Antimicrobial drug (Antibiotic)

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Antimicrobial agents which inhibit bacterial wall synthesis

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The beta-lactam family of antibiotics

1. Penicillins

Spectrum of activity

• Narrow spectrum : natural penicillins (penicillin G  , penicillin V  ):
  • Gram-positive bacteria, anaerobes, fastidious gram-negative bacteria, eg Haemophilusspp, Pasteurellaspp. NOT Enterobacteriaceae.
  • Unstable to beta-lactamases.
• Anti-staphlococcal : isdazoyl penicillins (cloxacillin, methicillin, oxacillin):
  • Gram-positive bacteria only. Less active than penicillin G.
  • Stable to beta-lactamases.
• Broad spectrum : aminopenicillins (ampicillin  , amoxycillin  , hetacillin, pivampicillin):
  • Gram-positive bacteria (less active than penicillin G), gram-negative bacteria including E. coli, P. mirabilis, Salmonellaspp. NOT Klebsiellaspp. and Pseudomonas aeruginosa.
  • Unstable to beta-lactamases, (resistance).
• Extended spectrum : carboxipenicillins, ureidopenicillins, (carbenicillin, carfecillin, ticarcillin  , ticarcillin plus clavulin-L acid):
  • Broader spectrum than aminopenicillins for Enterobacteriaceae.
  • Active against P. aeruginosa. Klebsiellaspp are resistant.
  • Unstable to beta-lactamase   developing gram-negative resistance.
• Gram-negative : amidinopenicillin:
  • Gram-negative only, (binds to PBP2).
  • Unstable to beta-lactamases.
  • Also produced as metabolite of pivmecillinam.
  • Rarely used for dogs and cats.

Pharmacokinetics

• Inorganic acids (pKa 2.7).
• Unstable in gastric acid - EXCEPT: penicillin V, isoxazoyl penicillins (not methicillin), aminopenicillins, carfecillin.
• Confined to extracellular fluids and some transcellular fluids, (joint, pleural, bile).
• Cross membranes poorly.
• Renal elimination. Short half-life in all species, (0.5-1.2 hours).
• Formulations to slow absorption and prolong duration of action   reduce peak blood levels obtained.
• Amoxycillin better absorbed orally than ampicillin.
• Hetacillin and pivamicillin broken down in body   ampicillin.
• Carfecillin broken down by gastrointestinal mucosa   carbenicillin.

Toxicity

• Generally very safe.
• Can see acute anaphylaxis or mild hypersensitivity.
• If contain procaine, DO NOT give IV.
• Can cause fatal Clostridium difficile  , colitis in guinea pigs and chinchillas.

2. Cephalosporins

Spectrum of activity

• Stable to staphylococcal beta-lactamase.
• Variable instability to gram-negative beta-lactamases.
• In general, as activity against gram-negative spectrum is increased, activity against gram-positive spectrum is reduced.
• Oral cephalosporins : eg cephalexin, cefadroxil, cephadrine, cefachlor:
  • Gram-positive and many gram-negative bacteria.
  • NOT indole positive Proteusspp and Pseudomonasspp.
• Parenteral cephalosporins : variable activity against gram-negative bacteria, high activity against gram-positive bacteria:
  • Group I: eg cefacetrile, cephalonium, cephaloridine, cephalothin, cephazolin. Pseudomonasspp resistant.
  • Group II: eg ceftiofur, cefuroxime, cefamandole, cefotetan. High activity against Enterobactericeae.
  • Group III: eg cefoperazone, cefsulodin, ceftazidine. High activity against Pseudomonasspp.
  • Group IV (cephamycins): eg cefoxitin, moxolactam, cefmetazole. None licenced for veterinary use. Good for Bacteroidesspp; NOT Pseudomonasspp except for moxolactam.

Toxicity

• Generally very safe.
• Can have acute anaphylaxis or mild hypersensitivity.
• Painful on IM injection.
• Nephrotoxicity at high doses, especially cephaloridine.
• Some cause bleeding problems due to interference with vitamin K in gut, especially moxolactam.

Beta-lactamase inhibitors

1. Clavulanic acid

• With amoxycillin to give 'Synulox'. With ticarillin to give 'Timentin'.
• Inhibits all beta-lactamases except cephalosporinases.
• Weak alone, but widens spectrum of other penicillins.
• Pharmacokinetics - match penicillin family.

2. Sulbactam

• Synthetic enzyme inhibitor.
• Broader spectrum than clavulanic acid. Less potent.

3. Carbapenems

• Human medicine, eg imipenem.
• Not well documented for veterinary use.

Spectrum of activity

• Almost all clinically important aerobes and anaerobes, (gram-positive and gram-negative).
• Some resistance starting to develop.

Pharmacokinetics

• Injectable only.
• Wider distribution in body than penicillins.
• Renal elimination - hydrolyzed by tubular brush border enzyme.
• Given with inhibitor of renal enzyme (cilastatin)   high urine concentrations of active drug

Other cell wall antibacterials

1. Glycopeptides

• Vancomycin, teicoplanin.
• Bactericidal.
• Possible indications: Clostridium perfringensenteritis, methicillin resistant staphylococcal mastitis?

Spectrum of activity

• Gram-positive bacteria only.
• Excellent against staphylococci.
• Resistance rare.

Pharmakokinetics

• No oral absorption.
• Poor tissue penetration.
• Half-life in dog: vancomycin - 2 hours; teicoplanin - much longer.
• Renal excretion.

Toxicity

• Highly irritant to tissues, (give vancomycin by IV administration only).
• Ototoxic in man.
• Nephrotoxic.
• Teicoplanin given IM.

2. Bacitracin

• Bactericidal.
• Indication: topical treatment of superficial skin and mucosal infections, (with polymixin B to give broad spectrum); growth promoter in cattle and pigs; Clostridium perfringensenteritis.

Spectrum of activity

• Gram-positive bacteria only.
• Resistance is rare.

Pharmacokinetics

• Not absorbed orally.

Toxicity

• Highly toxic parenterally - nephrotoxic.

Antimicrobial agents which target the cell membrane

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• Polymixin B and polymixin E, (colistin).
• Rapidly bactericidal.
• Topical for bovine mastitis due to Pseudomonas aeruginosa, Klebsiellaspp.
• Topical for otitis externa, eye infections, uterine infections due to P. aeruginosa, Klebsiellaspp.
• Oral for gram-negative enteritis (calves and piglets), Salmonellaspp, E. coli.

• Highly active against many gram-negative bacteria including P. aeruginosa, (resistance rare).
• NOT gram-positive bacteria (resistant).
• Inhibited by divalent cations, eg Ca++, and pus.
• Potentiated by chelating agents, eg EDTA, and cationic detergents, eg chlorhexidine .
• Synergistic with many other antibacterials.
• Cross-resistance complete between polymixins but not with other antibiotics.

• Parenteral route (IM), for systemic therapy.
• Little/no gastrointestinal tract absorption.
• Crosses membranes poorly.
• Binds to cell membranes   accumulates with long-term dosing.
• Renal excretion: unchanged   accumulated in renal disease.

• Well tolerated orally and topically.
• Systemic use   nephrotoxicity (especially dogs), neurotoxicity and neuromuscular blocking in man.
• Colistin less toxic than polymixin B.
• Pain and tissue necrosis at injection site if use sulphate salt.
• Methane sulfonate salt of colistin is most suitable for parenteral administration.

Nucleic acid synthesis and repair inhibitors

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1. The 4-quinolones

Fluoroquinolones

• Examples: enrofloxacin ('Baytril')  , marbofloxacin ('Marbocyl')  , danofloxacin.
• In humans: ciprofloxacin, norfloxacin.
• Should be reserved for resistant gram-negative infections in difficult site.
• Used if white blood cell count falls dangerously low due to chemotherapy.

Spectrum of activity

• Gram-negative aerobes including some Pseudomonas aeruginosa.
• Gram-positive aerobes, but not good for streptococci, enterococci.
• Mycoplasmaspp and Rickettsiaspp.
• Anaerobic activity is weak.
• pH dependent: poor atpH 7.4.
• Active at very low concentrations. Close relation between minimal inhibitory concentration and minimal bactericidal concentration.
• Bactericidal effect dependent on concentration rather than time.
• Spare protective intestinal enterococci and anaerobes.
• Low (but increasing frequency), mutational resistance. No plasmid-mediated resistance yet.
• Inhibit aminoglycoside and beta-lactam resistant bacteria.
• Do not select high-degree, cross-resistant isolates.

Pharmacokinetics

• Highly lipophilic, low degree of ionisation.
• Well absorbed from gastrointestinal tract, (variable).
• Low plasma protein binding - wide distribution in extracellular and transcellular fluids, (including cerebrospinal fluid, prostatic fluid).
• High intracellular concentrations   effective against intracellular organisms.
• Excreted in bile and urine (70:30). Some active metabolites.
• Urine concentrations high and for 24 hours after single dose.
• High concentrations in lungs and lung fluids.

Toxicity

• Erosion of articular cartilage in young growing dogs, (different species susceptibilities).
• Minor central nervous system problems in man: nausea, vomiting, headache.
• May predispose to seizures in epileptics, especially with IV injection on high dose.

• A product of Streptomyces.
• A coumarin antibiotic. A dibasic acid.

Spectrum of activity

• Narrow, mostly gram-positive bacteria.
• Very active against Staphyloccus aureus. Less so against streptococci and fastidious gram-negative bacteria, ( Haemophilus, Brucella).
• Least active against Enterobacteriaceae, Pseudomonasspp.
• Synergistic with penicillin G for staphylococci and streptococci.

Pharmacokinetics

• No systemic use in veterinary medicine.

Toxicity

• Skin eruptions.

• Product of Streptomyces mediterranei.
• First line oral treatment for tuberculosis in man.
• Can kill quiescent intracellular organisms.
• Used for macrophage-associated bacteria, eg Brucella, R. equi, Corynebacterium pseudotuberculosis, intracellular Staphyloccus aureus, (bovine mastitis).

Spectrum of activity

• Many microorganisms: bacteria, Chlamydia, protozoa, fungi, poxviruses.
• Narrow antibacterial spectrum: gram-positive mainly, Mycobacteriumspp.
• The most active drug known for staphylococci, (<0.002 ul effective).
• Gram-negative resistant, except fastidious bacteria ( Haemophilus, Brucella).
• Inhibits gram-negative and gram-positive bacteria at low concentrations.
• Ready development of high level resistance due to bacterial chromosomal mutation. NEVER use alone.

Pharmacokinetics

• Highly lipophilic, zwitterion, MW 822.
• Gastrointestinal tract absorption: high bioavailability in dogs, lower in horses.
• Rapid diffusion into tissues   concentration greater than serum.
• Cell penetration excellent.
• Poor central nervous system penetration, (improves with inflammation).
• Elimination via hepatic metabolism.

Toxicity

• Pain on IM injection - give orally to foals.
• Orange urine.
• May be teratogenic.
• Potential to cause hepatotoxicity.
• Induces hepatic enzymes   may enhance drug clearance by liver.

• Examples: nitrofurazone, nitrofurantoin, nifuratel, furazolidone.
• Synthetic derivatives of 5-nitrofuraldehyde.

Spectrum of activity

• Broad-spectrum antimicrobial - bacteria, some protozoa, some fungi.
• Bactericidal at concentration just above minimum inhibitory concentration.
• Gram-positive staphylococci, streptococci, many Corynebacteriumspp.
• Gram-negative bacteria ( E. coli, Klebsiella, Salmonella), usually sensitive. NOT Proteus, Pseudomonas.
• Resistance is chromosomal - intracellular reductase enzymes, permeability barrier.
• Sensitivity testing done with disks with concentration applicable to urinary tract   may be more resistance than apparent.

Pharmacokinetics

• Nitrofurantoin, nitrofurantel - well absorbed orally   rapid renal excretion   short half-life   blood and tissue concentrations too low for systemic treatment.
• May be used in urinary tract infections in dogs.
• Nitrofurazone, furazolidone - not absorbed orally   used for enteric infections ( Salmonella, E. coli), in farm animals, and topically for skin infections.

Toxicity

• Central nervous system - neurotoxicity.
• Bleeding problems, (fatal hemorrhage on long-term therapy in calves).
• Cardiotoxicity in poultry.
• Mutagenic and procarcinogenic - prohibited in food animals in some countries.

• Examples: metronidazole  , dimetronidazole, ronidazole, tinidazole, ipronidazole.
• Heterocyclic compounds similar to nitrofurans.
• Form unstable products which form inside bacterial walls under anaerobic conditions.
• Anaerobic infections in dogs and cats.
• Metronidazole and aminoglycoside together used in humans for intestinal spillage peritonitis.

Spectrum of activity

• All anaerobic gram-negative and gram-positive bacteria, anaerobic protozoa.
• Highly active against Treponema hyodysenteriae, Trichomonas fetus, Histomonasspp, Giardiaspp.
• Anaerobic resistance rare, (involves decreased intracellular activation of drug).

Pharmacokinetics

• Lipid soluble, small.
• Metronidazole well absorbed from gastrointestinal tract.
• Tissue penetration excellent, including brain, cerebrospinal fluid.
• Hepatic metabolism to less active forms. Two-thirds dose excreted in urine.

Toxicity

• Metronidazole can cause necrosis at injection site, (IM or SC).
• Neurologic signs at high doses, (cerebellar ataxia).
• Possibly teratogenic - avoid use in pregnancy.

• Derivatives of sulfanilamide.
• Various physiochemical and pharmacokinetic properties.
• Bacteriostatic alone.
• Replaced by trimethoprim combination.
• Used in food animals for foot rot, enteric diseases, calf diphtheria.
• Anticoccidial agent in dogs and cats, (sulfadimetroxine).
• With pyrimethamine for toxoplasmosis.

Spectrum of activity

• Broad spectrum: many aerobic, gram-positive cocci, some gram-positive rods, many gram-negative rods including Enterobacteriaceae.
• Moderate anaerobic spectrum.
• Widespread plasmid-mediated resistance in domestic animals.
• Antagonized by drugs with PABA nucleus.

Pharmacokinetics

• Weak acids, varying pKa.
• Most absorbed from gastrointestinal tract.
• Non-ionised form diffuses well across cell membranes. Penetrates tissue well.
• Present in high concentration at normal pH.
• Plasma protein binding 20-90%, varying with individual drug.
• Eliminated via combination of renal excretion and hepatic metabolism ? interspecies variation in half-lifes.
• Filtered at glomerulus, active secretion in proximal tubule, passive resorption from acid urine.
• Hepatic acetylation occurs in all domestic animals except dogs. Also, aromatic hydroxylation, gluconuride conjugation.

Toxicity

• Renal tubular damage due to precipitation in acidic urine.
• Polyarthropathy and fever in Dobermann.
• Keratoconjunctivitis sicca may be seen after weeks to months of medication in dogs.
• Blood dyscrasias (immune thrombocytopenia, hemolytic anemia), skin eruptions and liver toxicity can be seen as idiosyncratic adverse reactions.

• Examples: trimethoprim, baquiloprim (veterinary only), ormetoprim.
• Dihydrofolate reductase inhibitors.
• Weak bases, pKa 7.6.
• Bacteriostatic.
• Used alone in human medicine for urinary tract infections. Drug of choice for prostatic infections caused by gram-negative bacteria.

Spectrum of activity

• Gram-positive and gram-negative aerobes.
• NOT anaerobes, Psuedomonasspp.
• Inhibited by necrotic tissue.
• Increasing resistance in Enterobacteriaceae.

Pharmacokinetics

• Weak base, lipophilic, low MW.
• Well absorbed from gastrointestinal tract, wide distribution.
• Prostatic concentrations 10x plasma concentrations.
• High concentration in acidic fluids.
• Elimination via hepatic metabolism.
• Species variation in half-life and fraction excreted in urine trimethoprim,<3 hours most species, (man 10.6).
• Baquiloprim half-life more suited to domestic species.

Toxicity

• Relatively non-toxic.
• High doses   folic acid deficiency.
• Excessive salivation in cats.

Potentiated sulfonamides

• Examples: sulfadoxine/trimethoprim; sulfadiazine/trimethoprim; sulfatroxazole/trimethoprim; sulfamethoxazole/trimethoprim (human generic); sulfadimidine baquiloprim (cattle); sulfadimethoxine/baquiloprim (dogs).
• Bactericidal.
• Broad spectrum, good tissue penetration.
• Both penetrate blood brain barrier, (coliform meningitis - farm animals).
• Urinary tract infections, intestinal infections (Enterobacteriaceae), especially Salmonellaspp.

Spectrum of activity

• Wide range of organisms. NOT Pseudomonasspp.
• Synergism occurs when microorganism sensitive to both drugs, and still occurs when resistant to sulfonamides.
• Multiple resistant R factors, eg in Salmonellaspp and enterotoxigenic E. coli.

Pharmacokinetics

• Trimethoprim half-life short.
• Sulfadiazine has short half-life in many species.
• Half-lives of baquiloprim and sulfadimidine matched in many species (except dog). Cattle bolus release lasts 5 days.
• Inter-species variation due to extent of plasma protein binding, hepatic metabolism, renal excretion (urinary pH).
• Short acting , (rapid absorption, rapid excretion):
  • Sulfadiazine, sulfamerazine, sulfapyridine (all pKa 6.4) - combine as 'triple sulpha'.
  • Sulfamethoxazole, sulfadimidine, sulfamethazine, sulfafurazole (all pKa 7.4) - short half-life, but very soluble in urine.
  • Sulfathiazole (7.3) - short half-life. Coccidiosis in poultry.
• Intermediate acting , (rapid absorption, rapid excretion): sulfamethoxypyridazine, sulfadimethoxine - longer half-life.
• Long acting : sulfadoxine (6.1) - tubular resorption, extensive PPB - very long half-life.
• Gastrointestinal , (poorly absorbed):
  • Succinylsulfathiazole (4.5),<5% gastrointestinal absorption. Lumen activation to sulfathiazol.
  • Phthalylsulfathiazole - as above. Preoperative sterilization of colon - laxatives interfere with action.
• Topical preparations :
  • Sulfanilimide (10.4) - dusting powder.
  • Sulfacetamide (5.4) - aqueous solution on Na salt is nearly neutral - suitable for eye.
• Special : sulfasalazine - broken down to 5-aminosalycilates and sulfapyridine by colonic anaerobes - used to treat canine chronic colitis. Can cause keratoconjunctivitis sicca.

Toxicity

• Safe in most dogs and cats, but high incidence of idiosyncratic toxicity in dogs in comparison to other antibiotics.

Drugs which inhibit protein synthesis

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• Chloramphenicol .
• Dichloracetic acid derivative.
• From actinomycete.
• Simple molecule, produced synthetically.
• Bacteriostatic.
• Use restricted in USA. (Human side-effects - keep out of food chain.)
• Banned for food producing animals in EC.
• In UK, reserved for Salmonella typhiinfections in man.
• BSAVA/RCVS guideline: use should be restricted to local treatment of serious eye infections and systemic infections where clinical and laboratory assessment show no safer antibiotic.

• Broad spectrum.
• Most gram-positive and many gram-negative bacteria, all anaerobes.
• Rickettsiaspp, Chlamydiaspp, Haemobartonella.
• Resistance: plasmid-mediated.

• Lipid soluble, neutral, low MW.
• Well absorbed from gastrointestinal tract, good tissue penetration, good cellular penetration.
• Eliminated by hepatic metabolism - gluconuride conjugation   urine or bile.
• Half-life varies with species and age.

• Fatal aplastic anemia in man, (1/25000-60000).
• Reversible suppression of hematopoiesis with high doses in cats.
• Inhibits mixed function oxidaze enzymes - irreversible   long lasting effect.
• IV dosing   myocardial depression.
• Gastrointestinal irritation after oral dosing dogs and cats.

• Analogues of chloramphenicol. Similar activity, may be less broad spectrum.
• No conjugation - excreted unchanged in urine.
• May be lower frequency aplastic anemia in man.
• Florfenicol licenced for respiratory disease in calves in UK.
• Tetracyclines .
• Amphoteric substances, share same structure.
• Bacteriostatic.
• Avoid in horse by any route.
• Low cost.
• Drug of choice for Rickettsiaspp, Chlamydiaspp, Borrelia, Ehrlichia, Haemobartonella, Mycoplasma.

• Broad-spectrum antimicrobial agent.
• Most gram-positive bacteria. NOT enterococci, group D streptococci.
• Non-enteric, gram-negative bacteria. NOT Enterobacteriaceae, Pseudomonasspp.
• Chlamydiaspp, Rickettsiaspp, Mycoplasmaspp.
• Resistance: widespread, plasmid-mediated.
• All tetracyclines have equal antimicrobial activity in vitro.

• Absorbed form gastrointestinal tract in monogastrics.
• Food decreases absorption except very lipid soluble forms.
• Penetrate most body compartments - not cerebrospinal fluid (except doxycycline).
• 'Water soluble' compounds excreted unchanged in bile, urine.
• Doxycycline, minocycline are most lipid soluble.
• Minocycline undergoes some metabolism before excretion.
• Absorption impaired by divalent cations, (aluminium, calcium, iron, etc).

• Deposited in developing bones and teeth   enamel discoloration.
• Injectables irritate tissue, especially long-acting formulations.
• Oral administration can   gastrointestinal upset. Colitis X in horse.
• IV injection can   collapse.
• Nephrotoxic in several species, (dose related).
• Outdated tetracyclines are especially nephrotoxic.

• Polar organic bases.
• Examples: aminoglycosides - streptomycin, kanamycin, gentamicin, tobramycin, amikacin, neomycin (framycetin).
• Examples: aminocyclitols - apramycin, spectinomycin, (rarely used in veterinary medium).

• Much less active in purulent material.
• Local acidity of tissues markedly reduces efficacy.
• Gram-negative aerobes. Limited against gram-positive aerobes.
• Some Mycoplasmaspp, mycobacteria.
• Anaerobes resistant.
• Streptomycin - least active. Some staphylococci and mycobacteria. Resistance widespread; plasmid-mediated, often multiple plasmids.
• Neomycin - more active than streptomycin. Same activity as kanamycin - less activity than rest. Good for Staphylococcus aureus, poor for other gram-positive cocci. Active for many gram-negative opportunists including Pseudomonasspp. Resistance common - enteric commensals, plasmid-mediated, often multiple.
• Kanamycin - potency as for neomycin, plus some mycobacteria and mycoplasmas - NOT Pseudomonasspp. Plasmid-mediated resistance - cross-resistance with neomycin. One way cross-resistance with streptomycin.
• Gentamicin - most potent and broad spectrum. Good for Pseudomonasspp and other gram-negative rods - also gram-positive cocci. Resistance uncommon in veterinary pathogens. Common in human hospitals, plasmid-mediated.
• Tobramycin - more active than kanamycin. Resembles gentamicin except is more active against Pseudomonasspp. Resistance - fewer plasmids than gentamicin in humans.
• Amikacin - activity greater than kanamycin - less than gentamicin and tobramycin. Resistant to most enzymes produced by bacteria, including those which inactivate gentamicin and tobramycin.
• Apramycin - active against gram-negative bacteria, as well as Staphylococcus aureus, many streptococci, Treponema hyodysenteraeand some mycoplasmas (not fully researched yet). Resistance rare in gram-negative bacteria - good for E. coli, Salmonella spp.
• Spectinomycin - limited gram-positive activity - better gram-negative and mycoplasmas. Resistance widespread in enteric bacteria - plasmid-mediated, cross-resistance with streptomycin.

• Poor gastrointestinal tract absorption due to basic charge and polar nature.
• Do not cross cellular barriers readily, but bind selectively to renal tissue (bound residue).
• Eliminated unchanged by rapid renal excretion   half-life of 1-2 hours.
• Reduce dose or avoid in renal insufficiency.

• Varying degrees of ototoxicity - cochlear (C) or vestibular (V) - plus nephrotoxicity (N).
• Can cause non-depolarizing neuromuscular junction (NMJ) block   acute paralysis. Cardiovascular collapse after IV administration.
• Streptomycin - toxic in cats. N+, C++, V+++, NMJ block after anesthetic.
• Neomycin - most toxic of all, never given parenterally. N+++, C+++, V+.
• Kanamycin - safer than neomycin parenterally. N++, C++, V+.
• Gentamicin - nephrotoxicity - limits therapy to 7 days. N++, C+, V++.
• Tobramycin - least toxic of all. N+, C+, V+.
• Amikacin - N++, C+, V+.

• Structurally distinct but share many properties, (mechanism of action, pK).

• Macrolides = macrocyclic lactones.
• Examples - erythromycin  , tylosin, spiramycin, tilmicosin, (new for veterinary use).
• Tiamulin is a semi-synthetic derivative of pleuromutilin antibiotic.

• Bacteriostatic.
• Gram-positive cocci, particularly streptococci and staphylococci, the more fastidious gram-negative bacteria.
• All anaerobes - some Mycoplasmaspp, Chlamydiaspp, Rickettsiaspp.
• Plasmid-mediated resistance common  cross-resistance between the groups.
• Staphylococci and streptococci less resistant to erythromycin than lincomycin.
• Mycoplasmaspp resistance to tiamulin, tylosin.

• Weak bases, highly lipid soluble.
• Good gastrointestinal tract absorption in monogastrics. Very large volume of distribution.
• Drugs trapped in tissues where pH is less than blood.
• Spiramycin concentration in tissues   long withdrawal times.
• Tilmicosin provides effect lung levels against Pasteurellaspp for 4 days.
• Levels not adequate in cerebrospinal fluid.
• Hepatic metabolism.

• Local irritation.
• Dose-related gastrointestinal upset - serious in adult horses.
• Potential drug interactions with erythromycin due to inhibition of cytochrome P450 enzymes.
• Tylosin, tiamulin, tilmicosin - NOT in horses.
• Tilmicosin - NOT in pigs.
• Tiamulin can be fatal if fed in therapeutic doses with ionophore growth promoters.

• Monoglycosides.
• Examples - lincomycin, clindamycin.

• Bacteriostatic.
• Gram-positive bacteria, anaerobes, Mycoplasmaspp.
• High activity against anaerobes - except some Clostridiumspp.
• Clindamycin activity several times more potent than lincomycin.
• Plasmid-mediated resistance - complete between groups, except resistance to staphylococci and streptococci more common with lincomycin than erythromycin.

• Weak bases, highly lipid soluble.
• Good gastrointestinal tract absorption in monogastrics. Large volume of distribution.
• Cerebrospinal fluid levels inadequate.
• Hepatic metabolism.

• Transient vomiting and diarrhea may occur after oral administration.
• Contraindicated for use in horses, rabbits, herbivores.
• IV administration can  NMJ blockade and cardiodepression.

Antifungal drugs

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• Difficult to achieve selective fungal toxicity as yeasts and fungi are eucaryotic cells.
• In UK, topical agents are often suitable and effective.
• Toxic antifungals can be used in mastitis and otitis as long as they are not absorbed, eg monosulphiram.

• Fungicidal.
• Bind to ergosterol, (fungal equivalent of cholesterol)  disrupt fungal cytoplasmic membrane.

• Topical.
• Active against wide range of filamentous and dimorphic fungi and yeasts.
• Yeast mastitis: ringworm in cattle and horses, fungal ear and eye infections, nasal aspergillosis in horse.

• Topical.
• Candidaspp, Pityrosporumspp and Cryptococcusspp dermatophytes. Some filamentous and dimorphic fungi.

• Topical and systemic.
• Broad-spectrum, fungicidal against many systemic mycoses.
• Aspergillusspp often resistant.
• Gastrointestinal tract absorption negligible.
• IV   binds to lipoproteins (cell, plasma)   slow release.
• Synergistic with flucytosine, rifampin for certain organisms. Antagonistic sometimes with ketoconazole.
• Always nephrotoxic in dog and cat. Liposome-encapsulated amphotericin B much less nephrotoxic.

• Interfere with biosynthesis of ergosterol.
• Fungistatic.
• Broad spectrum.

• Topical.
• Yeast mastitis in cows - approximately 100% susceptible. Mycotic keratitis in horses.
• Intranasal topical treatment of nasal aspergillosis.

• Mostly topical.
• Poor gastrointestinal tract absorption - give IV for systemic infections.

• Good gastrointestinal absorption in dogs - give with food.
• Hepatic metabolism   inactive compounds   bile.
• Low toxicity: inappetence, pruritus, alopecia, reversible lightening of hair.
• Higher doses   severe hepatitis.
• Interferes with mammalian adrenal and gonadal steroid synthesis - alternative treatment for Cushing's disease (hyperadrenocorticism  ).
• Teratogenic, embryotoxic.
• Treatment of systemic mycoses in conjunction with amphotericin B; ringworm in dogs and cats nasal aspergillosis .

• Antibiotic product of Penicillium griseofulvum.
• Fungistatic.
• Disorganizes mitotic spindle microtubules.
• Narrow spectrum; dermatophytes only.
• Oral absorption depends on particle size and varies with formulation.
• Hepatic metabolism - half-life 6 hours in dog.
• Deposited in newly formed keratin of hair, nails and skin - moves superficially where dermatophytes reside. Slow treatment (weeks to months).
• May cause neutropenia, hepatotoxicity.
• Teratogenic.

• Imidazole.
• More potent, less toxic than ketaconazole.
• Hepatopathic vascultis of footpads, possible side effects.
• Oral treatment of systemic mycoses, ( Blastomyces, Coccidiomycosisetc).

• Fluorinated.
• Fluorinated pyrimidine   enters fungal cell   5-fluorouracil   disrupts mRNA.
• Narrow spectrum - mainly Candidaspp, Cryptococcus neoformans.
• Fungicidal at 5 times minimum inhibitory concentration.
• Synergistic with amphotericin B - causes enhanced cell entry of flucytosine.
• Good gastrointestinal tract absorption - good tissue penetration including cerebrospinal fluid.
• Well tolerated in cat for treatment of cryptococcosis .

Sources

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• Recent references from PubMed.
• Grave K & Tanem H (1999) Compliance with short-term oral antibacterial drug treatment in dogs. JSAP 40 (4), 158-162.

• J M Escala DVM MVM MRCVS , Pharmacia & Upjohn Ltd, Fleming Way, Crawley, West Sussex RH10 2LZ, UK. Tel: +44 (0)1293 582444; Fax: +44 (0)1293 537800.
• Maggie Fisher BVetMed CBiol MIBiol MRCVS , Brentknoll Veterinary Center, 152 Bath Road, Worcester WR5 3EP, UK.
• Dr Lauren Trepanier , Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive West, Madison, WI 53706-1102, USA.

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