis.Its unique binding site located on 23 S ribosomal
RNA of the 50 S subunit, results in no cross resistance with other drug classes
Has high oral bioavailability, half life of 4-6 hUses : staph, strep, enterococci, G(+) anaerobic cocci, G (+) rods, Corynebacterium, L. monocytogenes
- treatment of infections caused by vancomycin resistant E. faecium and other infections caused by multiple
drug resistant organisms
METABOLIC INHIBITORS:
SULFONAMIDES
- structurally similar to p-aminobenzoic acid (PABA) that competitively inhibits dihydropteroate synthase
- inhibits growth by reversibly blocking folic acid synthesis - mammalian cells do not make folic acid and are not affected- cross the placenta and secreted in breast milk and should not be given to pregnant Women- highly bound to plasma proteins esp, albumin- penetrates CNS well
SPECTRUM: - Gram (+) & Gram (-) Bacteria - Nocardia - C. trachomatis - Enteric bacteria (E. coli, Klebsiella, Salmonella, Shigella Enterobacter)
Ricketssia – sulfonamides do not inhibit these organisms but stimulate its growth Resistance: - occurs as a result of mutations that: 1. cause overproduction of PABA 2. cause production of a folic acid synthesizing enzyme that has a low
affinity for Sulfonamides 3. cause a loss of permeability to the sulfonamides
Pharmacokinetics:
- 3 MAJOR GROUPS: 1. ORAL, ABSORBABLE 2. ORAL, NON-ABSORBABLE 3. TOPICALIntravenous Preparation: - Na salts of sulfonamides in D5W
Oral, absorbable sulfonamides:
DRUGS HALF LIFE ORAL ABS
1.short actingSulfacytine
Sulfisoxazole
Sulfamethizole
Short
Short (6 h)
Short (9 h)
Prompt (peaks in
1-4h)
Prompt
Prompt
2. Medium acting
Sulfadiazine
Sulfamethoxazole
Sulfapyridine
Intermediate(10-17h)
Intermediate (10-12h)
No data
Slow (peak in 4-8h)
Slow
Slow
Long ActingSulfadoxine Long (7-9 days) Intermediate
absorbed from stomach and small intestine- distributed widely to tissues and body fluids
(CSF), placenta and fetus- protein binding 20% to over 90%- therapeutic concentration – 40-100 ug/ml of
blood- peak blood levels – 2h to 6 h after oral
ingestion- metabolism: glucoronidation or acetylation
in liver- eliminated in urine-mainly by glomerular
filtration
CLINICAL USES:1. Urinary tract infectionSulfisoxazole – 1 gm 4x daily }combined with PHENAZOPYRIDINESulfamethoxazole – 1 g 2-3 x daily } (U.T. anesthetic)2. Respiratory infections3. Sinusitis, bronchitis, pneumonia4. Otitis media5. Dysentery6. Acute Toxoplasmosis
Sulfadiazine + Pyrimethamine – SynergisticBlock sequential steps in folate synthesis:Sulfadizine- inhibits dihydropteroate synthasePyrimethamine – inhibits dihydrofolate reductase
Dosage – Sulfadiazine – 1 g 4x daily Sulfadiazine + pyrimethamine – 75 mg loading dose ffd by 25 mg OD
Folinic Acid – administered to minimize bone marrow
suppression7. Malaria
- sulfadoxine + pyrimethamine – 2nd line agent in the treatment for malaria
ORAL, NONABSORBABLE AGENTS
Sulfasalazine (Salicylazosulfapyridine)more effective than soluble sulfonamides or other antimicrobials taken orally in inflammatory bowel diseaseulcerative colitisenteritisother inflammatory bowel diseasesplit by intestinal microflora to yield:
Sulfapyridine – absorbed and may lead to toxic symptomsIf more than 4 g of sulfasalazine is taken per day esp. in persons who are slow acetylators5-aminosalicylate (5-ASA) – released in the colon in high
concentrations and is responsible for an anti-inflammatory effect
TOPICAL AGENTS:
Sodium Sulfacetamide ophthalmic solution or ointment effective for bacterial conjunctivitisadjunct therapy for trachoma
Mafenide acetateused topically to prevent bacterial colonization and infection of burn woundsinhibits also carbonic anhydrase – cause metabolic acidosis
Silver Sulfadiazineless toxic topical sulfonamidepreferred to mafenide for prevention of infection of burn woulds
ADVERSE REACTIONS:Cross allergy with the ffg.carbonic anhydrase inhibitors, thiazides, furosemide,
bumetanide, furosemide, diazoxide, sulfonylureas, hypoglycemicsMost common adverse effects:
Fever, skin rashes, exfoliative dermatitis, nausea, vomiting,
urticaria, photosensitivity
Urinary tract disturbances:sulfas may ppt. in urine at neutral or acid ph-Crystalluria – treated with sod. Bicarbonate to alkalinize urine and fluids to maintain adequate hydrationHematuriaObstruction
implicated in nephrosis and allergic nephritisOTHER SIDE EFFECTS:
Stevens-Johnson Syndrome – uncommon but serious and potentially fatal type of skin & mucous membrane eruptions
Hematopoietic disturbances:hemolytic or aplastic anemia, thrombocytopenia, granulocytopenia, leukemoid reaction, provoke hemolytic reactions in patients with deficient rbc glucose 6 phosphate dehydrogenaseincreased risk of kernicterus in newborns when sulfonamides were taken near the end of pregnancyStomatitis, Conjunctivitis, Arthritis, HepatitisPolyarteritis nodosa – rarePsychosis – rare
STEVENS JOHNSON SYNDROME
TOXIC EPIDERMAL NECROLYSIS
TRIMETHOPRIMwell absorbed from the gutwidely distributed in body fluids and tissues incldg. CSFfound in high concentrations in prostatic & vaginal fluidsEven if given orally alone or in combination with sulfonamides, it will have the same half-lifeMore lipid soluble – larger volume of distribution than
sulfonamidesRESISTANCE TO TM:
due to reduced cell permeabilitydue to overproduction of dihydrofolate reductasedue to production of an altered reductase & reduced drug binding
CLINICAL USES: Oral TM:
acute UTI 100 mg BIDcommunity acquired organisms – 200 ug to 600 ug/ml
concentration of TM in urineADVERSE EFFECTS:megaloblastic anemia, leucopenia, granulocytopeniaPrevention of adverse effects:simultaneous administration of folinic acid 6 mg-8 mg/day
TRIMETHOPRIM-SULFAMETHOXAZOLE (CO-TRIMOXAZOLE)
synergistically active antimicrobial agent which blocks two sequential steps in the obligate enzymatic reaction in bacteria preventing the formation of nucleotides:
Sulfamethoxazole – competitively inhibits the incorporation of PABA into folic acid
Trimethoprim inhibits dihydrofolate reductase preventing the reduction of dihydrofolate to tetrahydrofolate
ADVANTAGES OF THE COMBINATION:increased potencyincreases spectrumdecreased incidence of resistanceexhibits selective toxicity for bacteria which must
synthesize their own folic acidTrimethoprim is more potent, more lipid soluble and has a greater volume of distribution than sulfa drugsPenetrates CSF well
65-70% of each drug is protein boundEliminated in the urine within 24 h – reduce dose by half if creatinine clearance is 15-30 ml/min
CLINICAL USES:Oral TMP-SMX
urinary tract infection:
complicated UTI – 2 double strength tabs (TM-160 mg+SM 800 mg) q 12 hoursRecurrent UTI prophylaxis – ½ of regular size (single strength) 3x weekly
Prostatitis – 2 double strength tabs (TM 160 mg + SM 800 mg) q 12 hSusceptible strains of shigella and salmonella
2 double strength tabs q 12 hChildren with shigellosis, UTI, otitis media-8mg/kg TM and 40 mg/kg SM q 12 hoursP. carinii and other pathogens – orally 15-20 mg/kg
in immunosuppressed patients – one double strength tab daily or 3x weekly
Nontuberculous mycobacterial infectionRespiratory tract pathogens – useful alternative to B lactamase for community acquired bacterial pneumonia
CLINICAL USES:Inravenous TMP-SMX:
drug of choice for moderately severe to severe pneumocystis pneumonia esp. patients with AIDSTM 80 mgs + SM 400mg/5 ml diluted in 125 ml of D5WFolinic acid increases morbidity and treatment failures so not usedUsed for Gram (-) bacterial sepsis – incldg. Those caused by some multiple drug resistant species such as Enterobacter and SerratiaShigellosisTyphoid feverUTI caused by susceptible organisms if patient is unable to take drug orallyDosage- 10-20 mg/kg/day of TM componentOral Pyrimethamine + Sulfadiazine= used in the treatment of leishmaniasis and toxoplasmosisPyrimethamine + Sulfadoxine = used in the treatment of Falciparum malaria
ADVERSE EFFECTS:mostly due to untoward reactions to SMXdermatological effectsGI effects: glossitis, stomatitis, nausea and vomitingCNS disturbances: headache, depression, hallucinationsHematologic reactions- aplastic, hemolytic and macrocytic
anemia, coagulation disordersVasculitisRenal impairment or damage
AIDS PATIENTSmore sensitive to increased frequency of reactions toward TMP-SMX drug:-rashes, hemtologic effects-leukopenia, fever, diarrhea, elevated hepatic aminotransterases, hyperkalemia, hyponatremia
FLUOROQUINOLONESQUINOLONES
synthetic fluorinated analogs of nalidixic acidblock bacterial DNA synthesis by inhibiting bacterial
topoisomerase II (DNA Gyrase) and topoisomerase IV
INHIBITION OF DNA GYRASEprevents relaxation of positively supercoiled DNA that is
required for normal transcription and replication
INHIBITION OF TOPOISOMERASE IVinterferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division
EARLY QUINOLONES (Nalidixic Acid, Oxolinic acid, Cinoxacin)did not achieve systemic antibacterial levelsuseful only for treatment of lower UTI
ANTIBACTERIAL ACTIVITY:Gram (-) aerobic bacteria- excellent activityGram (+) organism – limited activity
NORFLOXACIN – least active against gm (+) and Gm (-)SECOND GROUP
excellent gm (-) activity, moderate gm (+) activityCiprofloxacin (prototype), Enoxacin, Lomefloxacin,
Levofloxacin, Ofloxacin, PefloxacinMethicillin susceptible S. aureus – susceptible to
fluoroquinolonesMethicillin resistant S. aureus – resistant to fluoroquinolonesCiprofloxacin – most active against gm (-) expecially P.
aeroginosaLevofloxacin – 2x more potent than ofloxacinsuperior activity against gm (+) org. incldg S. pneumoniae
THIRD GROUP:improved activity against gm (+) organism particularly S.
pneumoniae and some staphClinafloxacin – best activity against gm (+) activityGatifloxacinSparfloxacin – some activity against anaerobesnot as active as ciprofloxacin against gm (-)
FOURTH GROUPenhanced gm (+) activitygood activity against anaerobic bacteriaMoxifloxacin, Trovafloxacin
Other activities:Atypical pneumoniae ( Mycoplasma, ChlamydiaIntracellular pathoges (Legionella, Mycobacteria tb, and M.
avium complex)RESISTANCE:
Due to one or more point mutations in the quinolone binding region of the target enzyme
Due to a change in the permeability of the organism
DNA GYRASE – primary target in E. coli with single step mutants exhibiting amino acid substitution in the alpha subunit of the gyraseTOPOISOMERASE IV – secondary target in E. coli that is alerted in mutants expressing higher levels of resistanceIN STAPH AND STREP
Topoisomase IV – primary targetDNA gyrase – secondary targetcross resistance to other members
PHARMACOKINTEICS:well absorbed after oral intakebioavailability 80-95%distributed widely in body fluids and tissues
Half life3 hrs- norfloxacin and ciprofloxacin10 hrs. – pefloxacin & Fleroxacin> 10 hrs. – sparfloxacin
Long half life : Levofloxacin, moxifloxacin, sparfloxacin, trovafloxacin
Ofloxacin and Levofloxacin – identical pharmacokineticsOral absorption impaired by divalent cations including those
antacindsAlatrovafloxacin – inactive prodrug of trovafloxacin for
parenteral administrationConcentration is higher in prostate, kidney, neutrophiles and
macrophages than in serum
ELIMINATION: Renal – tubular secretion, Glomerular filtration- If creatinine clearance < 50%ml/min – adjust dosageSparfloxacin – a50 % fecal, 50% renalIf creatinine clearance <50 ml/min -400 mg LD followed by 200 mg q other dayNon renal – trovafloxacin and moxifloxacin_ CI in patients with hepatic failureCLINICAL USES:UTI – even when caused by multi drug resistant bacteria like pseudomonasNorfloxacin 400 mg BidCiprofloxacin 500 mg BIDOfloxacin 400 mg BIDProstatitis – 4-6 wksNorfloxacin, Ciprofloxacin, Ofloxacin
Bacterial Diarrhea
Shigella, Salmonella, toxigenic E. coli, campylobacterInfection of soft tissues, bones, joints, intraabdomina and respiratory tract infection even caused by Pseudomonas and EnterobacterGonococcal infection, including disseminated diseaseCiprofloxacin, ofloxacin oral single doseChlamydia urethritis or cervicitisofloxacin x 7 daysLegionellosisCiprobay – 2nd line agentTB and atypical mycobacteria infectionEradication of meningococci carrierProphylaxis in neutropenic patientUpper and lower RTINewer fluoroquinolones enhanced gm (+) activity and atypical pneumonia
ADVERSE EFFECTS:most common – nausea, vomiting and diarrheaOthers – headache, dizziness, insomnia, skin rash, abn liver function testTrovafloxacin – associated rarely with acute hepatitis and hepatic failurePhotosensitivity – lomefloxacin, pefloxacinCV toxicity – GrepafloxacinDamage growing cartilage and cause arthrpathy- not recommended < 18 y/oTendinitis – may rupture
DRUG INTERACTION:
Theophylline – increase metabolism of theophylline – elevated concentration-seizuresCONTRAINDICATIONS:Nursing mothers, children, pregnancy
NALIDIXIC ACIDFirst antibacterial quinolone introduced in 1963Not fluorinatedVery rapid elimination, no systemic bacterial effectsUsed only for UTIOxolinic Acid and Cinoxacin – similar structure
NOVOBIOCIN:Acidic antibiotic prod. By Streptococcus niveiusInhibitor of B subunit of DNA gyraseActive mainly against gm (+) bacteriaRapid emergence of resistance; inc. incidence of adverse
effectsNo clear indication
URINARY ANTISEPTICS:
Methenamine Mandelate and Hippuratereleases mandelic acid, hippuric acid or formaldehyde in sufficiently acidic urinebactericidal or bacteriostatic to most organisms causing UTI except ProteusNalidixic Acid and Cinoxacin:interferes with DNA polymerization by binding to DNA gyrasecauses nausea, vomiting, skin rashes and CNS effects
Nitrofurantoinwell absorbed after ingestionexcreted into the urine100 mg q 6 h with food or milkcontraindicated in severe renal insufficiencybactericidal or bacteriostatic for many gram (+) and gram (-)antagonizes the action of nalidixic acidcauses hypersensitivity, nausea, vomiting, neuropathies and hemolytic anemia in G6PD
Trimethoprimselective inhibition of bacterial dihydrofolate reductasemay be bacteriostatic or bacteridial+ Sulfamethoxazole – P. carinii, shigellosis, prostatitis, some nontuberculous mycobacterial infections, systemic salmonella infections, complicated UTI
MISCELLANEOUS ANTIBACTERIAL DRUGS:
Metronidazolepenetrates CSF, metabolism-livertreatment of amoebic infections, intraabdominal infections, vaginitis, antibiotic associate enterocolitis, brain abscessoral, IV, rectal suppositorycauses metallic taste, glossitis and anorexia
Polymyxin B
group of basic peptides active against Gram (-), bactericidaltreatment of serious enteric infections(Pathogenic E. coli, Shigella, Enterobacter, Klebsiella and Pseudomonas , not Proteus)poor tissue distributionattach to and disrupt bacterial cell membrane, bind and inactivate endotoxintoxicity includes neurological and renal effectstopical (+Bacitracin+Neomycin)
Mupirocin
ointment for topical applicationactive against staph aureus; inh. Isoleucyl tRNA synthetaseindicated for impetigo, intranasal application for elimination of methicillin resistant S. aureus carriage by patient or health care workers