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Veterinary Antimicrobial Drugs

WJ Brad Hanna, DVM, PhD, Department of Biomedical Sciences, University of Guelph

Antimicrobials are among the most commonly-used drugs in veterinary medicine. Of thetremendous number available to practitioners, most fit into five major drug families: the betalactams (which include the penicillins and cephalosporins), the aminoglycosides, the

tetracyclines, the fluoroquinolones, and the sulfonamides. Other antimicrobials (e.g.macrolides, lincosamides, etc.) are used less often but may be indicated in specific situations.

Some definitions with which you should be familiar:

“ Antimicrobial: A chemical of any origin that, at low doses, is toxic to microbes.“ Antibiotic: An antimicrobial produced by a microorganism.“ Bacteriostatic: A chemical that stops the replication of bacteria.“ Bactericidal: A chemical that kills bacteria.“ MIC (Minimum inhibitory concentration) : The lowest concentration of an

antimicrobial drug that will prevent the growth & replication of a microbe.“ MBC (Minimum bactericidal concentration) : The lowest concentration of an

antimicrobial drug that will kill bacteria.

General mechanisms of action of antimicrobial drugs:

1) Disruption of cell wall synthesis:These drugs bind to certain protein components of the cell wall as it is being assembled,resulting in a defective or incomplete cell wall.- most effective early in an infection when during the rapid growth phase- work best against gram positive bacteria that have a thick cell wall (the gram negative cell wallis thinner but more complex)

- generally bactericidal- Examples: Penicillins: e.g. penicillin G, ampicillin, amoxicillin, cloxacillin Cephalosporins: e.g.

1st generation: e.g. cefazolin, cephalexin2nd generation: e.g. cefaclor, cefoxitin3rd generation: e.g. cefotaxime, ceftiofur

Bacitracin

2) Damage to cell membrane (or decreased production of cell membrane):These are surface-active agents that act like detergents to disrupt the lipid bilayer of bacterialmembranes. Gram negative bacteria are far more sensitive than gram positives.- generally bactericidal (or fungicidal)- Examples:

Polymyxins: e.g. Polymyxin B (topical) - these affect bacterial cell membranes Azoles: e.g. ketoconazole, itraconazole - these affect fungal cell membranes

3) Inhibition of nucleic acid synthesis (or damage to DNA/RNA):By binding to various enzymes, these drugs inhibit folic acid synthesis which is needed fornucleic acid formation.- generally bactericidal- Examples:

Last updated Mar 8, 2002



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Rifampin: inhibits RNA synthesis Fluoroquinolones: e.g. enrofloxacin, orbifloxacin - inhibit DNA supercoiling Metronidazole: organism metabolizes drug into reactive radical which damages DNA Nitofurans: e.g. nitrofurantoin - mechanism of action unknown

Sulfonamides: resemble PABA, a substrate needed for nucleic acid synthesis- compete with PABA for enzymes needed for DNA & RNA synthesis- bacteriostatic

Trimethoprim: also bacteriostatic

- the combination of trimethoprim & a sulphonamide is generally bactericidal Dapsone: similar to PABA, works like sulfonamides

4) Inhibition of protein synthesis:This is usually the result of the drug binding to bacterial ribosomes.- generally bacteriostatic- Examples:

Aminoglycosides (bactericidal )e.g. gentamycin, amikacin, neomycin, streptomycin, spectinomycin(bind bacterial ribosomes misreading of mRNA non-functional proteins)

Tetracyclines: e.g. oxytetracycline, doxycycline, tetracycline HCl(bind irreversibly to bacterial ribosomes stop protein synthesis)

Macrolides: e.g. erythromycin, tilmicosin, tylosin(bind to ribosomes stop protein synthesis) Chloramphenicol - binds irreversibly to bacterial ribosomes stops protein synthesis Aminocyclitols & Lincosamides* e.g. spectinomycin, lincomycin*, clindamycin*

(bind to ribosomes stop protein synthesis)

Important!Resistance to antimicrobial drugs is a world-wide problem. All health professions have contributed tothe development of resistant bacteria through the excessive and/or inappropriate use of antimicrobials.In the 1990s Ontario physicians were singled out in the media and scientific literature as being especiallyirresponsible, particularly regarding their use of fluoroquinolones. Fortunately, the situation is improvingand physicians are now less likely to prescribe fluoroquinolones in particular, and second- and third-line

drugs in general, in situations where older, first-line drugs, or perhaps nothing, is indicated. Some recentscientific surveys indicate that a significant proportion of Canadian veterinarians prescribe second- andthird-line antimicrobial drugs indiscriminately. If we do not use these drugs prudently, we leave thereputation of our profession, as well as the health of our patients and clients, at risk.



General Properties of Major Classes of Antimicrobial Drugs

Major Drug FamiliesMechanism of

actionGeneral antimicrobial activity*

Route ofelimination

Majoradverseeffects

Use forfood

animals?

First line?

Gram + Gram - Anaerobes Mycoplasma Chlamydia Rickettsia

Beta-lactams inhibit cell wallassembly

+/- kidney hyper-sensitivity

OK mostpenicillins

1st gencephalo-sporins

Aminoglycosides inhibit p roteinsynthesis

+/- none kidney nephro-toxicity

Avoid(Voluntary

off-label”ban® in

foodanimals)

genta-micin

Tetracyclines inhibit proteinsynthesis

+/- kidney &liver

several OK most

Trimethoprim +Sulfonamides

inhibitDNA/RNAsynthesis

no no kidney KCS OK most

Fluoroquinolones damage DNA +/- none kidney &liver

cartilagelesions

Avoid none

Others:

Chloramphenicol inhibits proteinsynthesis

+/- liver idio-syncraticaplastic

anemia in

humans

BANNED yes

Erythromycin inhibits proteinsynthesis

Campylo-bacter

liver pain / irritation

OK (e.g.bovineintra-

mammaryinfusion)

2nd due topain

* Development of resistance over time can change this.

We need to continue the on-going process of improving and fine-tuning prudent use guidelines in companion animal practice, so that we avoid creating resistance problems.As a simple example, the Angell Memorial Animal Hospital (USA) has 3 categories of antimicrobial drug use:First line: empirical use: (no pending culture & susceptibility results needed): amoxicillin with or without clavulanic acid; 1st generation cephalosporins; trimethoprim-sulphamethazine; tetracyclinSecond line: to be used only when justified by culture and susceptibility results: amikacin, 2nd and 3rd generation cephalosporins, fluoroquinolones, lincosamides, oxacillinLast resort: use not justifiable, or possibly only by culture and susceptibility results and in consultation with named infectious disease specialists: vancomycin, imipenem-cilastasin(from Prescott, Hanna, Reid-Smith & Drost, Canadian Veterinary Journal 2002, 43:107-116)



Last updated Mar 1, 2002



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Beta-lactam AntimicrobialsThe beta-lactams, which include the penicillins and cephalosporins, are among the most commonly usedantimicrobials in veterinary and human medicine. All beta-lactams contain a common structure known asthe ”beta-lactam ring®, which is essential for their bactericidal action but is also rather unstable. Becauseof this instability, some beta-lactams, such as penicillin G sodium, are sold as a powder that must be

mixed just prior to administration, and those sold in liquid form, such as penicillin G procaine, must beprotected from heat and from freezing (remember this if you will be transporting drugs in your vehicle, asin large animal practice).

The PenicillinsPenicillin G was the first antibiotic discovered (1928). It is generally safe, effective, and cheap. Manyforms are available, including the narrow-spectrum but highly effective penicillin G, a few penicillinaseresistant forms (e.g. methicillin, cloxacillin), and some ”broad-spectrum® types (e.g. ampicillin,carbenicillin). The list is long and new types are synthesized each year. Penicillin G procaine (an

injectable) is probably the most commonly used antimicrobial in large animal practice, and amoxicillin(oral tablet form) is one of the most widely used in small animal practice.

Mechanism of action:- bactericidal to growing cells- prevention of cell wall formation

Spectrum of Activity:Penicillin G- excellent activity against non resistant gram positive bacteria but is effective against only a smallnumber of gram negative bacteria- newer derivatives have been designed for greater effectiveness against resistant organisms:

Penicillinase Stable (antistaphylococcal) Penicillins (cloxacillin)- good activity against penicillinase-producing Staphylococcus aureus, but less effective than penicillin Gagainst other bacteria

Broad-spectrum Penicillins (ampicillin, amoxicillin)- much more effective against gram negative bacteria than penicillin G, but slightly less active againstgram positive and anaerobic bacteria and their effectiveness has been reduced due to acquiredresistance by many gram negative bacteria- inactivated by beta-lactamases produced by many bacteria- the effectiveness of ampicillin and amoxicillin, however, has been improved by the combination of thesedrugs with beta-lactamase inhibiting chemicals such as clavulanic acid or sulbactam:

small animal: amoxicillin + clavulanic acid = Clavamox½

large animal: ampicillin + sulbactam = Synergistin½

Antipseudomonal penicillins (piperacillin)- can penetrate outer cell wall of Pseudomonas spp. and other gram negative bacteria- less effective against gram positive bacteria



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Potentiated penicillins:A potentiated penicillin is the combination of a penicillin with a penicillinase inhibitor.There are two on the market that are labelled for veterinary use:Small animal: Clavamox½: amoxicillin + clavulanic acid- sold for oral administration (tablets or liquid)- clavulanic acid is the penicillinase inhibitor - renders most beta-lactamase-producing bacteriasusceptible to amoxicillin, making the combination useful for a wide variety of infections (UTI, URT, LRT,

skin)Beta lactamase is the major resistance factor against amoxicillin and ampicillin, which is why clavulanicacid in combination with amoxicillin is so effective against beta-lactamase-producing strainsLarge animal: Synergistin½: sulbactam + ampicillin- for IM injection- labelled for bovine respiratory disease only- contraindicated in horses (diarrhea)- used less and less due to resistance

Major properties of selected penicillins

Drug Destroyed bypenicillinase?

Acid stable fororal use?

Oralabsorption?

General efficacy

Penicillin G yes no variable Strep., Staph., Neisseria,other gram positive(POOR: gram negative)

AmpicillinAmoxicillin

yes yes good(amoxicillin>90%)

above plus:HaemophilusE coliProteus

Cloxacillin no yes good Mainly Staph aureus

AdministrationIntravenous:- water soluble penicillin salts (mainly Na+ salts - Na+ penicillin G)- 100% bioavailability, but leave tissues quickly & therefore have a shorter half-life- may require several injections/day- often the most expensive penicillinsIntramuscular and subcutaneous:- "depot" forms, e.g. procaine penicillin G ("white penicillin") & benzathine penicillin G ("pink penicillin®)- not very water soluble, remain with injection vehicle resulting in slow release from injection site- procaine penicillin G may require only 1 or 2 injections/day- benzathine penicillin G may require administration only every few days, but probably never reachestherapeutic levels and therefore should not be used

Oral:- penicillin G is not acid-stable & therefore is not given orally- of the acid-resistant, oral penicillins, amoxicillin has the highest bioavailability (>90%); others usually~40 - 60% available- ruminants: penicillins are destroyed in rumen (OK for pre-ruminant calves)- absorbed best on empty stomach (except amoxicillin which is unaffected by food)



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Intramammary:- anti-staphylococcal penicillins- cloxacillin is the only one labelled for use in veterinary medicine and comes in a form for bovineintramammary use (cloxacillin sodium for lactating cows; cloxacillin benzathine for dry cows only)- some veterinarians use human-labelled cloxacillin, oxacillin, dicloxacillin (etc.) tablets for chronicpyodermas in small animals

Distribution- distributes well to all tissues except CNS & CSF (unless inflamed - can then cross damaged blood-brainbarrier)

Elimination- via kidney- urine levels can be much higher than plasma levels, therefore good for treating urinary tract infections(penicillins are passively filtered but also actively pumped into the urine; cephalosporins are eliminated via thesame pump in the kidney; therefore concurrent administration of penicillins and cephalosporins increases the half-lives and plasma levels of both drugs)

- IV half-life: ’ to 1 hr

Resistance- common:(1) Penicillins cannot penetrate the complex cell wall of gram negative bacteria, and are thereforeineffective against gram negative bacteria(2) Some bacteria (especially Staphylococci) produce penicillinase which cleaves the penicillinbeta-lactam ring, destroying its activity- because penicillinases are plasmid-encoded, they can be transferred to other bacteria- bacterial penicillinase enzymes can be inactivated by inhibitors such as clavulanic acid or sulbactam,which bind irreversibly to penicillinase- due to their modified chemical structure (in which the beta-lactam ring is protected), penicillins likecloxacillin and oxacillin are "penicillinase-resistant penicillins" which can be used against Staphylococci,esp. in bovine Staph. mastitis (sodium or benzathine forms; see above)

Main Potential Adverse Effects1) Hypersensitivity- usually mild allergy but anaphylactic reaction (IgE mediated) can occur- frequency of hypersensitivity is approximately 5%- anaphylaxis is most likely with IV administration but can occur with IM and even oral administration2) Colitis- penicillins (especially ampicillin) can disturb normal gastrointestinal flora- this is less of a problem in dogs & cats due to the almost complete absorption of amoxicillin, althoughmild diarrhea sometimes occurs- it is a big problem with horses: large oral doses of penicillins are likely to disturb the normal microflora ofthe equine colon, so oral administration is contraindicated

Case (1998, Southern Ontario):

Veterinarian prescribes oral penicillin (in water) for treatment of respiratory infections on a

rabbit farm- all rabbits develop severe colitis, 40% die

According to Prescott, Baggot & Walker, 2000, p657: "It is now fairly common knowledge that

the incidence of antimicrobial toxicity in rabbits and rodents is relatively high whencompared with that of other species." Death is usually caused by iota toxin from Clostridium spiroforme .



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Beta-lactams (especially ampicillin) kill many members of the normal gut flora, allowing pathogens,especially gram negative bacteria and Clostridia (anaerobic gram positive) to proliferate, causingclostridial colitis which can be fatal. While mice, rats, ferrets, and possibly gerbils are relativelyresistant to this, hamsters, guinea pigs, rabbits and chinchillas are particularly susceptible.

So remember:

- Beta lactams (esp. ampicillin) should not be administered to small rodents (guinea pigs,

hamsters, gerbils) or rabbits (although penicillins other than ampicillin have been used IM or SQwith caution in rabbits [not in other rodents])

- identify the disease and look up recommended antimicrobials for that species (e.g.chloramphenicol, sulfonamides, tetracycline, possibly a fluoroquinolone)

3) Irritation at injection siteOther adverse effects are rare

Primary uses of Penicillins(Prescott, Baggot & Walker 3 rd edn [2000] pp 121-123):

Horses- infected wounds, LRT, UTI, uterus- Strep. zooepidemicus polyarthritis & meningitis of foals

- the drug of choice for strangles (Strep. equi), tetanusDO NOT GIVE ORALLY

Dogs & cats- drug of choice for Strep., clostridia- use potentiated penicillin for P. multocida- infected wounds, tooth abscesses, etc.- UTI- (Note: Clavamox is used to treat bacterial infections in almost every tissue - it is even highlyrecommended in the literature for the treatment of meningitis)

Cattle & sheep

- penicillin G is the most commonly used antibiotic in food animal medicine- drug of choice for clostridia, Corynebacterium renale, H. somnus, Fusobacterium- Strep. Mastitis - cloxacillin (sodium or benzathine; see above) is often given intramammarily (this is theonly approved use of cloxacillin in veterinary medicine)- listeriosis (ampicillin)- pinkeye

(For your information: Antipseudomonas penicillins:- can penetrate outer cell wall of Pseudomonas spp. and other gram negative bacteria- less effective against gram positive bacteria- only available in injectable form- not labelled for veterinary use- expensive- only use if you have culture & sensitivity results and no other choice of drugs

- e.g.: Piperacillin)



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The CephalosporinsCephalosporins are inherently resistant to penicillinases, however some can be destroyed bycephalosporinases (variants of penicillinase). They are similar to penicillins with regard to mechanism ofaction, distribution, elimination, half-life (30-90 min) and main adverse effects (hypersensitivity).While it would be preferable to group the cephalosporins according to their pharmacological effects, they

are traditionally grouped according to when they were discovered (1st

, 2nd

, 3rd

, and 4th

”generation®cephalosporins). Still, there are certain common properties shared by members of the differentgenerations.

Notes regarding administration:- unusual among beta-lactams in that very few cephalosporins can be given orally without beingdestroyed- the oral cephalosporins have the narrowest spectrum of activity

Notes regarding distribution:- 3rd generation cephalosporins enter the CNS/CSF well, unlike other beta-lactams

(FYI only: Cephalosporins are eliminated from CSF by metabolic pump similar to that in the kidney. Both pumps

can be inhibited by probenecid , which was developed to slow excretion of penicillins when penicillins were veryexpensive. It is rarely used today; e.g. possibly use with cephalosporins for treating meningitis to maintain tissueconcentrations (probenecid doubles the dosing interval).

Notes regarding adverse effects:- To be safe, do not use cephalosporins in animals with history of penicillin allergy (and vice versa),although only 3-7% of humans with a penicillin allergy are allergic to cephalosporins- Thrombophlebitis can occur following IV or IM injections (except ceftiofur which is well tolerated)

Spectrum of Activity1st generation (early cephalosporins):- primarily gram positive activity

2 nd generation: - gram positive and gram negative activity- cefoxitin is effective against many anaerobes including Bacteroides fragilis - none are approved for use in veterinary medicine

3 rd generation: - less effective against gram positive but better against gram negative aerobic bacteria- activity is due to a metabolite produced in liver

4 th generation: - gram positive and negative activity (broad-spectrum)- primarily used in human medicine to treat infections resistant to other cephalosporins

Antipseudomonal cephalosporins (from 3rd & 4th ”generations®):- specifically active against Pseudomonas spp., e.g. cefotaxime



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Clinical Uses-1st generation (early cephalosporins):

Oral:- small animals (not horses & ruminants because absorption is poor & erratic)- e.g. cefadroxil (veterinary); cephalexin (human; often cheaper)- useful for non-specific infections caused by gram positive (Staph, Strep) and sometimes gram negative

pathogens (E.coli, Klebsiella Proteus )- e.g. UTI, skin (30 days for chronic Staph. intermedius pyodermas in dogs), wounds, abscesses

Injectable:- cefazolin - very beta-lactamase resistant- often used for surgical prophylaxis IV

Intramammary infusion:- cephapirin sodium (Cefa-Lak ½) - for lactating cows- cephapirin benzathine (Cefa-Dri ½) - chronic Staph. mastitis in dry cows

2 nd generation:

- administer IV due to pain on IM injection- not absorbed orally (except cefuroxime)

- none are approved for use in veterinary medicine- most 1st & 2nd generation cephalosporins don–t cross the BBB into the CNS

3 rd generation: - IM, SC, IV, few are oral- some enter CNS/CSF well - can be used for meningitis (cefotaxime)- expensive, rarely used in veterinary medicine, except ceftiofur (!) in large animal medicine:

- ceftiofur sodium (Excenel ½)- extensively used in large animals due to activity against gram negative bacteria- relatively cheap

- when given by IM injection according to the label there is no label milk WDTUses: e.g. acute, undifferentiated bovine pneumonia (shipping fever), foot rot in cattleImportant: the label dose of ceftiofur sodium does not produce therapeutic levels in udder sincethe drug does not distribute to the udder, so it is not useful for the treatment of mastitis when usedaccording to the label

- now also licenced for use in small animals

Other Beta-Lactams

Carbapenems

e.g. imipenem- the broadest spectrum antimicrobial available- extremely expensive- used for humans with resistant, life-threatening nosocomial infections- not used to any extent in veterinary medicine, mainly to help prevent the development of resistance- avoid



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AminoglycosidesAminoglycoside antibiotics are generally reserved for the treatment of severe gram negative aerobicinfections. They are unusual in that they have limited ability to cross membranes and must therefore begiven by injection for systemic treatment. Gentamicin is by far the most important of these antibiotics.

Mechanism of Action- bactericidal (at appropriate concentrations)- inhibit protein synthesis (by binding bacterial ribosomes)

- penetration of the bacterial cell envelope requires energy and oxygen-dependent transport systems- work synergistically with beta-lactams (esp. for Strep)

Spectrum of activity- most aerobic gram negative bacteria incl. Pseudomonas, and Staphylococci- limited effectiveness against non-Staph gram positive bacteria- ineffective against anaerobes

Resistance:

1) natural: anaerobes do not have oxygen-dependent transport processes necessary for aminoglycosidesto enter cell2) plasmid-acquired: aminoglycosidase (e.g. streptomycin, neomycin have lost most activity)

Administration:- IM, IV, SC- exceptional in that they are not absorbed orally and hence, oral administration does not give systemiceffects - excreted in feces- reach therapeutic levels in 30-60 min after IM injection.- less toxicity with once-a-day administration - important that blood concentrations be allowed to fall belowa certain level for part of the day in order to minimize nephrotoxicity

Distribution:- remain in extracellular fluid space (highly charged polar nature of drug limits its distribution across membranes)

- low (but effective) levels reached in most tissue fluids except: 1. CNS (do not cross BBB) and2. renal cortex (very HIGH levels due to selective binding)

Elimination:- filtered unchanged into the urine- half-life ~2-3 hr

Adverse effects:

1) NEPHROTOXICITY(gentamicin has been shown to enhance the formation of oxygen-free radicals by renal mitochondria throughaccumulation in proximal convoluted tubules)

- ordinary dose can be very damaging to kidneys of patients with renal disease, dehydrated animals(remember this!)- risk factors: prolonged (>7day) therapy, acidosis- concurrent use of diuretics such as furosemide enhances toxicity - if it must be used reduce the dose- toxicity is also enhanced by concurrent use of other nephrotoxic antibiotics such as cephaloridine or



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amphotericin B as well as the inhalant anesthetic methoxyflurane- serum levels should be checked often in high-risk patients

2) ototoxicity - with chronic administration drug accumulates in inner ear - may damage nerves (CN VIII):permanent deafness & vertigo - mainly a problem with the older, more ototoxic aminoglycosides thataren–t often used systemically (e.g. streptomycin)

3) neuromuscular blockade - rare, mainly in combination with anesthesia: bind free calcium in body fluids- reduces ACh release at NMJ: transient paralysis; also cardiodepression: by binding calcium in the heartwhen given rapidly IV (problems rarely observed)

Examples:Old aminoglycosides (<1962):- streptomycin, neomycin, kanamycin- streptomycin is the most effective aminoglycoside for the treatment of mycobacteria and the leasteffective against other organisms- much resistance; ototoxic; paralytic- formerly often used with penicillin for mixed infections (”pen-strep® formulations)

- do not use in cats (increased sensitivity to toxicity)- used topically for skin, ear, eye infections and by infusion for mammary gland infections(Why are they effective topically if most bacteria are resistant? because topical application allows localconcentrations 100s or 1000s of times higher than what is possible with systemic administration >resistance is overcome)- only ~ 3% absorbed from gut - used orally for coliform enteritis- other current uses are in cattle:

- to eliminate Leptospira pomona from kidneys of carriers; drug of choice for treatment ofCampylobacter carrier bulls; best agent for actinobacillosis (wooden tongue)

Newer (1963+)Gentamicin

- the broadest-spectrum & most widely used aminoglycoside- effective against broad spectrum of gram negative & a few gram positive bacteria, and mycoplasma- not effective against anaerobes- Pseudomonas are often resistant

Uses:- limited by its toxicity- not for everyday, non-life-threatening infections- general: used for severe gram negative infections e.g. septicemia (providing patient is well hydrated andhas adequate renal function)- exception: many topical preparations are available for eye and ear infections - toxicity much less likelydue to local application - caution however re: accumulation in ear; avoid if eardrum not intact

- used in combination with a beta-lactam due to the synergistic effect, but remember to administer eachdrug separately since mixing a beta-lactam with an aminoglycoside in the syringe prior to administrationwill inactivate the aminoglycoside

Horses:- approved for intrauterine use- with penicillin G for life-threatening infections: septicemia, peritonitis, bacterial endocarditis,pleuropneumonia, neonatal bacterial pneumonia



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- topical: bacterial keratitis, penetrating eye wounds- Note: not useful for treatment of meningitis

Swine:- used orally (stays in gut) to treat E. coli diarrhea- single IM injection can cure neonatal colibacillosis

Cattle/sheep/goats:- avoid(only approved for intrauterine infusion (Warning: IM or intramammary use in cattle causes 14-19 monthdrug residues) - penicillin G or oxytetracycline are recommended for metritis/endometritis anyway, sobest to avoid aminoglycosides completely in cattle)

Dogs/cats:(1) life-threatening gram negative infections, e.g. bacterial peritonitis/abscessation (may combine withe.g. doxycycline); with a beta-lactam for bacterial pneumonia(2) used topically for gram negative bacteria and Staph

e.g. otitis externa (effective against P. aeruginosa), penetrating eye wounds

Tobramycin- veterinary use is generally limited to the treatment of melting corneal ulcers due to gentamicin-resistantPseudomonas- less toxic than gentamicin

Amikacin- resistant to aminoglycosidase; other resistance mechanisms developing but still useful for gentamicin-resistant infections- e.g. has been used in joints of horses at teaching hospitals for gentamicin-resistant organisms- last resort for the treatment of certain resistant human infections, so should be used as little as possible,if not avoided completely- toxicity is similar to that of gentamicin

Aminocyclitols

A minor group of antimicrobials related to the aminoglycosides. Spectinomycin is the only one used inveterinary medicine.

Spectinomycin- lacks most toxicity of aminoglycosides but resistance develops rapidly- kills many gram positive & negative microorganisms incl. P. multocida, E. coli, mycoplasma, Treponema- anaerobes are resistant

- approved for turkeys, chickens & pigs- e.g. chronic respiratory disease in chickens - administered SQ(Caution: cattle have died after IV treatment due to endotoxin in some batches)

Spectinomycin-lincomycin combination:- approved for chickens & pigs in feed or water- e.g. chronic respiratory disease in chickens - oral (in water)



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(Caution: can cause high mortality in cattle when given parenterally by causing severe pulmonary edema)

Beta-Lactam/ Aminoglycoside Combinations

Generally speaking, this combination is synergistic because the beta-lactam (usually used to targetgram positive and anaerobic bacteria) will damage the cell wall, allowing the aminoglycoside (ordinarilyused to target gram negative aerobes) to enter the bacterial cell (even gram positive or anaerobicbacteria).

This combination of drugs is especially useful when:

“ a resistant Pseudomonas or Proteus is encountered, in which case a specific anti-pseudomonalagent such as a 4th generation cephalosporin could be used together with gentamicin

“ the full regular dose of aminoglycoside is too toxic to the kidneys - in this case you may use thefull dose of a penicillin with a lower-than-normal dose of gentamicin; this combination will be lesstoxic than the normal dose of gentamicin alone



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FluoroquinolonesFluoroquinolones are a relatively new class of antimicrobial drugs used in small animal medicine.Enrofloxacin ("Baytril ” ") was the first of these licenced for veterinary use and the only fluoroquinolone somarketed until the past two years. When administered orally these drugs are absorbed better than anyother major class of antimicrobials. None of the fluoroquinolones should be treated as ”first-line® drugs.

A dramatic rise in resistance to fluoroquinolones in human and veterinary medicine has accompaniedtheir widespread overuse by practitioners.

Examples:- enrofloxacin (”Baytril ½®), orbifloxacin (”Orbax ½®), marbofloxacin, difloxacin- ciprofloxacin - labelled for use in humans - expensive

Note: Many other new fluoroquinolones have been marketed for human use (enoxacin, norfloxacin,lomefloxacin, sparfloxacin, levofloxacin, fleroxacin, pefloxacin, trovafloxacin, moxifloxacin, etc. etc.), andsome have subsequently been withdrawn or restricted due to serious cardiac and hepatic toxicity (e.g.grepafloxacin).

Mechanism of Action:

- damage DNA (inhibit supercoiling primarily by binding the A subunit of bacterial DNA-gyrase

)- bactericidal

Spectrum of activity:- sometimes called broad-spectrum, but are they?- many gram negative, but Staph are the only gram positive bacteria- ineffective against all anaerobes and many cocci

(with the exception of the fourth generation drug trovafloxacin, which is reserved forresistant infections in humans)

- rickettsia, mycoplasma, chlamydia- the only oral antimicrobials effective against Pseudomonas, except enrofloxacin to which resistance hasemerged recently due to indiscriminate use: a recent study has found 91% susceptibility to marbofloxacinand only 52% susceptibility to enrofloxacin

Absorption:- oral & IM good- the only oral antimicrobials for which oral absorption is essentially completeNote: oral absorption is reduced by divalent cations (e.g. antacids)

Distribution:- most tissues - high VD

- high: respiratory and urogenital secretions, therefore good for treating infections inthese areas

- poor: skin, brain, eye, fat, mammary

Elimination:- via kidneys or liver or both depending on the drugenrofloxacin:

- 50% excreted in urine (active form)- 50% hepatic metabolism(including 25% metabolized to ciprofloxacin, but this is variable and not expected to havea significant effect on therapy)



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Drug interactions:- antagonistic with chloramphenicol or rifampin- synergistic with beta-lactams and aminoglycosides in some cases

Adverse effects:- GI irritation: most common (as with many oral antimicrobials)

- vomiting, diarrhea, anorexia

- damage to cartilage:- foals: rapid onset of cartilage lesions at moderate doses- puppies: do not use in growing dogs(or <1wk & monitor for joint pain? - best just to use another drug)

- avoid in pregnant animals

- blindness: enrofloxacin causes blindness in cats if used at high label doses or for long term therapy -DO NOT EXCEED DOSES OF 5 mg/kg/day ENROFLOXACIN (BAYTRIL) ORALLY IN CATS- may cause seizures (inhibit the inhibitory NT GABA)

- potentiated by concurrent NSAID use- DO NOT USE IN EPILEPTIC PATIENTS

- IM injections are very irritating - DO NOT REPEAT AT THE SAME SITE

- other:- inhibit metabolism of theophylline- hallucinations? - occur in humans on enrofloxacin ( ”Baythrill®)

Clinical Uses:- fluoroquinolones are ”second-line® drugs

Small AnimalsApproved in dogs and cats only (tablets or IM)

Second line drugs for a variety of infections. Examples include:1. urinary tract infections2. skin infections (despite low-level distribution to the skin)3. respiratory tract infections4. osteomyelitis/ septic arthritis

Like all higher-generation antimicrobials, fluoroquinolones should not be used as first line drugs in orderto minimize the development of resistance. Bacterial pathogens of humans that possess resistance tofluoroquinolones have been found across Canada, especially in Ontario where they have been prescribedmost heavily by physicians. The same is happening in small animal practice, probably becausefluoroquinolones are being used unnecessarily.



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Something to consider:

From the Lancet , July 31, 1999:

Fluoroquinolone-resistant Streptococcus pneumoniae spread across Canada.Author: Peter Mitchell

”Pneumococcal strains resistant to fluoroquinolones are starting to occur across Canada,researchers at the Canadian Bacterial Surveillance Network in Toronto report (N Engl J Med,

1999; 341: 233-9). Canada is the first country to encounter widespread resistance to fluoroquinolones, one of the most recently introduced antibiotic classes with only a 15-year history of clinical use.“

Among Canadian adults, the prevalence of fluoroquinolone-resistant S pneumoniae is now 3%.Resistance is most common among the elderly and in Ontario--where fluoroquinolone prescribing is highest. The data suggest that resistance has arisen after fluoroquinolone treatment of acute exacerbations of chronic bronchitis, 20% of which are caused by pneumococci.“

"It is now a major concern that a particularly fit fluoroquinolone-resistant S pneumoniae could spread globally."

Coincidentally, a meta-analysis recently showed that other types of antibiotics have little effect on acute bronchitis in otherwise healthy patients.“

Exotic and Avian Species- enrofloxacin use is common in these species (therefore resistance is developing)- being studied in fish, dolphins, and many zoo animals- possibly first-line drug (?) for various bacterial infections in reptiles

Large AnimalsFLUOROQUINOLONES SHOULD NOT BE USED IN FOOD PRODUCING ANIMALS DUE TO THEDEVELOPMENT OF RESISTANT PATHOGENS AND THE SUBSEQUENT TRANSMISSION OFTHESE PATHOGENS OR THEIR RESISTANCE GENES TO HUMANS

Cattle:- avoid (US: enrofloxacin was banned in food animals due to resistance fears, now permitted in non-dairy cattle only according to label - i.e. NO OFF-LABEL USE)- not licensed for use in Canada for any food animal species, but not specifically banned (personal

communication, Bureau of Veterinary Drugs, Sep 2000). Be aware that this may change in Canada, and thata ban may be in place at any time.- danofloxacin has been promoted in the UK for treatment of BRD associated with mycoplasma- it is possible that approval for the use of these drugs in any food producing animal will be withdrawn in

the near future



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From the Illinois Veterinary Bulletin Volume 6, Number 2, November 1998:

”Fluoroquinolone Approved by CVM (USA)

Enrofloxacin, a fluoroquinolone has been approved by the CVM for the treatment of bovine respiratorydisease associated with Pasteurella and Haemophilus. The product, Baytril 100 Injectable Solution, isproduced and distributed by Bayer Corporation and remains a prescription product. Baytril is not for use incattle intended for dairy production or in veal calves. Extra-label use of fluoroquinolones in food animals

has been and is still prohibited by the FDA.®

Fluoroquinolones are administered in human medicine for refractory cases where other antibiotics haveproven of little or no use...The company has voluntarily committed to the FDA to immediately take action, including removal of theBaytril from sale, should the FDA conclude that there is a risk to public health. Veterinarians with acavalier attitude toward extra-label use of Baytril in lactating dairy cattle will not only be violating theAMDUCA law, they will be jeopardizing the use of the product for approved uses. ®

Horses:- avoid use due to arthropathies

Poultry:

- avoid use due to transmission of resistant bacteria to humans

Resistance:- appearing in many jurisdictions- most important mechanism is mutation of bacterial DNA gyrase to a sudden, high-level resistance tomost, and sometimes all, fluoroquinolones

- resistance has been shown to develop much more rapidly where sublethal doses of fluoroquinolonesare used- concentrations above 10 x the MIC were associated with little or no development of resistance- the problem of resistance is particularly important with fluoroquinolones as these drugs are important fortreating life threatening illnesses in humans

“ in the United States, fluoroquinolones were first licenced for use in poultry in 1995“ in 1997, ciprofloxacin-resistant C. jejuni was isolated from 14% of domestic chicken products from

retail markets in the US“ the incidence of quinolone-resistant C. jejuni in humans increased from 1.3% to 10.2% between

1992 and 1998 in the US, much of which has been attributed to the use of these drugs in poultry“ in 2001, the FDA withdrew approval for fluoroquinolone use in poultry

IN LARGE ANIMALS:- the introduction of fluoroquinolones as therapeutic and prophylactic agents in food animals has been amajor factor in the development of decreased susceptibility to drugs such as ciprofloxacin in zoonoticallytransmitted pathogens- resistance is an emerging problem where fluoroquinolones are used in feed (esp. resistant Salmonella& Campylobacter)

IN SMALL ANIMALS:- resistance is occurring most rapidly where fluoroquinolones are used for chronic skin & ear infections(e.g. with Pseudomonas) in small animalsIn 1992, an Expert Group on Animal Feedingstuffs in the UK (the Lamming Committee) recommended that any



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new antibiotics which possess cross resistance to those used in human medicine should not be used forprophylaxis in animal husbandry. Unfortunately, these recommendations were not approved. It is possible that aCode of Practice for the use of fluoroquinolones and other important drugs will soon be implemented on a globalscale. In the meantime it is the responsibility of the practicing veterinarian to use discretion when choosingtherapeutic drugs for all animals and it is very likely that certain drugs such as fluoroquinolones should neverbe used to treat food producing animals and as for any later-generation antimicrobial should not be usedroutinely as first-line drugs in any species.



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Sulfonamides & Potentiated SulfonamidesAcquired resistance has diminished the effectiveness of the sulfonamides to the point where they arealmost never used alone in the treatment of infections. Sulfonamides disrupt one step in the bacterialfolic acid synthesis pathway, and their activity is restored in the presence of chemicals(diaminopyrimidines) such as trimethoprim (TM) that act at a second step in the same (folic acid)

pathway. The effect is synergistic, and trimethoprim + sulfonamide combinations (TMS) are referred toas a ”potentiated sulfonamides®. The potentiated sulfonamides are an important family of antimicrobialsin veterinary medicine. Examples of these first-line drugs include sulfadiazine + TM, sulfadoxine + TM,and sulfamethoxazole + TM.

Mechanism of action:- it is unclear to what extent trimethoprim is effective when used on its own, but neithertrimethoprim nor most sulfonamides are clinically effective in many situations whenused alone

- sulfonamides are bacteriostatic, but the combination (TMS) is bactericidal- sulfonamides inhibit nucleic acid synthesis as follows:Unlike mammalian cells which use pre-formed folic acid,

bacteria must produce their own in order to make nucleicacids. To do this, bacteria use a multi-step metabolicpathway that converts para-aminobenzoic acid (PABA) intofolic acid. Sulfonamides resemble PABA, and bindcompetitively to the bacterial enzyme which ordinarily wouldbind PABA, inhibiting the formation of folic acid (for thisreason the sulfonamides are also called ”folate antagonist®antimicrobials.) Bacteria can develop resistance tosulfonamides by acquiring a plasmid encoding adihydropteroate synthetase enzyme that doesn–t bindsulfonamides. This resistance can develop extremelyrapidly, even during the treatment of one patient.

Remember that TMS combinations are ineffective in pusand necrotic tissue because the pus provides anoverwhelming source of PABA.

Trimethoprim inhibits a different enzyme in the folicacid synthesis pathway of bacteria, so that, even if theyacquire a dihydropteroate synthetase enzyme that does notbind sulfonamides, folic acid cannot be formed. Theacquisition of resistance to both trimethoprim andsulfonamides does not occur as rapidly as the acquisition ofresistance to either drug alone. (More detail: Prescott,Baggott & Walker, 2000.)

Spectrum of activity (TMS):- most bacteria, protozoa (coccidia, toxoplasma etc)- examples of resistant organisms: Pseudomonas,Bacteroides , mycoplasma , enterococci

Administration:- small animals: the examples listed above are well absorbed orally- Cattle: TMS combinations are given IM or IV



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Distribution:- all tissues (TM & S)

Elimination:- via the kidneys- sulfonamides & TM: mainly glomerular filtration of active drug

(metabolized sulfonamides [acetylated] may precipitate in renal tubules - see Adverseeffects below)

Resistance Resistance to sulfonamides:(1) rapid development via acquisition of an altered dihydropteroate synthetase enzymeencoded by a plasmid, such that the new bacterial enzyme binds PABA but not thesulfonamide - can occur during treatment

(2) increased PABA uptake due to presence of pus, cellular debris(3) reduced uptake of drug

Resistance to TM:- usually due to the acquisition of an altered form of dihydrofolate reductse that can–tbind TM

Resistance to the combination (TM & S) is much less common

Adverse effects (TMS):- variable reactions that are often transient and reversible (urinary tract disturbances,hematopoietic disturbances, dermatologic reactions)

- KCS (keratoconjunctivitis sicca or ”dry eye®): sulfas are lacrimotoxic to dogs > sometimes permanent, esp. with chronic therapy

- precipitation in renal tubules in dehydrated animals- polyarthritis, esp. Dobermans after >1 week therapy- protein binding displacement- GI upsets (as with any antimicrobial)- collapse during IV administration

Drug Interactions- fatal dysrhythmias in horses with concurrent use of detomidine

Clinical Uses

Examples of uses in dogs & cats:- urinary tract infections (UTI)- bacterial pneumonia- prostatitis, meningitis, osteomyelitis- enteric infections

Cattle:- many uses- acute peritonitis (with penicillin G)



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- undifferentiated diarrhea (neonatal colibacillosis), Salmonella (incl. septicemia)- neonatal polyarthritis (E. coli, A. pyogenes), neonatal meningitis (E. coli)- foot rot (Fusobacterium necrophorum)- bacterial pneumonia (H. somnus, P. multocida, A. pyogenes, some P. haemolytica)

Horses: salmonellosis, UTI, protozoal myeloencephalitis

Sheep: prevention of Toxoplasma abortion

Swine: neonatal post-weaning colibacillosis, salmonellosis, atrophic rhinitis



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TetracyclinesThis is an important group of antimicrobial drugs that is used routinely in veterinary medicine.Examples: tetracycline, oxytetracycline, chlortetracycline, doxycycline, minocycline

Mechanism of action:

- blocks protein synthesis by binding to bacterial ribosomes (bacteriostatic)- enter bacterial cells by a transport mechanism not present in mammalian cells- may work synergistically with macrolides against some bacteria

Spectrum of activity:- broad-spectrum- inhibit gram positive & gram negative aerobic and anaerobic bacteria, rickettsia, chlamydia,mycoplasma , some protozoa

Administration:- oral bioavailability generally good (except poor for chlortetracycline)- food and antacids can inhibit absorption (e.g. milk, cheese) due to multivalent cations (Ca2+) (except

minocycline and doxycycline)

Distribution:- good to most tissues except CNS- cross placenta; enter milk; become bound in bone- doxycycline (and minocycline) are highly lipid-soluble, enter cells readily unlike other tetracyclines whichremain extracellular

Elimination:- most excreted unchanged in urine- good for treating urinary tract infections due to the high concentration of drug in the urine- some drug is conjugated in liver and excreted into bile, resulting in a significant fecal concentration after

parenteral administration > enterohepatic recycling occurs and much of the drug is reabsorbed from thegut- the exception is doxycycline which is completely metabolized in liver > good for patients with renaldysfunction

Resistance:- has considerably reduced the usefulness of these drugs (but they are still useful!)- usually plasmid-mediated, often results in decreased uptake or increased removal of drug from thebacterial celle.g. Proteus , Salmonella, E. coli - many Pasteurella, Haemophilus, Streptococci have evolved to become resistant- widespread use of low concentrations in livestock feeds may be largely responsible

Adverse effects:Several:- renal damage due to:

1. administration of expired (outdated) tetracyclines2. dose-dependent functional changes in renal tubules

(doxycycline is not nephrotoxic)- hypersensitivity - skin rashes, urticaria



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- irritation at injection site - especially oxytetracycline- nausea, vomiting, diarrhea due to GIT irritation- enterocolitis due to overgrowth of pathogenic microbes - especially horses- discoloration of teeth (deciduous & permanent) occurs in utero or in young animals:

yellow-brown stain- long bone development hindered with chronic therapy- photosensitization- increased serum enzyme levels- possible liver damage - with drug overdose- IV admin may cause collapse - give slowly (5 min)

Clinical Uses:- used for many infections resistant to beta-lactams, e.g. mycoplasma, chlamydiaCattle:many uses, e.g.- AUBRD (treatment or prophylaxis via IM injection)- acute septic metritis (1 g in saline IU)- Listeriosis and clostridial infections- ITEME (H. somnus)

- oxytetracycline is drug of choice for AnaplasmosisSwine:- commonly used to treat atrophic rhinitis (P. Multocida), enzootic pneumonia (mycoplasma)- there is evidence that the bioavailability of tetracyclines with oral administration is poorHorses:- not IM (local necrosis at injection site)- avoid as treatment for bacterial infections due to the potential for adverse effects- drug of choice for Potomac fever (rickettsia) - oxytetracycline hydrochloride slow IV- mycoplasmal mastitis- don–t use minocycline or doxycycline - more lipophilic and thus higher potential for digestivedisturbances in the gut regardless of the route of administrationDogs & cats:

- drug of choice for rickettsia- Borrelia burgdorferi- chlamydial URTI (cats; 14 days) - doxycycline suspension

Macrolides

Macrolides are a minor group of drugs that would be more heavily used if not for the tissue damage andsevere pain they cause on injection. They are toxic to herbivores if administered orally. Serumconcentrations are typically low, but in tissues such as lung they reach very high concentrations (e.g. 20-70x higher than in serum). Most drugs in this group enter cells readily. Macrolides are especially usefulagainst Campylobacter, Chlamydia, Mycoplasma and Legionella. Erythromycin is the prototype.

Mechanism of Action- inhibit protein synthesis by binding to bacterial ribosomes- generally bacteriostatic

Spectrum of activity:- similar to penicillins, i.e. gram positive bacteria and anaerobes



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- only a few gram negative aerobes incl. Leptospira, Campylobacter- advantage that drug is not destroyed by beta-lactamases- tylosin is less active against bacteria but more active against Mycoplasma

Distribution:Therapeutic levels in all tissues, especially high levels in lung; enter cells

Elimination:- metabolized in liver > enters bile(only ~5% of dose enters urine in active form)

Resistance:- often develops rapidly (e.g. during treatment)- plasmid-acquired, or one-step mutation to high-level resistance (but is unstable)- cross-resistance with other macrolides, lincosamides is extensive

Drug interactions:- antagonistic with chloramphenicol, other macrolides/lincosamides

Adverse effects:- can cause a variety of problems in cattle (rumen stasis to shock) especially if given orally- not ”first-line® antimicrobials due to tissue irritation that causes severe pain - biggest problem is severepain on IM injection, and carcass damage- most animals experience mild/moderate GI upsets due to increased smooth muscle

activity, e.g. dose-related nausea, vomiting, diarrhea, GI pain(NOTE: in adult horses biliary excretion of erythromycin causes changes in gut flora - severe diarrhea >rarely used; also rabbits - may be lethal)

Tilmicosin - used in cattle SC - fatal IV, causes necrosis IM- TOXIC to horses, sheep, goats, swine, humans - can be immediately fatal upon injection

(can be fatal to swine by IM injection - give orally only)

Clinical uses:Erythromycin- Horses: a drug of choice for R. equi pneumonia in foals, with rifampin; given orally

(IM inj > PAIN) - the only common use for macrolides/lincosamides in horses- Cattle:

- mainly for intramammary infusion (gram positive mastitis) in lactating cattle dueto short (36 hr) WDT

- IM: chronic bacterial pneumonia? (usually use tilmicosin (see below))distributes to and becomes concentrated in lung tissue

- Dogs & cats (PO): drug of choice for Campylobacter jejuni enteritis; second choice for infections

resistant to beta-lactams, tetracyclines (e.g. resistant pyodermas)

Tylosin- mainly for mycoplasma. e.g. feed additive for control of mycoplasma in pigs- Dogs & cats: used as a second choice to erythromycin for gram positive bacteria,

URTI, abscesses, infected wounds, (cats > Chlamydia & mycoplasma),Staph intermedius pyoderma of dogs

- Horses: contraindicated (IM - severe pain; oral - Clostridium difficile colitis)- Cattle/Swine: used in feed as growth promoter and to reduce liver abscesses in cattle



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(IV in cattle --> possible shock, dyspnea, depression)(can cause contact dermatitis in veterinarians)(Remember IM injections PAINFUL/IRRITATING)

Tilmicosin- given SC only- developed as a long-acting treatment for bovine respiratory disease

(mycoplasma, P. haemolytica, A. pyogenes, H. somnus)- single SC dose gives >72 hrs of levels above MIC

(concentration in lung can reach 70x the serum concentration)- WDT 28 days- popular in western feedlots, but expensive- use in place of erythromycin for chronic bacterial pneumonia? - consider cost

Spiramycin- used as for tylosin in swine & cattle- problems with prolonged drug residues

Tiamulin- better activity against anaerobes and mycoplasma than macrolides- mainly used as water additive for pigs to control swine dysentery and chronic pneumonia

Lincosamides

The lincosamides are another minor group of bacteriostatic drugs related to the macrolides. They have aspectrum of activity similar to the penicillins. Lincomycin and clindamycin are the main examples.

Mechanism of action:- inhibit protein synthesis by binding to bacterial ribosomes; bacteriostatic

Spectrum of Activity:- similar to penicillins (gram positive bacteria, anaerobes, mycoplasma)- less active than macrolides against gram negative bacteria- clindamycin is more active than lincomycin, esp against anaerobes- resistance can develop rapidly; complete cross-resistance between lincomycin and clindamycin; usuallyalso cross-resistance with the macrolides

Administration:- well absorbed orally in non-herbivores (lincomycin or clindamycin tablets or drops for small animals;injections are painful)- absorption is significantly reduced by the presence of food in the gut- lincomycin injectable approved for swine only (painful)

Distribution:- distributes to all tissues (including prostate, mammary)

Elimination:- primarily via hepatic metabolism



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Adverse effects:- may cause fatal diarrhea in horses, rabbits, humans (~2%)

Clinical uses:Lincomycin (mainly cattle, swine, poultry)- Cattle: used in combination with spectinomycin for respiratory disease

- Swine: mycoplasma, swine dysentery (but tiamulin is much better)- Poultry: orally for mycoplasmal airsacculitis(Horses: has been used IM but toxicity is often a problem and may be serious > do not use in horses)

Clindamycin (dogs & cats)- generally, where gram positive bacteria or anaerobes are resistant to penicillins- given orally (IM is very painful)- routinely used to treat abscesses and in periodontal surgery(but may wipe out normal gut flora and cause problems)

- osteomyelitis



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Chloramphenicol and florfenicol

Chloramphenicol would be an ”ideal® antimicrobial if not for its toxicity to humans, which in a very smallnumber of cases is lethal. It is still used relatively often in small animal practice, however, due to its lowcost and efficacy. It is a miscellaneous drug that is not a member of any of the major antimicrobialfamilies. Florfenicol is similar to chloramphenicol but is not fatal to humans and is licensed for thetreatment of bovine respiratory disease.

Mechanism of action:- inhibits protein synthesis- usually bacteriostatic

Antibacterial Activity:- broad-spectrum- effective against most gram positive and many gram negative bacteria, rickettsia, chlamydia, somemycoplasma, all anaerobes

Resistance:- Mycobacteria and Nocardia are resistant- resistance acquired by Enterobacteriaceae mainly via ”r® factor plasmid

Absorption: well absorbed from gut

Distribution: all tissues except prostate (unless inflamed)

Elimination:- metabolized in liverHalf life:- varies widely with species, agee.g. horse: 1 hr

cat: 6-8 hr- much longer in neonates

Adverse effects:Drug interactions are common and may be lethal:- inhibits liver metabolism of many other drugs, which then reach toxic levels- e.g. barbiturates: dogs on low-dose phenobarbital may die if treated with chloramphenicol- chloramphenicol + ionophores (e.g. broiler chickens) > severe muscle degeneration- antagonistic effect with penicillin G, aminoglycosides (and possibly with lincosamides, macrolides)- do not use with a bactericidal antimicrobial - may inhibit activity

Unfortunately, chloramphenicol inhibits mitochondrial protein synthesis in mammalian bone marrowcells (in addition to inhibiting bacterial protein synthesis), and can therefore cause a dose-related,reversible anemia in humans, neonatal animals, and cats on prolonged therapy

Do not confuse this reversible problem with the reason the drug has been banned in food animals, whichis fatal bone marrow depression (aplastic anemia) - seen in 1 out of 25,000 - 60,000 humans (not seen in domestic animals)- not dose related, may be a genetic idiosyncrasy- probably requires oral or parenteral administration, but may be possible even after handling the drug



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- short-lived metabolite thought to be responsible- recommend use of gloves when handling drug

Cats have a deficient enzyme system (glucuronide conjugation) needed for chloramphenicol metabolism,and may therefore develop reversible bone marrow suppression after prolonged treatment (> 14 days)

- may be wise not to vaccinate animals being treated with chloramphenicol because of the inhibition ofprotein synthesis

Clinical uses:Food animals: BANNED

Other species: an inexpensive alternative to other antimicrobials (but used less and less):Dogs & cats:- systemic salmonellosis resistant to other antimicrobials- deep gram positive infections of the eye- usually excellent for otitis externa, mastitis, prostatitis, canine tracheobronchitis

Florfenicol- similar to chloramphenicol but does not cause aplastic anemia- still causes dose-related, reversible bone marrow suppression- considered bactericidal

Clinical uses:- approved for respiratory disease in cattle (Haemophilus + Pasteurella)- IV half life short (3 hr), but long (18 hr) after IM injection in cattle- meat WDT 36 days

- drug interactions: thought to be the same as for chloramphenicol(Caution: do not use in horses: alters gut microflora, causes severe diarrhea)

Other Miscellaneous Antimicrobial Drugs

Rifampin

Rifampin is used mainly as a first-line anti-tuberculosis agent in human medicine. It is always used incombination with another antimicrobial because of the rapid development of resistance. Because of itsability to kill intracellular bacteria, rifampin–s main use in veterinary medicine is in the treatment of R. equi pneumonia of foals. In time, it may be used in an increasing number of veterinary applications whereintracellular bacteria are a problem.

Mechanism of action:- prevents RNA synthesis (by inhibiting RNA polymerase); bactericidal

Spectrum of activity- gram positive aerobes and anaerobes (gram positive and negative)

(most gram negative aerobes are resistant)- the most active drug known against Staph. aureus



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- effective against intracellular bacteria including Mycobacterium tuberculosis and paratuberculosis (butmost other mycobacteria are resistant); intracellular Staph. aureus (in mastitis); Brucella;Corynebacterium pseudotuberculosis ; R. equi ; possibly also Chlamydia psittaci

Absorption:- reasonable oral absorption (ruminants: IM injection)

Distribution:- all tissues; becomes concentrated in neutrophils & macrophages

Elimination:- active drug and metabolites are excreted in the bile and urine- enterohepatic recycling occurs to some extent

Resistance:- chromosomal mutation to high-level resistance is stable, occurs in most bacteria, anddevelops so rapidly (1 in 107 bacteria!) that rifampin should NEVER be used alone

Adverse effects:

- stains everything red:red urine, tears, sweat, saliva (but apparently not harmful) > warn the client!- induces cytochrome P450 which shortens the half-life of other drugs includingketoconazole, itraconazole, and barbiturates and may lead to clinical hepatitis

> don–t use in animals with a history of liver disease

Clinical use:- main use is with erythromycin to treat R. equi pneumonia - including pulmonaryabscesses

- various other infections caused by macrophage-associated bacteria

Metronidazole

This is the main nitroimidazole used in veterinary medicine. Metronidazole is especially useful againstprotozoa, and is commonly used to treat Giardiasis in small animals. It is not used in food animalpractice due to its potential carcinogenicity.

Mechanism of action:- causes extensive damage to DNA (bactericidal)

Spectrum of activity:- anaerobes (Clostridia, Fusobacteria, Bacteroides)

- protozoa (Giardia, Trichomonas)- ineffective against aerobes - don–t metabolize it to active form

Absorption:- rapid & complete oral absorption- may also be given IV

Distribution: - all tissues including the CNS, abscesses



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Elimination:- primarily in the urine (active form)- extensive hepatic metabolism also occurs

Resistance: - rare

Adverse effects:

- possible carcinogen, teratogen

> DO NOT use in FOOD animals or pregnant animals- necrosis if administered IM or SQ (give orally or IV)- may cause nausea following oral administration

Clinical uses:- anaerobic infections (small animals and horses only)- used to treat Giardiasis in dogs (although fenbendazole - usually used to treat nematode infestations- is apparently more efficacious and has fewer side effects)- often used to treat undiagnosed chronic (”stress) diarrhea in dogs, as for tylosin (Campylobacter

jejuni ? Clostridium difficile ?)- can be combined with numerous other antimicrobials (e.g. clindamycin, erythromycin, various beta-

lactams, rifampin, gentamicin, tobramycin)



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Nystatin

Amphotericin B

Antifungal AgentsThe three main types of antifungal agents are the polyenes, which are fungicidal but very toxic to thehost, the safer but fungistatic azoles, and griseofulvin, which is specific for dermatophytes.

1) The Polyenes: Amphotericin B and Nystatin

Amphotericin BThis is a broad-spectrum drug used for potentially life-threatening fungalinfections particularly in immunocompromised patients. It is so toxichowever, that many private practitioners do not use it.

Mechanism of action:- damages fungal cell membranes (fungicidal)- also damages host cell plasma membranes to a lesser extent by bindingcholesterol > toxicity

Administration: given only by IV infusion over 4-6 hours

Distribution:-most extracellular body fluids (reaching ~30-50% of plasma levels)

Elimination: - hepatic metabolism- LONG half-life (slow phase ~10-15 days )

Adverse effects:- the most toxic antimicrobial in clinical use- expect some toxicity (fever, nausea, vomiting) including nephrotoxicity(monitor BUN at least twice/week)

- perivascular leakage causes severe cellulitis

- often thrombogenic- newer, more expensive lipid formulations which are less toxic have recently enteredclinical use

Clinical use:- many serious systemic mycotic infections, e.g. candida, cryptococcus, coccidia > esp. in immunocompromised patients due to the fungicidal nature of the drug- for immunocompetent patients it is likely that newer, safer alternatives (such as the azole itraconazolewhich is fungistatic) are a better choice- can be used with rifampin or ketoconazole- now often replaced with safer antifungal drugs such as ketoconazole, or even safer,newer drugs such as itraconazole

Nystatin- mechanism of action similar to amphotericin B- topical application only- used in various topical ear medications in combination witha steroid



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Ketoconazole

Itraconazole

2) The Azoles (imidazoles, triazoles)Systemic use: ketoconazole, itraconazoleTopical use: clotrimazole, miconazole, enilconazole

Mechanism of action:- generally fungistatic- damage fungal membranes (inhibit sterol formation)

- lower toxicity than many older antifungals

Spectrum of activity- many fungi, yeast, some protozoa

KetoconazoleOver the past decade, this drug has been the most commonly used antifungal in veterinary medicine dueto its high efficacy and safety but it is now being replaced by the even safer itraconazole andenilconazole.

Administration: oral (except horses - NO oral absorption)

Distribution:- limited- reaches saliva, skin, bone, pleura & peritoneum, synovial and aqueous humor- long half-life (6-10 hr)

Elimination:- hepatic metabolism

Resistance:- rare; e.g. some Aspergillus

Drug interactions:

- antagonistic with other antimicrobials (except sulfamethoxazole for candida)

Adverse effects:- common- inappetance, pruritus, alopecia, icterus- inhibits steroid synthesis > used to treat hyperadrenocorticism- hepatotoxicity in cats- mummified fetuses, stillbirths in dogs

Clinical uses:- alternative to amphotericin B (safer, oral admin.)- local & systemic mycotic infections, e.g. cryptococcus, candida, malassezia

- systemic infections require 3-6 month treatment to prevent relapse since fungistatic

Itraconazole- for systemic use- less toxic, broader-spectrum than ketoconazole- reaches all tissues possibly including the CNS- accumulates in hair, stratum corneum- better tolerated in cats than ketoconazole, but may see anorexia



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Griseofulvin

Enilconazole

and hepatotoxicity in some cats (rare in dogs)- best absorbed with a fatty meal- coming into widespread use

Clotrimazole- topical for localized dermatophytosis (e.g. in Otomax ½ ear medication)- drug of choice for Aspergillus infections of cornea

- has been used to treat candidal stomatitis

Enilconazole- topical preparation- approved for dermatophytosis in dogs & horses- effective in the treatment of nasal aspergillosis- some practitioners add it to ear medications- very safe & effective- coming into widespread use

3) GriseofulvinThis drug inhibits virtually all dermatophytes (but only dermatophytes). It isgiven orally, not topically. Cats are especially susceptible to its adverseeffects.

Mechanism of action:- enters newly forming keratin layers- inhibits mitosis (fungistatic)- takes 4 to 6 weeks or longer to replace infected keratin

(4 to 12 months may be required for nails)

Administration:- oral administration: give with a fatty meal

- may vomit on empty stomach- fat also improves absorption

- not effective topically

Adverse effects:Cats are most susceptible to adverse effects

- anorexia, depression, vomiting, diarrhea, etc.- toxicity is idiosyncratic, not dose-related, so only occur in certain individuals

- e.g. idiosyncratic anemia may occur in cats, especially (but not only) FeLV +ve cats > use itraconazole instead (or lime sulphur e.g. for Microsporum)

- teratogenic (especially in cats) - do not use in pregnant animals- may cause bone marrow hypoplasia in cats and neutropenia in cats with FIV- generally recommended that something else be used (e.g. itraconazole) instead forcats

Clinical use:



- kills essentially all dermatophytes, but only dermatophytes- popular for treatment of Microsporum & Trichophyton in horses, cats & dogs- often used with topical therapy

Antifungal AgentsDisease Amphotericin B Ketoconazole Itraconazole Enilconazole * Griseofulvin Tolnaftate *

Dermatophytes + + + + +

Candidiasis + (combination) + + +

Aspergillosis + + + +

Blastomycosis + + + NA

Coccidiomycosis + + + NA

Cryptococcosis + (combination) + + NA

Sporotrichosis + + NA

Histoplasmosis + + + NA

*topical preparation

ATMDrogas en Vet

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