Antimicrobial Therapy in Reptiles
The importance of infectious diseases as causes of illness and mortality in captive reptiles is well documented (Austwick and Keymer 1981; Clark and Lunger 1981; Cooper 1981; Jacobson 1980). While a variety of bacteria have been incriminated as either primary or secondary pathogens, it appears that infections caused by Gram-negative bacteria are more common than those caused by Gram-positive bacteria. Pseudomonas aeruginosa, Aeromonas hydrophila, Providencia rettgeri, Morganella morganii, Salmonella arizonae, and Klebsiella oxytoca have frequently been isolated from healthy and ill captive reptiles, becoming invasive when conditions either change the resistance of the host or select for pathogenic organisms (Cooper 1981). These organisms may also become invasive following a primary viral disease such as ophidian paramyxovirus pneumonia (Jacobson and Gaskin 1992). Some groups of reptiles seem particularly prone to infection with specific types of bacteria. For instance, the American alligator, Alligator mississippiensis, is susceptible to Aeromonas hydrophila infections. An unusual Neisseria spp. has been commonly isolated from the oral cavity and bite wounds of the green iguana, Iguana iguana (Plowman et al, 1987). A chronic upper respiratory disease has been seen in the desert tortoise (Gopherus agassizii) and other tortoises (Jacobson 1991) and a new mycoplasma, Mycoplasma agassizii, has been identified as the causative agent of this disease (Brown et al, 1995). A new mycoplasma also has been identified as the cause of arthritis and pneumonia in Nile crocodiles (Crocodylus niloticus); Mohan et al, 1995) and the American alligator (Clippinger et al, 2000). While Infections with chlamydia have been reported in reptiles (Homer et al, 1994; Telford and Jacobson 1993; Jacobson et al, 1989), it is unknown whether the scarcity of reports is because they have been missed or whether infections with chlamydia are uncommon in reptiles. Images depicting various infectious diseases of reptiles can be found linked to figures at the end of this narrative.
Mycotic infections are also commonly seen in all major groups of captive reptiles, with the integumentary and respiratory system most often involved (Austwick and Keymer 1981). While the dermatomycoses of mammals caused by Microsporum and Trichophyton are rarely reported in reptiles, fusariosis, geotrichosis, phycomycosis and chromomycosis appear to be more common. Predisposing factors such as suboptimal cage temperatures and filthy environmental conditions are often involved. Based upon the literature, most cases of mycotic disease in reptiles are diagnosed at necropsy. As a result, there are relatively few reports which discuss medical management.
Antimicrobial therapy is an important part of medically managing reptiles ill with bacterial and mycotic disease, with selection of specific chemotherapeutics made more difficult than with mammals because of the broad range of behavioral, anatomic and physiological peculiarities of the various species within the class Reptilia. Added upon this, relatively few pharmacokinetic studies have been performed in a handful of species (Table 1). Thus, at times, the selection of appropriate chemotherapeutics is often more of an art than a science. Extrapolation from one species to the next and metabolic scaling of antibiotics are often used when determining drug dosages in a species which no pharmacokinetic data are available. In this paper I will review the antimicrobial drugs that are most commonly administered in ill reptiles, citing the relevant literature that has been published on specific drug therapy in reptiles.
ANTIMICROBIAL DRUGS USED FOR MICROBIAL INFECTIONS
There are few pharmacokinetic studies involving penicillins in reptiles. A study was conducted with carbenicillin in nine snakes of five different species, including a mangrove snake (Boiga dendrophila), two king snakes (Lampropeltis getulus), a reticulated python (Python reticulatus), a Great Plains rat snake (Elaphe guttata emoryi), a yellow rat snake (E. obsoleta quadrivittata) and three black rat snakes (E. o. obsoleta); all snakes were ill with a variety of pathologic conditions (Lawrence 1984). In snakes receiving carbenicillin at 400 mg/kg of body weight, intramuscularly (IM), peak plasma concentrations of 177 and 270 µg/ml were reached 1 hour after the initial injection, and therapeutic levels greater than 50 to 60 µg/ml were maintained for at least 12 hours. This dose is significantly higher than doses previously recommended in the literature for mammals. No recommendations were given concerning frequency of administration.
A study of carbenicillin in the Greek tortoise (Testudo graeca) and Hermann's tortoise (T. hermanni) indicated a biphasic rise in serum levels of carbenicillin after administration of 400 mg/kg of body weight (Lawrence et al, 1986). Since tortoises have an extremely large bladder, it was hypothesized that the bladder may act as a reservoir of antibiotic, which is available for recycling. In spite of this, carbenicillin proved to be safe and effective if administered at a dose of up to 400 mg/kg every 48 hours.
Piperacillin, which is highly active against many aerobic gram-negative organisms, including Pseudomonas aeruginosa, has been evaluated in blood pythons (Python curtus) (Hill et al, 1991). In this study, minimum inhibitory concentrations (MICs) of piperacillin were determined for several species of Gram-negative bacilli isolated from the upper respiratory tract of snakes ill with pneumonia. Piperacillin at 100 mg/kg of body weight, given IM, resulted in blood levels that far exceeded the MIC of all bacteria evaluated. The serum half-life was 12.3 to 17 hr and the recommended dosing interval was every 48 hr.
A preliminary serum concentration study has been conducted on ampicillin in Hermann's tortoises Sporle et al, 1991). While Pseudomonas aeruginosa, and most strains of Salmonella spp. and Klebsiella spp. were resistant to this antibiotic, an average MIC of 2.85 µg/ml was found to be sufficient against Staphylococcus spp. Administration of ampicillin at 50 mg/kg, IM every 12 hours resulted in blood levels considered therapeutic against this organism.
Because of its enhanced antipseudomonal activity and minimal nephrotoxic effects, the third generation cephalosporin, ceftazadime, is often selected for use in reptiles. In a study, ceftazidime showed a high level of in vitro activity against Enterbacteriaceae and other Gram-negative bacilli, with only 9 of 32 strains tested by disc diffusion being resistant (Lawrence 1984). In 5 species of snakes maintained at 30°C, peak plasma antibiotic levels after a single IM injection of 20 mg/kg were reached 1 to 8 hours after the initial injection, and therapeutic levels were maintained for at least 96 hours. No obvious side effects were noted. A dose rate of 20 mg/kg every 72 hours was recommended.
A study of ceftazidime (20 mg/kg IM and IV) in juvenile (1.48 +0.18 kg) loggerhead sea turtles (Caretta caretta) demonstrated that plasma concentrations were above the MIC for Pseudomonas up to 72 hr after injection (Stamper et al, 1997).
There are few pharmacokinetic studies for antimicrobials in lizards. Cefoperazone, a third-generation, beta-lactam antibiotic, was administered as a single IM dose of 200 mg/kg to tegus (Tupinambis teguixin; Klingenberg 1996) maintained at 24°C. Peak serum levels were reached at 4 hr following injection and at 24 hr had declined to subtherapeutic levels. The recommended dose was 125 mg/kg every 24 hr. In the false water cobra, Hydronastes gigas, the recommended dose was 100 mg/kg every 96 hr (Klingenberg 1996).
In a Hermann’s tortoise, Testudo hermanni, MICs for Staphylococcus spp. and Klebsiella spp. were found to be 8.9 µg/ml and 5.6 µg/ml respectively (Sporle 1991). Pseudomonas aeruginosa, and Salmonella spp were found to be resistant. For doxycycline, a loading dose of 50 mg/kg and then 25 mg/kg, given IM every 3 days, was considered a therapeutic dose for Staphylococcus and Klebsiella infections. In juvenile American alligators (Alligator missippiensis) weighing 2.85-4.70 kg, and maintained at 27°C, oxytetracycline was administered at 10 mg/kg IV (Helmick et al, 1997). The mean plasma concentration was 6.52 µg/ml at 96 hr following administration. At all sampling intervals following administration and up to 96 hr, plasma concentrations were above the MIC for a new mycoplasma that was isolated from alligators with arthritis and pneumonia.
In bull snakes administered chloromycetin succinate subcutaneously (SQ) at 40 mg/kg body weight, the half-life in these snakes was 5.2 hr compared to 1.5 to 3 hr for mammals (Bush et al, 1976). Based on this study, the author recommended that this dose be administered every 24 hr for 5 to 14 days, depending upon the clinical situation and clinical response. In another study involving indigo snakes (Drymarchon corais couperi) and water snakes (Nerodia sipedon), the half-life was quite different be (Clark et al, 1985). While the recommended dose was 50mg/kg, the frequency of administration varied from every 12 hr to every 72 hr.
The aminoglycoside antibiotics gentamicin and amikacin are two of the most common antibiotics used for treating Gram-negative infections in reptiles. Unfortunately, gentamicin has a narrow safe therapeutic range and cases of nephrotoxicity have been reported in reptiles, particularly snakes (Jacobson 1976; Montali et al, 1979) (Figures 19A-B). There are no reports in the literature of amikacin induced nephrotoxicity in reptiles.
Several pharmacokinetic studies of gentamicin in reptiles have been performed. In American alligators (Alligator mississippiensis) maintained at a water temperature of 22°C, gentamicin was absorbed rapidly after IM administration, with a biphasic distribution having both rapid and slow phases for both dosages administered (Jacobson et al, 1988). The T1/2 values for the 1.25 mg/kg and 1.75 mg/kg dosages were 37.8 hr and 75.4 hr respectively. The recommended dose of gentamicin in American alligators was 1.75 mg/kg every 72 to 96 hrs.
In the painted turtle (Chrysemys picta) maintained at 26°C, T1/2 for gentamicin was 32 hr and the suggested dose was 10 mg/kg every 48 hours (Bush et al, 1977). In the red-eared slider (Chrysemys scripts elegans), 6 mg/kg produced therapeutic plasma concentrations for 2 to 5 days (Raphael et al, 1985). In bull snakes (Pituophis melanoleucus) kept at 24°C, the T1/2 for gentamicin was 82 hr and a dose of 2.5 mg/kg every 72 hr was recommended (Bush et al, 1978). Pharmacokinetic studies of amikacin have also be conducted in reptiles. In juvenile American alligators maintained at a water temperature of 22°C, amikacin was absorbed rapidly after intramuscular administration, with a biphasic disposition having both rapid and slow phases (Jacobson et al, 1988). The T1/2 for alligators administered 1.75 mg/kg and 2.25 mg/kg were 49.4 and 52.8 hr, respectively. The peak concentrations following administration of a second dose at 96 hr were greater than that achieved following the first injection. The recommended dose was 2.25 mg/kg, IM every 72 to 96 hr.
In the gopher tortoise (Gopherus polyphemus) pharmacokinetic studies were conducted in two groups of tortoises administered 5 mg/kg body weight (shell included) acclimated at either 20°C or 30°C (Caligiuri et al, 1990). As part of this study, the effect of multiple dose administrations and effects of acclimation temperature on oxygen consumption were also studied. The mean residence time for amikacin in the 30°C tortoises (22.67 + 0.50 h) was significantly less than that of the 20°C group (41.83 + 3.23 h). The clearance rate of the warmer acclimated tortoises was approximately twice as fast as that of the cooler acclimated tortoises. Similarly, oxygen consumption was found to be approximately twice as great at the higher acclimation temperature. Results of this study indicated that in gopher tortoises acclimated to 30°C, amikacin should be administered IM at 5 mg/kg every 48 h.
There are only two pharmacokinetic study of amikacin in snakes. In gopher snakes, Pituophis melanoleucus, those animals housed at 37°C had a larger volume of distribution and a more rapid body clearance of amikacin than those at 25°C, while the half-life did not significantly change (Mader et al, 1985). The authors recommended that amikacin be administered IM at 5 mg/kg (loading dose) followed by 2.5 mg/kg every 72 hours. In another study in ball pythons (Python regius), snakes were either acclimated at 25°C or 37°C and serum concentrations of amikacin were determined following intracardiac and IM administration (3.48 mg/kg) (Johnson James Harvey 1987). No significant pharmacokinetic differences were found among the snakes housed at these temperatures. It was the view of the authors that the dose administered in this study should produce maximum serum concentrations against most pathogenic bacteria.
Fluoroquinolones have become popular antibiotics for treating reptiles ill with bacterial infections. Over the last few years, several experimental studies have been performed to determine proper dosaging and frequency of administration of reptiles. In a study with IM administration of enrofloxacin in box turtles, Terrapene carolina, results indicated that this species should be dosed at 5 mg/kg of body weight every 4-5 days (Aucoin, pers. comm.). In another study in Hermann's tortoises, the recommended dose for enrofloxacin administration was 10 mg/kg given IM every 24 hours (Sporle et al, 1991). This dose and frequency of administration was based on blood concentrations and MICs of several bacterial isolates including Pseudomonas aeruginosa, Klebsiella spp., and Salmonella spp. Based upon the results of a pharma-cokinetic study in adult gopher tortoises (Gopherus polyphemus), enrofloxacin should be administered at 5 mg/kg IM every 24 to 48 hr to maintain blood Concentrations above the MIC of bacteria considered to be potential pathogens in this species (Prezant et al, 1994). In this study, administration of enrofloxacin daily for 5 days resulted in increased mean trough and peak plasma concentrations of enrofloxacin. In Indian star tortoises (Geochelone elegans), a pharmacokinetic study indicated that enrofloxacin should be administered every 12 hr for treatment of Pseudomonas sp. and Citrobacter sp. infections and every 24 hr for other bacterial infections (Raphael et al, 1994). Results of a study involving the oral administration of ciprofloxacin in reticulated pythons, Python reticulatus, indicated that this drug should be administered at 2.5 mg/kg of body weight every 48-72 hours (Klingenberg and Backner 1991). In juvenile Burmese pythons (Python molurus bivittatus) that received an IM injection of enrofloxacin at 5 mg/kg of body weight, the mean maximal plasma concentration was reached at 5.75 hr post-injection (Young et al, 1997). Multiple dose studies indicated that over a 5 day period of sampling, while there was a stepwise increase in mean trough plasma concentrations of enrofloxacin, peak plasma concentrations did not significantly increase during the sampling period.These results indicated that when treating young Burmese pythons for Pseudomonas infections, enrofloxacin should be administered at an initial dose of 10 mg/kg followed by 5 mg/kg every 48 hr.
In green iguanas (Iguana iguana) administered enrofloxacin at 5 mg/kg either per os (PO) or IM, and maintained at 30°C, mean maximal plasma concentrations were reached at 2.7+2.6 hr a,d 1.0+0 hr respectively (Maxwell and Jacobson 1997). The mean maximal plasma concentrations was 1.16+0.54 µg/ml after oral administra-tion and 2.03+0.52 µg/ml after IM administration. Therapeutic plasma concentrations were maintained 31.7+32.1 hr after oral administration and 16+6.9 hr following IM administration. Because of the great variability in the plasma levels following oral administra-tion, the authors recommended the use of the parenteral route for critically ill iguanas.
In savanna monitors (Varanus exanthematicus) weighing 1.2 to 2.0 kg, and maintained at 27°C, enrofloxacin was administered either at 10 mg per kg orally (injected into mice) or by IM injection (Hungerford et al, 1997). In monitors receiving enrofloxacin orally, the highest plasma concentration was at 36 hr post ingestion. By IM injection, the highest plasma concentration was at 6 hr postinjection. The calculated half life for IM injection was 56 hr and based upon results of this study the authors recommended a dosing interval of every 5 days. In savanna monitors being treated with enrofloxacin, an initial IM dose of 10 mg/kg can be followed with subsequent oral administrations.
In juvenile American alligators weighing 2.85-4.70 kg, and maintained at 27°C, enrofloxacin was administered as a single IV dose of 5 mg/kg IV (Helmick et al, 1997). In order to maintain the target MIC for two-thirds of the dosing interval, enrofloxacin at 5 mg/kg should be administered every 36 hr.
A major disadvantage of enrofloxacin relates to tissue necrosis following injection. I generally will not use more than 1 ml at an injection site, even in large snake. I have seen several animals develop necrotizing lesions following IM injection (Figure 20). I have had to amputate the leg of a gopher tortoise as a result of IM injection. As more data is becoming available regarding oral upatke in reptiles, this, along with initial IV administration, will be the preferred route of administration in reptiles.
There are no pharmacokinetic studies in reptiles of trimethoprim, either alone or in combination with a sulfonamide. All doses appear to be empirically derived. The author has used injectable trimethoprim/sulfadiazine at 30 mg/kg, the first two doses administered 24 hr apart and then every 48 hr. No toxic effects have been seen in any of a wide variety of reptile species medicated.
The author is not aware of any pharmacokinetic studies of tylosin in reptiles. Still, this antimicrobial has been administered IM to reptiles, particularly those with respiratory disease, at 5 mg/kg every 24 hr (Jenkins 1991).
Clarithromycin is an advanced generation macrolide that is a 6-0-methyl derivative of erythromycin. By weight it is twice as active as erythromycin and the half-life in mammals is twice that of erythromycin. It is active against certain intracellular organisms such as Mycobacterium avium. It is also efficacious against Mycoplasma. A pharmacokinetic study has been performed in desert tortoises and based on this work the recommended dose is 15 mg/kg, given orally every 2 to 3 days (Wimsatt et al, 1999).
Infections with anaerobic bacteria are being appreciated as clinically important in reptiles. In one study of 39 specimens collected from reptiles, 21 yielded the following anaerobic bacteria: Bacteroides, Fusobacterium, Clostridium, and Peptostreptococcus (Stewart 1990). In vitro sensitivity testing indicated that all isolates which were tested were sensitive to metronidazole. In a study performed in yellow rat snakes (Elaphe obsoleta quadrivitatta) the data indicated that a metronidazole dosage of 20 mg/kg po every 48 hr should be adequate for treating anaerobic infections in this species (Kolmstetter et al, 1991).
Metronidazole also has been commonly used in reptiles with amebiasis and trichomoniasis. The dose used for treating reptiles with amebic and trichomonad infections is generally 100 mg/kg given as a single dose and repeated in 2 weeks.
There is only a single study concerning blood concentra-tions and pharmacokinetics of this antifungal drug in a reptile. In a multiple dose study in gopher tortoises, Gopherus polyphemus, the administration of ketoconazole, given orally at 15 and 30 mg/kg of body weight, resulted in concentrations of drug in plasma that were considered therapeutic (Page et al, 1991).
There is a single pharmacokinetic study of itraconazole in a reptile. Itraconazole (23.5 mg/kg) was administered PO with a food bolus to spiny lizards (Sceloporus sp.) for 3 consecutive days (Gamble et al, 1997). Blood and tissue samples were then collected up to 18 days following administration. A peak concentration of 2.48 µg/kg was obtained and it was expected that a steady state of 3.1 µg/kg would be achieved in 10 days. With this dosing regimen, plasma and liver concentrations would persist within reported MICs for many fungal pathogens for 6 days beyond peak concentration.
Though there are no pharmacokinetic studies of nystatin in the literature, this drug has been administered orally to reptiles with Candida infections of the oral cavity and gastrointestinal tract. The recommended dose is 100,000 IU/kg every 24 hr (Jacobson 1980).
The aminoglycosides gentamicin and amikacin are commonly used in combination with penicillins and cephalosporins for treatment of severe Gram-negative infections in reptiles, such as those caused by Pseudomonas and Proteus. The two drugs that the author has used most commonly in combination with aminoglycosides are carbenicillin and ceftazidime. Since clinical studies have demonstrated antagonisms between gentamicin and carbenicillin, these drugs should not be mixed prior to injection because chemical interaction will result in complex formation and inactivation of these antibiotics (Riff and Jackson 1972). The dosage regimen that the author has used begins with the administration of gentamicin or amikacin on day one, followed by carbenicillin on day 3 (48 hr later). Both drugs are then administered every 3 days for a total of 7-9 treatments for each antibiotic.
The other drug combination that the author routinely uses is gentamicin or amikacin in combination with ceftazidime. No antagonisms have been reported between these antibiotics. The aminoglycoside is administered on day one followed by ceftazidime on day 2. Both drugs are then administered every 3 days, with a total of 7-9 treatments for the aminoglycoside and up to 21 treatments with ceftazidime. The author has never experienced any negative side-effects of ceftazidime in reptiles.
The anaerobes Bacteroides, Fusobacterium, Clostridium, and Peptostreptococcus have been cultured from a variety of lesions in reptiles including subcutaneous and hepatic abscesses (Stewart 1990). Because aminoglycosides are uniformly ineffective against anaerobes, the author recommended that antibiotics effective against anaerobes such as carbenicillin, ceftazidime and metronidazole be used in treating reptiles infected with these organisms. Since in most of the cases where anaerobes were isolated, aerobes were also cultured, combined antibiotic therapy with an aminoglycoside and one of the above antibiotics efficacious against anaerobes would be indicated.
SELECTION OF ANTIMICROBIALS
There are a number of considerations when selecting the most appropriate antimicrobial to be used in treating a reptile ill with an infectious disease. Primary is identification of the causative agent. If a lesion is present, in addition to collecting a swab specimen for culture, a biopsy specimen should be collected for cytologic and histologic evaluation. This is essential when interpreting the significance of cultured microbes. In reptiles suspected of being septic, blood samples should be obtained for culture. Techniques for collecting specimens from reptiles have been discussed elsewhere (Jacobson 1992).
As mentioned above, identifying the causative agent is primary. Following isolation and identification of the causative agent(s), for bacteria, minimum inhibitory concentrations (MICs) of antibiotics should be determined. Once MICs are known, selection of the most appropriate antibiotic will depend upon the following: 1) system affected and type of lesion, 2) antibiotic pharmacodynamics and pharmacokinetics, and 3) size, clinical condition, temperament and immune status of the host.
In selecting an antibiotic, the clinician should choose a drug that will reach therapeutic concentrations in the affected tissue. While this approach is similar to that used in mammals, there are several special biological features of reptiles that will influence treatment and requires some discussion. First, reptiles often produce granulomatous inflammation in response to a variety of pathogens (Montali 1988). Since most antibiotics do not readily penetrate well developed granulomas, the list of affective drugs may be quite short. In those cases where mature granulomas are located subcutaneously, concurrently with use of appropriate antimicrobials, most of these lesions should be removed surgically. Another special feature of some reptiles is the spectacle. The spectacle embryologically represents a fusion of the upper and lower eyelids which have become transparent. It is present over the cornea in all snakes with eyes and in some lizards. Infections of the subspectacular space have been reported and topical antibiotics do not appear to move across this barrier (Jacobson et al, 1983; Jacobson 1987). In treating reptiles with such infections, a wedge needs to be removed from the spectacle and then appropriate topicals applied directly onto the globe and within the space.
Pharmacologic properties of antibiotics need to be considered. As mentioned above, the clinician needs to select a drug that will penetrate the affected tissue and lesion. Further, potential side-effects and toxicities of the drugs need to be considered. For instance, in treating a reptile ill with severe renal disease, the use of nephrotoxic antibiotics such as gentamicin would be contraindicated.
As already discussed, there are relatively few scientifically derived antibiotic and antifungal drug dosages in reptiles. This information is critical when administering drugs that are potentially toxic. For instance, gentamicin associated visceral gout has been reported in reptiles when this antibiotic was administered at mammalian therapeutic dosages (Jacobson 1976; Montali et al, 1979). The half-lives of a number of antibiotics appears to be considerably longer in reptiles compared to mammals. Since reptiles are a highly diverse group, both anatomically and physiologically, it may not be scientifically correct to extrapolate from one species to the next. For instance, while enrofloxacin was found to have prolonged blood concentrations following an intramuscular injection of 5 mg/kg of body weight in box turtles (Aucoin, pers. comm.), in Hermann's tortoise the therapeutic blood concentrations lasted only 24 hr following an intramuscular injection of 10 mg/kg (Sporle 1991). Differences more than likely also exist within a species, varying with age and size. As an example, a hatchling Burmese python (Python molurus) weighing 125 grams would probably require a higher dose of antibiotic per kg of body weight compared to an adult weighing over 100 kg. Antimicrobial dosage regimens have been determined by metabolic scaling, utilizing the daily minimum energy cost rather than live body weight (see below). Obviously, a great deal of work needs to be conducted on blood concentrations of antibiotics in reptiles.
The immune status of the ill reptile will also be important in selecting the most suitable antimicrobial drug. Since many ill reptiles, especially those with chronic infections, appear to be immunocompromised, the use of bacteriocidal antibiotics is often recommended (Jacobson 1997). Further, since the immune system of reptiles is affected by body temperature, maintaining the ill reptile under optimum environmental conditions is imperative. Snakes ill with respiratory disease have been successfully treated only by maintenance at elevated environmental temperatures, without concurrent antibiotic administration (Ross 1984). This has been termed thermotherapy.
Size and temperament of the patient may also influence the drug being selected, including the route of administration.Most species of reptiles are under 100 g and many are under 30 g. There are species of lizards which as adults weigh only a few grams. Dosing drugs to these animals can be extremely difficult. The clinician may be limited to those antibiotics which can easily be diluted to a concentration that can be precisely and safely injected. At the other end of the spectrum are those reptiles which are quite large in size and dangerous to approach. In such cases the clinician may have to choose a drug that can be administered in a relatively small volume via an injection dart. In those dangerous reptiles such as venomous snakes, a drug that can be administered every few days rather than daily would be preferred. Some reptiles are extremely timid and nervous, and may not be suitable for injection. In such cases the antibiotic will have to be administered orally, preferentially in food if the animal is still feeding. Thus, the route of administration will also influence the choice of antibiotics to be administered.
ADMINISTRATION OF ANTIMICROBIALS
In most cases, antimicrobials will be given by injection, either SC or IM. The author generally administers oral antimicrobials only in those cases where there is primary infection of the gastrointestinal tract, in those species that do not tolerate injections and have to be medicated in their feed, and in those disease conditions requiring a drug that is only available in an oral form. In farming operations of reptiles such as with crocodilians and sea turtles, when large numbers of reptiles are ill and have to be treated, it may not be practical to administer drugs by injection. In such cases, oral medication is generally the preferred route of administration.
Several problems exist with oral medication of reptiles. First, very few pharmacokinetic studies have been performed on drugs administered orally to reptiles. Thus, for the vast majority of antimicrobials the dose selected will not be based on science. The gastrointestinal transit time varies greatly between the various groups and species of reptiles, being the slowest in the large herbivorous reptiles. Even in some carnivorous reptiles the transit time may be quite prolonged. Thus, in these animals it may be difficult to achieve optimum therapeutic concentrations of antimicrobials in blood following administration of oral medicants.
While many oral medicants can be administered in the food of ill reptiles that are feeding, orally medicating reptiles that are not feeding may not be a simple task in all cases. Venomous snakes and large crocodilians are dangerous to handle and manipulate for administration of oral drugs. It may be impossible to extricate the head beyond the shell margins and force open the mouths of many species of turtles and tortoises. The keratinized epidermal hard parts over the mandibles and dentary bones are easily traumatized, and extreme care must be taken in trying to force the mouth open. The giant tortoises are particularly difficult to administer oral medicants. These reptiles will have to be anesthetized and a pharyngostomy tube inserted (Figure 21) for oral medication (Norton et al, 1985).
As a generalization, snakes are the easiest group of reptiles to orally medicate. The mouths of most snakes are simple to open and because the glottis is in an extremely cranial position, is easily avoided. A lubricated French catheter or nasogastric tube can be passed down the esophagus of the snake with minimal resistance. Catheters that are very rigid should be avoided. It is important to have the snake relatively straight when passing the catheter. Since the cranial esophagus is extremely thin in most species, the end of the catheter should be round and smooth. While the stomach of most snakes is from one-third to half way down the distance from the head to cloaca, it is not necessary to pass a catheter as far as this organ. In most situations passing the catheter half way between the stomach and oral cavity is satisfactory.
Most of the antibiotics commonly used in reptile medicine are administered either IM or SQ. The problem with IV administration of antibiotics is that except in tortoises, peripheral vessels cannot be visualized (Jacobson et al, 1992). While blood can be collected from a number of sites in different species of reptiles (Olson et al, 1975; Samour et al, 1984) most of this sampling is "blind" and may not be suitable for repetitive infusions. With SQ and IM drug administrations, the author tends to avoid administering drugs that require large volumes per kg of body weight, especially if the drug is irritating to surrounding tissues. For instance, the author has had several snakes develop necrotizing skin lesions following injection of more than 1 ml of enrofloxacin at a single site (Figure 20).
Since most species of reptiles have a renal portal system, with blood from the caudal half of the body going to the kidneys before reaching systemic circulation, it has been recommended that SQ and IM injections be given in the cranial half of the body. However, there are few studies which have looked at this potential problem scientifically. In a study in red-eared sliders, Trachemys scripta elegans, blood from the caudal region of the body did not necessarily flow through the kidney via the renal portal system (Holz et al, 1997). Blood draining the caudal portion of the body in the red-eared slider perfuses the liver in addition to, or instead of, the kidneys. Thus hepatic metabolism also must be considered. When red-eared sliders received either gentamicin (10 mg/kg) or carbenicillin (200 mg/kg) in a forelimb or hindlimb no significant differences were found in any of the pharmacokinetic determinants in turtles treated with gentamicin while those that received carbenicillin in a hindlimb had significantly lower blood levels for the first 12 hr post-injection than those that received it in a forelimb (Holz et al, 1997). However, since blood levels for both injection sites were still well above the MIC for organisms generally treated with carbenicillin, this difference was not considered clinically significant. Still, the renal portal system varies in development between various groups of reptiles and further work is needed before broad generalizations can be made. This is particularly important when injecting drugs that are potentially nephrotoxic and those that are eliminated primarily through the renal system.
Snakes are the easiest reptiles to inject because of the large dorsal muscle masses associated with the ribs and vertebrae. In lizards, the muscle masses associated with the forelimbs are not very substantial and small volumes of drug will be needed in these animals. Tortoises, especially the large tortoises, have extremely thick epidermal hard parts on the cranial aspect of their forelimbs, therefore injections are generally made through the thinner skin on the caudal (posterior) aspect of the forelimbs.
Metabolic scaling has become popular in attempting to determine the most appropriate dosage of an antibiotic in a species or size range of animal for which no pharmacokinetic studies have been conducted. Since pharmacokinetic studies have only be performed in a handful of the 6000 species of extant reptiles, most dosages of antibiotics (and other drugs) are given based upon extrapolation from one species to another. In using metabolic scaling, dosages of drugs administered are based upon metabolic size rather than mass. In expressing metabolic rate (Pmet or minimum energy costs), as a function of body mass (Mb) in kilograms, for most mammals the following allometric equation best describes this relationship (Kleiber 1961):
Pmet = 70Mb 0.75
While a similar allometic equation [MEC=10(Kg)0.75] has been suggested for use in reptiles (Pokras et al, 1992); Sedgwick et al, 1984), in a recent review of the subject, no single equation was considered appropriate for all reptiles since the mass constant varies from 1 to 5 for snakes and 6 to 10 for lizards; no values for chelonians or crocodilians are available (Jacobson 1996). In regard to reptiles, the major problem with this approach is a general lack of metabolic data for the majority of extant reptiles. Additionally, there appears to be significant variability in these data between those groups where scientific studies have been performed. For instance, Bartholomew and Tucker (Bartholomew and Tucker 1976), in looking at metabolic data on lizards ranging in size from 2 g to 4.4 kg, calculated the allometric equation to be Pmet = 6.84Mb0.62. This is different than findings by Bennet and Dawson (1976) for 24 species of lizards, ranging from 0.01 to 7 kg, for which the equation Pmet = 7.81Mb0.83 was determined. Further, when one looks at studies with snakes, still different equations can be calculated (Galvao et al, 1965). In determining resting metabolic rate of 34 species from genera of boas and pythons, the mass exponents of different species showed considerable variation (Chapell and Ellis 1987). The problem with metabolic scaling is that reptiles represent a very heterogenous group of vertebrates, and because of this, no single equation relating metabolic rate to body mass can be developed for calculating antibiotic dosages. Differences in body temperature, season, reproductive status, nutritional, and overall physiology are just a few of the variables which may ultimately influence metabolic rates and thus make single equation application invalid. While on the surface this appears to be better than extrapolation, this method needs confirmation. Metabolic scaling will be most useful when calculating doses in a species for which a specific equation has been determined.
Austwick PKC, Keymer IF: Fungi and actinomycetes, in Cooper JE, Jackson OF (eds): Diseases of the Reptilia. London, Academic Press, 1981; 1:192-231.
Bartholomew GA, and Tucker VA: Size, body temperature, thermal conductance, oxygen consumption, and heart rate in Australian varanid lizards. Physiol Zoo 37:341-354, 1964.
Bennet AF, and Dawson WR: Metabolism, in Gans C, and Dawson WR (eds), Biology of the Reptilia, Physiology A. New York, Academic Press,1976; 5:127-223.
Brown MB, Schumacher IM, Klein PA, et al: Mycoplasma agassizii causes upper respiratory tract disease in the desert tortoise. Inf Immun 62:4580-4586, 1995.
Bush M, Smeller JM, Charache P, et al: Preliminary study of Antibiotics in snakes. Ann Proc Amer Assoc Zoo Vet, St. Louis. 1976, pp 50-54.
Bush M, Custer R, Smeller JM, et al: Preliminary study of gentamicin in turtles. Am Assoc Zoo Vet Annu Proc, Honolulu, 1977, pp 71-1978.
Bush M, Smeller JM, Charache P, et al: Biological half-life of gentamicin in gopher snakes. Am J Vet Res 39:171-173, 1978.
Caligiuri, RL, Kollias, GV, Jacobson, ER, et al: The effects of ambient temperature on amikacin pharmacokinetics in gopher tortoises. Vet Pharmacol Therap 13:287-291, 1990.
Chappell, MA and Ellis TM: Resting metabolic rates in boid snakes: allometric relationships and temperature effects. J Comp Physiol B 157:227-235, 1987.
Clark HF, Lunger PD: Viruses, in Cooper JE, Jackson OF (eds): Diseases of the Reptilia. London, Academic Press, 1981; 1:135-164.
Clark CH, Rogers ED, Milton SL: Plasma concentrations of chloramphenicol in snakes. Am J Vet Res 46:2654-2657, 1985.
Clippinger TL, Bennett RA, Johnson CM, et al: Mycoplasma epizootic in a herd of bull alligators (Alligator mississippiensis). Ann Proc Amer Assoc Zoo Vet, Puerto Vallarta, Mexico, 1996, pp 230-233.
Cooper JE: Bacteria, in Cooper JE, Jackson OF (eds): Diseases of the Reptilia. London, Academic Press, 1981; 1:165-191.
Galvao PE, Tarasantchi J, and Guertzenstein P: Heat production of tropical snakes in relation to body weight and body surface. Amer J Phys 209:501-506, 1965.
Gamble KC, Alvarado TP, and Bennett CL: Itraconazole plasma and tissue concentrations in the spiny lizard (Sceloporus sp.) following once daily dosing. J Zoo Wildlf Med 28:89-93, 1997.
Helmick KE, Papich MG, Vliet KA, et al: Preliminary kinetics of single-dose intravenously administered enrofloxacin and oxytetracycline in the American alligator (Alligator missippiensis). Ann Proc Amer Assoc Zoo Vet, October 26-30, Houston, TX, 1997, pp 27-28.
Hilf M, Swanson D, Wagner R, et al: Pharmacokinetics of piperacillin in blood pythons (Python curtus) and in vitro evaluation of efficacy against aerobic gram-negative bacteria. J Zoo Wildlf Med 22:199-203, 1991.
Holz P, Barker IK, Crawshaw GJ, et al: The anatomy and perfusion of the renal portal system in the red-eared slider (Tracheyms scripta elegans). J Zoo Wildl Med 28:378-385, 1997.
Holz P, Barker IK, Burger JP, et al: The effect of the renal portal system on pharmacokinetic parameters in the red-eared slider (Trachemys scripta elegans). J Zoo Wildl Med 28: 386-393, 1997.
Homer BL, Jacobson ER, Schumacher J, et al: Chlamydiosis in green sea turtles. Vet Pathol 31:1-7, 1994.
Hungerford C, Spelman L, and Papich M: Pharmacokinetics of enrofloxacin after oral and intramuscular administration in savanna monitors (Varanus exanthematicus). Ann Proc Amer Assoc Zoo Vet, October 26-30, Houston, Texas, 1997, pp 89-92.
Jacobson ER: Gentamicin-related visceral gout in 2 boid snakes. Vet Med/Small Anim Clin 71:361-363, 1976.
Jacobson ER: Infectious diseases of reptiles, in Kirk RW (ed): Current Therapy. Philadelphia, WB Saunders, 1980; 7:625-633.
Jacobson ER. 1987. Reptiles,in Harkness J (ed), The Veterinary Clinics of North America. Philadelphia, WB Saunders, 1987, pp 1203-1225.
Jacobson ER: Laboratory investigations, in Beynon, PH, Lawton MPC, and Cooper JE (eds), Manual of Reptiles. Glaucestershire, England, British Small Animal Veterinary Association, 1992, pp 50-62.
Jacobson ER: Metabolic scaling of antibiotics in reptiles: basis and limitations. Zoo Biol 15:329-339, 1996.
Jacobson ER, Gaskin JM: Paramyxovirus infection of viperid snakes, in Biology of Pit Vipers. Selva. Tyler, Texas, 1992, pp 415-419.
Jacobson ER, Brown MP, Chung M, et al: Serum concentration and disposition kinetics of gentamicin and amikacin in juvenile American alligators. J Zoo Anim Med 19:188-194, 1988.
Jacobson ER, Gaskin JM, Mansell J: Chlamydial Infection in Puff Adders, Bitis arietans. J Zoo Wildlf. Med 20:364-369, 1989.
Jacobson ER, Gaskin JM, Brown MB, et al: Chronic upper respiratory tract disease of free-ranging desert tortoises (Xerobates agassizii). J Wildlf Dis 27:296-316, 1991.
Jacobson ER, Schumacher J, Green ME: Techniques for sam-pling and handling blood for hematologic and plasma biochemical determinations in the desert tortoise, Xerobates agassizii. Copeia 1:237-241, 1992.
Jenkins JR: Medical management of reptiles.Compend Continuing Educ 13:980-988, 1991.
Johnson James Harvey, Jensen JM, Brumbaugh GW, et al: Amikacin pharmcokinetics and the effects of ambient temperature on the dosage regimen in ball pythons (Python regius). J Zoo Wildl Med 28:80-88, 1997.
Kleiber M: The Fire of Life: An Introduction to Animal Energetics. New York, Wiley, 1961.
Klingenberg RJ, and Backner B: The use of ciprofloxacin, a new antibiotic, in snakes. In Proceeding of the 15th International Symposium on Captive Propagation and Husbandry of Reptiles and Amphibians, Seattle, Washington, 1991, pp 127-140
Klingenberg RJ: Therapeutics, in Mader DR (ed): Reptile Medicine and Surgery.Philadelphia, WB Saunders Co, 1996, pp 299-321.
Kolmstetter CM, Frazier, D, Cox S, et al: Metronidazole pharmacokinetics in yellow ratsnakes (Elaphe obsoleta quadrivitatta). Ann Proc Amer Assoc Zoo Vet, Houston, TX, Oct 26-30, 1997, pp 26.
Lawrence K, Needham JR, Palmer GH, et al: A preliminary study on the use of carbenicillin in snakes.J Vet Pharmacol Ther 7:119-124, 1984.
Lawrence K, Palmer GH, Needham JR: Use of carbenicillin in 2 species of tortoise (Testudo graeca and T hermanni). Res Vet Sci 40:413-415, 1986.
Lawrence K: Preliminary study on the use of ceftazidime, a broad spectrum cephalosporin antibiotic, in snakes. Res Vet Sci 36:16-20, 1984.
Mader DR, Conzelman GM, Baggot JD: Effects of ambient temperature on the half-life and dosage regimen of amikacin in the gopher snake. J Am Vet Med Assoc 187:1134-1136, 1985.
Maxwell LK, and Jacobson ER: Preliminary single-dose pharmcokinetics of enrofloxacin after oral and intramuscular administration in green iguanas (Iguana iguana). Proceedings of the American Association of Zoo Veterinarians, October 26030, Houston, Texas, 1997, pp 25.
Migaki G, Jacobson ER, and Casey HW: Fungal diseases of reptiles, in Hoff GL, Frye FL, and Jacobson ER (eds): Diseases of Amphibians and Reptiles. New York, Plenum Press, 1984, pp 183-204.
Millichamp N, Jacobson ER, and Wolf E: Diseases of the eye and ocular adnexae in reptiles. J Am Vet Med Assoc 183:1205-1212, 1983.
Mohan K, Foggin CM, Muvavarirwa P, et al: Mycoplasma-associated polyarthritis in farmed crocodiles (Crocodylus niloticus) in Zimbabwe. Onderstepoort Jorun Vet Res 62:45-49, 1995.
Montali RJ, Bush M, Smeller JM: The pathology of nephrotox-icity of gentamicin in snakes:a model for reptilian gout. Vet Pathol 16:108-115, 1979.
Montali R: Comparative pathology of inflammation in the higher vertebrates (reptile, birds and mammals). J Comp Path 99:1-26, 1988.
Norton TM, Jacobson ER, Caligiuri R, et al: Medical manage-ment of a Galapagos tortoise (Geochelone elephantopus) with hypothyroidism. J Zoo Wildlf Med 20:212-216, 1989.
Olson GA, Hessler JR, and Faith FE: Techniques for blood collec-tion and intravascular infusions of reptiles. Lab Anim Sci 25:783-786, 1975.
Page CD, Mautino M, Derendorf H, et al: Multiple dose pharmacokinetics of ketoconazole administered to gopher tortoises (Gopherus polyphemus). J Zoo Wildlf Med 22:191-198, 1991.
Plowman CA, Montali RJ, Phillips LG, et al: Septicemia and chronic abscesses in iguanas (Cyclura cornuta and Iguana iguana) associated with a Neisseria species. J Zoo Anim Med 18:86-93, 1987.
Pokras MA, Sedgwick CJ, and Kaufman E: Therapeutics, in Beynon, PH, Lawton MPC, and Cooper JE (eds), Manual of Reptiles. British mall Animal Veterinary Association. Gloucestershire, England, 1992, pp 194-213.
Prezant RM, Isaza I, and Jacobson ER: Plasma concentrations and dipsosition kinetics of enrofloxacin in gopher tortoises(Gopherus polyphemus). J Zoo Wildl Med 25:82-87, 1994.
Raphael B, Clark CH, Hudson R: Plasma concentrations of gentamicin in turtles. J Zoo Anim Med 16:138-139, 1985.
Raphael BL, Papich M, and Cook RA: Pharmcokinetics of enrofloxacin after a single intramuscular injection in Indian star tortoises (Geochelone elegans). J Zoo Wildl Med 25:88-94, 1994.
Riff LJ, Jackson GG: Laboratory and clinical conditions for gentamicin inactivation by carbenicillin. Arch Intern Med 130:887-890, 1972.
Ross RA: The Bacterial Diseases of Reptiles. Institute for Herpetological Research, 1984.
Samour HJ, Rishey D, March T, et al: Blood sampling techniques in reptiles.Vet Rec May 12:472-478, 1984.
Sedgwick CJ, Moffat S, and Kollias GV: Scaling antimicrobial drug dosage regimens to minimum energy cost rather than body weight. Ann Proc Amer Assoc Zoo Vet, 1984, pp 15-20.
Spörle H, Göbel T, Schildger B: Blood-levels of some anti-infectives in the Hermann's tortoise (Testudo hermanni). In 4th International Colloquium on Pathology and Medicine of Reptiles and Amphibians. Abstract, 1991.
Stamper MA, Papich M, Lewbart G, et al: Single dose pharmacokinetics of ceftazidime in loggerhead sea turtles (Caretta caretta). Ann Proc Amer Assoc Zoo Vet, Houston, TX, Oct, 1997, 26-30, pp.16.
Stewart JS: Anaerobic bacterial infections in reptiles. J Zoo Wildlf Med 21:180-184, 1990.
Telford SR and Jacobson ER: Lizard erythrocytic virus in east african chameleons. J Wildl Dis 29: 57-63, 1993.
Wimsatt J, et al: Clarithromycin pharmacokinetics in the desert tortoise (Gopherus agassizii). J Zoo Wildl Med 30:36-43, 1999.
Young LA, Schumacher J, Papich MG, et al: Disposition of enrofloxacin and its metabolite ciprofloxacin after IM injection in juvenile Burmese pythons (Python molurus bivittatus). J Zoo Wildl Med 28:71-79, 1997.
1. Peninsula cooter, Pseudemys peninsularis, with otitis media and interna. This lesion is generally seen as a mass bulging the skin caudal to the eye. Mixed gram-negative bacteria are commonly isolated from these lesions.
2. Red eared slider, Trachemys scripta elegans, with sepsis. The scutes are sloughing and there is hemorrhage in the dermal plates. Photo courtesy of Dr. R. Avery Bennett.
3. Green turtle, Chelonia mydas, with distal necrosis of a forelimb. Enterococcus was isolated from infected tissue.
4. Cervical abscess in a gopher tortoise, Gopherus polyphemus.
5. Desert tortoise, Gopherus agassizii, with chronic upper respiratory tract disease. Mycoplasma agassizii has been identified as the causative agent of this disease.
6. American alligator, Alligator mississippiensis, with bumblefoot. This is commonly seen in captive alligators kept in cement enclosures. Mixed gram-negative bacteria and fungi are commonly isolated from these lesions.
7. Internasal abscess in a green iguana, Iguana iguana.
8. A. Savanna monitor (Varanus exanthematicus); B. albino eastern diamondback rattlesnake (Crotalus adamanteus); C. blood python (Python curtus); and D. Russian viper (Vipera raddei) with stomatitis. The Russian viper also has osteomyelitis of the maxillary bone.
9. Girdled tailed lizard, Cordylus giganteus, with bacterial dermatitis and cellulitis of the tail.
10. Jackson’s chameleon, Chamaeleo jacksonii, with osteomyelitis of a hindlimb digit.
11. Puff adder (A), Bitis arietans, with systemic chlamydial infection. By light microscopy granulomas were seen in the heart (B) and liver (C). By electron microscopy (D) stages of an organism consistent with chlamydia were seen (IB: initial body; EB: elementary body; ITB: Intermediate body).
12. Albino Texas ratsnake (Elaphe obsoleta lindheimeri; A) and boa constrictor (Boa constrictor; B) with necrotizing proliferative stomatitis. Mycobacterium was isolated from this lesions and identified in tissue section.
13. Lung of a snake containing granulomas with acid-fast bacteria.
14. Lung of a rattlesnake with paramyxovirus pneumonia. Hemorrhage is seen throughout the lung. Gram-negative bacteria such as Pseudomonas are secondary invaders.
15. Burmese python (A), Python molurus bivittatus, with chronic respiratory disease. While mixed gram-negative bacteria are commonly isolated from lung washings of affected snakes, the exact cause of this disease is unknown.Exudate removed from the lung of a Burmese python with chronic respiratory disease (B).
16. Burmese pythons, Python molurus bivittatus, with edema of the mouth and head (A & B) and tail necrosis (C & D). These snakes have septic thrombi within the heart and caudal vessels of the tail.
17. Green tree python (A), (Chondropython viridis), rosy boa (B), (Lichanura trivirgata, and rhinoceros viper (C), (Bitis nasicornis) with subspectacular infections. Mixed gram-negative bacteria are often isolated from the exudate.
18. Ribbon snake, Thamnophis sauritus, wityh necrotizing dermatitis and ophthalmitis. Fungi were observed histologically and 7 different fungi were isolated from the lesion.
19. Urate deposition in the heart (A) and adjacent to vessels in the oral cavity of a ball python (Python regius) that died of gentamicin nephrotoxicity.
20. Necrosis of the epidermis and dermis of a Burmese python following an injection of Baytril.
21. Pharyngostomy tube inserted in a gopher tortoises and used for both feeding and administration of medicants.