Therapeutics

CHAPTER 7
Therapeutics
Paul M. Gibbons
DIAGNOSIS clinician to evaluate the probability that a published dose is

The standard of today’s reptile practice calls on clinicians to use likely to be effective in a particular species under the individual
an ever-increasing array of diagnostic tools to gather informa- circumstances of a clinical case. Dosage, dosing interval, and
tion and obtain a credible diagnosis. Few, if any, pathognomon- administration route must be evaluated in light of the indi-
ic signs exist, and most clinical syndromes are not understood vidual circumstances of each case. Consult up-to-date, peer-
well enough to be able to define standard therapeutic protocols reviewed literature to identify species and their environmental
for a set of clinical signs without objective diagnostic infor- needs, optimal body temperature, and the pharmacokinetics
mation. For example, in the relatively distant past, clinicians and pharmacodynamics of the drug in that species.9 Consider
treating reptiles would routinely administer parenteral calcium how physical and physiologic changes caused by disease might
to Green Iguanas (Iguana iguana) with the chief presenting affect absorption, distribution, metabolism, excretion, side
sign of muscle tremors; today we recognize that the risk of effects, and required therapeutic levels of a drug.
soft tissue mineralization and permanent damage to arteries, Managed thermoregulation, hydration, and nutrition are
renal tubules, and other tissues almost always outweighs the paramount for safe, effective drug therapy. Thermal options
potential short-term benefit. We know that administering cal- and gradients must be provided for conscious, active reptiles to
cium without knowledge of the patient’s ionized calcium con- behaviorally thermoregulate, and body temperature should be
centration is unwise. A problem-oriented diagnostic approach monitored during therapy. In cases of weakness and decreased
directed toward minimizing risk and maximizing therapeutic activity, the patient’s thermoregulation should be actively man-
benefit is now the standard of reptile practice. aged as a part of the therapeutic plan. Dehydrated, anorexic
Similar to class Mammalia, class Reptilia includes a diverse reptiles may not absorb, distribute, metabolize, or eliminate
group of species, each with a unique pharmacologic response chemotherapeutic agents in the same manner as the healthy
to every chemotherapeutic agent. As a result, therapeutic safety animals tested under controlled conditions in pharmacologic
and efficacy differ among species. Unlike mammals, conscious research, so nursing care also must include management of
reptiles are ectothermic, so physiologic and biochemical pro- fluids, electrolytes, and nutrition.4,5,10
cesses are strongly influenced by body temperature.1 Reason- Few therapeutic agents are approved for use in reptiles by
able assumptions about each individual species’ metabolism the United States Food and Drug Administration (FDA), so
and immune response can therefore only be made under certain almost all drug use is “extralabel.” In the United States, the Ani-
conditions. In most cases, the body temperature of a reptile mal Medicinal Drug Use Clarification Act of 1994 (AMDUCA)
patient must match that of the subjects in a given pharmacoki- and the Minor Use and Minor Species Animal Health Act of
netic study for a treatment plan to be designed, although phar- 2004 (MUMS) serve as guides for extralabel drug use. Prescrip-
macokinetics and pharmacodynamics do not necessarily differ tion drugs may be used to treat disease in reptiles under the
at different temperatures.2-5 Species-specific pharmacokinetics, supervision of a veterinarian if (1) they are approved by the
pharmacodynamics, therapeutic efficacy, and environmental FDA for any purpose in any species, (2) a valid veterinarian–
requirements must be known before administration of any drug client–patient relationship exists, and (3) the FDA has not spe-
can be considered. This is not only to predict absorption, dis- cifically prohibited extralabel use of the drug. Certain medical
tribution, metabolism, excretion, and the therapeutic window record and prescription label requirements must be followed to
but also to meet the environmental needs of a reptile so that meet the obligations of veterinary licensure.11
an appropriate immune response and healing can occur.4,6-8 It
remains true that, even though many pharmacokinetic studies
have been published in reptiles, not all drugs have been studied ADMINISTRATION AND DOSING
in all of the species presented to reptile veterinarians. Published Dosage and route of administration are determined by the
doses are available for many drugs, and these may have been chemical, pharmacokinetic, and pharmacodynamic properties of
selected empirically, may have been calculated with the use each agent in each species. Much work has been done to under-
of allometric or other scaling technique, or may be from pub- stand the mechanism of action, therapeutic window, absorp-
lished pharmacokinetic research data collected from healthy tion, distribution, metabolism, and excretion variables of many
animals under laboratory conditions. It is incumbent on the drugs in many species of reptiles, although many questions
57
58 SECTION I • ADVANCES IN REPTILE MEDICINE
remain unanswered and informed, empiric dosing is still used

in many cases.4,9 Veterinarians administer therapeutic agents to
reptiles via oral, enteral via gavage, subcutaneous (SC), intra-
muscular (IM), intravenous (IV), intracoelomic, intratracheal,
intrapulmonary, intraosseous, intraperitoneal, intrathecal, and
intracardiac routes, as well as via nebulization. These adminis-
tration routes have been described.4
Parenteral administration has proven to be more reliable
than the enteral route for many drugs in reptiles.4 Sufficient
evidence exists to support administration of most parenteral
drugs in the cranial half of the body when possible so that the
first-pass effect for drugs that are eliminated via renal tubular
excretion or hepatic metabolism is avoided. Venous blood from
the caudal half of the body enters the caudal vena cava through
either the renal portal system and peritubular capillaries or the
hepatic portal system from the abdominal or mesenteric veins
and through the hepatocellular parenchyma.12,13 Administra-
tion in the caudal half of the body has proven to be acceptable FIGURE 7-1 Alzet osmotic pumps (Durect Corp., Cupertino,
for a few specific drugs and should be considered for those Calif; model 1002 shown) can deliver medications continu-
ously without the need for periodic injections. Although early
drugs in circumstances when the cranial half is not available
clinical trials have not been successful, these do show prom-
for injections.5,14,15 Dosing adjustments must be made to ise for future drug delivery in reptiles that are difficult or
account for the effects of renal tubular or hepatic metabolism dangerous to handle.
as determined in these reports. Intracoelomic administration
of fluids or systemic drugs cannot be recommended, except
in rare, specific cases in which other routes are unsatisfac- The use of osmotic pumps has been reported in Corn-
tory. Absorption across coelomic membranes is difficult to snakes (Elaphe guttata), Mojave Rattlesnakes (Crotalus scu-
assess in clinical patients and is not guaranteed, particularly tulatus), and Green Iguanas with amikacin, florfenicol, and
in cases of abnormal blood proteins, coelomitis, or ascites. gonadotropin-releasing hormone.18-20 It is important to con-
Accidental needle puncture or laceration of an organ and acci- sider the tissue environment of the implant (availability of
dental deposition of the agent into the intestines, reproductive free water) and the pharmacokinetic and pharmacodynamic
tract, or urinary bladder rather than the coelomic space have properties of the drug to be administered because some drugs,
been observed and probably occur undetected in many cases; including amikacin, may be safer and more effective when
adverse effects have been reported.16 Some therapeutic chal- administered in pulses rather than continuously.21 In addi-
lenges in reptiles can be overcome by novel approaches to drug tion, substantial local necrosis and death occurred in five of
administration, including osmotic pump, dermal patch, depot six Mojave Rattlesnakes that were given florfenicol via subcu-
formulation, cardiac access port, and topical administration. taneously implanted osmotic pumps.20 In spite of disappoint-
ing results in recently published studies, further investigation
Osmotic Pump using different implantation sites, other drugs, and other spe-
Alzet osmotic pumps (Durect Corp., Cupertino, Calif.) (Fig- cies should be considered. Implantable, bioresorbable devices
ure 7-1) are implanted, miniature infusion pumps designed also deserve consideration, particularly for use in treatment of
for continuous infusion of therapeutic agents to unrestrained dangerous and venomous animals in which multiple surgical
animals. They are available with fixed delivery rates between procedures are impractical.22
0.11 and 10 μL per hour and delivery durations between
1 day and 6 weeks. Marketed for laboratory animals, they Transdermal Patch
range in size from 15 to 51 mm in length and 6 to 14 mm in Fentanyl, scopolamine, nicotine, buprenorphine, naloxone,
diameter and have been used to deliver dozens of different nitroglycerine, ketoprofen, and many other drugs can be
therapeutic agents.17 The “pumps” operate via an osmotic delivered by transdermal patch to humans and domestic mam-
pressure difference between the tissue environment and a mals. Recently, one study tested fentanyl that was suspended
salt-containing osmotic sleeve. The high osmolality of the salt in an ethanol and cellulose gel and enclosed by a plastic bar-
sleeve causes water to diffuse into the pump, across the outer rier with a permeable adhesive membrane impregnated with a
semipermeable membrane and into the salt sleeve, which loading dose of fentanyl on Prehensile-tailed Skinks (Corucia
puts pressure on a flexible (impermeable) internal reservoir zebrata).23 The study showed that all of the skinks in the
that contains the therapeutic agent. This pressure causes the study obtained measurable plasma concentrations of fentanyl
agent to be expelled via a flow moderator at a controlled, within 24 hours of patch application, and fentanyl concentra-
predetermined, continuous rate that is independent of the tions reached the human analgesic range by 36 hours. The
chemical properties of the agent being dispensed. Different most important finding of this study is that the scaled skin of
dosing rates can be achieved by varying the concentration of Prehensile-tailed Skinks does not present an insurmountable
the agent used to fill the pump reservoir. Virtually any com- barrier to systemic absorption of fentanyl delivered via trans-
monly used parenteral drug can be delivered by these pumps dermal patch. It is possible that other drugs could be delivered
because they are loaded by the user just before the time of via transdermal patch, and further investigations are warranted
implantation. in Prehensile-tailed Skinks and other species.
CHAPTER 7 • Therapeutics 59
Depot Formulations treatment in a relatively large (n = 417), uncontrolled clinical

Numerous chemotherapeutic agents are available in long- trial of emodepside/praziquantel in species from four differ-
acting formulations. Examples of long-acting formulations ent reptilian families.35 The safety of this topical combination
that have been used in reptiles include oxytetracycline, should be specifically studied because it holds great promise.
doxycycline, ivermectin, and leuprolide acetate.24-27 Reports As opposed to these promising therapeutic innovations,
of pharmacokinetic studies of these formulations in reptiles several techniques that were proposed and have not gained
provide support for the use of long-acting oxytetracycline for broad clinical acceptance include percloacal deworming of tor-
treatment of mycoplasmosis in American Alligators (Alligator toises, intrapulmonic therapy in chelonians, and intracoelomic
mississippiensis) but not the other drugs.24-27 administration of anesthetic agents.36-38
Vascular Access Ports Antibiotics
Vascular access ports are used to repeatedly collect blood Several antibiotics are currently used in reptile antibacterial
samples or administer IV medications over time. They are therapy. Many pharmacokinetic studies have been published,
particularly useful in pharmacokinetic studies and for cancer so background information is available for assisting in selec-
chemotherapy. Several authors have placed the rubber stopper tion of dose and dosing interval for several drugs in a number
from an evacuated blood collection vial into a round plastros- of species, although more research is necessary in the most
tomy drilled ventral to the cardiac ventricle in tortoises. This common species presented to reptile veterinarians. A num-
has been used to collect multiple blood samples over time and ber of individual circumstances guide antibiotic selection in
can lead to myocardial fibrosis.28,29 Vascular access ports were each case. Empiric antibiotic selection may be necessary in
placed into the common carotid artery to study blood gasses critical cases and should be based on the prevalence of specific
in seven Green Iguanas and remained functional in most cases pathogenic organisms for the disease syndrome, antimicrobial
for several weeks.30 A vascular access port (CompanionPort, spectrum of activity, distribution of the antimicrobial to the
Norfolk Medical Products Inc., Skokie, Ill) was placed into diseased tissues, potential side effects, metabolic and excretory
the ventral abdominal vein in a Green Iguana for lymphoma pathways, volume of the formulation necessary to deliver the
chemotherapy.31 This port was replaced after 28 days because necessary dose, dosing interval, and ease of administration.
of dermal necrosis over the port, and the second port was used In many cases antibiotics can be withheld until culture and
for 6 months without a complication.31 sensitivity results are available and antimicrobials are selected
accordingly. Selection of antibiotics with a narrow spectrum
Topical Administration of activity may help reduce the risk of therapy shifting the
Numerous topical medications are used in reptiles, primar- balance between enteropathic and commensal bacteria in the
ily to treat wounds or skin disease. Ivermectin, ophthalmic favor of the pathogens with the potential risk of infection. Mul-
drugs, disinfectants, creams, ointments, and lavage solutions tiple antimicrobials may be used to combat resistant strains of
are all applied via the topical route. These applications are bacteria, and current guidelines for achieving synergy should
generally intended to deliver local therapy, and systemic be followed.39
uptake is usually an undesired side effect. Recently, several Antibiotics often used in reptile medicine include amikacin,
topical preparations for systemic therapy have been evaluated. azithromycin, ceftazidime, ciprofloxacin, clarithromycin, dano-
Topical administration is ideal for antiparasitic agents because floxacin, enrofloxacin, marbofloxacin, metronidazole, oxytetra-
most traditional antiparasitic drugs are delivered via orogastric cycline, piperacillin, ticarcillin, trimethoprim/sulfamethoxazole,
intubation, which can be difficult in some lizards and many and tylosin. Most of these have been in use for decades and
chelonians. Two antiparasitic products have been evaluated have been previously described.4 Information presented here is
for systemic uptake of topical preparations. A commercially limited to agents with recent advances.
available topical treatment for intestinal parasites containing Azithromycin is an azalide, a subclass of macrolide antibi-
imidacloprid and moxidectin (Advantage multi/Advocate, otics that exert their bacteriostatic effect by inhibiting protein
Bayer, Shawnee Mission, Kans) is available for domestic com- synthesis by binding to the 50S ribosome.40,41 It concentrates
panion animals. The product was applied to the skin of Frilled in phagocytes and fibroblasts, which may increase its distribu-
Dragons (Chlamydosaurus kingii) and Bearded Dragons (Pog- tion to inflamed tissues. It is available as an oral suspension,
ona vitticeps). After treatment, the feces no longer contained oral tablets, and an IV injection and, as a dihydrate, is soluble
Kalicephalus spp. or oxyurid ova.32 The safety of this imida- in water. On administration it is widely distributed in human
cloprid/moxidectin topical formulation was not evaluated, and tissues but not cerebrospinal fluid. Its antimicrobial activ-
pharmacokinetic research is needed. A commercially available ity is pH-related and appears to be reduced with decreasing
topical preparation containing emodepside and praziquantel pH. It is eliminated unchanged via biliary and some urinary
(Profender, Bayer HealthCare, Shawnee Mission, Kans) was excretion in humans. Renal impairment has a minor effect
tested for absorption, elimination time, and efficacy in several on elimination. Drug–drug interactions are minor and not
lizards, snakes, and chelonians.33,34 Both drugs were absorbed sufficient to warrant altered dosing. Its antimicrobial spec-
via the skin, except emodepside in a Red-eared Slider (Trache- trum includes many gram-positive and gram-negative agents,
mys scripta elegans) that was returned to the water about including aerobes such as Staphylococcus spp., Streptococcus
1 hour after application.33,34 Treatment with emodepside/pra- spp., Haemophilus spp., Bordetella spp., Neisseria spp., and
ziquantel at doses much greater than those used in mammals Moraxella spp.; anaerobes including Peptostreptococcus spp. and
was followed by a marked decrease in the number of nematode Prevotella bivia, and other notable bacteria including Legionella
ova in feces within 48 hours. Similarly, no adverse effects pneumophila, Chlamydophila spp., Mycoplasma spp. Azithromy-
were observed and fecal nematode egg counts decreased after cin demonstrates cross-resistance with erythromycin-resistant
gram-positive strains; most strains of Enterococcus faecalis (when diluted to 100 mg/mL) and prolonged dosing interval of
are resistant, and methicillin-resistant staphylococci are also 48 to 72 hours. Further research with boids, lizards, tortoises,
resistant. Hepatotoxicity has been reported in humans, and and freshwater turtles is needed to determine appropriate dos-
azithromycin could cause reversible nonregenerative anemia ing in these species.
in reptiles. It can contribute to dysbiosis and overgrowth of Clarithromycin is a semisynthetic, bacteriostatic, macrolide
enteropathogens. Oral preparations should not be given con- antibiotic that inhibits protein synthesis by binding to the
currently with aluminum-containing or magnesium-containing 50S ribosome.47 It is soluble in acetone, slightly soluble in
antacids or phosphate binders.40 In a single-dose pharmacoki- methanol, ethanol, and acetonitrile, and practically insoluble
netic study in Ball Pythons (Python regius), the authors found in water. It is available in the United States as immediate-
that the drug is distributed and excreted similar to humans, and release tablets, extended-release tablets, and granules for oral
the dose, 10 mg/kg per os (PO), is given at different frequencies suspension. It is rapidly absorbed from the gastrointestinal
based on the location of the infection: skin, every 3 days; respi- tract in humans, with approximately 50% bioavailability, and
ratory tract, every 5 days; and liver/kidneys, every 7 days.42 it is metabolized by the liver into 14-hydroxy clarithromycin,
Ceftazidime is a semisynthetic, broad-spectrum, bacterio- which is also microbiologically active. Clarithromycin and
cidal, beta-lactam antibiotic for parenteral administration.43 It the 14-hydroxy metabolite distribute readily into human tis-
exerts its effect by disrupting the synthesis of the peptidoglycan sues and fluids; intracellular concentrations were greater than
layer in bacterial cell walls. It is highly stable to most clinically serum concentrations but cerebrospinal fluid was not tested.47
important beta-lactamases, either plasmid or chromosomal, Both clarithromycin and the 14-hydroxy metabolite are excret-
so it is active against many organisms that are resistant to ed primarily in urine. The antimicrobial spectrum includes a
penicillins and other cephalosporins. Solutions for injection variety of gram-positive and gram-negative bacteria as well as
range from light yellow to amber depending on the diluent and Mycobacterium avium complex bacteria. Clarithromycin has
volume used, and the pH ranges from 5 to 8. It is administered been shown to be active against Staphylococcus spp., Streptococ-
either IV or IM, is minimally metabolized, and is primarily cus spp., Haemophilus spp., Moraxella spp., Mycoplasma spp.,
excreted unchanged in urine. The dose should be reduced in Chlamydophila spp., various mycobacteria, and Helicobacter
patients with renal insufficiency, and in humans, elevated lev- pylori (particularly when in combination with amoxicillin and
els of ceftazidime can cause neurologic signs. Prolonged thera- either omeprazole or lansoprazole). It may also be effective
py with ceftazidime may lead to a fall in prothrombin activity, against aerobes including Bordetella spp. and Pasteurella spp.,
and vitamin K therapy may be needed.43 It can contribute to and anaerobes including Clostridium perfringens, Peptococcus
dysbiosis and overgrowth of enteropathogens such as Clos- niger, Propionobacterium acnes, and Prevotella melaninogenica
tridium difficile. It is active against numerous bacteria. Gram- (Bacteroides melaninogenicus). Most methicillin and oxacillin-
negative aerobes include Acinetobacter spp., Citrobacter spp., resistant isolates are resistant to clarithromycin. Side effects
Enterobacter spp., Escherichia coli, Haemophilus spp., Klebsiella may include hepatotoxicity, and hepatic enzymes should be
spp., Neisseria spp., Morganella spp., Proteus spp., Providen- tested before and monitored during therapy. It should not
cia spp., Pseudomonas spp., Salmonella spp., Shigella spp., be administered concomitantly with several drugs including
Serratia spp., and Yersinia enterocolitica. Gram-positive aerobes colchicine, anticoagulants, statins (HMG-CoA reductase inhib-
include Staphylococcus spp., and Streptococcus spp. Anaerobes itors), cisapride, terfenadine, pimozide, or astemizole. Clar-
include Bacteroides spp. (although many strains of Bacteriodes ithromycin may affect metabolism or serum concentrations of
fragilis are resistant), Clostridium spp. (but not C. difficile), midazolam, alprazolam, digoxin, theophylline, itraconazole,
Peptococcus spp., and Peptostreptococcus spp. It is synergistic carbamazepine, omeprazole, and ranitidine. It should not be
with aminoglycosides against Pseudomonas aeruginosa and the used in gravid or pregnant animals. It can contribute to dys-
enterobacteriaceae. It is synergistic with carbenicillin against P. biosis and overgrowth of enteropathogens such as C. difficile.
aeruginosa. It is not active against methicillin-resistant strains. Clarithromycin may be used to treat severe cases of mycoplas-
A single-dose pharmacokinetic study was performed in five mosis in tortoises.48,49 A recent long-term dosing study showed
snake species kept at 30°C (86°F) in which the half-life of that clarithromycin therapy can be safe and effective (at resolv-
20 mg/kg IM was 24 hours and a dosing interval of 72 hours ing clinical signs but not eliminating the organism) in Desert
was proposed at that temperature.44 A single-dose pharmaco- Tortoises (Gopherus agassizii) when 15 mg/kg clarithromycin
kinetic study in Loggerhead Sea turtles (Caretta caretta) main- oral suspension (50 mg/mL Biaxin oral suspension, Abbott
tained at 22° to 26°C (75°F) found a serum half-life of 19 to Labs, Abbott Park, Ill) is administered by gavage every 3.5 days
20 hours, and the authors proposed a dose of 22 mg/kg every (every 84 hours).50 This dose results in median clarithromy-
72 hours.45 In a single-dose pharmacokinetic study of ceftazi- cin concentrations in plasma that rose from 3.32 μg/mL at
dime 22 mg/kg IM at the same time as fluconazole 21 mg/kg 14 days to 4.79 μg/mL at 6 months, which is above the proposed
SC in cold-stunned Kemp’s Ridley Sea turtles (Lepidochelys target range of 2.0 μg/mL; no 14-hydroxy clarithromycin was
kempii) maintained at 21° to 24°C,46 two of the turtles died detected.50 The study also showed that per rectum administra-
during the study, and E. faecalis was cultured from the blood tion did not achieve plasma concentrations in the target range
and lung of one of them. The maximum concentration (Cmax) when given every 12 hours for 48 hours followed by every
was similar to the study in Loggerhead Sea turtles (61.3 μg/mL 24 hours for 8 days.50
versus 69.9 μg/mL, respectively), but the half-life in Kemp’s Danofloxacin mesylate is a synthetic fluoroquinolone for
Ridley Sea turtles was more than double that of Loggerheads SC injection in cattle.51 It exerts its bacteriocidal activity by
(43.9 versus 19.1 hours, respectively).45,46 Ceftazidime is inhibiting the bacterial DNA gyrase enzyme to block DNA
widely prescribed to numerous species in reptile clinical medi- replication. The FDA-approved label dose is 8 mg/kg once or
cine because of its broad-spectrum, low administration volume 6 mg/kg repeated in 48 hours for bovine respiratory disease
associated with Mannheimia (Pasteurella) haemolytica and was administered IV or PO to animals maintained at 30°C, and
Pasteurella multocida. It is rapidly absorbed, highly bioavail- testing continued for only 24 hours, so the half-life could
able, distributed widely in tissues, and has concentrations not be calculated; however, the authors proposed a dosage of
exceeding that in plasma. Danofloxacin has a half-life in cattle 10 mg/kg every 48 hours.59 The pharmacokinetic studies in
of 3 to 6 hours and has negligible accumulation. It can cause Loggerhead Sea turtles maintained at 26° to 28°C included dos-
a transient local tissue reaction at the injection site. It is active ing of 2 mg/kg IM, IV, and PO. While maximum concentrations
against gram-negative and gram-positive bacteria.51 Like other and half-life differed somewhat among administration routes,
fluoroquinolones, danofloxacin causes articular chondropathy the authors proposed administration of 2 mg/kg every 24 hours
in adult animals at doses exceeding 18 mg/kg and should be is sufficient for all three administration routes.56,57 Marbofloxa-
used with caution in juveniles. A study assessing the effects of cin, 2 mg/kg, was administered IV and IM to Red-eared Sliders
concomitant treatment with ivermectin and danofloxacin in in the forelimbs and hindlimbs. Bioavailability was 77% for
sheep showed that the danofloxacin elimination half-life and IM forelimb and 63% for IM hindlimb administration, but no
systemic exposure (area under the curve [AUC]) increased.52 significant difference was found for AUC, clearance, or half-life
A pharmacokinetic study in healthy and experimentally between locations. The authors determined that IV administra-
infected chickens with P. multocida showed that a dose of tion of 2 mg/kg every 24 hours is appropriate at this dose for
5 mg/kg via gavage was sufficient to provide tissue levels above organisms with an MIC ≤1μg/mL, and IM administration of
the minimum inhibitory concentration (MIC) of the organism; 2 mg/kg every 24 hours is appropriate for organisms with an
tissue levels were less in infected chickens but still above the MIC ≤0.25μg/mL.58 Higher doses should be investigated.
MIC.53 A single-dose pharmacokinetic study was performed in Metronidazole is an oral, synthetic, nitroimidazole anti-
Loggerhead Sea turtles after IV, IM, and SC administration of protozoal and antibacterial agent. It is bacteriocidal against
6 mg/kg.54 Elimination half-life was 18.7 hours after SC obligate anaerobes (MIC ranging from 0.25 to 8 μg/mL) and
administration and 14.7 hours after IM administration. Maxi- is protozoacidal against numerous protozoa with an in vitro
mum plasma concentration and time to maximum concentra- MIC of ≤1μg/mL.61 The antimicrobial action targets DNA syn-
tion after SC and IM administration were similar for both thesis, in that metronidazole acts as an electron acceptor in the
routes (approximately 10 μg/mL and 1.5 hours, respectively). phosphoroclastic reaction and causes breaks in the adenine–
The authors speculate that danofloxacin 6 mg/kg IM or SC thymine base pairing. Although resistance is uncommon, it
every 48 hours could be safe and effective against bacteria with can occur. Metronidazole is available as an IV infusion (met-
an MIC ≤0.5 μg/mL in Loggerhead Sea turtles and called for ronidazole HCl) and as oral tablets (metronidazole base) in the
a multidose pharmacokinetic study to test the hypothesis.54 United States. Metronidazole is a basic compound with a pKa
Danofloxacin has been administered at 6 mg/kg SC every value of 2.62; it is moderately soluble in water (approximately
48 hours for 30 days to treat chronic mycoplasmosis in Gopherus 10 mg/mL at 25°C) at pH 2.5 to 8.0; the pH of the IV infusion
species tortoises.9 is 5.8.61,62 Oral suspensions using pH-appropriate suspending
Marbofloxacin is a synthetic, broad-spectrum, bacteriocidal agents can be procured from licensed compounding pharma-
fluoroquinolone antibiotic approved by the FDA for skin and cies and are generally the most appropriate formulation for
soft tissue infections in dogs and cats and for urinary tract accurate dosing in reptile patients. Metronidazole is well-
infections in dogs.55 It is available as an oral tablet in the United absorbed after oral administration and is widely distributed
States and Europe and as an injectable product in Europe. Its to most body tissues and fluids.62 The major route of elimi-
antimicrobial action is via inhibition of DNA gyrase, like other nation of metronidazole and its metabolites is via the urine
fluoroquinolones. It is soluble in water, but solubility decreases (60% to 80% in humans), and fecal excretion accounts for 6%
in alkaline conditions. Marbofloxacin is rapidly and almost to 15% of the dose.61,62 Metabolism to the 2-hydroxymethyl
completely absorbed from the gastrointestinal tract after oral metabolite occurs, and decreased plasma clearance occurs in
administration to fasted dogs and cats. Bioavailability in dogs patients with decreased liver function but not in patients with
is 94%. Ten percent to 15% is metabolized by the liver in dogs. renal insufficiency. Side effects are primarily gastrointestinal
Approximately 40% of the oral dose is excreted unchanged in in humans, although neurotoxic, hepatic, and hematopoietic
the urine of dogs, and 70% of the drug (85%) and its metabo- effects can occur. They include nausea, vomiting, and ataxia,
lites (15%) are excreted in the urine of cats. The remainder reversible neutropenia, dysuria, yeast overgrowth, encepha-
is eliminated in feces via biliary excretion. Marbofloxacin lopathy, seizures, and peripheral neuropathy. Metronidazole
is bacteriocidal against a broad range of gram-negative and potentiates the effect of coumarin anticoagulants, and con-
gram-positive organisms including Staphylococcus spp., E. coli, comitant administration with drugs that induce microsomal
Proteus mirabilis, Streptococcus spp., P. multocida, E. faecalis, liver enzymes (e.g., phenytoin or phenobarbital) may accel-
Klebsiella pneumonia, Pseudomonas spp., Corynebacterium spp., erate the elimination of metronidazole. Drugs that decrease
and Bacillus spp. Divalent cations diminish the absorption of microsomal liver enzymes (e.g., cimetidine) may prolong its
fluoroquinolones, including calcium, magnesium, aluminum, half-life and decrease its plasma clearance.61 It should be used
and zinc, and drugs including sucralfate, so concomitant with caution in patients with blood dyscrasia, and it may cause
administration is contraindicated. Marbofloxacin, like other mild leukopenia. It is contraindicated in the first trimester of
quinolones, is contraindicated in immature animals because it human pregnancy. Elevated liver enzyme activities in plasma
can cause articular chondropathy, and it should be avoided in have been reported in reptiles.4 Serious toxic side effects in
animals with known central nervous system disorders. Pharma- reptiles can occur at doses between 40 and 100 mg/kg.4,63 Met-
cokinetic studies have been performed in Ball Pythons, Logger- ronidazole is bacteriocidal against (1) gram-negative anaerobic
head Sea turtles, and Red-eared Sliders, and its metabolites have bacilli including Bacteroides spp. (including B. fragilis group)
been studied in Ball Pythons.56-60 In the Ball Python, 10 mg/kg and Fusobacterium spp., (2) gram-positive anaerobic bacilli
including Clostridium spp. and Eubacterium spp., and (3) gram- triphosphate. Acyclovir triphosphate stops replication of
positive anaerobic cocci including P. niger and Peptostreptococ- herpesviral DNA by competitive inhibition of viral DNA poly-
cus spp.61 It is trichomonacidal and amoebacidal for protozoa merase, incorporation into and termination of the growing
with in vitro MIC ≤1μg/mL.61 Pharmacokinetic studies in DNA chain, and inactivation of viral DNA polymerase.72,74
Red-eared Sliders, colubrid snakes (Elaphe guttata and Ela- Acyclovir is available in tablets, capsules, oral suspension, and
phe obsoleta), and Green Iguanas have been published.16,64-66 by injection. Its average bioavailability after oral administra-
In Red-eared Sliders, a single intracoelomic dose of 20 mg/kg tion is 10% to 20%, and food does not affect absorption. The
was administered; the maximum plasma concentration was elimination half-life and total body clearance of acyclovir are
25 μg/mL at 5 hours after injection, and the elimination half- dependent on renal function in humans, and the dose should
life was 27 hours.16 The authors suggest an intracoelomic dos- be reduced in patients with renal insufficiency.74 Coadminis-
age of 20 mg/kg every 48 to 72 hours, depending on the MIC tration of probenecid with acyclovir increases the elimination
of the organism it is directed against, but caution that adverse half-life of acyclovir. Adverse effects are rare in humans. An
effects did occur; thus the intracoelomic route may not be safe. in vitro study of acyclovir efficacy against a herpesvirus iso-
In colubrid snakes, single doses of 20, 50, 100, and 150 mg/kg lated from a Hermann’s Tortoise (Testudo hermanni) indicated
PO have been studied, and multiple 20-mg/kg doses have also that 50 μg/mL reduced the virus content of cultures to below
been studied.64,65 The maximum plasma concentration varies the limit of detection.71 The pharmacokinetics of acyclovir
from 12.8 μg/mL after 20 mg/kg PO every 48 hours for 6 days in Marginated Tortoises (Testudo marginata) over a 24-hour
to 2039 μg/mL after a single dose of 150 mg/kg PO. The half- period after 80 mg/kg PO every 24 hours for 7 days have been
life was 15 hours after the first 20-mg/kg dose, 23 hours after reported.73 The maximum plasma concentration occurred
the sixth dose, and 26 hours after the 150-mg/kg dose.64,65 6.9 ± 4.2 hours after administration and was 1.40 ± 0.45 μg/mL;
No clinically significant adverse behavioral, hematologic, or the tissue concentrations were not evaluated.73 The elimina-
biochemical effects were observed other than mildly elevated tion half-life was 8.9 ± 3.8 hours, and the authors proposed
plasma lactate dehydrogenase activity after the last 20-mg/kg that a higher milligram dose be administered every 12 to
dose and mildly decreased glucose after the 50- and 150-mg/kg 24 hours. A recently published study72 on the pharmacokinet-
single doses.64,65 Taken together, the results support a dosage ics of acyclovir in North American Box Turtles (Terrapene
of 20 mg/kg every 48 hours in Elaphe spp. snakes. Higher doses carolina) after a single oral dose of 40 mg/kg valacyclovir
should be reserved for resistant infections so that the risk of (the esterified form that is rapidly converted to acyclovir
adverse effects is avoided. A pharmacokinetic study of a single after oral administration) found the elimination half-life to be
20-mg/kg dose followed by 20 mg/kg every 24 hours for 10 14.6 hours, and the Cmax of 1.94 μg/mL was reached 13.0 ±
days in Green Iguanas found a maximum plasma concentra- 7 hours after administration. Prolonged lethargy was noted in
tion (Cmax) of 7.6 μg/mL after the single dose with a half-life one turtle after receiving the dose of valacyclovir. The authors
of 12.7 hours and a Cmax of 22.8 μg/mL after 10 days.66 No proposed that a dosage of valacyclovir of 40 mg/kg PO every
adverse hematologic, biochemical, or behavioral effects were 24 hours would be sufficient to achieve a steady-state level
observed after the 10-day treatment trial. The authors conclud- above 0.8 μg/mL in plasma. It is possible the proposed doses
ed that 20 mg/kg every 48 hours would be sufficient for “most” of valacyclovir in the Common Box Turtle and acyclovir in the
infections and that the dosing frequency could be increased Marginated Tortoise may be sufficient to treat herpesvirus in
to every 24 hours for resistant strains with MICs ≥8 μg/mL.66 tortoises even though plasma levels are much lower than the
necessary in vitro inhibitory concentration because acyclo-
Antiviral Agents vir concentrates in herpesvirus-infected tissues; the MIC in
Numerous viruses infect reptiles, and a causal relationship humans is 0.45 μg/mL, 3 μg/mL in horses, and 18 μg/mL in
between disease and the viral pathogen has been established cats. A topical preparation is also available (5% acyclovir, Zovi-
for a few; diagnostic tests are currently available for several of rax, GlaxoSmithKline, Inc., Research Triangle Park, NC). A few
them.67,68 Nursing care is the mainstay of antiviral therapy for clinicians suggest it may be useful in treatment of herpesvirus
individuals, and immune-stimulators and antiviral drugs may stomatitis in tortoises.75,76 Further research measuring the tis-
be useful in some cases.69 Vaccine trials have shown promise sue levels of acyclovir achieved in herpesvirus-infected tissue
for poxvirus in crocodilians but not herpesvirus in tortoises after oral administration and the efficacy of treatment are nec-
or paramyxovirus in snakes.4,67,70 Reptiles testing positive for essary. Valacyclovir may also have some effect on iridoviruses,
a virus should be isolated from uninfected reptiles to prevent and further research is warranted.72
further transmission. A few antiviral drugs have been evalu- Ganciclovir is a synthetic guanine derivative that is active
ated for reptiles and may help improve an individual patient’s against human cytomegalovirus and herpesvirus.77 Its mecha-
clinical condition; however, in general, antiviral drugs are not nism of action is similar to acyclovir. It has a solubility of
expected to eliminate infection, and it is possible that a reptile 2.6 mg/mL in water at 25°C and pKa values of 2.2 and 9.4. As
could shed infective virus after treatment. Antiviral agents that the monosodium salt, ganciclovir sodium, it has a solubility
have been evaluated in reptiles include acyclovir, ganciclovir, of approximately 6 mg/mL at 37°C. When reconstituted with
and valacyclovir.71-73 water, the pH of the IV solution is 11. The in vitro MIC for
Acyclovir is a synthetic purine nucleoside analogue that cytomegalovirus ranges from 0.02 to 3.48 μg/mL. Ganciclovir
interferes with nucleic acid synthesis and is active against her- inhibits mammalian cell proliferation at concentrations as low
pesviruses.74 The inhibitory activity is highly selective because as 30 μg/mL. It is eliminated primarily via the kidneys, so the
of an affinity for thymidine kinase encoded by herpesviruses, dosage should be reduced in patients with renal insufficiency.
which phosphorylates acyclovir into a nucleotide analogue Viral resistance to ganciclovir has been found in humans that
that is further converted by a series of enzymes into acyclovir have never been treated with it before.77 Pharmacokinetics
have not been studied in reptiles, but an in vitro study showed 2 and should be taken under fasting conditions for best absorp-
that it was effective at 25 and 50 μg/mL against a herpesvirus tion in humans, as opposed to the capsules, which should be
cultured from a Hermann’s Tortoise. taken with food because low pH is required for absorption.84
It is metabolized by the cytochrome P450 isoenzyme system
Antifungal Agents (CYP3A4), which results in several metabolites, primarily
Fungal infections are common enough in reptiles that anti- hydroxyitraconazole. It may undergo saturable metabolism
fungal therapy has become a routine part of clinical practice. with multiple doses, and the dosing interval may be longer
Similar to antibiotics, antifungal agents are best selected in than predicted by single-dose pharmacokinetic studies.81,84
response to a specific etiologic diagnosis. Fungal culture About 40% of the dose is excreted as inactive metabolites in
should precede therapy, but antifungal sensitivity testing is urine, up to 18% is excreted unchanged in feces, and less than
not practical in most cases. Empiric selection of antifungal 0.03% is excreted unchanged in human urine. Itraconazole
drugs may be necessary while awaiting culture results, which is widely distributed to tissues, especially lipophilic organs
can take weeks. Selection should be based on the prevalence of including skin. It is minimally distributed to aqueous humor
a specific fungal organism for a disease syndrome, antifungal of the eye, cerebrospinal fluid, urine, and saliva when inflam-
spectrum of activity, distribution of the antifungal drug to the mation is not present.85 Because it is primarily metabolized by
diseased tissues, potential side effects, metabolic and excre- the liver, blood levels should be monitored in patients with
tory pathways, volume of the formulation required to deliver hepatic insufficiency, and dosing intervals should be adjusted
the necessary dose, dosing interval, and ease of administra- to maintain blood levels above the MIC of the target fungus. It
tion. Multiple antifungal drugs may be used concomitantly to is active against species of Blastomyces, Aspergillus, Histoplas-
overcome the limitations of one drug alone or to expand the ma, Coccidioides, Cryptococcus, Paracoccidioides, Sporothrix,
spectrum of activity. Topical agents are frequently combined and Trichophyton. It can be active against some isolates of Can-
with systemic agents for severe fungal dermatitis (e.g., Chryso- dida, but many are resistant. It is not active against Zygomy-
sporium anamorph of Nannizziopsis vriesii [CANV]). A vaccine cetes, Fusarium, Scedosporium, and Scopulariopsis. It has been
trial showed no difference between dermatologic lesions or used to effectively treat CANV infections in reptiles. Itracon-
septicemia between vaccinated and control Bearded Dragons azole can cause rapid hepatotoxic effects including liver failure
experimentally infected with CANV.78 This review is limited to and death in humans, and its use is contraindicated in patients
those agents in which new information is available. with hepatic insufficiency.84 It can cause anorexia and weight
Amphotericin B is a polyene antifungal produced from a loss in Bearded Dragons. In one treatment trial, five of seven
strain of Streptomyces nodosus. It acts to increase membrane Bearded Dragons died on days 5, 20, 22, 36, and 54 of treat-
permeability by binding to sterols in cell membranes of sensi- ment with itraconazole oral solution (Sporanox, Janssen-Cilag,
tive fungi. It also binds to the sterols in vertebrate cell mem- Berchem, Belgium) 5 mg/kg every 24 hours PO, although
branes, which is believed to account for its toxicity in animals histopathologic evidence of hepatotoxicity was absent.81,86
and humans. It is available as an injectable product and in lipid Itraconazole accumulates over time in CANV-infected Bearded
complex.79 The lipid complex formulation has increased peak Dragons, reaching a steady-state plasma concentration of 4 to
concentration, clearance time, volume of distribution, and ter- 8 μg/mL after approximately 10 days.81 In vitro MIC90 of itra-
minal elimination half-life when compared with amphotericin conazole for CANV cultured from infected Bearded Dragons
B desoxycholate.79 Several drugs interact with amphotericin B was 0.25 μg/mL.81 The fungus could no longer be cultured
when used concomitantly. These include antineoplastic chemo- from lesions after 4 weeks of treatment. In a different treat-
therapeutics, corticosteroids, cyclosporin A, digitalis glycosides, ment trial, seven Bearded Dragons were successfully treated
flucytosine, imidazole antifungal agents (e.g., ketoconazole, for CANV with itraconazole (and clotrimazole), but six were
clotrimazole, and fluconazole), other nephrotoxic agents, tubo- euthanized.87 A group of Green Anacondas (Eunectes murinus
curarine, and zidovudine.79 Treatment can cause increases in murinus) infected with CANV were treated with itraconazole
levels of blood urea nitrogen, uric acid, aspartate aminotrans- (Sporanox Oral Solution, OrthoBiotech, Raritan, NJ) at one of
ferase, alanine aminotransferase, alkaline phosphatase, lactate two dosages, either 10 mg/kg every 48 hours for 14 days or
dehydrogenase, and amylase. Treatment can cause decreased 10 mg/kg every 24 hours for 7 days then every 48 hours for
blood phosphorus and increases or decreases in blood glucose 7 days; plasma levels of itraconazole reached 4.3 to 9.0 μg/mL
levels. It is likely to cause nephrotoxicosis in reptiles and is and persisted for at least 14 d after treatment.88 A series of
contraindicated in reptiles with renal insufficiency.80 It is active cases showed that itraconazole was effective without adverse
against species of Aspergillus, Blastomyces, Candida, Coccidioi- effects at metabolically scaled doses (0.5 to 1.7 mg/kg PO every
des, Cryptococcus, and Histoplasma in mammals. Resistance can 53 to 75 hours for 148 to 184 days) in the treatment of Asper-
occur, particularly with prolonged therapy. The in vitro MIC gillus spp. in two lizard species and two snake species (total
against CANV cultured from captive lizards was 2 μg/mL.81 of seven cases).89 Therefore, because itraconazole appears to
There are clinical reports of its use in nebulization, intratra- be well-absorbed after oral administration, has efficacy against
cheal, and intrapulmonary therapy in reptiles.63,82,83 fungal infections, and is of questionable safety, further phar-
Itraconazole is a synthetic triazole antifungal agent. It macokinetic studies, preferably in fungus-infected patients,
exerts its antifungal action by inhibiting 14C-demethylation of are warranted.
ergosterol, a cell wall component of fungi. It is available in cap- Voriconazole is a triazole antifungal agent that exerts
sules and oral solution. It is insoluble in water, slightly soluble its antifungal effect by inhibiting fungal cytochrome P450-
in alcohols, and freely soluble in dichloromethane. It has a mediated 14 alpha-lanosterol demethylation, which is essential
pKa of 3.70 and a log–log(n-octanol/water) partition coef- for ergosterol inhibition. It is more selective for fungal than
ficient of 5.66 at pH 8.1. The oral solution has a target pH of mammalian cytochrome P450 enzyme systems.90 It is available
as a lyophilized powder for IV infusion, film-coated tablets for studied in reptiles, but in mammals it is well-absorbed after
oral administration, and as a powder for oral suspension.90 oral administration; peak plasma concentrations generally
Pharmacokinetics in humans are similar after the oral and IV occur within 2 hours after administration.94 It is lipophilic and
routes, and maximum plasma concentrations are achieved 1 to becomes concentrated rapidly in the stratum corneum of the
2 hours after dosing.90 It is widely distributed into tissues and skin; it has a terminal half-life of 200 to 400 hours in tissues
is metabolized by cytochrome P450 enzymes to metabolites such as adipose and skin, making it well-suited for treating
including N-oxide voriconazole, which has minimal antifungal fungal dermatoses.94 It is metabolized in the liver via several
activity and accounts for 72% of the circulating metabolites.90 CYP isoenzymes but not cytochrome P450; the metabolites
It is eliminated primarily via hepatic metabolism; less than 2% have little antifungal activity.93 It is primarily excreted in
of the oral dose is excreted unchanged in the urine of humans, urine, and dosing should be adjusted in patients with renal
and more than 80% of the metabolites are recovered in the insufficiency. Terbinafine is active against species of fungi
urine. Doses should be adjusted accord to plasma levels of the including Trichophyton, Candida, Epidermophyton, and Scopu-
drug in patients with hepatic insufficiency. No adjustment is lariopsis. In vitro sensitivity of CANV isolated from the skin of
necessary in patients with renal insufficiency after oral admin- Bearded Dragons (MIC90) to terbinafine was 2 μg/mL.81 It has
istration, but IV administration should be avoided because the been administered to reptiles, but no pharmacokinetic data
IV vehicle (sulfobutyl ether beta-cyclodextrin sodium) accu- are available. Topically applied terbinafine (Lamisil, Novartis
mulates. The terminal elimination half-life is dose dependent Farmaceutica, S.A., Barcelona, Spain) was administered con-
because the pharmacokinetics of voriconazole are nonlinear. comitantly with topical chlorhexidine (Cristalmina solucion
Serious drug interactions occur with concomitantly adminis- cutanea, Laboratorios Salvat A.A., Esplugues de Llobregat,
tered agents that are also metabolized via the cytochrome P450 Barcelona, Spain) and oral ketoconazole (Panfungol suspen-
enzyme system. Side effects in humans include visual distur- sion, Doctor Esteve S.A., Barcelona, Spain) to treat CANV in a
bances, gastrointestinal disturbances, hepatic toxicity, fetal Bearded Dragon and two Green Iguanas.95,96 The therapeutic
toxicity in pregnant women, and electrocardiac disturbances. combination brought about clinical resolution of CANV infec-
It is effective against species of fungi including Aspergillus, tion, but it is unclear what treatment effect could be attributed
Candida, Fusarium (except Fusarium solani), and Scedospo- to terbinafine because of the confounding effects of the other
rium. Drug resistance has not been studied thoroughly, but therapeutic agents. Terbinafine was used to successfully treat
strains that are resistant to fluconazole or itraconazole may Exophiala oligosperma phaeohyphomycosis of the carapace in
also show reduced sensitivity to voriconazole.90 In vitro vori- an Aldabra Giant Tortoise (Aldabrachelys [Geochelone] gigan-
conazole sensitivity (MIC90) of CANV that was isolated from tea). Initially it was used topically in combination with oral
captive lizards was 0.0625 μg/mL.81 itraconazole and then, because of lack of clinical response,
When used for treatment of CANV in Bearded Dragons, only switched to oral terbinafine (Lamisil, Norvartis Pharmaceu-
one of seven died compared with five of seven treated with itra- ticals, East Hanover, NJ) 3.4 mg/kg PO every 24 hours for
conazole; in those that survived, the disease was cleared with 15 months.97 Plasma concentrations of terbinafine were not
treatment of voriconazole (Vfend, Pfizer, Ixelles, Belgium) 10 measured during treatment.
mg/kg PO every 24 hours for 4 to 9 weeks.81 The steady-state
plasma concentration of voriconazole was 3.4 to 5.7 μg/mL, Antiparasitic Agents
but substantial interindividual variation was observed.81 A A number of antiparasitic agents are currently being used to
Giant Girdled Lizard (Cordylus giganteus) was treated for treat endoparasites and ectoparasites in reptiles. Effective treat-
CANV with voriconazole tablets (Vfend, Pfizer, Ltd, Sandwich, ment addresses the life cycle and ecology of the parasite. For
England) suspended in water, 10 mg/kg PO every 24 hours for example, it is essential to know what tissues it affects, whether
10 weeks.91 This resulted in a steady-state plasma concentra- it is directly transmitted, has intermediate hosts, has free-living
tion of approximately 2.0 to 3.5 μg/mL after 3 days of treat- life stages, and whether it participates in the transmission of
ment. In vitro MIC of the cultured CANV was 0.25 μg/mL for other infectious agents. Treatment may or may not include
voriconazole. Weekly fungal culture of the skin wounds was antiparasitic drug therapy. Commonly used antiparasitic drugs
negative during weeks 7 to 10 of treatment and for 3 weeks include albendazole, fenbendazole, fipronil, ivermectin, metro-
after treatment.91 Pharmacokinetics of voriconazole were nidazole, oxfendazole, paromomycin, permethrin, ponazuril,
determined after a single SC injection (5 mg/kg) in Red-eared praziquantel, pyrantel pamoate, toltrazuril, and trimethoprim/
Sliders.92 The maximum plasma concentration was greater sulfas. Promising newer products include combinations of
than 1 μg/mL at 1 hour and 2 hours after injection. This route imidacloprid/moxidectin and emodepside/praziquantel that
of administration is likely to require a much higher dose and are administered topically (see previous sections in this
short dosing interval to maintain a plasma concentration that chapter). This review is limited to a few notable agents about
is above the MIC of many organisms.92 which there are recently published data. Topical treatment
Terbinafine hydrochloride is an allylamine antifungal agent. with imidacloprid/moxidectin (Advantage multi/Advocate,
It can be fungicidal in vitro depending on the concentration Bayer, Shawnee Mission, Kans) and emodepside/praziquantel
and the fungal species.93 Terbinafine exerts its antifungal (Profender, Bayer HealthCare, Shawnee Mission, Kans) show
action by inhibiting biosynthesis of ergosterol via inhibition promise for the treatment of internal parasites in reptiles and
of squalene epoxidase enzyme, which causes fungal death have already been reviewed in this chapter.
primarily due to increased membrane permeability from high Albendazole, fenbendazole, and oxfendazole are frequently
concentrations of squalene but not ergosterol deficiency.93 It is used benzimidazole antiparasitic agents that exert their anti-
freely soluble in methanol and methylene, soluble in ethanol, parasitic action by selectively binding and damaging tubulin,
and slightly soluble in water. Pharmacokinetics have not been preventing tubulin polymerization and inhibiting microtubule
formation.98,99 At higher concentrations, benzimidazoles treatment of toltrazuril in the drinking water (7 mg/kg) is
disrupt metabolic pathways within helminths and inhibit sufficient to treat intestinal coccidiosis in poultry, and daily
enzymes such as malate dehydrogenase and fumarate reduc- oral administration of ponazuril (5 mg/kg) for 28 days is rec-
tase. Fenbendazole is insoluble in water and only marginally ommended for treatment of EPM in horses.106,107 A clinical
absorbed after oral administration; peak blood levels of 0.07 to trial in chameleons reported that toltrazuril was effective at
0.11 μg/mL are seen in mammals, and up to 50% is excreted eliminating shedding of coccidium, and no side effects were
unchanged in the feces. The small amount of absorbed fen- observed.110 Similarly, a pilot study in Bearded Dragons report-
bendazole is metabolized by cytochrome P450 and other ed that coccidian oocysts were found on fecal flotation before
microsomal enzymes in the liver to metabolites including treatment with ponazuril 30 mg/kg PO every 48 hours for two
oxfendazole; some extrahepatic metabolism also occurs.100 treatments but not after.111 An incidental finding in a group
Benzimidazoles are effective against a range of nematodes, of 10 Bearded Dragons in an experimental cryptosporidiosis/
some trematodes, a few cestodes, and a few flagellated proto- paromomycin study was that treatment of a naturally occurring
zoans. Benzimidazole toxicity is generally rare in most species, coccidiasis (presumed Isospora amphiboluri) with ponazuril
but mortality has been reported, particularly after overdoses in (Marquis, Bayer, Inc., Montreal, Quebec, Canada) 30 mg/kg
birds and reptiles.100-103 Relative toxicity of these anthelmintics PO every 48 hours for three treatments and then again after
in order of most toxic to least toxic appears to be albendazole 3 months 30 mg/kg every 48 hours for six treatments was not
>oxfendazole>fenbendazole.104 Toxicosis leads to lesions that effective.112 Histologic examination of the intestines immedi-
mimic radiation, which targets rapidly dividing cells includ- ately after the second treatment period showed mild to moder-
ing bone marrow and intestinal epithelium. They also cause ate intracellular Isospora in the enterocytes of all but one of the
hepatotoxicosis, teratogenic effects, and tumor promotion.102 10 dragons.112 Toltrazuril (Baycox 5%, oral suspension, Bayer
Benzimidazoles should be used with caution in gravid and Vital GmbH, Germany), 15 mg/kg, every 48 hours for 30 days,
pregnant animals and should be avoided in animals with sep- and ponazuril (90 mg/mL compounded), 30 mg/kg PO every
ticemia. Fenbendazole and oxfendazole were compared with 24 hours for 4 days and repeated for 2 to 4 treatments at least
regard to their efficacy against intestinal oxyurid nematodes in 2 weeks apart, have been used to treat intranuclear coccidio-
Hermann’s Tortoises after single oral doses of 100 mg/kg and sis of testudines in several species of tortoise, and both drugs
66 mg/kg, respectively.105 Both treatments eliminated shedding appear to be associated with improved survival, cessation of
of oxyurid ova in feces after 32 days, and a second treatment shedding (negative results on polymerase chain reaction test-
was not necessary. ing after treatment), and resolution of clinical signs in cases
Toltrazuril and its principle metabolite ponazuril are tri- that are treated early in the course of the disease.113 Controlled
azinetrione antiprotozoal compounds with activity against clinical trials and pharmacokinetic studies are needed for
several genera of the Apicomplexa including Eimeria, Isospora, ponazuril and toltrazuril in reptiles.
Hepatozoon, Toxoplasma, Sarcocystis, Neospora, and possibly Paromomycin is an oral aminoglycoside antiparasitic agent
others.106-108 Ponazuril is available as an oral paste (Marquis, closely related to neomycin. Like all aminoglycosides, it exerts
15% w/w, Bayer Animal Health, Shawnee Mission, Kans) in the its cidal effect by binding to the 16S ribosomal RNA subunit
United States, and it can be compounded into an oral suspen- to inhibit protein synthesis. Paromomycin is very soluble in
sion by a licensed pharmacist. Toltrazuril is available outside water but, similar to other aminoglycosides, is poorly absorbed
of the United States as a solution for the drinking water of after oral administration, except in cases of severe intestinal
poultry (Baycox solution 2.5% and 10%, Bayer) and as an oral ulceration. It is eliminated almost exclusively unchanged in
suspension (Baycox 2.5 and 5% suspension, Bayer). The pH the feces. It has antibacterial activity, which is a side effect
of ponazuril oral paste is 5.7 to 6, and the pH of 2.5% toltra- when used to treat intestinal amoebiasis, cutaneous leishmani-
zuril solution is 8 to 10. Toltrazuril is rapidly metabolized in asis, or cryptosporidiosis. Intestinal dysbiosis can occur when
the liver to the sulfone derivative, ponazuril.108 These drugs used for prolonged periods at high doses. Paromomycin has
exert a coccidiocidal effect on intracellular coccidial stages by been used with limited success in reptiles to treat refractory
interfering with division of the nucleus, amino acid and fatty intestinal amoebiasis and cryptosporidiosis.112,114-118 Treat-
acid metabolism, and the electron transport system of mito- ment with paromomycin 100 mg/kg PO every 24 hours for
chondria through ballooning of the endoplasmic reticulum 7 days, then every 84 hours for 90 days in a group of Her-
and, in macrogametes, by damaging the wall-forming bod- mann’s Tortoises with cryptosporidiosis initially controlled
ies.106,107,109 There is no effect on oocysts. An additive effect clinical signs and shedding, but the disease recrudesced after
can be achieved by concomitant administration of toltrazuril 9 months.114 A colony of Leopard Geckos (Eublepharis macu-
with an ionophore in the treatment of coccidiosis in poultry.107 larius) with naturally occurring cryptosporidiosis were treated
A concentration of 0.1 to 1.0 μg/mL ponazuril is sufficient to with 50 to 800 mg/kg paromomycin (Humatin, Parke-Davis,
kill Sarcocystis neurona, which causes equine protozoal myelo- Morris Plains, NJ) PO every 24 hours; the treatment was asso-
encephalitis (EPM) when horses serve as aberrant hosts for the ciated with improvement in clinical signs and reduced oocyst
organism. The peak serum concentration was 5.6 μg/mL 18 days shedding that returned when treatment was suspended.118 In
after oral administration in horses, and the peak concentration a different clinical trial, treatment of four Leopard Geckos
in cerebrospinal fluid was 0.21 μg/mL after 15 days.106 The with paromomycin (100 mg/kg every 24 hours for 7 days,
elimination half-life in horses is about 4.5 days. Acute toxicity and then every 84 hours for 72 days) brought about improve-
of toltrazuril in rats, mice, and chickens required overdoses of ment of clinical signs and negative fecal examinations in three
100 times the recommended therapeutic dose, with an LD50 of the geckos but did not eliminate infection.115 Two Gila
range of 1600 to 5000 mg/kg; no observable effect occurred Monsters (Heloderma suspectum) with naturally occurring
in mammals after a ponazuril dose of 90 mg/kg.107,109 A 2-day cryptosporidium infection were treated with paromomycin at
a dosage of 300 to 360 mg/kg PO every 48 hours for 14 days, substantial after oral administration, so the authors concluded
which was repeated at 6 months; fecal samples were negative that the IM route is preferable.121 Pharmacokinetics were
for cryptosporidia after 2 weeks of treatment and for at least determined in Green Iguanas after administration of 0.2 mg/kg
1 year.117 A group of 10 hatchling (1-month-old) Bearded meloxicam via IV and oral routes, toxicity was assessed after
Dragons were experimentally infected with Cryptosporidium 1 or 5 mg/kg PO every 24 hours for 12 days.122 Pharmacoki-
from a naturally infected adult, and five of them were treated netic variables were similar between the two administration
with paromomycin (Humatin 250 mg capsules, Erfa, Montreal, routes, except that the maximum plasma concentration was
Quebec, Canada) in saline (500 mg/5 mL) 100 mg/kg every greater after IV administration (0.6 μg/mL) than after oral
24 hours for 7 days, followed by every 84 hours for 72 days; administration (0.2 μg/mL). No histologic evidence of toxicity
the other five Bearded Dragons served as controls.112 This was found after administration of the high doses. The authors
treatment did not control shedding of the organism into the concluded that 0.2 mg/kg IV or PO would result in plasma
feces, so a second round of treatment with 360 mg/kg every concentrations above 0.1 μg/mL for 24 hours.122
48 hours for 10 days was administered. This second treatment
regimen did eliminate the cryptosporidia: infection was pres-
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CHAPTER 7

DIAGNOSIS clinician to evaluate the probability that a published dose is

remain unanswered and informed, empiric dosing is still used

Depot Formulations treatment in a relatively large (n = 417), uncontrolled clinical

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