Introduction

Many of the therapeutic agents commonly used to manage disease conditions in domestic species are also commonly used to treat exotic animal cases presented to the veterinarian. Unfortunately, very few studies have been done to evaluate the efficacy of these compounds for the many different species of exotic animals presented to veterinarians. Drug pharmacokinetics in these animals would be expected to vary with the physiologic and metabolic condition of the patient. Metabolic states in exotic animal species can vary significantly within and between the different classes. For example, the metabolic rate of a canary is exponentially different from that of a macaw. In the case of reptiles, which are ectotherms, their metabolic rate, immune function and general well-being are dictated by their ability to thermoregulate. The metabolic rate of reptiles is also significantly lower than that of the endothermic vertebrates. Body temperature can also affect the half-life of a drug, with the half-life increasing with decreasing body temperature. Although the metabolic rate is significantly lower in reptiles than in mammals and birds, veterinarians routinely rely on drug dosages reported for higher vertebrates. The purpose of this presentation is to review therapeutics commonly used to manage wildlife cases in captivity.

Antibiotics

Aminoglycosides are polycations that are minimally bound to protein, are poorly absorbed from the gastrointestinal tract, and are excreted unchanged via the kidneys.¹ "Aminoglycosides are bactericidal and are generally indicated for gram-negative bacterial infections, including E. coli, Klebsiella spp., Enterobacter spp., Pseudomonas spp., Proteus spp., Providencia spp., Salmonella spp., and Serratia spp.⁶ The aminoglycosides can be used in combination with penicillins to treat gram-positive infections.⁶ The minimum inhibitory concentrations (MIC) required to control gram-negative aerobes with aminoglycosides is dependent on the drug used. In most cases, the dose must be more than 3 times the MIC to eradicate certain pathogens.¹ Aminoglycosides are generally used once to twice a day in mammals and birds, but only once every 3 days in reptiles.⁶ Side effects seen with these compounds include nephrotoxicity and ototoxicity.

Carbenicillin and piperacillin are semisynthetic penicillins with extended spectrum against gram- negative bacteria.⁶ These drugs were originally found to have antipseudomonal activity; however, increased resistance is being reported with increased usage.⁴ The semisynthetic penicillins also have some effect against anaerobes. The primary action of the semisynthetic penicillins is against cell wall synthesis.⁶ This class of drugs is susceptible to beta-lactamase. Variable amounts of the semisynthetic penicillins are bound to protein. Distribution of these drugs is greater via the parenteral route.⁶ The drugs are generally excreted primarily via tubular secretion and glomerular filtration. Semisynthetic penicillins cross the placenta in mammals, but are not known to have teratogenic effects. The semisynthetic penicillins are generally dosed one to three times a day depending on species and infectious agent.

The cephalosporins are an important broad-spectrum antibiotic used in veterinary medicine. The cephalosporins, like the penicillins, were originally derived from a microbe (Cephalosporium acremonium).⁶ These drugs are bactericidal and act to inhibit mucopeptide synthesis in the cell wall.⁶ The cephalosporins are generally represented by four to five classes or generations. The cephalosporins are widely distributed through the tissues in mammals and are especially useful for treating bone infections. Third-class cephalosporins can enter the central nervous system when the meninges are inflamed. The cephalosporins may be metabolized by the liver, and are excreted via the kidneys. Side effects associated with this class of drugs are rare, and generally are associated with hypersensitivity reactions. Although routinely used in veterinary medicine, there are few studies evaluating the pharmacokinetics of these drugs in exotic animals. Cephalosporins may have to be dosed two to three times a day in birds, once to twice a day in mammals, and once a day up to every 3 days (depending on the drug) in reptiles.

Chloramphenicol is a broad-spectrum bacteriostatic to bactericidal drug, depending on concentration and bacterial susceptibility.⁶ This antibiotic was originally isolated from Streptomyces venezuelae.⁶ Chloramphenicol has been found to have activity against aerobic and anaerobic gram-positive and gram-negative bacteria. Chloramphenicol inhibits protein synthesis by binding to the 50S ribosomal subunit of the bacteria and possibly mammalian cells.⁶ The binding to mammalian cells is the cause of the aplastic anemia reported in humans. Chloramphenicol is widely distributed throughout the tissues in mammals. The drug is primarily excreted via the liver, while a small quantity is excreted unchanged via the kidneys. Clients treating their pets should be made aware of the potential side effects associated with handling chloramphenicol and the drug should never be handled by humans with hepatic disease and non-regenerative anemias. Availability of this drug has become more difficult over time.

Fluoroquinolones are one of the most commonly used groups of antibiotics in human and veterinary medicine. Fluoroquinolones alter the action of bacterial DNA gyrase, a type II topoisomerase.³ Enrofloxacin is highly lipophilic and the addition of a carboxylic acid and a tertiary amine contribute to the amphoteric properties of enrofloxacin. The metabolism of enrofloxacin varies among species. Although enrofloxacin is an active antibiotic, biotransformation to ciprofloxacin may also occur.⁶ The amount of biotransformation that occurs can vary widely between different species within the same class, with some animals producing measurable amounts and other producing non-measurable amounts. Fluoroquinolones are highly effective bactericides with relatively low minimum inhibitory concentrations (MIC). Enrofloxacin can be dosed once to twice a day in both birds and mammals. In reptiles daily dosing to dosing every 2 days has been recommended.⁶

Macrolides, like the tetracyclines, were one of the original groups of antibiotics available in veterinary medicine and were also originally isolated from bacteria (erythromycin - Streptomyces erythreus).⁶ Macrolides are bacteriostatic; however, high doses can be bactericidal in susceptible bacteria. By inhibiting the 50S ribosomes, these compounds restrict protein formation by the bacteria.⁶ Macrolides can be excreted unchanged via the bile or partially metabolized by the liver. A limited quantity may also be excreted via the kidneys. In mammals, both food and gastric pH can affect absorption of the macrolides. Macrolides are moderately to significantly bound to protein and have good distribution to most tissues in the body. Although these compounds are generally broad spectrum, overuse of these compounds in human and veterinary medicine have led to increased resistance. Macrolides are generally dosed twice daily in birds and mammals and once a day in reptiles.⁶

The potentiated sulfas (e.g., trimethoprim sulfadimethoxine) are broad-spectrum antibiotics that are routinely used to treat bacterial and protozoal pathogens in wildlife patients. Sulfa drugs are generally bacteriostatic; however, the synergism with trimethoprim creates a bactericidal compound.⁶ The bactericidal effect may also be dose dependent. These compounds affect folic acid synthesis. Oral doses are well absorbed in monogastric mammals. This compound has widespread tissue distribution, including the CNS when the meninges are inflamed. Potentiated sulfas are metabolized by the liver and excreted by the kidneys by both glomerular filtration and tubular secretion.⁶ The primary side effects associated with this drug are attributed to hypersensitivity and the potential for crystallization in the urine. The author does not recommend using this antibiotic in cases with cystic calculi or severe dehydration. The potentiated sulfas are generally dosed twice daily in mammals and birds and once daily in reptiles.

The tetracyclines represent one of the oldest classes of antibiotics available in human or veterinary medicine. Tetracycline was originally isolated from Streptomyces aureofaciens.⁶ Tetracyclines are bacteriostatic and act by inhibiting protein synthesis by reversibly binding to the 30S ribosome. At high doses, these compounds can also affect eukaryotic cells. Although these compounds are generally reserved for aerobic bacteria, they have been found (in vitro) to be effective against anaerobes isolated from reptiles. Tetracyclines are not metabolized, but are excreted primarily through the gastrointestinal tract or kidneys.⁶ These compounds can be chelated by fecal material, thus reducing their effectiveness. In mammals, food can also diminish the absorption by chelating tetracyclines. Because these compounds are excreted via glomerular filtration, wildlife patients with renal dysfunction may accumulate the compound over time. Tetracyclines are variably bound to protein and have good distribution to most tissues in the body. Although these compounds are generally broad spectrum, overuse in human and veterinary medicine have led to increased resistance. These compounds, especially doxycycline, have excellent spectrum against Chlamydophila spp., Mycoplasma spp., and rickettsial organisms. Tetracyclines are generally dosed twice daily in birds and mammals and once daily in reptiles. Doxycycline is an exception. There is a long-acting depot available from Europe that can be dosed once every 7 days. This compound has been used with great success by the author to treat birds with chlamydiosis.⁶

Antivirals

Many of the newly documented or emerging diseases being reported in exotic pets are attributed to viruses. Our current understanding of viruses is limited because we do not have the diagnostic assays to isolate or confirm the presence of these pathogens in many of the species presented to our hospitals. Until we have described the epidemiology of these viruses, it will be difficult to effectively treat and manage cases presented for a primary viral infection. Currently, acyclovir is the only antiviral that has been evaluated across the different classes of higher vertebrates. This drug works by inhibiting the replication of certain viruses (e.g., herpesvirus), but should not be expected to eliminate a viral infection.⁵

Antifungals

Fungal diseases are being reported with an increased frequency in exotic pet cases. Although it might appear that these microbes are recent introductions or emerging pathogens, the increased number of cases should be attributed to improved diagnostic capabilities and the fact that veterinarians are looking for pathogens other than bacteria. With the increased number of fungal infections being reported in exotic pets, veterinarians are interested in finding appropriate antifungals to manage these cases.

The most common systemic antifungals used in exotic pet medicine are ketoconazole (Janssen Pharmaceutica, Piscataway, NJ), fluconazole (Pfizer, New York, NY), and itraconazole (Ortho Biotech, Raritan, NJ). A review of the literature reveals a combination of empirical and pharmacokinetic reports regarding the specific use of these antifungals in non-domestic species (Jacobson et al. 1980). Because of the limited number of pharmacokinetic studies associated with antifungal chemotherapeutics, veterinarians should use caution when determining dosages for untested species.

Ketoconazole is an imidazole antifungal that can be fungistatic to fungicidal depending on fungal sensitivity and serum levels of the drug. Ketoconazole is thought to affect fungal cell membrane permeability by interfering with ergosterol synthesis. Ketoconazole is metabolized by the liver and primarily excreted in the feces. The drug is highly protein bound. Ketoconazole is a teratogen in mammals and should not be given to pregnant placental animals. It is not known what effect ketoconazole has on developing avian or reptile embryos. Other side effects associated with ketoconazole include gastrointestinal upset and hepatic toxicity.

Fluconazole and itraconazole are triazole compounds that are being used extensively in veterinary medicine to manage mycoses. The triazoles, like the imidazoles, are thought to affect fungal cell membrane permeability and limit the absorption of purine and pyrimidine precursors. While itraconazole is highly protein bound, fluconazole has reduced affinity for proteins. Absorption of fluconazole is not affected by gastric pH or the presence of food in the stomach, while these factors do affect the absorption of itraconazole. Both triazole compounds are well distributed throughout the tissues. Itraconazole, like ketoconazole, is a teratogen in mammals. Both triazole compounds have been associated with gastrointestinal upset and mild hepatic toxicity in mammal; however, the incidence of toxicity is lower than for imidazoles because the triazoles are more specific for fungal cytochromes.

Conclusions

There is a great number of therapeutic agents available to the exotic pet veterinarian. It is important to recognize that most treatment recommendations found in the literature are empirical. Because of this limitation, veterinarians working with exotic pets should monitor their patients closely and be prepared to make changes in the dosing regimen, frequency of administration, or therapeutic plan altogether if improvement in the case is not noted in an appropriate amount of time.

References

1.  Conzelman GM. Pharmacotherapeutics of aminoglycoside antibiotics. J Am Vet Med Assoc. 1980;176(10):1078–1080.

2.  Heatley JJ, Mitchell MA, Williams J, et al. Fungal periodontal osteomyelitis in a chameleon (Furcifer pardalis). J Herp Med Surg. 2001;11(4):7–12.

3.  Hooper D, Wolfson J. The fluoroquinolones: structures, mechanisms of action and resistance and spectra of activity in vitro. Antimicrob Agents Chemother. 1985;28:581–586.

4.  Lawrence K, Palmer GH, Needham JR. Use of carbenicillin in two species of tortoise (Testudo graeca and T. hermanni). Res Vet Sci. 1986;40:413–415.

5.  Marschang RE, Gravendyck M, Kaleta EF. Herpesvirus in tortoises: Investigations into virus isolation and the treatment of viral stomatitis in Testudo hermanni and T. graeca. J Vet Med. 1997;44:385–394.

6.  Plumb DC. Veterinary Drug Handbook. 4th ed. Ames, IA: Iowa State Press; 2002.