Antimicrobial therapy is an important component in clinical management of reptiles affected with various infectious diseases but is complicated by limited species‐specific pharmacokinetic and safety data, limitations in extrapolation of in vitro susceptibility testing designed for endothermic species, and little objective efficacy data. Selecting the appropriate antimicrobial agent for reptiles is based on similar principles and considerations common to antimicrobial selection in domestic species. However, this process is more complicated in reptiles because of the number and diversity of species, their unique anatomical and physiological features, the diversity of infectious agents, and even behavioral characteristics that make safety an important factor in drug and route considerations.

This chapter will focus on the process of antimicrobial selection in reptiles while highlighting the unique differences and challenges associated with selecting antimicrobial agents for these species.

Infectious Agents

A diverse range of bacterial, viral, and fungal infections are important causes of morbidity and mortality in captive reptiles (Austwick and Keymer, 1981; Cooper, 1981; Jacobson, 1999, 2007). While some of these also affect humans and domestic animals, a large proportion are mainly or solely pathogens of reptiles and amphibians, limiting the amount of available data.

Infections caused by Gram‐negative bacterial pathogens are common in captive reptiles (Paré et al., 2006), often with bacteria from environmental reservoirs and water. Although not as well documented, Gram‐negative bacterial infectious diseases are also reported in wild populations of reptiles. For instance, die‐offs of American alligators (Alligator mississippiensis) have been associated with Aeromonas hydrophila infections (Shotts et al., 1972). Gram‐positive aerobic bacteria, anaerobes, and other organisms such as mycobacteria, Mycoplasma, and Chlamydophila can also cause disease (Jacobson, 2007; Stewart, 1990; Homer et al., 1994; Jacobson and Telford, 1990; Jacobson et al., 1989, 2002; Soldati et al., 2004).

Fungal infections are also common in captive reptiles (Paré et al., 2006; Austwick and Keymer, 1981; Migaki et al., 1984), including a wide range of fungi of environmental origin. Fungal infections are often difficult to treat because disease can be advanced by the time the diagnosis is made and/or there may be serious co‐morbidities that have predisposed to fungal infection. While knowledge about antibacterials is limited, there are even less clincal and pharmacological data on antifungals in reptiles.

Other pathogens, including protozoal, helminth, and viral agents, have been described in reptiles (Jacobson, 2007). However, given the relative importance of bacterial and fungal infections and the greater body of evidence regarding treatment, this chapter will focus on bacterial and fungal pathogens. Tables 37.1–37.3 provide examples of more common diseases and potential treatment options. Selected dosage regimens for reptiles are shown in Table 37.4.

Diagnostic Testing

Principles of diagnostic testing for reptiles are no different than for other species and both lack of testing and suboptimal diagnostics can compromise treatment decisions. However, there are various challenges that must be considered in reptiles.

Once a bacterial or mycotic infection is suspected in a reptile patient, the accurate identification of the primary pathogen is an essential step in choosing the most appropriate antimicrobial. Proper sampling is at the core of testing, and this can be complicated in some reptiles based on their housing (e.g., water contamination in aquatic species), infection site (difficulty in safely obtaining a sample), animal size (e.g., too small to collect an optimal volume of blood for culture), and the potential impacts of physical or chemical restraint. Diagnostic specimens should be collected, whenever possible, using approaches to minimize contamination with commensal, surface, and environmental bacteria. If a discrete lesion is present, a biopsy specimen is ideally obtained for both cytological and histological examination. Concurrent with the morphological assessment, a specimen of the lesion is also submitted for culture. Concurrent use of other diagnostic methods such as PCR or immunohistochemistry should be considered, when available.

Laboratory issues must also be considered. Reptile specimens would typically comprise a very small percentage of specimens tested by commercial veterinary diagnostic laboratories which can lead to interpretation challenges. For example, laboratories are supposed to only report growth of organisms that are considered potentially clinically relevant and not report commensal bacteria or those that are likely contaminants. This can create problems with specimens from species where uncommon (for the laboratory) organisms are more likely and where environmental opportunists may be much more relevant than they would be in domestic mammals. This can result in lack of reporting of potentially relevant organisms.

Testing conditions also need to be considered, as culture plates are usually incubated at mammalian body temperature. Organisms that grow suboptimally at those higher temperatures may be missed. Some reptile pathogens such as Chlamydophila, Mycoplasma, and mycobacteria are relatively difficult to isolate from routine cultures and also often difficult to see in standard histopathological preparations. Special histological stains, immunohistochemical stains, and molecular techniques are sometimes necessary to detect their presence (Bodetti et al., 2002; Jacobson et al., 2004; Johnson et al., 2007). Similarly, antimicrobial susceptibility testing is usually performed at 35 °C, and it is unclear how well results would reflect susceptibility in vivo and at lower temperatures. Another issue is the lack of clinical breakpoints for any antimicrobials for reptiles. Thus, susceptible/intermediate/resistant determination (if provided) would be based on the susceptibility of the organism to drug levels achieved in serum of mammalian species, something that may not well (or at all) reflect the situation in the target species. It is important to inform the laboratory that the culture specimen is from a reptile and may need special laboratory handling to isolate the pathogen (Origgi and Paré, 2007).

Husbandry and Immunological Considerations

The next consideration in the process of antimicrobial selection should be an understanding that captive husbandry and the immunological status of the reptile are important. Bacterial and fungal infections tend to become more invasive and clinically apparent in captive reptiles when husbandry conditions are suboptimal (Cooper, 1981). For example, maintaining reptiles below their optimal temperature range may induce an immunocompromised condition in the patient. Furthermore, Vaughn et al. (1974) demonstrated that some lizards experimentally infected with Gram‐negative bacteria voluntarily selected higher ambient temperatures. This behavior was interpreted as an induced fever, and is thought to help the lizards fight bacterial infections. Given that reptile body temperature affects immune system function, it is imperative to maintain the ill reptile under optimum environmental conditions as an important part of the therapeutic plan.

Our understanding of reptile bacterial and mycotic infections has advanced to recognize that reptiles become more susceptible to bacterial diseases when exposed to other pathogens. For example, primary viral infections, such as ophidian paramyxovirus pneumonia and herpes virus stomatitis of tortoises, are associated with severe secondary bacterial infections (Jacobson, 1992; Origgi et al., 2004). Exposure to contaminated environments and a lack of proper quarantine program are important and potentially modifiable risk factors for infection with multiple pathogens.

Anatomical and Physiological Considerations

Reptile anatomy and physiology differ significantly from domestic mammals and can also differ greatly between different reptile species. Reptiles have several unique features that can potentially influence the pharmacokinetics of antimicrobials and the subsequent response to treatment.

The carapace and plastron form the characteristic shell of chelonians. This unique anatomical feature is composed of an outer keratinized epidermis overlying a base of dermal cartilage and bone. The dermal bone is highly vascularized and considered a metabolically active tissue (Jacobson, 2007). The relative metabolic activity and blood perfusion of the chelonian shell have led to the recommendation that antimicrobials should be dosed based on their entire body weight and not adjusted to subtract the weight of the turtle shell.

An anatomical feature of all snakes with eyes and some lizards is the transparent palpebral spectacle (Millichamp et al., 1983). This spectacle embryologically represents a fusion of the upper and lower eyelids that permanently covers the cornea, leaving a potential subspectacular space. Infections of this subspectacular space have been reported and are difficult to treat with topically applied antimicrobial agents that do not appear to penetrate this barrier (Millichamp et al., 1983). In treating reptiles with subspectacular infections, a wedge can be carefully excised from the lower half of the spectacle and the appropriate antimicrobial drug applied directly through the wedge‐shaped hole onto the surface of the cornea.

Most species of reptile have a renal portal system that can shunt blood from the caudal half of the body through the kidneys before reaching the systemic circulation. This blood flow pattern can potentially alter the pharmacokinetics of drugs and is the basis for recommendations that intramuscular and subcutaneous injections be given in the cranial half of the reptile body. However, few studies have tested this hypothesis and the theoretical impacts would vary between different antimicrobials. Holz et al. (1997a) reported that in red‐eared sliders (Trachemys scripta elegans), the blood from the caudal region of the body did not necessarily flow through the kidney via the renal portal system. Instead, the blood draining the caudal portion of the body perfused both the liver and the kidneys, indicating that the renal portal shunt was only partially functional. In a related study, Holz et al. (1997b) also found that red‐eared sliders receiving gentamicin in either a forelimb or hindlimb had no significant differences in pharmacokinetic parameters, indicating a minimal pharmacokinetic effect from the renal portal system. In contrast, the same study noted that red‐eared sliders receiving carbenicillin in the hindlimb had significantly lower blood concentrations for the first 12 hours post injection than those that received the same dose in a forelimb. Despite this finding for carbenicillin, the authors concluded that this difference was not clinically important and questioned the necessity of forelimb injections (Holz et al., 1997b). Because the renal portal system varies in development, anatomy, and function between various groups of reptiles and the pharmacokinetic evidence is conflicting, many clinicians still recommend injecting potentially nephrotoxic drugs and drugs eliminated primarily through the renal system in the cranial half of the body.

In contrast to mammalian pus, reptiles infected with bacterial and fungal pathogens tend to develop solid exudates within discrete granulomatous lesions (Montali, 1988; Jacobson, 2007). These pathogens are located within the necrotic center of heterophilic granulomas, within histiocytes (macrophages) in histiocytic granulomas, or near the capsule of chronic granulomas. Granulomas can limit the penetration of many antimicrobial agents into the sites of infection. When possible, surgical removal of the granulomatous mass prior to antimicrobial therapy can improve the chances of a positive therapeutic outcome.

Physiological and husbandry factors can also influence drug pharmacokinetics and therefore drug selection in reptiles. The ambient temperature of the reptile enclosure directly affects the pharmacokinetics of antimicrobials. Mader et al. (1985) studied gopher snakes (Pituophis melanoleucus catenifer) given amikacin and housed at ambient temperatures of either 25 °C or 37 °C. When housed at 37 °C, the apparent volume of distribution was larger and body clearance of amikacin was faster. In another study of gopher tortoises (Gopherus polyphemus), the mean residence time of amikacin was significantly shorter in tortoises acclimated to 30 °C than those kept at 20 °C, and clearance at 30 °C was approximately twice that in the tortoises kept at 20 °C (Caligiuri et al., 1990). In contrast, Johnson et al. (1997) found no significant pharmacokinetic differences among snakes given amikacin and housed at 25 °C and 37 °C. No explanation for this discrepancy was offered, suggesting that the effect of temperature on drug pharmacokinetics is either species specific or requires further evaluation.

It is challenging to determine how to apply results such as these to clinical situations. However, it is important to consider the impact of species and environment when determiningg antimicrobial dosing regimens. Therefore, while it can be useful to base dosing decisions on published pharmacokinetic data, it is important to remember that those data may not reflect results at different temperatures or in different reptile species.

Behavioral and Safety Considerations

The size and temperament of a reptile can influence antimicrobial drug selection and the route of administration. Some reptiles are extremely timid and nervous, and may not be suitable for repeated handling and intramuscular injections. In such cases, the antimicrobial must be administered orally, preferably in food if the animal is still eating.

Most species of reptiles weigh less than 100 g and many lizards are under 30 g as adults. This may limit antimicrobials that can easily be diluted to a concentration that can be precisely and safely injected. At the other end of the spectrum, some reptiles are quite large in size and dangerous to approach. In such cases, a choice may need to be made between a drug that can be administered in a relatively small volume via remote injection dart or orally in food. Oral administration in food can also be challenging when sick animals are hyporexic or anorexic, or in species that go long periods of time between feedings. Venomous snakes present a similar treatment challenge, since they are dangerous to handle and manipulate for administration of drugs. For these dangerous species, drugs that can be administered every few days are preferred over drugs that must be administered each day.

Routes of Antimicrobial Administration

Oral antimicrobials are generally used in species not tolerant of injections, when the optimal antimicrobial is available in an oral formulation, or when safety considerations make injections dangerous. Oral medication may also be indicated in rare situations when large numbers of reptiles are infected and must be treated simultaneously. In these situations, the individual administration of drugs may not be practical, and the usage of medicated food may be warranted.

However, several problems exist with oral medication of reptiles. 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 existing literature. Gastrointestinal transit time impacts drug absorption and varies greatly among the various reptile species. Transit time is usually slowest in the large herbivorous reptiles. For example, the transit time in large tortoises may be as much as 21 days. Even in some carnivorous reptiles, the transit time may be quite prolonged. Carnivorous reptiles, such as pythons, are adapted to infrequent meals and increase their gastric and intestinal mucosa in response to feeding (Secor, 2008). This massive change in gastrointestinal metabolism is likely to influence antimicrobial absorption and treatment frequency. Thus, in reptiles it may be difficult to achieve optimum and consistent therapeutic concentrations of antimicrobials in blood following oral administration. Martelli et al. (2009) published a pharmacokinetic study of enrofloxacin in estuarine crocodiles (Crocodylus porosus) where delayed absorption and subtherapeutic drug concentrations were measured with the oral route. In contrast, repeated twice‐weekly oral doses of clarithromycin in desert tortoises (Gopherus agassizii) attained target drug concentrations (Wimsatt et al., 2008). Clearly, oral absorption in reptiles is species and drug specific and requires further investigation.

While clinicians can often administer oral antimicrobials in the food of reptiles actively feeding, orally medicating reptiles that are anorexic or that feed infrequently is often difficult. In giant tortoises, extracting the head beyond the shell margins and then forcing the mouth open is usually impossible. Furthermore, these overzealous efforts to force the mouth open can injure the keratinized epidermal hard parts over the mandibles and dentary bones. In general, giant tortoises must be anesthetized and a pharyngostomy tube inserted for oral medication. Pharyngostomy tubes are easy to insert and routinely used in tortoises and other chelonians (Norton et al., 1989).

As a generalization, nonvenomous snakes are the easiest group of reptiles to medicate orally. The mouth of most snakes is simple to open and the glottis is easy to see and avoid. In these snakes, a lubricated French catheter or nasogastric tube is passed down the esophagus with minimal resistance. Since the cranial esophagus is extremely thin in most snake species, the end of the catheter should be round and smooth. The use of excessively rigid catheters should be avoided as they may penetrate the esophageal mucosa. While the stomach of most snakes is located from one‐third to half the distance from the head to the cloaca, it is not necessary to pass a catheter this far. In most situations, passing the catheter halfway between the stomach and oral cavity is satisfactory.

Most of the injectable antimicrobials commonly used in reptiles are injected intramuscularly, subcutaneously and occasionally intracoelomically. Intravenous administration is challenging because peripheral vessels are difficult to catheterize (Jacobson et al., 1992). While blood can be collected from several vascular sites in different species of reptiles, most of this sampling is “blind” and is not suitable for repetitive intravenous infusions (Olson et al., 1975; Samour et al., 1984).

Intramuscular and subcutaneous injections are practical and provide the most predicable drug absorption. Snakes and lizards are the easiest reptiles to inject intramuscularly because of the large epaxial dorsal muscles of the body associated with the ribs and vertebrae. In lizards, the forelimb muscle masses are usually small, which limits injection volumes. The best site for intramuscular injections in chelonians is the pectoralis musculature located medial and caudal to the base of the forelimbs just within the cranial margins of the shell.

Despite the ease of intramuscular and subcutaneous drug administration, placing large volumes of irritating drugs into reptile muscles can result in significant irritation and tissue damage, including development of necrotizing skin and soft tissue disease from a single injection. Anecdotally, numerous severe reactions have been reported with enrofloxacin injection. This may be in part because of frequent use of the drug but it is not unreasonable to suspect that this drug truly poses a higher risk for tissue damage, and enrofloxacin administered by injection is best avoided in reptiles whenever possible.

Injectable drugs with a prolonged elimination are potentially useful in reptiles that are difficult or dangerous to handle. Adkesson et al. (2011) reported that a long‐acting formulation of ceftiofur maintained adequate plasma concentrations for five days in ball pythons (Python regius). However, care must be taken when extrapolating across species. For example, cefovecin has a long elimination half‐life in dogs (133 h) (Stegemann, 2006a) and cats (166 h) (Stegemann, 2006b) and is typically dosed at 14‐days interval, but much shorter or more variable half‐lives have been reported in some other species, including green iguanas (3.9 h) (Thuesen et al., 2009), red‐eared sliders (6.8h) (Sypniewski et al., 2017), and Hermann’s tortoises (20.8 h) (Nardini et al. 2014).

Intracoelomic injections are a potential route of delivery, but this is infrequently used because of limited pharmacokinetic and safety data. The potential injury from an inappropriately placed or irritating drug in the coelomic space requires further investigation and intracoelomic injection should be avoided unless adequate safety and dosing data are available for the particular animal species and drug.

Local and topical antimicrobials may be useful in some situations. Topical administration may be viable for superficial infections in nonaquatic species that are amenable to frequent handling. Local antimicrobial approaches, through antimicrobial impregnated beads or gels, can provide sustained therapeutic levels at deep sites, and can be particularly useful in situations where frequent administration of systemic antimicrobials is not possible or the optimal antimicrobial cannot be safety administered at the doses required for systemic use. Local antimicrobials can also be used alongside parenteral antimicrobials. Absorbable materials (e.g., gels, calcium sulfate) are preferred over PMMA beads as they do not require a secondary surgical procedure for removal.

Antimicrobial Drug Selection

Ideally, antimicrobial selection is based on culture and susceptibility results from a proper specimen, using validated methods, and evaluated with breakpoints that are relevant to the treated animal species. This unfortunately is rarely (if ever) available. Despite the limitations described above, culture and susceptibility testing can be an important guide. However, empirical treatment is often needed in lieu of, or in advance of, laboratory testing results. Suggestions are made in Tables 37.1–37.3.

Testing decisions are ideally made based on clinical trial data, alongside species‐ and drug‐specific pharmacokinetic data that are relevant to the disease (e.g. location of infection) and management conditions (e.g. temperature). These are also uncommonly available. Of the 7,500 species of reptiles, pharmacokinetic studies have been reported for a few drugs in a small number of species commonly kept in captivity. As in most scientific literature there is a publication bias toward reporting pharmacokinetic studies that lead to dosage recommendations, versus those that fail to produce useful recommendations (Stamper et al., 2003; Thuesen et al., 2009). Studies focused on the metabolism, tissue concentrations, and potential toxicity of antimicrobials in reptiles are rare in the literature (Hunter et al., 2003).

Understanding of likely pathogens, typical susceptibility patterns and clinical experience with response to treatment are often the maintay of antimicrobial decision‐making, albeit with numerous potential limitations. Various formularies can be found, and some can provide excellent guidance. However, limitations of these must be recognized as dosing recommendations are often made with little or no supporting data, and some recommendations are not consistent with current understanding of pharmacology or antimicrobial therapy.

Allometric Scaling to Estimate Drug Dosages

The lack of pharmacokinetic studies and even the paucity of empirical dosage recommendations may require extrapolation of drug dosages from domestic mammals. It should be recognized that this is a highly tenuous approach, and it is presumably best to extrapolate dosing from other reptile species, whenever available. However, data gaps may require highly empirical decision making. In practice, there are three main methods to estimate proper therapeutic drug dosages (Hunter and Isaza, 2008).

The first method is to use an established drug dose derived from pharmacokinetic studies in other species. By this method, a 20 mg/kg dose of amoxicillin in dogs is applied across all reptile species regardless of size. Using a set dose results in a linear increase in the amount of drug administered as body weight increases. Although common, this method tends to overdose larger animals and underdose smaller animals.

The second method is similar except that it takes the established dosage in a specific species and makes an additional assumption that links the dosage to the metabolic rates of both species. Using this method, the established drug dosage from one species is adjusted based on the ratio of the calculated metabolic rate of the patient over the calculated metabolic rate of the target species:

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