chap17

BRANSON W. RITCHIE, DVM, PhD Assistant Professor, Avian and Zoologic Medicine Department of Small Animal Medicine College of Veterinary Medicine University of Georgia Athens, Georgia

GREG J. HARRISON, DVM Director, The Bird Hospital Lake Worth, Florida President, Harrison’s Bird Diets Omaha, Nebraska

LINDA R. HARRISON, BS President, Wingers Publishing, Inc. Former Editor, Journal of the Association of Avian Veterinarians Lake Worth, Florida

AVIAN MEDICINE: PRINCIPLES AND APPLICATION

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icrobial diseases are common in compan-ion and aviary birds, and careful drugselection and delivery can greatly influ-ence the outcome of many clinical cases.

In contrast to mammals in which it may be possibleto try an empirical treatment regimen, birds areoften presented in an advanced state of illness, ne-cessitating immediate and correct diagnosis andtreatment. For best results, antimicrobial therapyshould be maximized early in the disease process.

Published avian drug doses are often based on clini-cal experience or data extrapolated from other spe-cies. Suggested doses may or may not be optimal, andavian veterinarians should be attentive to the possi-ble toxic effects or lack of efficacy when treating birdswith empirically derived doses. Sub-therapeutic dos-ing can result in treatment failure and encourage thedevelopment of microbial resistance. Excessive drugtreatment may be toxic and damage the kidneys orliver. In particular, care should be extended whentreating rare birds in which the effects of a specificdrug have not been investigated.

The goal of antimicrobial therapy is to aid elimina-tion of the infecting organism from the host. Antibi-otics play only a partial role in this process, and thehost immune system is usually required to resolve aninfection. Supportive care is therefore an importantcomponent of the overall therapeutic plan. The clini-cal outcome of using an antimicrobial agent dependsupon the intrinsic susceptibility of the agent andmicrobiological activity of the drug (efficacy), theability of the drug to reach the site of infection atadequate concentrations (pharmacodynamics), andthe ability of the drug to kill the pathogen withoutharming the host (selective toxicity). Other consid-erations include the route and frequency of admini-stration, cost and ability of the bird owner to accom-plish the treatment regimen. Because birds are oftenpresented in a state of advanced illness and immuno-suppression, the best drug should be given via thebest route to maximize the chances for treatmentsuccess. A general approach to the treatment of micro-bial diseases is provided in Table 17.1.

MC H A P T E R

17ANTIMICROBIAL

THERAPY

Keven Flammer

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Avian Medecine : Principles and Application, B.W. Ritchie, G.J Harrison and L.R. Harrison (Eds.)

Factors InfluencingSelection of an Antibiotic

There are no exact criteria to determine which anti-biotic is best for each situation. Some of the impor-tant factors influencing the rational selection of anantibiotic are discussed below.

TABLE 17.1 General Approach to Treatment of Bacterial Diseases

1. Identify the pathogen and location of infection.

2. Determine the antimicrobial susceptibility of the isolate if thesusceptibility cannot be predicted.

3. Select an antimicrobial drug based on susceptibility, ability to reachthe site of infection, available routes of administration, requiredfrequency of administration and minimal toxicity to the host.

4. Determine if it is feasible for the bird owner to complete thetreatment regimen.

5. Treat with appropriate antibiotics.

6. Maintain host defenses by reducing stress and maximizing sup-portive care.

7. Find and eliminate the source of bacteria.

8. Decontaminate the bird’s environment.

Antimicrobial Spectrum

The target organism must be susceptible to the anti-biotic at concentrations achievable at the site of in-fection if treatment is to be effective. Some microbialorganisms have predictable susceptibility. For exam-ple, all strains of chlamydia are presumed to besusceptible to tetracyclines. If chlamydiosis is diag-nosed, it is rational to begin therapy without a sus-ceptibility test. Unfortunately, the most common infec-tious agents in psittacine birds (gram-negativebacteria, streptococcus and staphylococcus) have un-predictable antimicrobial susceptibilities, and an invitro susceptibility test is required to aid drug selection.

Laboratories can determine the antimicrobial sus-ceptibility of a bacterial isolate by two primary meth-ods: disk diffusion and dilution tests. The Kirby-Bauer disk diffusion susceptibility test is a semi-quantitative method, and the test organism is classi-fied as susceptible, of intermediate susceptibility, orresistant to the drug. It is important to understandthat the classification “susceptible” is based on the

antibiotic serum concentrations that are achieved bya standard treatment regimen in humans (or a testanimal if the drug is veterinary-labeled). A pathogenthat is classified as susceptible by an in vitro test willbe susceptible in the bird only if similar concentra-tions are maintained at the site of infection. As ex-plained below, the achievable drug concentrationsare influenced by many factors including dose, fre-quency and route of administration. Therefore, if adisk diffusion susceptibility test indicates that anorganism is resistant, treatment with that drug willnot be successful. If the test indicates the organismis susceptible, then treatment may be successful ifdrug concentrations similar to those in humans areachieved in the bird.

Antimicrobial susceptibility tests using dilutionmethods determine the minimal inhibitory concen-tration (MIC) of the antibiotic. Since the MIC isquantitative, it allows the clinician to select the drugto which the organism is most susceptible and pro-vides a better prediction of treatment success. Anexample illustrates how disk diffusion and dilutiontests differ. When using a disk diffusion test to deter-mine microbial susceptibility to enrofloxacin, all iso-lates with a zone of inhibition corresponding to anMIC of 2 µg/ml (based on achievable concentrationsin dogs) would be reported as susceptible. It wouldnot indicate if the organism was at the low end ofsusceptibility (0.03 µg/ml) or the high end (2.0 µg/ml).If a dilution susceptibility test were performed, theprecise MIC for that organism would be determined.Figure 17.1 illustrates the plasma concentrations

FIG 17.1 Plasma concentrations of enrofloxacin in African GreyParrots vary with the route of administration. Bacteria must behighly susceptible (MIC <0.05 µg/ml) to be effectively treated withwater-based administration.

CHAPTER 17 ANTIMICROBIAL THERAPY

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achieved when enrofloxacin is administered to Afri-can Grey Parrots by intramuscular, oral (gavage) orwater route. This data shows that isolates with anMIC of 1-2 µg/ml would not be successfully treated byenrofloxacin in African Grey Parrots under any cir-cumstances; oral and IM administration would beeffective against isolates with an MIC < 1.0 µg/ml;and water administration would be effective onlyagainst isolates with an MIC < 0.05 µg/ml. The dilu-tion test enables selection of a drug and route ofadministration that will have a high likelihood ofsuccess. Information on the pharmacokinetics of an-tibiotics in avian species is expanding, making deci-sions based on MIC data increasingly possible andeffective.

In a severely ill patient, or in one that has an infec-tion in an area that is difficult to culture, it may benecessary to start treatment without the benefit of aculture and susceptibility test. In these cases it ishelpful to know the common causes of infection andthe antimicrobial drugs most likely to be effective.There are many exceptions to the comments madebelow; however, following these suggestions can re-sult in successful therapy. Figure 17.2 displays thepredictive efficacy for using various antimicrobialdrugs to treat gram-negative bacteria isolated frompsittacine patients at the Veterinary Teaching Hospi-tal, College of Veterinary Medicine, North CarolinaState University. Antimicrobial susceptibility pat-terns vary geographically, so this data may not beapplicable to all areas.

The most common causes of primary and secondarymicrobial infections in psittacine birds are gram-

negative bacteria, chlamydia and yeast. Gram-nega-tive bacteria are frequently resistant to routine anti-biotics (eg, ampicillin, tetracycline, chloramphenicoland erythromycin); however, most isolates are sus-ceptible to trimethoprim/sulfa combinations, en-rofloxacin, amikacin, and the advanced generationcephalosporins (eg, cefotaxime) and penicillins (eg,piperacillin). Yeast are usually confined to the ali-mentary tract and can be readily identified by per-forming a Gram’s stain of a fecal smear. Most yeastare susceptible to treatment with nystatin, ketocona-zole or fluconazole. Chlamydia are susceptible totreatment with tetracyclines.

CL I N I CA L AP P L I C AT I O N SProlonged tetracycline therapy may be catabolic, cause im-munosuppression, reduce normal gut flora or render a birdmore susceptible to secondary pathogens.

Nystatin must come in direct contact with yeast to be effec-tive. If nystatin is delivered by gavage tube, infections in themouth will not be treated.

Medicated food and water are traditionally favored routes forpoultry but seldom achieve therapeutic drug concentrationsin companion and aviary birds.

Birds receiving antibiotics should be monitored for secondaryinfections with cloacal cultures and fecal Gram’s stains.

Trimethoprim/sulfadiazine is often effective for treating gram-negative infections in nestling birds.

Critically ill birds should be treated via parenteral routes toestablish effective drug concentration quickly.

On a body weight basis, a 0.05 ml injection in a canary isequivalent to a 40 ml injection in a 25 kg dog.

Given orally, the IM formulation of enrofloxacin producestherapeutic plasma concentrations.

FIG 17.2 Susceptibility of gram-negative bacteria to commonly used antibiotics in one study of psittacine birds.

SECTION FOUR TREATMENT REGIMENS

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Less common infectious agents of psittacine birds aregram-positive bacteria (Staphylococcus aureus andsome Streptococcus spp.), mycoplasma, systemicfungi and mycobacteria. Many of the S. aureus andstreptococcus isolates tested by the author are sus-ceptible to cephalexin or cephalothin. Mycoplasmaare presumed to be susceptible to enrofloxacin,tetracyclines and tylosin. Systemic fungal infectionsare difficult to treat under any circumstances andrequire multiple drug therapy with amphotericin Band itraconazole, fluconazole or flucytosine. Myco-bacteria are extremely difficult to eliminate. Myco-bacterium avium can cause fatal infections in immu-nosuppressed humans, and therapeutic managementmust be considered with caution (see Chapter 33). Asummary of the susceptibilities of common avianinfectious agents to antimicrobial therapy is given inTable 17.2.

Pharmacodynamics of the Drug

Antibiotics penetrate tissues differently, so the site ofinfection will also influence drug selection. Most bac-teria remain extracellular while causing infection;however, there are a few notable exceptions (eg, sal-monella, mycobacteria and some staphylococci).Treatment of intracellular infections may requiredrugs that are highly lipophilic and can penetratecells (eg, chloramphenicol). Polar drugs (eg, the betalactams and aminoglycosides) are frequently ex-cluded from pharmacologically privileged spacessuch as the cerebrospinal fluid (CSF) and ocularfluids.

Conditions at the site of infection are also important.Exudates, abscesses and granulomas create a hostileenvironment for the action of antibiotics. Perfusionof fibrous tissue is limited, and this may prevent thedrug from reaching the site of infection. Changes inpH, oxygen tension, binding by intracellular proteinsand slow microbial division may reduce antimicro-bial activity. Surgical drainage or removal of an in-fected mass may be required before antibiotics can beeffective.

The pharmacokinetics of the drug are also important.With bacteriostatic drugs, it is desirable to maintainthe concentration of drug above the bacterial MIC forat least half of the dosage interval, and preferablythroughout the interval, if this is attainable and nottoxic. With most bacteriocidal drugs, it is not neces-sary to maintain the drug above the MIC for theentire dosage interval; however, if concentrationsdrop below the MIC for too long, the bacteria will

multiply, and a “break-through bacteremia” may oc-cur. Drugs with a short half-life, like the beta lac-tams, must be given frequently to maintain effectiveconcentrations.

Pharmacokinetic information is invaluable and hasbecome available for specific drugs in some avianspecies, but it is likely that the use of extrapolateddrug treatment regimens to untested species willcontinue to be a common practice in avian medicine.The extrapolation of pharmacokinetic data to un-tested species is complicated by the fact that theremay be differences in the way that even individualsand closely related species absorb and excrete anti-microbial drugs.15 For example, the aminoglycosidesare excreted unchanged by the kidney, and the phar-macokinetics are similar across species lines. Therecommended dose and elimination half-life are simi-lar in cockatiels and macaws despite a 10-fold differ-ence in body weight. The pharmacokinetics of drugsthat are metabolized show greater variability.

For some drugs there is good correlation betweendose and metabolic rate calculations based on bodysize. It has been suggested that the techniques of“allometric scaling” be used to extrapolate the dosesof these drugs from human and mammalian medi-cine to birds.15,55 Although allometric scaling has va-lidity for some compounds, veterinarians should beaware of its limitations. Evaluation of drug excretionand potential metabolic pathways are important, asnumerous exceptions to scaling exist — some withpotentially toxic results. For example, the elimina-tion half-life of chloramphenicol in budgerigars istwice as long as in macaws, despite a 30-fold differ-ence in body weight. In this instance, scaling a dosefrom a macaw to a budgerigar would result in toxicdoses, while scaling from a budgerigar to a macawwould result in completely ineffective doses. Unex-pected differences are also seen with doxycycline.The elimination half-life of orally administered doxy-cycline in Goffin’s Cockatoos is approximately 20hours, but in similarly sized Orange-winged AmazonParrots it is approximately 10 hours.19 Finally, scal-ing of a compound with a narrow therapeutic rangesuch as gentamicin could result in potentially lethaldosage recommendations if the drug is scaled fromdoses from small to large species. Allometric scalingis a useful tool when pharmacokinetic data is notavailable, but it should be used with caution and theeffects of dosing closely monitored. The adverse ef-fects of improper antimicrobial therapy are discussedbelow in the section on toxicity and side effects.


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Route of Administration

Selecting the route of drug administration in birdsrequires careful consideration. Available routes in-clude medicated water, medicated food, oral, intra-muscular, intravenous, subcutaneous, intraosseous,intratracheal, inhalation and topical. Factors to con-sider when selecting a route include: 1) The severityof the infection. Critically ill birds should be treatedwith parenteral medications to establish effectivedrug concentrations quickly. 2) The number of birdsto be treated. Medicated food or water may be theonly practical way to treat multiple-bird flocks (Fig-ure 17.3). 3) The availability of appropriate drugformulations. 4) The frequency of administration,resultant stress to the bird and the labor involved incompleting the treatment regimen. 5) The ability ofthe owner to complete the treatment regimen.

As noted previously, the route of delivery greatlyinfluences the drug concentration achieved in thehost. For example, Figure 17.1 shows that the con-centration of enrofloxacin achieved in African GreyParrots by offering medicated water is one-tenth ofthat achieved by oral or parenteral administration.This data must be considered when interpreting an-timicrobial susceptibility tests, as the achievabledrug concentrations will depend on the route of ad-ministration.

The advantages and disadvantages of various routesare discussed below. In general, medicated food andwater are traditionally favored routes for poultry butseldom achieve therapeutic drug concentrations incompanion and aviary birds. Most serious microbialinfections must be treated by the oral or a parenteralroute.

Water-based Drug AdministrationAdvantages: It is easy, handling of the birds is notrequired and the birds will self-medicate severaltimes daily. The presence of medication may decreasedisease transmission via contaminated drinkingwater.

Disadvantages: Consumption is erratic and thera-peutic serum concentrations are rarely achieved, es-pecially during the night when less water is con-sumed. Medicated water is often unpalatable, andreduced water consumption not only decreases thera-peutic drug concentrations but may also result indecreased water consumption and dehydration.Many antibiotics are not stable or soluble in water.

Comments: At first glance, medicated water wouldappear to be the ideal way to medicate many avianspecies. Unfortunately, with a few exceptions, medi-cated water will not adequately treat most compan-ion and aviary bird diseases. Psittacine birds simplyfail to drink enough water to consume adequate dosesof most antimicrobial drugs, especially if they are ill.If water is consumed, low drug concentrations areusually sustained in the bird because small amountsof drug are consumed often. Only highly susceptiblebacterial infections in a stable patient should betreated in this manner. Water-based drugs shouldnot be used in sick birds where the rapid estab-lishment of therapeutic drug concentrations is re-quired. Water-based medications can be used as anadjunct to direct drug administration or in situationswhere direct medication is impossible. Water-baseddrugs are most successful against mild infections ofthe alimentary tract where the drug may have a localeffect in the gut.

There are some specific drugs and therapeutic situ-ations where water-based administration may besuccessful. Enrofloxacin may successfully treathighly susceptible gram-negative bacteria (MIC<0.05 µg/ml). Sulfachlorpyridizine may be effectiveagainst alimentary tract infections caused by highlysusceptible strains of Escherichia coli. Spectinomy-cin may be effective against alimentary tract infec-tions caused by highly susceptible strains of E. coli.Nitrofurazone may slow the spread of salmonellawithin a flock. Aminoglycosides (eg, gentamicin, neo-mycin and amikacin) are not absorbed but may have

FIG 17.3 An adult cockatiel with a three-day history of anorexiawas found on the bottom of the enclosure. Depression is a hallmarkclinical sign of septicemia. These emergency cases usually requireparenteral administration of broad-spectrum antibiotics, paren-teral fluid therapy and corticosteroid administration to preventendotoxic shock due to degenerating gram-negative bacteria.


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a local effect against pathogens in the gut. Tetracycli-nes may slow the spread and alleviate clinical signsin birds with chlamydiosis but will not consistentlyclear birds of infection. Tetracyclines degrade rapidlyin water. Chlorhexidine may inhibit the spread andseverity of candida infections of the alimentary tract.

Food-based Drug AdministrationAdvantages: It is easy, the birds will self-medicateseveral times daily, capture and handling are notrequired and food consumption is often more consis-tent than water consumption. It may be possible tomedicate nestling birds by adding medication to thefood of their parents.

Disadvantages: Food often reduces drug absorptionand sick birds consume less food, especially if themedicated ration is unpalatable. As with medicatedwater, it is difficult to achieve therapeutic concentra-tions with food-based administration. Psittacinebirds are notorious for refusing new foods and mayreject even palatable medicated rations if the dietmust be changed to provide a food that will carry thedrug.

Comments: Powders, ground tablets and oral sus-pensions can be added to a palatable food vehicle suchas cooked mashes, rolled corn, canned and frozenvegetables or fruit mixtures. A cooked mash contain-ing 13% dry oatmeal and 29% each cooked kidneybeans, rice, and corn is nutritious and well acceptedby many psittacine birds. If a favorite treat food iswell accepted and quickly consumed, it may be possi-ble to lace it with the divided daily drug dose and offerit several times daily. If the drug must be added tofood consumed on an intermittent basis throughoutthe day, the total daily dose plus extra (based onwastage and estimated reduced drug availability)should be placed in the amount of food the bird willconsume in one day. As with medicated water, theachievable serum drug concentrations are usuallymuch lower than those reached with oral or paren-teral administration, so only highly susceptible bac-teria should be treated with food-based medications.

Formulated diets containing chlortetracycline arecommercially available and can be used to treatchlamydiosis. Chlortetracycline-impregnated milletseeda is also available and is readily accepted bybudgerigars and finches. These products sustainchlortetracycline blood concentrations of 0.5-1.5µg/ml when fed with diets containing < 0.7% calcium.It is also possible to prepare a medicated mash usingpowdered chlortetracycline.

Research on developing doxycycline-medicated dietsillustrates the importance of standardizing the com-ponents of a medicated ration. Consumption of thediet determines the amount of drug ingested and isdependent on energy content, palatability and fa-miliarity of the diet. For example, cockatoos receiv-ing ad libitum diets medicated with identical concen-trations of doxycycline (0.1%) achieved toxic plasmaconcentrations (8-10 µg/ml) when fed a medicatedcorn and soybean mash, adequate concentrations (1-2 µg/ml) when fed a medicated rice, corn, bean, andoatmeal mash, and low concentrations (< 0.5 µg/ml)when fed medicated pellets. The primary differenceamong these diets is the energy content. Drug con-centrations for medicated feed cannot be extrapo-lated from one diet to another without knowing theenergy content and palatability of the diets.

Oral MedicationAdvantages: A precise dose can be administeredand, because many drugs are available as oral sus-pensions in flavored pediatric strengths, dosing iseasy. Sick birds frequently require assisted feedings,and these drugs can easily be added to the feedingformula.

Disadvantages: Unless the bird is tame and findsthe medication palatable, the bird must be capturedand fully restrained to deliver the medication. This isstressful, and some birds will refuse to swallow medi-cations or may aspirate them into the nasal passages.It is often necessary to pass a tube and deliver oraldrugs into the crop of recalcitrant birds. Drug selec-tion is restricted since not all drugs are absorbedorally (eg, aminoglycosides, advanced generationpenicillins and cephalosporins). Some birds, (eg, ma-caws) may regurgitate medications delivered per os.

Comments: It is surprisingly difficult to force psit-tacine birds to accept oral medications. Bird ownersmay initially be able to administer the drug, but astreatment progresses the bird may become more dif-ficult to medicate. Sometimes the stress of handlingexceeds the benefits of the drug itself. Acceptance canbe improved if the drug is mixed with a palatablevehicle such as lactulose syrup or fruit juice. Oralsuspensions and solutions are appropriate for use inall birds; tablets and pills are probably not appropri-ate for use in birds with a crop. Capsules that rapidlydissolve can be used in those birds that are “pillable”(eg, pigeons, waterfowl and gallinaceous birds).


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Intramuscular InjectionAdvantages: An exact dose can be administered, andabsorption is usually rapid. The bird must be cap-tured, but restraint time is minimal.

Disadvantages: Not all antibiotics can be given IM,and injections may be painful and cause muscle ne-crosis (Figure 17.4). The volume of injected fluid mustbe carefully monitored in small patients.

Comments: Intramuscular injection is often thequickest and least stressful method of directly admin-istering drugs to companion birds. It is often easierto administer drugs IM than orally, and most birdowners can be taught to perform this procedure. Theproximal two-thirds of the pectoral muscles providethe optimal injection site. Drugs injected into themuscles of the legs may pass through the renal portalsystem first, clearing the drug before it can reach thesystemic circulation. Injection sites can be rotated toavoid excess trauma in one area. Short, 26 ga x 3⁄8“intradermal needles or insulin syringes work well.

Intramuscular injection may not be feasible in allbirds. Nestling birds of all species have relativelylittle pectoral muscle mass, and it is easy to piercethe sternum, which is non-ossified at this age. Rat-ites, even as adults, lack large pectoral muscles.Owners of racing pigeons, raptors and some gamebirds may refuse to give medications IM in the breastbecause they fear muscle damage will interfere withflight or normal activity.

The injection volume in relation to body size mustalso be considered. For example, on a body weightbasis, a 0.05 ml injection in a canary is equivalent toa 40 ml injection in a 25 kg dog. Injection volumes inpsittacine birds should be small but permit accuratemeasurement of the medication.

Subcutaneous InjectionAdvantages: An accurate dose and large volumes canbe administered. This is a good site for fluid admini-stration if the bird is not volume depleted or severelydehydrated. The best sites are the groin and dorsalcervico-thoracic area.

Disadvantages: Full restraint is required. Birdshave very thin skin and fluid will often leak out of theinjection site. Irritating drugs may cause skin ne-crosis and ulceration.

Comments: The subcutaneous route is not ideal butcan be used for irritating drugs when muscle necrosis

or injection trauma is to be avoided. This site is oftenused by pigeon and game bird breeders.

Intravenous InjectionAdvantages: An exact dose can be given and thera-peutic levels are rapidly achieved.

Disadvantages: The bird must be fully restrained;anesthesia may be helpful. Because avian veins arefragile, leakage of drug from the vessel and hema-toma formation are common.

Comments: Intravenous injection should be re-served for emergencies and one-time drug admini-stration. Veins may also be needed for blood with-drawal for diagnostic tests. The right jugular,superficial ulnar, basilic vein on the ventral humerusand superficial plantar veins are most accessible.Intravenous catheters are available but are poten-tially dangerous to leave in unattended birds. Intra-venous fluids can be delivered as a slow bolus at adose of 10 ml/kg without pulmonary compromise.

Intraosseous InjectionAdvantages: If repeated drug administration is re-quired the intraosseous route may be selected (Figure17.5). The intraosseous route allows stable access tothe intravascular space. A cannula can be insertedand used for repeated fluid or drug administration. Ifproperly bandaged, psittacine birds will usually tol-erate cannulas for short periods of time. Intraosseouscannulas are well tolerated in raptors, pigeons, wa-terfowl and other less temperamental species. The

FIG 17.4 Muscle necrosis secondary to a single IM injection ofticarcillin. Many of the drugs available for parenteral administra-tion in birds can cause mild to severe muscle necrosis.


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distal ulna and proximal tibia are the best locationsfor cannulation.

Disadvantages: Only fluids or non-irritating drugsshould be delivered via intraosseous cannulas. Steril-ity is critical, as infection may result in osteomyelitis.

NebulizationAdvantages: Nebulized antibiotics are useful forpulmonary, sinus and trachea infections, and areoften combined with mucolytic and penetratingagents (eg, DMSO) to break down caseous materialand increase antibiotic uptake. Simple humidifica-tion of the lungs is also helpful. Therapeutic serumlevels are seldom achieved but effective concentra-tions may be achieved in restricted sites in the upperrespiratory tract.

Disadvantages: At rest, there is little or no air ex-change in much of the respiratory tract. It has beensuggested that only 20% of the respiratory tractwould be reached by nebulization.2 The nebulizedparticle size should be less than 1-3 µm. Nebulizationshould usually be combined with systemic therapy.

Topical MedicationsSkin: Topical medications should be used carefullyand sparingly. Oily and toxic compounds should beavoided, as they will mat the feathers and be ingestedwhen the bird preens. A water-soluble formulationshould be selected if available. If it is necessary to use

greasy compounds, the site should be bandaged or thebird collared to prevent preening and ingestion. Pro-pylene glycol can be added to some preparations (eg,ivermectin) to allow systemic absorption of cutane-ously applied drugs.

Eye: Liquid eye drops retard corneal healing lessthan ointments but must be given more frequently.Ointments should be applied very sparingly, as ex-cess ointment will cause matting and loss of featherssurrounding the eye. Misting the eye with a water-soluble, topical spray may also be effective. Subcon-junctival injections may be considered for deliveringrepository drugs.

Nasal Flushes: Nasal irrigation can be very helpfulfor treating upper respiratory infections. Antibioticscan be added to flushing solutions, but in many casesunmedicated saline works as well. Isotonic solutionsshould be delivered with minimal pressure to avoiddamage to inflamed tissues.

Infraorbital Sinus Injection: Sinus injection isuseful for flushing and delivering medication into theinfraorbital sinus in birds with sinusitis. The injec-tion is made at the level of the commissure of thebeak, just ventral to the zygomatic arch, the same siteas for cytologic sampling (see Chapter 10). Care mustbe taken not to penetrate the globe of the eye. Ifsinusitis has resulted in blockage of the outflowtracts, low volumes of fluid must be slowly injected toprevent exophthalmus. Only non-irritating drugsshould be used.

Intratracheal (through the glottis): This is an effec-tive route for delivering amphotericin B to birdssuffering from tracheal and pulmonary aspergillosis.

Toxicity and Adverse Effectsof Antimicrobial Therapy

All antimicrobial drugs have the potential to harmthe host. Direct toxic effects and the reduction ofnormal alimentary tract flora can occur even whenantibiotics are used properly, requiring that birdsshould be monitored during treatment. Treatmentfailure and the development of resistant strains ofbacteria occur most often when drugs are used im-properly. Because the interplay between effectivetreatment, toxicity and adverse side effects is com-plex, the use of antimicrobials in birds should bepursued with caution, and routine prophylactictreatment of birds without a clear indication of infec-tion is not suggested in any circumstance.

FIG 17.5 It may be safe to deliver some drugs designed for IVadministration through indwelling intraosseous cannulas. If sev-eral days of therapy are necessary, the cannula can be placed inthe ulna. For birds that need only a single administration of a drugthat must be given slowly (most IV products), a cannula can beplaced in the tibia. It has not been determined which of the IV drugpreparations can safely be delivered through IO cannulas.


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Misuse of antimicrobials can have serious conse-quences, especially in an avicultural facility or mul-tiple-bird household. Selection of the wrong agentcan result in treatment failure and spread of disease-causing organisms by the inappropriately treatedbird. Use of low-dose administration (eg, drinkingwater-based) often generates resistant strains of bac-teria that may become established in the aviary.This, coupled with the stress and adverse effects ofdrug delivery on normal flora, can actually make adisease problem worse rather than better. When pre-scribing antimicrobials, it is important to explain tothe client the necessity of giving the full treatmentregimen without skipping doses, even if the birdimproves before treatment ends. This is necessary toprevent a recurrence of the infection and generationof resistant strains of bacteria.

Direct Toxic EffectsDrug toxicity varies with the compound, dose andphysiologic status of the patient. Toxic effects of spe-cific agents are listed in the section below, but somegeneralities can be made. The beta lactam antibioticshave relatively few direct toxic effects. The aminogly-cosides are nephrotoxic at therapeutic doses andshould be used with extreme caution in juvenile anddehydrated birds. Sulfa drugs should also be usedcautiously in birds that are uricemic, because theyare potentially nephrotoxic in dehydrated animalsand are metabolized via the same metabolic pathwayin the liver as uric acid. The fluroquinolones causedefects in the articular cartilage of some species ofgrowing animals (eg, dogs, pigeons and horses) butnot others (eg, cats). These effects are both species-and dose-dependent. To date, toxic effects have notbeen proven in psittacine birds treated with recom-mended doses of fluroquinolones.

Adverse Effects on Normal Alimentary Tract FloraMost of the antibiotics used in avian practice arebroad spectrum and their use will reduce or elimi-nate normal alimentary tract flora. Normal florahelp reduce infection by potentially harmful microor-ganisms by competing for nutrients and occupyingcellular attachment sites. Eliminating normal floramay render the bird more susceptible to colonizationby potential pathogens such as yeast, viruses andgram-negative bacteria. Birds receiving antibioticsshould be monitored for secondary infections withcloacal cultures and fecal Gram’s stains.

Inappropriate antimicrobial therapy may potentiatean infection if the pathogen is resistant but the drugselected eliminates normal flora. This will favor

growth of the pathogen in a competition-free environ-ment (eg, digestive tract, skin, nasal passages). Forthis reason, drugs and the route of administrationshould be selected with care, and non-specific pro-phylactic use of antimicrobials should be avoided. Itmay also be advisable to culture the cloaca prior toantimicrobial treatment of all birds, even if the ali-mentary tract is not the primary site of infection. Ifpotential pathogens are isolated, the treatment regi-men should include a drug that will be effective forthese organisms as well as the primary pathogens;otherwise minor alimentary tract pathogens mayproliferate and cause illness if the competition fromnormal flora is eliminated. Environmental sources ofharmful microorganisms should be eliminated dur-ing antimicrobial treatment by improving hus-bandry. Young and immunocompromised birdsshould be monitored every day during antimicrobialtherapy to prevent potential yeast infections.

Treatment FailureBirds are perceived to be masters at hiding theirsigns of disease and are often in an advanced state ofillness by the time they are presented for treatment.It is important to establish a correct diagnosis andimplement an effective treatment plan early in thedisease process because there is seldom time to sim-ply try a drug and see what happens. If the wrongdrug or route of administration is selected, or if theproblem is not due to a microbial infection, the birdmay die while waiting to determine if prophylactictherapy is successful.

Some pet stores may sell over-the-counter (OTC)antibiotics with label claims that they are beneficialfor treating a variety of avian respiratory and gastro-intestinal complaints. Most of these products containtetracycline, erythromycin or a sulfa drug, and arecompounded for water administration. These prod-ucts are seldom effective at the doses and routesrecommended, and many bird owners waste valuabletime attempting treatment with these products be-fore consulting an avian veterinarian. By the timethe bird receives appropriate care, it is usually toolate. Bird owners should be educated to avoid theseuseless medications and to use more effective diag-nostic and therapeutic methods with their pets.

Development of Resistant Strains of BacteriaBacteria develop resistance to drugs by two primarymethods: transfer of plasmids and chromosomal mu-tation. These methods may: 1) induce production ofan enzyme that degrades the antibiotic; 2) altermembrane permeability and therefore prevent the


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antibiotic from penetrating the bacteria; or 3) createan alternate metabolic pathway that bypasses theaction of the antibiotics. Plasmids are cytoplasmicbundles of nucleic acid that can be transferred amongdifferent species of bacteria, and are therefore themost important mechanism of developing, maintain-ing and transferring resistance in a bacterial popula-tion. Resistance is most common among gram-posi-tive and gram-negative bacteria and less common inanaerobes, chlamydia and yeast.

Sub-therapeutic treatment can encourage the devel-opment of resistant bacteria. If low antibiotic concen-tration is achieved at the site of infection (such astypically occurs with water-based treatment re-gimes), only the highly susceptible bacteria will bekilled. The remaining resistant bacteria will thenmultiply to use the space and nutrients formerlyconsumed by the susceptible bacteria. Over time,resistant bacteria may become established in a hos-pital or aviary. Sub-therapeutic or random non-spe-cific treatment would be considered worse than notreatment at all if resistant bacterial strains aregenerated at the same time normal alimentary tractflora is reduced.

Cost

The small size of most avian patients makes it possi-ble to economically use antibiotics that would be tooexpensive in traditional small animal species. Thispermits use of a variety of advanced generation anti-biotics, especially among the beta lactams. In appro-priate situations, these antibiotics are quite effec-t i ve ; ho we ve r, t he y s ho uld no t be us edinappropriately, or microbial resistance will occur.

Antibacterial Therapy

The following sections were written to provide con-cise, practical information about the pharmacologyand use of antimicrobial drugs in birds, primarilypsittacines. More exhaustive reviews of drug phar-macology and use in poultry are available in thereferences (see Chapter 18).47,51

Fluoroquinolones

PharmacologyThe fluoroquinolones are a relatively new class ofantimicrobial drugs that inhibit bacterial gyrase, theenzyme responsible for coiling DNA within the bacte-rial nucleus. They are bactericidal, widely distrib-uted to tissues and the extracellular space, and areexcreted primarily through renal tubular secretionand glomerular filtration. There is some hepatic me-tabolization, and enrofloxacin is partially metabo-lized to ciprofloxacin, an equipotent metabolite.Fluoroquinolones are generally well tolerated, al-though gastrointestinal upset and anorexia havebeen occasionally reported, and they may induce sei-zures in seizure-prone animals. High-dose or pro-longed treatment may cause permanent articulardefects in growing juveniles of certain species, in-cluding dogs, pigeons and horses.36

Use in Companion Avian MedicineEnrofloxacin: Enrofloxacin is currently the onlyveterinary-labeled fluoroquinolone. It has excellentactivity against mycoplasma, some gram-positivebacteria and most gram-negative bacteria. Resis-tance of Pseudomonas spp. is occasionally seen. En-rofloxacin is highly active against most Enterobacte-riaceae recovered from psittacine birds. It reducesclinical signs in birds infected with Chlamydia psit-taci, but anecdotal comments indicate that enroflox-acin treatment does not routinely clear the carrierstate. Currently, only tablets and IM preparationsare available in the United States. A water-solubleliquid is available in some countries.

Studies on the single-dose kinetics of enrofloxacin inhealthy African Grey Parrots, Blue-fronted and Or-ange-winged Amazons, and Goffin’s Cockatoos indi-cate that a dose of 7.5-15 mg/kg administered IM orPO BID should maintain effective concentrations inthese species.26,27 Elimination in the African GreyParrot was more rapid than in the Amazon parrot orcockatoo. For highly susceptible bacterial infections(MIC ≤ 0.03 µg/ml) in the Amazon parrot and cocka-too, SID therapy may be adequate. Intramuscularinjection achieves greater peak concentrations (3-5µg/ml versus 1-1.5 µg/ml with oral administration at15 mg/kg), but concentrations after two to four hoursare similar to those achieved with oral administra-tion of the water-soluble solution. The IM formula-tion causes irritation at the site of injection, butgiven orally, the IM formulation induces higher peakplasma concentrations (1.5-2.5 µg/ml at 15 mg/kg)than the water-soluble formulation.


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Mean plasma concentrations of approximately 0.1µg/ml were maintained in African Grey Parrots feddrinking water medicated at 0.19-0.38 mg/ml. Theseconcentrations might be effective for highly suscepti-ble gram-negative bacteria.25 Effective clearance ofgram-negative bacteria from psittacine birds hasbeen reported using IM (10 mg/kg SID) or water-based administration (100-200 ppm) for ten days.36

Combination therapy in Senegal Parrots treatedwith enrofloxacin-medicated drinking water (100ppm) and ketoconazole (30 mg/kg PO SID) for 10days produced evidence of renal toxicity.36 The half-life of enrofloxacin in pigeons was 2.6-4.7 hours withtissue concentrations exceeding those of serum inone hour. Recommended doses are 5 mg/kg, BID IM,PO or SC, or 100-200 ppm (0.1-0.2 mg/ml) in thedrinking water for highly susceptible bacteria.14

Enrofloxacin and ciprofloxacin have been widelyused in psittacine nurseries without reports of sideeffects. However, the drug should be used with cau-tion in growing birds since toxic effects are species-specific and dose-related, and the drug has not beenstudied in all species. There have been scattered,anecdotal reports of aggressive, irritable behavior inadult Amazon parrots treated with quinolones.

Ciprofloxacin: Ciprofloxacin is a human-labeledfluoroquinolone with an antibacterial spectrum andpharmacology similar to enrofloxacin. Ciprofloxacintablets appear to be more water soluble than en-rofloxacin. Ciprofloxacin has not been shown to havea therapeutic advantage over enrofloxacin.

CommentsThe fluoroquinolones, especially enrofloxacin, areamong the most effective drugs for treating gram-negative bacterial infections (Figure 17.6). Effectivetreatment with BID (or in some species, SID) admini-stration is a clear advantage over some other antibi-otics. Enrofloxacin can be administered orally but isbitter, and many birds will refuse to accept it. It maybe necessary to dilute the drug in a palatable vehiclesuch as fruit juice or lactulose syrup, or to deliver itvia a gavage tube. The major disadvantage to paren-teral administration is intramuscular pain and irri-tation at the site of injection.

Penicillins

Characteristics: The penicillins are beta lactam an-tibiotics. They inhibit the formation of the bacterialcell wall and are bactericidal for growing and dividingorganisms. The spectrum and route of administrationvary with the generation of the product. Older agents,such as ampicillin and amoxicillin, are effectiveagainst many gram-positive and some gram-negativeorganisms, and are available in oral and injectableformulations. Later-generation penicillins such asticarcillin and piperacillin have enhanced activityagainst gram-negative bacteria, including Pseudo-monas spp., but are primarily available in parenteralformulations.40

Penicillins are widely distributed to the extracellularspace but poorly penetrate the CSF. Excretion israpid (half-lives are usually less than 60 minutes)and is accomplished primarily through renal tubularsecretion and glomerular filtration. Penicillins areconsidered relatively nontoxic, although allergic re-actions (anaphylaxis) can occur. Procaine penicillinmay cause adverse reactions in small patients (eg,

FIG 17.6 A duck with osteomyelitis of the tibiotarsal/tarsometa-tarsal area. Surgical debridement and long-term antibiotic ther-apy are usually required to resolve bone infections.


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finches, canaries, budgerigars and cockatiels) due tothe procaine component. Penicillins have reducedefficacy in the presence of overwhelming numbers oforganisms (“inoculum effect”). Penicillins are syner-gistic when combined with aminoglycosides, and thiscombination can be used to treat severe infections,especially those caused by Pseudomonas spp.. Thesetwo agents should not be combined in the same syr-inge or the aminoglycoside will be inactivated.

Use in Companion Avian MedicineNatural Penicillins: Natural penicillins have a nar-row spectrum restricted to Pasteurella spp. and somegram-positive organisms with MIC’s less than 1µg/ml. They are rarely used in avian medicine due tothe availability of more effective drugs.

Ampicillin / Amoxicillin: Many gram-positive bac-teria are susceptible to ampicillin and amoxicillin,but most gram-negative isolates are resistant at con-centrations achievable in birds. Oral absorption ofampicillin is highly erratic, so treatment failures arecommon even when laboratory tests suggest the iso-lated organisms are susceptible. Tests in chickensand ducks indicate that oral amoxicillin induces dou-ble the plasma concentrations of oral ampicillin.37

Parenteral administration results in much higherand more consistent plasma concentrations. Am-picillin sodium doses of 100 mg/kg IM induced meanpeak plasma concentrations of 60 µg/ml that declinedto 0.65 µg/ml in four hours in Blue-naped Parrots.Based on this study, and another in Amazon parrots,it was recommended that ampicillin be dosed at 150mg/kg PO QID.17 Clark suggested that ampicillin inbirds may be eliminated via hepatic and intestinalroutes, in addition to renal excretion.9

Ticarcillin: The pharmacology of ticarcillin is simi-lar to that of carbenicillin; however, it is often two tofour times more active against Pseudomonas spp. Itis available for parenteral administration only.

Piperacillin: In humans, piperacillin has greateractivity against more gram-negative bacteria thanother penicillins. It is widely used by avian veteri-narians to treat systemic gram-negative bacterialinfections. It is available for parenteral administra-tion only. Serum and intestinal concentrations ofpiperacillin after an IM dose of 100 mg/kg in budgeri-gars were very high, and doses up to 1000 mg/kg didnot induce clinically apparent toxic effects.32 The half-life of piperacillin in Blue-fronted Amazon Parrotsdosed with 100 mg/kg IM was less than 30 minutes,and doses of 75-100 mg/kg IM administered three to

six times daily have been recommended.23 Higher andmore frequent doses should be used in more severeinfections.

Clavulinic Acid: Clavulinic acid has no antimicro-bial activity of its own, but when combined with apenicillin, it inhibits beta-lactamase, a bacterial en-zyme that inactivates many penicillins. Formula-tions combining clavulinic acid with amoxicillin orticarcillin are available. Reports of use in birds arerare, but this drug may offer safe, effective activityagainst gram-negative and gram-positive pathogens.

CommentsEarly generation penicillins are appropriate fortreating infections caused only by highly susceptiblepathogens. The advanced generation penicillins havean excellent gram-negative spectrum and are appro-priate for treating severe infections caused by theseorganisms. Penicillins have a very high therapeuticindex, an advantage when treating patients withcompromised renal or hepatic function. A major dis-advantage of using penicillins is the frequency ofadministration required to maintain effective con-centrations.

Cephalosporins

PharmacologyLike penicillins, the cephalosporins are beta lactamantibiotics; they share similar pharmacology but dif-fer in spectrum.41 Cephalosporins inhibit the forma-tion of the bacterial cell wall and are bactericidal forgrowing and dividing organisms. They are widelydistributed in the extracellular space, but most prod-ucts poorly penetrate the cerebrospinal fluid andother pharmacologically privileged spaces. Excretionis primarily through renal tubular secretion andglomerular filtration. Cephalosporins are consideredto be relatively nontoxic. They are classified intofirst, second and third generation products. In gen-eral, first generation products are effective againstmany gram-positive and some gram-negative bacte-ria, while increasing generations demonstrate en-hanced gram-negative activity but reduced activityagainst gram-positives. Like the penicillins, cepha-losporins also suffer from the “inoculum effect,” andshow reduced activity in the presence of overwhelm-ing numbers of organisms. They are potentially syn-ergistic when combined with aminoglycosides.

Use in Companion Avian MedicineFirst Generation Agents (eg, cephalexin and cepha-lothin): The antimicrobial spectrum of first genera-


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tion agents includes most gram-positive cocci, somegram-negative bacteria and some anaerobes. Oralcephalexin is readily absorbed after oral administra-tion in quail, ducks, cranes and emus. Doses of 35-50mg/kg QID for larger birds and BID to TID for smallerbirds have been recommended.42 Cephalothin isavailable as a parenteral formulation, and, based onsingle-dose studies, therapeutic concentrationsshould be maintained with doses of 100 mg/kg IMQID in pigeons, cranes and emus, and BID to TID inquail and ducks. The author has successfully treatedpsittacine birds with cutaneous infections caused byS. aureus using administration of cephalexin at adose of 100 mg/kg PO TID for 14-21 days.

Second generation agents (eg, cefoxitin and cetaxi-tin) have increased gram-negative activity and areavailable primarily in parenteral formulations.There are few reports of their use in birds. Presum-ably, the pharmacology would be similar to first andthird generation products.

Third generation agents (eg, cefotaxime andceftriaxone) have an expanded gram-negative spec-trum (including increased activity against Pseudo-monas spp.) and variable activity against gram-posi-tive bacteria. Cefotaxime is unusual amongcephalosporins because it penetrates the CSF in ef-fective concentrations. Ceftriaxone has an extendedhalf-life in humans (eight hours versus one hour formost other cephalosporins); however, the half-life isthe same as other cephalosporins in Amazon par-rots.23 Doses of 75-100 mg/kg IM given three to sixtimes daily should maintain effective plasma concen-trations. These agents are mostly available in paren-teral formulations; the use of newer drug prepara-tions that can be given orally has not been reportedin birds.

CommentsRecommendations are similar to the penicillins.First generation products have shown good activityagainst staphylococcus infections of the alimentarytract and skin of birds. The third generation productshave an excellent gram-negative spectrum. Cepha-losporins have a high therapeutic index, an advan-tage when treating patients with compromised renalor hepatic function. A major disadvantage of usingcephalosporins is the frequency of administrationrequired to maintain effective plasma concentra-tions.

Aminoglycosides

PharmacologyThe aminoglycoside antibiotics interfere with bacterialprotein synthesis and are bactericidal.42 They are notabsorbed from the GI tract and must be administeredparenterally. Aminoglycosides are confined to the ex-tracellular space and poorly penetrate the eye andcerebrospinal fluid. Excretion is almost exclusivelyby glomerular filtration. Aminoglycosides must pene-trate the bacterial cell wall to interfere with proteinsynthesis. This process requires oxygen, so amino-glycosides are not active against anaerobes or at siteswith low oxygen tension (eg, large abscesses). Al-though aminoglycosides are poorly bound to bloodproteins, they are extensively bound to intracellularproteins and may be inactivated in proteinaceousenvironments such as abscesses and exudates.

The aminoglycosides are relatively toxic when com-pared to other antibiotics. Nephrotoxicity and oto-toxicity are relatively common, even in humanswhere dosage regimens are tailored for individualpatients. The nephrotoxicity associated with recom-mended dosage regimens and short-term treatmentis usually reversible once treatment stops. Chronicrenal dysfunction occurs when high-dose or pro-longed therapy is attempted. Since excretion is de-pendent on glomerular filtration, aminoglycosidesshould be used with caution in dehydrated patients.Another side effect, neuromuscular synaptic dys-function and paralysis, can occur if the drug is givenintravenously at a rapid rate.

Use in Companion Avian MedicineEarly Generation Aminoglycosides: Streptomycin,dihydrostreptomycin, neomycin and kanamycin havelimited spectrum and greater toxicity, and are seldomused systemically in birds. Neomycin is used in topi-cal and ocular formulations and can be administeredorally to sterilize the gut.

Gentamicin: Gentamicin is effective against manygram-negative and gram-positive bacteria. It is moretoxic than amikacin, and signs of nephrotoxicity (eg,polyuria and polydipsia) are often encountered evenwhen birds are treated with low doses. The degree oftoxicity varies with individuals and species. For ex-ample, toxic reactions were more severe in Rose-breasted Cockatoos than in Scarlet Macaws treatedwith 5 mg/kg IM BID for seven days (Figure 17.7).The cockatoos remained polyuric for more than 30days after treatment ended.24 Based on these studies,gentamicin doses of 2.5-5 mg/kg IM BID should pro-


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vide efficacious plasma concentrations and reducetoxicity. Variability in toxicity has also been demon-strated in raptors. Renal toxicity was found in LannerFalcons treated with 5 mg/kg/day for four days,18 anddoses of 10 mg/kg administered BID for five days inGreat Horned Owls produced reactions ranging fromno signs to death. Doses similar to those in psittacinebirds (2.5 mg/kg IM TID) are recommended for rap-tors.4 Previously recommended doses (10 mg/kg IMTID) are excessive and may cause severe toxicity anddeath.

Tobramycin: The pharmacology of tobramycin inmammals is similar to that of gentamicin, but it hasgreater activity against Pseudomonas spp. and someother gram-negative bacteria. Pharmacology studiesin birds are lacking, but it is probably similar togentamicin. In dogs and humans, tobramycin is con-sidered slightly less toxic than gentamicin but moreso than amikacin. The estimated dose for tobramycinis 2.5-5 mg/kg IM BID.

Amikacin: Amikacin has excellent activity againstmany gram-negative bacteria, including some strainsthat are resistant to gentamicin and tobramycin.Amikacin is approximately four times less activethan gentamicin but is correspondingly less toxic, sohigher doses can be used safely. Amikacin causesfewer toxic side effects and is the aminoglycoside ofchoice for use in birds.

Pharmacokinetic studies have been completed inseveral psittacine species. Doses of 13 and 20 mg/kgIM in healthy Blue-fronted Amazon Parrots pro-duced peak plasma concentrations of 40 and 75 µg/mlrespectively that declined to zero by eight hours.20

When these doses were administered for seven days,mild signs of toxicity (polyuria) occurred but rapidlyresolved when treatment ended. Similar single-dosepharmacology was observed in cockatiels, Goffin’sCockatoos,20 and Orange-winged Amazon Parrotsand in African Grey Parrots.28 Based on these stud-ies, amikacin doses of 10-15 mg/kg IM administeredBID or TID should provide effective plasma concen-trations for most susceptible gram-negative bacteria.The higher end of the dosage range should be usedwith more resistant organisms, sites of infection withpoor perfusion or in critically ill patients. In dehy-drated birds and those with compromised renal func-tion, the dose should be reduced or a less toxic drugselected.

CommentsThe aminoglycosides are excellent drugs for treatingresistant gram-negative bacterial infections in birds.They are active against Pseudomonas spp., especiallywhen combined with a third generation cepha-losporin (eg, cefotaxime) or late generation penicillin(eg, piperacillin). However, these two agents mustnot be combined in the same syringe. Aminogly-cosides should be avoided or used with care in dehy-drated patients. Amikacin is currently the aminogly-coside of choice for avian use because of its broadspectrum and reduced toxicity compared to otheraminoglycosides.

Tetracyclines

PharmacologyTetracyclines interfere with bacterial protein synthe-sis and are bacteriostatic.43 In mammals, they areeffective against a broad spectrum of gram-positiveand some gram-negative bacteria. It is difficult toachieve concentrations that are effective for treatingbacterial infections in companion and aviary birds,and tetracyclines are primarily used to treat chlamy-diosis and mycoplasmosis. Tetracyclines are lipid sol-uble and are widely distributed to tissue. They aremostly available as oral formulations. Injectable for-mulations are available for some compounds butcause necrosis at the site of injection. Oral absorptionis generally good except in the presence of cationssuch as calcium or magnesium, which chelatetetracyclines. The route of excretion varies with thecompound. Oxytetracycline and chlortetracycline areexcreted primarily by hepatic metabolism and renalexcretion; minocycline is metabolized by the liverand excreted in the bile; and doxycycline is excretedas an inactive conjugate in the feces. Toxicity varieswith the compound used, species of animal and dura-tion of treatment. Tetracyclines will chelate calciumin the teeth and bone. GI upset and photosensitiza-tion have been reported. Prolonged treatment mayhave catabolic and immunosuppressive effects, re-duce normal gut flora and render the animal moresusceptible to opportunistic infections.

Use in Companion Avian MedicineChlortetracycline: Diets containing 1% chlortetra-cycline are recommended for treating psittacinechlamydiosis in the United States.12 Diets containing0.5% chlortetracycline have been shown to be effec-tive in Europe. Powdered chlortetracycline can beadded to a cooked mash, or medicated pellets arecommercially available. The efficacy of these diets


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will vary with the nutritional composition of theration. Birds will tend to consume less of a diet witha high-energy content (eg, formulated diets) andmore if the energy content is reduced (eg, cooked cornmashes). Although medicated diets may be successfulin reducing the clinical signs of chlamydiosis, com-mon sequelae to treatment include diet refusal, star-vation, treatment failures and secondary microbialinfections.21

Oxytetracycline: Water-soluble formulations ofoxytetracycline are available, but oral absorption ispoor. A long-acting injectable formulationc is avail-able and may maintain plasma concentrations effec-tive for controlling chlamydiosis in Goffin’s Cockatoosfor two to three days; however, this drug preparationis irritating and will cause necrosis at the injectionsite.22 The single dose kinetics of intramuscular injec-tion has been investigated in pheasants, GreatHorned Owls and Amazon parrots.59 It can be nebu-lized for treating respiratory infections, but must bedosed every four to six hours.16

Minocycline: This drug has an extended half-life inmammals. It has been used experimentally to coatmillet seeds and treat chlamydiosis in small psittac-ine birds.54

Doxycycline: Doxycycline has a prolonged half-lifeand differs from conventional tetracyclines becauseit is more lipophilic. The half-life varies with thespecies. At oral doses of 50 mg/kg, the half-life aver-ages ten hours in cockatiels and Amazon parrots andgreater than 20 hours in cockatoos and macaws.19

This is the drug of choice for treating chlamydiosis,and oral dosage recommendations are: 40-50 mg/kgPO BID in cockatiels and Blue-fronted and Orange-winged Amazons; 25 mg/kg PO BID in African Grey

Parrots, Goffin’s Cockatoos and Blue and Gold andGreen-winged Macaws. In untested species it is im-possible to precisely extrapolate dosages; however,25-30 mg/kg is the recommended starting dose incockatoos and macaws, and 25-50 mg/kg is recom-mended in other species.

If regurgitation occurs, the dose should be reduced by25% or divided and administered BID. Hepatotoxic-ity, as detected by elevated AST and LDH tests, mayoccur in macaws. Dosage recommendations for treat-ing chlamydiosis in psittacine birds with injectabledoxycycline (Vibravenös formulation only!) is 75-100mg/kg IM every five to seven days. In macaws, thelower dose and more frequent administration shouldbe administered in the last three weeks of treat-ment.29 There have been anecdotal reports of use ofpharmacist-compounded injectable doxycyclineproducts; however, kinetic studies are lacking and itis impossible to extrapolate dosage schedules fromone formulation to another.

CommentsIn companion and aviary birds, tetracyclines are pri-marily used to treat chlamydiosis and, to a lesserextent, mycoplasmosis and pasteurellosis. Dosageregimens are based on attaining sustained blood con-centrations of 1 µg/ml — a concentration thought toinhibit chlamydiosis.1

Trimethoprim / Sulfonamide Combinations

PharmacologyA combination of trimethoprim and a sulfonamide issynergistic, as both drugs interfere with microbialfolic acid synthesis.7 This combination has good effi-cacy against many gram-positive and gram-negativebacterial pathogens, with the exclusion of Pseudo-monas spp. Use of these drugs in combination haslargely replaced use of either component alone fortreatment of systemic bacterial infections. This com-bination is probably bacteriostatic at the doses usedin birds. Oral and parenteral formulations are avail-able and readily absorbed. The sulfa drugs are pri-marily distributed to the extracellular space, whiletrimethoprim is more lipophilic and has good tissuepenetration. Excretion is primarily renal, and thedegree of hepatic metabolism varies with the species.A number of side effects, including rashes, photosen-sitization, arthritis and hepatic disorders, have beenreported in mammals but not in birds.

FIG 17.7 Adverse effects of gentamicin in Scarlet Macaws (opencircles) and Rose-breasted Cockatoos (Flammer, et al: Am J VetRes 51[3]:406, reprinted with permission).


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Use in Companion Avian MedicineThe pharmacology of trimethoprim/sulfonamidecombinations has been investigated in poultry,65

geese52 and pigeons,13 but not in psittacine birds.Empirical doses of 16-24 mg/kg trimethoprim/sul-fonamide (oral solution) administered BID, and 8mg/kg IM (40 mg/ml trimethoprim + 200 mg/ml sul-fadiazine) BID have been widely used clinically withgood success.

Trimethoprim and sulfonamide combinations havefew toxic effects, but many birds (especially macaws)suffer GI upset and will regurgitate one to threehours after an oral dose. The incidence of GI upsetcan be reduced if the drug is added to a small amountof food or if the dose is reduced. Sulfonamides formcrystals and damage renal glomeruli in dehydratedbirds and those with compromised renal function.The injectable product may cause irritation and ne-crosis at the site of injection.

Two formulations are available, each combiningtrimethoprim with a different sulfa drug. There is noclear advantage for either preparation. Trimeth-oprim/sulfadiazine (veterinary formulation) is avail-able in injectable and oral forms. Trimethoprim/sul-famethoxazole (human formulation) is available inoral suspension.

CommentsTrimethoprim/sulfadiazine is an excellent broad-spectrum bacteriostatic drug. It is often the drug ofchoice when using the oral route to deliver antibiotics(eg, treating gram-negative infections in nestlingbirds).

Macrolides and Lincosamides

PharmacologyThe macrolides and lincosamides interfere with bac-terial protein synthesis, are bacteriostatic and sharesimilar pharmacology.6 Their spectrum of action in-cludes gram-positive bacteria, pasteurella, borde-tella, some mycoplasma and obligate anaerobic bac-teria. Injectable formulations are available but areseldom used in birds due to irritation and necrosis atthe site of injection. Oral absorption is good in mam-mals, but there are few pharmacokinetic studies inbirds. All are well distributed to tissues and elimi-nated primarily by hepatic metabolism. Toxicity isusually limited to gastrointestinal irritation andvomiting.

Use in Companion Avian MedicineThe primary uses for the macrolides are to treatgram-positive infections in finches, suspected or con-firmed mycoplasma in psittacine birds and gram-positive or anaerobic osteomyelitis. These drugs arealso active against Campylobacter spp. and Clos-tridia spp. Clindamycin is the most active of thelisted drugs.

Tylosin: The pharmacokinetics of intramuscularlyadministered tylosin has been studied in quail, pi-geons, cranes and emus.38 Peak concentrations of 3-5µg/ml were achieved, and doses of 15-25 mg/kg TIDto QID were recommended, with the cranes receivingthe lower dose. Unfortunately, tissue necrosis at thesite of injection would preclude a multi-day treat-ment regimen using the IM formulation at this fre-quency. Effective pulmonary concentrations wereachieved with nebulization of 1 gram tylosin in 50 mldimethyl sulfoxide (DMSO) for one hour.39 Treatmentof conjunctivitis in cockatiels with a tylosin and waterspray has been suggested.33

Erythromycin: Erythromycin is active against cam-pylobacter and mycoplasma. Dosages have been in-vestigated in pigeons,44 but it is rarely used in com-panion and aviary birds. In humans, erythromycin isactive against chlamydia, but it is not likely to elimi-nate this organism in birds at accepted avian dos-ages. A water-soluble powder has been used to treatmild respiratory infections in psittacine birds at arate of 500 mg/gallon of water but is of questionableefficacy. A popular over-the-counter productb is avail-able for medicating drinking water, but it is doubtfulthat this product achieves plasma concentrations ef-fective for treating most microbial infections in com-panion birds.

Clindamycin: Clindamycin is the most active of themacrolides mentioned. It is used to treat anaerobicinfections and osteomyelitis caused by susceptiblegram-positive pathogens. The author treatedosteomyelitis in a macaw with a combination of en-rofloxacin and clindamycin for seven months withoutdetectable toxic effects.

New Macrolides: Research on treating Chlamydiatrachomatis infection in humans has focused on theuse of new macrolide (azalide) antibiotics (ie, azithro-mycin and clarithromycin). These drugs are well tol-erated and have a prolonged tissue half-life. Studiesin humans have demonstrated that a single dose ofeither drug is as effective in eliminating C. trachoma-tis infection as a seven-day course of doxycycline. The


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disposition and safety of these drugs in birds remainto be investigated.

Lincomycin: Lincomycin is usually combined withspectinomycin and has been used in finches to treatrespiratory and alimentary tract infections caused bygram-positive bacteria and mycoplasma in other spe-cies.

Chloramphenicol

PharmacologyChloramphenicol interferes with bacterial proteinsynthesis and is bacteriostatic.58 Its antimicrobialspectrum includes many gram-positive and somegram-negative bacteria. It will inhibit chlamydialgrowth and alleviate clinical signs in infected birds,but will not routinely clear a bird of infection. Oraland parenteral formulations are available; however,oral absorption is highly erratic. Chloramphenicol ishighly lipid-soluble and is widely distributed to mosttissues, including the central nervous system. Tissueconcentrations often exceed serum levels. The routeof excretion varies with different species, but in mostcases it is metabolized by the liver.

Potential toxic effects include reversible dose-relatedbone marrow depression, inhibition of hepatic mi-crosomal enzyme synthesis, inhibition of host proteinsynthesis resulting in decreased wound healing anddecreased immunoglobulin synthesis.58 In a smallpercentage of the human population, non-dose-re-

lated, irreversible, aplastic anemia may occur, evenwith mild cutaneous contact. For this reason, clientsare instructed to handle this drug carefully and weargloves when treating birds.

Use in Companion Avian MedicineOral Formulation (palmitate ester): This formula-tion is readily accepted by most birds but achieveserratic blood concentrations.10 It is infrequently usedin avian medicine due to the potential toxicity inhumans and the availability of more effective oraldrugs (eg, trimethoprim/sulfa combinations and en-rofloxacin).

Injectable Formulations (succinate, propylene gly-col-based): These formulations yield more predictableserum concentrations than the oral preparations.The succinate formulation yields lower serum con-centrations, but is less irritating to muscle. There iswide pharmacokinetic variation among species. Forexample, the elimination half-life in budgerigars waslonger than in macaws.10 Doses of 50 mg/kg IM TIDare recommended for most psittacine birds.

CommentsUse of chloramphenicol has been largely replaced byother antibiotics that are more effective and can beadministered less frequently. Chloramphenicol isstill useful for treating infections caused by suscepti-ble intracellular bacteria (eg, salmonella) and wherepenetration into the central nervous system is de-sired. Chloramphenicol is bacteriostatic and is prob-ably not the drug of choice for initial treatment ofsevere, life-threatening infections.

Antifungal Therapy

The most common fungal infections encountered inpsittacine birds, raptors and waterfowl are candidi-asis (usually confined to the alimentary tract) andaspergillosis (respiratory and cutaneous).47 Otherfungal infections such as cryptococcosis, sporotricho-sis, blastomycosis and histoplasmosis are infre-quently encountered.

Historically, nystatin, flucytosine and amphotericinB have been widely used in birds. Development of theorally active, broad-spectrum azole antifungals (first

FIG 17.8 Bacterial-induced pruritic dermatitis that was respon-sive to systemic antibiotic therapy. Many cases of bacterial derma-titis recur when therapy is stopped (photo courtesy of LouiseBauck).


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ketoconazole and more recently, fluconazole and itra-conazole) may offer similar or greater efficacy, easieradministration and lower toxicity. The major draw-back to the use of azoles is the lack of pharmacoki-netic and toxicologic information to guide dosageselection. However, empirical doses have been estab-lished, and use of these drugs is becoming estab-lished in avian medicine. As with antibacterialagents, spectrum, ability to reach the site of infec-tion, route of administration and potential toxicityare important considerations when selecting an anti-fungal agent.

Nystatin

PharmacologyNystatin is a polyene antimicrobial that disrupts thefungal cell membrane by substituting for ergos-terol.48 It is effective against most strains of candidaand some other yeasts, although clinical evidencesuggests resistant yeast strains may occur in somepsittacine nurseries.46 It is not absorbed from the GItract and is available for oral or topical use only.Nystatin is relatively nontoxic due to the lack ofsystemic absorption, and is suitable for treating ali-mentary tract infections caused by candida and othersusceptible yeast. It must come in direct contact withthe yeast to be effective. Treatment failures mayoccur if the nystatin is delivered via a tube or syringeto the back of the oral pharynx, bypassing morerostral sites of infection in the mouth.

Use in Companion Avian MedicineNystatin is a highly useful drug for yeast infectionsthat are confined to the alimentary tract. It has lowtoxicity and is safe for use in nestling birds. Somebirds suffer GI upset and may regurgitate followingrepeated or large doses. With oral infections, nys-tatin or a more potent topical drug (eg, amphotericinB cream) can be applied directly to the lesions. Ifresistance or a non-alimentary tract infection is en-countered, a systemically active antifungal should beused.

Nystatin dosage recommendations have been empiri-cally derived but are supported by effective, long-term clinical use. Individual birds can be treatedwith 300,000 IU/kg orally BID or TID for five to tendays. Nystatin can also be added to hand-feedingformulas for prophylactic treatment in nurseries ex-periencing chronic yeast problems. If the yeast ishighly susceptible to nystatin, food-based admini-stration will be effective. A nystatin feed premixd hasbeen used to medicate a mash diet to treat flocks.

Amphotericin B

PharmacologyAmphotericin B is a polyene antimicrobial drug thatdisrupts the fungal cell membrane by substitutingfor ergosterol.3 It is active against most of the yeastand fungi of medical importance. Resistance by somestrains of Aspergillus spp. has been reported in manand other animals. Comparison studies in humanshave shown that amphotericin B is still one of themost efficacious antifungal drugs, especially forchronic infections and infections in immunocom-promised hosts. Clinical data demonstrating im-proved efficacy when amphotericin B is combinedwith flucytosine or an azole antifungal are conflict-ing, but combination therapy is a common practicefor treating serious fungal infections in humans. Am-photericin B is not well absorbed after oral admini-stration and is too irritating for intramuscular orsubcutaneous injection; thus, it must be deliveredintravenously or used topically. It is widely distrib-uted to tissue and extracellular spaces where it ismetabolized and slowly excreted in the urine. Am-photericin B is highly nephrotoxic in mammals, al-though this can be reduced by instituting a step-wisedosing scheme based on renal function calculatedfrom creatinine clearance levels.

Use in Companion Avian MedicineAmphotericin B is one of the drugs of choice forinitially treating serious, systemic fungal infections.Major disadvantages are potential toxicity and theneed for IV administration. It has been used in com-bination with flucytosine in raptors and swans withfair results.48 A new, orally active azole, itraconazole,may offer similar activity or may potentiate the ef-fects of amphotericin B.

Amphotericin B can be nebulized or injected into anaffected air sac for respiratory infections. It can alsobe injected through the glottis or administered trans-tracheally to treat tracheal and syringeal aspergil-losis. A topical cream in a plasticized base is availablefor treatment of topical lesions and oral candidiasis.

The pharmacokinetics of amphotericin B in turkeysand selected raptors indicate that these birds elimi-nate the drug much more rapidly than mammals.52

Based on these findings and clinical experience,doses of 1.5 mg/kg IV BID are recommended. Phar-macokinetic data in psittacine birds is lacking. Long-term use in raptors was not associated with nephro-toxicity, so the drug may be safer in avian thanmammalian species.49 However, until more informa-


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tion on avian use is available, patients receiving thisdrug should be monitored for signs of nephrotoxicity(polyuria and uricemia).

Flucytosine

PharmacologyFlucytosine is converted by the liver to 5-fluorouracil,and exerts its antifungal effect by inhibiting DNAsynthesis.34 It is always used in combination withamphotericin B in humans, and this combination isconsidered useful for treating candida and cryptococ-cus infections. Resistance develops quickly when thedrug is used alone. It is well absorbed orally, showslittle protein binding and is widely distributed totissues that are difficult to penetrate such as theCSF, eye and joints. This drug is excreted almostentirely unmetabolized in the urine, and dosagemodifications are necessary in patients with reducedrenal function. Dose-related, reversible bone marrowdepression is the major toxic change seen in humans,presumably due to the conversion of flucytosine into5-fluorouracil by GI tract bacteria. Hepatotoxicityand GI toxicity are occasionally reported in mam-mals.

Use in Companion Avian MedicineFlucytosine has been used singly as a prophylactictreatment to prevent aspergillosis in highly suscep-tible avian species undergoing stress (eg, hospitaliza-tion of swans) and in combination with other drugsto treat respiratory aspergillosis. In vitro susceptibil-ity of eleven strains of Aspergillus fumigatus indi-cated that flucytosine doses of 20-30 mg/kg QIDwould maintain inhibitory plasma concentrations.49

Because reported in vitro susceptibility data variesgreatly, a combination of flucytosine, amphotericin Band rifampin has been suggested for treating respi-ratory aspergillosis in raptors.48 Clinically, doses of50 mg/kg orally BID for two to four weeks appears toprevent aspergillosis when prophylactically adminis-tered to swans (Degernes L, unpublished). Flucytos-ine has been safe for long-term use (two to fourweeks) in raptors and waterfowl.49 Rosskopf, et al.reported successful treatment of esophageal and sub-cutaneous aspergillosis in a cockatoo using a combi-nation of flucytosine (65 mg/kg orally BID) and keto-conazole (20 mg/kg orally BID) for approximately onemonth.53

Recently available azole compounds may replaceflucytosine with drugs that are safer and more effec-tive.

Ketoconazole

A major breakthrough in antifungal therapy oc-curred in 1979 with the release of the azole drugketoconazole, the first orally active, systemic anti-fungal with a broad spectrum. Further research re-sulted in release of fluconazole in 1990 and itracona-zole in 1992. All three of these drugs are labeled forhuman use only. Older azole antifungals, miconazoleand clotrimazole, are suitable for intravenous andtopical use only and are more toxic than more re-cently available drugs.

The use of the azole antifungals in veterinary medi-cine has been reviewed.30 They inhibit synthesis ofthe primary fungal sterol, ergosterol, which is impor-tant in fungal cell membrane integrity. This is accom-plished by inhibition of a P450 enzyme system, and therelative potency of the azoles is determined by theiraffinity for this P450 enzyme moiety. Vertebrates alsohave a P450 enzyme system, and the selective toxicityof the azoles depends on their relative specificity forbinding fungal P450 enzymes. Potential toxic effects ofinterfering with vertebrate P450 enzymes include de-creased synthesis of cholesterol, cortisol and repro-ductive steroid hormones. Ketoconazole has the leastaffinity and specificity and is therefore consideredless active and potentially more toxic than flucona-zole and itraconazole; however, it is still a highlyuseful drug. All three azoles are fungistatic and sev-eral days of therapy are needed to achieve steady-state concentrations.

PharmacologyKetoconazole is effective against many of the yeastand fungi of medical importance, but Aspergillus spp.are often resistant.45 It is readily absorbed in an acidenvironment such as exists in the stomach followinga meal. It is widely distributed to tissues but is highlyprotein-bound and does not significantly penetrateinto the cerebrospinal or ocular fluids. It is elimi-nated via hepatic metabolism, and significant inter-actions occur with drugs that inhibit or induce he-patic enzyme metabolism (eg, rifampin andbarbiturates). Ketoconazole is considered more toxicthan either itraconazole or fluconazole. Reports oftoxicity are rare in birds, but anorexia, vomiting,jaundice and elevated liver enzymes have been re-ported in other animals. Long-term use in dogs hasresulted in decreased cortisol levels and decreasedtestosterone synthesis.

Ketoconazole is available in 200 mg tablets. Crushedtablets can be compounded with 0.15% methylcellu-


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lose into an oral suspension that is stable for sixmonths if refrigerated. Ketoconazole is water insol-uble unless in an acid environment. Medicated wateris therefore of questionable benefit except for infec-tions caused by highly susceptible yeast that arelimited to the GI tract.

Use in Companion Avian MedicineKetoconazole is currently the most widely used, leastexpensive, orally available and systemically activeantifungal. It is useful for treating resistant yeastinfections and yeast infections where systemic drugdelivery is required. It is not usually effective againstaspergillosis alone, but may have a synergistic effectwhen combined with other antifungals.

Limited pharmacokinetic studies have been per-formed in pigeons and cockatoos.35 Following oraladministration at 30 mg/kg, peak concentrationswere achieved in 0.5 to 4 hours and the eliminationhalf-life was 2 to 3.8 hours in pigeons and 3.8 hoursin Moluccan Cockatoos. No significant toxic reactionswere seen in pigeons given 30 mg/kg orally BID for30 days or Amazon parrots treated with 30 mg/kgBID for 14 days. Because absorption is increased inan acid environment, ketoconazole should be admin-istered with food. It is not necessary to pre-dissolvethe drug in acid.

Tracheal aspergillosis in an Amazon parrot wastreated using ketoconazole (approximately 25 mg/kgorally BID for 14 days) and intratracheal am-photericin B (50-75 mg/kg SID for seven days).53

Itraconazole

PharmacologyItraconazole is a triazole that was recently licensedfor use in humans in the United States.30 It is similarto ketoconazole but has 5 to 100 times greater po-tency, better in vitro and in vivo activity againstaspergillus infections and meningeal cryptococcoses,and fewer side effects. It is insoluble in water, highlylipophilic and is well absorbed if taken with a meal.It is highly protein-bound and widely distributed totissues. Tissue concentrations (especially fat, liver,adrenal cortex and skin) are substantially greaterthan plasma concentrations, and therapeutic concen-trations are maintained longer in tissue than inplasma. The volume of distribution greatly exceedsbody water (11-17 l/kg). It is poorly distributed toCSF, ocular fluids and plasma. It is degraded byhepatic metabolism, and the primary route of elimi-nation is via the bile. Elimination half-life in man is

longer than for ketoconazole (17 to 25 hours versus 8hours), and steady-state concentrations are achievedin approximately six days. Itraconazole is consideredsafe for long-term treatment in humans at a dose ofapproximately 4-6 mg/kg/day, and dogs receiving upto 40 mg/kg/day for three months did not show signsof toxicity.60 Maternal toxicity, embryo toxicity andteratogenicity were absent in mice treated with 10mg/kg/day, but did occur when the dose was in-creased to 40 and 160 mg/kg; use in pregnant ani-mals is not recommended.61

In man, itraconazole has shown promising results fortreating aspergillosis; however, there are conflictingreports when efficacy is compared to other drugs(primarily amphotericin B and flucytosine). Evenwith prolonged treatment (eg, several months), re-lapses and treatment failures are common. If reportsin the literature are any indication, itraconazolealone or in combination with amphotericin B appearsto be the treatment of choice for aspergillosis inhumans.

There is limited data on the use of itraconazole inanimals. It was as effective as ketoconazole whenused for three months in cats with cryptococcosis, butless toxic.44 Variable success has been seen with itra-conazole used to treat superficial dermatophyte in-fections and systemic blastomycosis.5 It was unsuc-cessful as a sole treatment in resolving four cases ofcanine nasal aspergillosis; better success wasachieved in another study when itraconazole wascombined with topical enilconazole infusion.64

Use in Companion Avian MedicineReports of itraconazole use in birds are limited, butit has been used to treat aspergillus and candidainfections in macaws and penguins.31 A severe Can-dida krusei tracheitis was resolved in a Blue andGold Macaw that received itraconazole at 10mg/kg/day for 35 days. Presumed ocular aspergillosisin a King Penguin was successfully resolved aftertreatment with 8 mg/kg/day for 29 days. Two pen-guins with candida infections of the uropygial glandwere successfully treated with 10 mg/kg/day for 20days. A Gentoo Penguin with a pulmonary aspergil-loma showed marked improvement and reduction inthe size of the aspergilloma after receiving itracona-zole at 8.3 mg/kg for 30 days and 17 mg/kg for anadditional 19 days. However, the bird died from cere-bral aspergillosis three weeks after therapy ended.In man, pulmonary aspergillosis is treated for six tonine months, so the treatment failure in this casemay have been due to the short duration of therapy.


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Fluconazole

PharmacologyFluconazole is a synthetic bistriazole that becameavailable in the United States in 1990.30 In vitropotencies are up to 100 times greater than ketocona-zole. Most yeast and fungi of medical importance aresusceptible to fluconazole in vitro. In vivo, it hasexcellent activity against yeast and variable activityagainst aspergillus. In contrast to ketoconazole anditraconazole, fluconazole is highly water soluble andis readily absorbed from the GI tract regardless ofacidity or food intake. It is not highly protein-boundand penetrates the CSF, brain tissue, ocular fluidsand sputum; the volume of distribution is similar tobody water (0.7 l/kg). It is eliminated primarily bythe kidney, and the prolonged serum half-life of 4 to5 hours in rats and mice, 14 hours in dogs, and 22-30hours in humans is presumably due to tubular reab-sorption. The dose should be modified if renal func-tion is impaired. Fluconazole alters the kinetics ofdrugs that undergo hepatic metabolism, but not tothe degree described with ketoconazole. The manu-facturer recommends giving a double loading doseduring the first 24 hours, because five to seven daysare needed to achieve steady-state concentrations inman. Fluconazole is well tolerated in humans, al-though mild GI, CNS and skin reactions are occa-sionally reported. Hematologic abnormalities arerare. Doses of 30 mg/kg/day in dogs caused increasedhepatic fat and hepatic weight.

Clinical studies in humans are still investigating theefficacy of fluconazole in vivo. It has been highlysuccessful for treating tissue candida and coc-cidiomycosis infection and variably successful fortreating pulmonary aspergillosis. It is probably thedrug of choice in situations where penetration intothe CSF is desirable.

Clinical studies in animals with fluconazole are evenmore limited. Six of ten dogs with nasal aspergillosiswere successfully treated with 2.5-5 mg/kg/day orallyfor eight weeks.56 Fluconazole was considered effec-tive treatment in animal models for blastomyces,cryptococcus, candida, coccidioides and histoplasmainfection. As with clinical trials in humans , flucona-zole was variably effective against aspergillosis.30

Use in Companion Avian MedicineJuvenile psittacine birds treated with fluconazolewere found to be fecal negative for yeast as deter-mined by Gram’s stain; clearance of yeast required48 hours.2 Based on this limited study, dosage recom-

mendations of 2-5 mg/kg/day were suggested. Tran-sient regurgitation, increased AST and LDH levelswere observed in some birds. Further studies areneeded to establish the safety and efficacy of flucona-zole in birds.

Enilconazole

PharmacologyEnilconazole is an imidazole antifungal agent with abroad spectrum. It is not approved for use in theUnited States. It is poorly soluble and its use islimited to topical application and inhalation. Inhala-tion of burned enilconazole has been used to treataspergillosis in poultry.50 It has also been infused intothe nasal passages and sinuses to treat canine nasalaspergillosis.57 Reports of use in companion and avi-ary birds are lacking.

Summary of Antifungal Treatment

Spectrum, ability to reach the site of infection, routeof administration and potential toxicity are impor-tant considerations when selecting an antifungalagent. Spectrum is difficult to determine for antifun-gal drugs because the methods for in vitro testing areexpensive, are poorly standardized and there is oftenlittle correlation between in vitro and in vivo efficacy.This makes drug selection somewhat empirical, butsome generalities can be made. Most candida aresusceptible to nystatin, and almost all yeast of medi-cal importance are susceptible to ketoconazole, itra-conazole, fluconazole and amphotericin B. In humanand animal studies, itraconazole and fluconazole aremore active than ketoconazole, with itraconazoleshowing greater activity against aspergillosis, andfluconazole showing greater activity against yeastinfections. A combination of amphotericin B andflucytosine or an azole, or an azole and flucytosinemay provide better efficacy than either drug alone.

The ability of the drug to reach the site of infection isalso important. Nystatin is not absorbed from thealimentary tract and must come in contact with theyeast. Systemic infections by hypheal fungi (eg, as-pergillus) usually cause a granulomatous responsethat inhibits drug penetration to the site of infection.Ketoconazole and itraconazole are highly protein-bound and develop high tissue concentrations, butare found in low concentrations in the CSF and ocu-lar fluids. In contrast, fluconazole is water-soluble,minimally protein-bound, and able to treat the CNS,eye and sputum. In general, fungal infections require


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longer treatment periods than bacterial infections.Sometimes many months of therapy are needed tocontrol aspergillosis.

Finally, the route of administration and potentialtoxicity are important considerations. All of the anti-fungal drugs mentioned are delivered orally with theexception of amphotericin B, which must be admin-istered IV. Nystatin is virtually nontoxic. Ketocona-zole has greater potential toxicity than either itra-conazole or fluconazole, especially if long-durationand high-dose therapy are used. Drug interactionsshould also be considered. Ketoconazole and flucona-zole may significantly alter the hepatic metabolismof drugs such as barbiturates and rifampin.

Nystatin is the drug of choice for uncomplicated yeastinfections of the alimentary tract. It is inexpensiveand virtually nontoxic. Resistant or severe yeast in-fections can be treated with ketoconazole or flucona-zole. Ketoconazole is less expensive but potentiallymore toxic; few side effects have been observed whenused for fewer than two to three weeks. Systemicyeast infections can be treated with either ketocona-

zole, fluconazole or itraconazole, depending on thesite of infection.

Drug selection for treatment of aspergillosis infec-tions is more problematic. Cutaneous aspergillosis isprobably best treated with fluconazole or itracona-zole (ketoconazole might be effective in limitedcases). Topical administration of enilconazole or mi-conazole may also be effective. Severe pulmonary ordisseminated aspergillosis carries a poor prognosisfor recovery regardless of the treatment program.Amphotericin B is the primary drug of choice forchronic infections and infections in immunocom-promised patients because it rapidly develops fungi-cidal concentrations. Prior to the availability of thenew azole antifungals, a combination therapy withamphotericin B, flucytosine and rifampin was recom-mended. Based on human clinical studies, it is prob-ably more effective to use amphotericin B incombination with itraconazole for initial treatment,and then continue long-term treatment for monthswith itraconazole alone. Flucytosine also has sub-stantial anti-aspergillus activity and may be prefer-able if there is CNS involvement. Intratracheal ad-

TABLE 17.2 Susceptibility of Common Avian Infectious Agents to Antimicrobial Therapy

ANTIBACTERIAL G– bacteria Pseudomonas G+ bacteria Mycoplasma Chlamydia Anaerobes

Amikacin +++++ +++ +++ – – –

Ampicillin / Amoxicillin + – +++ – – –

Chloramphenicol + – +++ – + –

1st generation Cephalosporins + – +++++ – – –

3rd generation Cephalosporins +++++ +++ + – – –

Enrofloxacin ++++ + +++ +++++ + –

Gentamicin +++ +++ +++ – – –

Macrolides (Tylosin, Clindamycin) + – ++++ + – ++++

New Macrolides – – ++++ + possible ++++

Tetracycline + – + ++++ +++++ –

Trimethoprim / Sulfa ++++ – ++++ – – –

ANTIFUNGAL Yeast Aspergillus Other Fungi

Amphotericin +++++ ++++ +++++

Fluconazole ++++ +++ –

Flucytosine +++++ + +++++

Itraconazole ++++ +++++ +++++

Nystatin ++++ – –

+++++ = most isolates susceptible; ++++ = many isolates susceptible; +++ = some isolates susceptible; ++ = few isolates susceptible; + = almost no isolates susceptible


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ministration of amphotericin B is very useful whentreating syringeal or tracheal infections. Systemicinfections caused by other fungi (eg, mucormycosisand cryptococcosis) can be treated in the same man-ner as systemic aspergillosis.

Antifungal drug research is currently an active field,spurred by the increasing numbers of opportunisticfungal infections in immunocompromised humanHIV patients. New drugs may soon be available.

Products Mentioned in the Texta. Keet Life, Hartz Mountain, Harrison, NJb. Ornacin, Mardel Laboratories, Glendale Heights, ILc. LA-200, Pfizer Laboratories, New York, NYd. Myco 20, Squibb Laboratories, Princeton, NJe. Bactrim, Roche, Nutley, NJ

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