Colette L. Wheler and Patricia M. Dowling Veterinarians may treat small mammals as laboratory animals (e.g., rabbits, rodents), as household pets (e.g., rabbits, rodents and ferrets), and as food‐producing animals (e.g., rabbits, guinea pigs). There are many challenges when using antimicrobials in these species. Some antimicrobials are known to be toxic to rabbits and some rodents, so careful selection of the most appropriate drugs is critical. Globally, there are very few antimicrobials specifically approved for treatment of these patients, necessitating extra‐label drug use (ELDU). An alternative source or formulation of drug may be needed, which may involve compounding or importing medications from other countries (following strict federal regulations) or the use of human drug formulations. Many antimicrobials must be reconstituted prior to administration, and have a fairly short shelf‐life, even if refrigerated. Often, very little of the drug formulation is needed to treat an individual patient, so the remainder is often frozen in aliquots for economic reasons and to avoid wastage. However, information on the stability of these frozen, reconstituted products is often unavailable or difficult to find. While many antimicrobial stewardship programs have been developed for other areas of food and companion animals, attention to small mammals has lagged. Antimicrobials are used extensively for the clinical treatment of infectious disease in laboratory animals, meat animals and pets, and spontaneous and research‐related conditions in research animals. This is an area where stewardship calls for adding two newer “Rs” of review and responsibility to the original “3Rs” of reduce, replace, and refine promoted in experimental use of animals (Narver, 2017). The following sections discuss these many challenges in more detail, and conclude with a series of tables listing some reported dosages of antimicrobials and common conditions in small mammal pets. Some information is also included for hedgehogs and sugar gliders, since their popularity as pets is increasing in North America, and this information can be difficult to find. Much of the antimicrobial use in small mammals is empirical; that is, without identification of a pathogen and subsequent susceptibility testing. Even if veterinarians are able to collect and submit samples to a diagnostic laboratory, there are no validated breakpoints for bacteria affecting small mammals and the quality of the testing may be below the standards acceptable in human diagnostic microbiology (Boot, 2012). Additionally, the minimum inhibitory concentration (MIC) breakpoint values for most antimicrobials are based on studies in humans or larger animals; the high metabolic rates of small lab animals such as rodents make it challenging to achieve drug concentrations above the pathogen MIC for many drugs. Infections should be treated as soon as possible to maximize the efficacy for the initial bacterial kill, either to eradicate the bacteria at the site of infection or to decrease the bacteria to numbers that can be eradicated by the animal’s immune system. Some antimicrobials (e.g., sulfonamides) are time dependent, with their efficacy dependent on the duration for which the plasma concentrations of the drug exceed the MIC for the pathogen. Concentration‐dependent antimicrobials (e.g., fluoroquinolones) rely on the peak plasma concentration for efficacy. Enteral dosing in the feed and water may be effective for time‐dependent antimicrobials, while parenteral injectable (bolus) dosing is more appropriate for concentration‐dependent antimicrobials. If systemic antimicrobials are used, then they should be administered for the shortest time that is clinically appropriate; there is no minimum duration of treatment necessary for antimicrobials. Ideally, the animal’s total exposure to an antimicrobial should be limited, both to minimize perturbations to the normal microbiome and physiology and to decrease selecting for resistant bacteria. Antimicrobial resistance in bacteria from small mammals has not been well studied. The close interaction between pet small mammals and their owners facilitates the transmission of pathogenic bacteria between humans and animals. While gerbils are first, rabbits are the second most common specialty/exotic pet mammals among US households, and are the most well studied for AMR (AVMA, 2022). According to a Spanish study of bacterial diseases of pet rabbits, the most prevalent genera were Staphylococcus spp. (15.8%), Pseudomonas spp. (12.7%), Pasteurella spp. (10%), Bordetella spp. (9.6%), and Streptococcus spp. (6.8%). Enterobacterales represented around 18% of the isolates, with Enterobacter spp., E. coli, and Klebsiella spp. being the most frequent isolates (Fernández et al., 2023). Infections of the respiratory tract (53%) were most common, followed by otitis (18%), abscesses, principally located in the head (16%), conjunctivitis (5%), reproductive tract (3%), skin disease/dermatitis (2%), urinary tract (2%), and dental disease (1%). Gram‐positive cocci (Staphylococcus, Streptococcus and Corynebacterium [Trueperella] pyogenes) and Gram‐negative bacteria, such as Pasteurella multocida, were susceptible to a wide panel of conventional antimicrobials. While fluoroquinolones are the most common therapeutic option in small mammals, for respiratory infections caused by P. multocida or B. bronchiseptica, results of this study suggest that trimethoprim/sulfonamides would be a good candidate for first‐line treatment in pet rabbits. Most veterinary practitioners are aware that some antimicrobials are toxic to rabbits and some rodents, especially when given orally. Disruption of the normal population of intestinal flora occurs, and this dysbiosis allows proliferation of clostridial or coliform bacteria, and subsequent release of toxins. Hindgut fermenters, such as rabbits, guinea pigs, chinchillas, and hamsters, are particularly susceptible to this condition, and narrow‐spectrum antimicrobials such as beta‐lactams, macrolides, and lincosamides are most responsible. Diarrhea usually appears within 24–48 hours following administration of the drug, and most cases of dysbiosis are fatal. Pathogenic conditions and sudden alterations in diet may also predispose the animal to dysbiosis, and even antimicrobials that are considered safe can sometimes cause problems. Rats, mice, gerbils, and ferrets are less vulnerable to this condition. As in other species, aminoglycosides are potentially nephrotoxic and ototoxic to small mammal species. Streptomycin has been reported to be toxic in gerbils. Although normally safe in rabbits, rodents, and ferrets, fluoroquinolone antimicrobials (e.g., enrofloxacin) may cause arthropathies in young animals. Chloramphenicol is generally safe to use in small mammals, and many bacteria infecting these animals are highly susceptible to this drug. However, chloramphenicol has been associated with a dose‐independent irreversible aplastic anemia in humans, so appropriate directions for prevention of exposure, such as wearing gloves and hand washing, must be given when this antimicrobial is prescribed. In addition, chloramphenicol is prohibited for use in food‐producing animals, such as meat rabbits. Potential toxicities must always be kept in mind when selecting an antimicrobial based on culture and susceptibility results, as the most appropriate choice may result in dysbiosis or other problems in a particular species. Supportive ancillary therapies, such as administration of fluids along with aminoglycosides and good nursing care, as well as provision of adequate nutrition and a comfortable, stress‐free environment, will also aid in successful treatment. In Canada and the US, there are a limited number of drugs labeled for use in rabbits, rodents, and ferrets, and very few of these are antimicrobials. Some antimicrobials are approved for use in mink, and dosages for mink would likely be valid in ferrets since they are closely related species. In Canada, chlortetracycline feed premix is approved for the treatment of mink. In Canada, antimicrobials labeled for use in rabbits include procaine penicillin G (IM use only) and tilmicosin (SC and in feed), and salinomycin and robenidine for the control of coccidiosis. In the US, only sulfaquinoxaline as an antimicrobial and lasalocid for coccidiosis are approved for use in rabbits. In the EU, most meat rabbit production occurs in France, Spain, and Italy, and there are a number of approved antimicrobials including trimethoprim/sulfas, sulfadimethoxine, chlortetracycline, apramycin, and colistin. Therefore, in order to provide appropriate care for small mammal patients, veterinarians are required to use many drugs in an extra‐label manner. In Canada and the US, ELDU refers to the use of a federally approved drug in a manner that is not in accordance with the label or package insert. It is the responsibility of the veterinarian to be aware of, and follow, the rules and regulations in their particular jurisdiction. In the US, further clarification of ELDU was provided in 1994 with the introduction of the Animal Medicinal Drug Use Clarification Act (AMDUCA). This act clearly explains legitimate extra‐label drug use by veterinarians, and outlines the specific conditions that must be followed for acceptable extra‐label drug use (see Chapter 26). Extra‐label use of human antimicrobial formulations is fairly common for treatment of small mammals. Many of these products are single‐dose vials that have a fairly short shelf‐life once reconstituted (e.g., cefazolin). Treatment of the small mammal patient may occur for a longer period than the shelf‐life of the drug, or the total amount needed may be very small. Rather than discard the remainder, veterinarians often freeze small aliquots of the product for future use. Details on the stability of these reconstituted products after freezing are often not easy to find; however, some information can be found in the Handbook of Injectable Drugs by Lawrence Trissel, which is available in hardcopy and electronic format, and Plumb’s Veterinary Drug Handbook by Donald Plumb, as well as in some package inserts. An alternative source of drug sometimes needs to be explored by veterinarians for the treatment of small mammal patients, such as compounding or importing medications from other countries. Compounding is a type of ELDU whereby the original drug dosage form is manipulated by a veterinarian or pharmacist, or an entirely new product is manufactured by a compounding pharmacy, to create a customized medication to meet a specific need. This could involve anything from altering the concentration of a drug by diluting it other than according to the package instructions, or mixing a crushed tablet into a liquid, to the custom creation of a medicated tablet or liquid that is particularly palatable to the intended species. Importation of a more suitable drug or drug formulation from another country is another option for veterinarians. For example, a suspension of metronidazole is available in some countries that is much more accurate for dosing small patients than the tablet form available in the US. Regulations for such importations must be followed. Although there are many antimicrobial dosages published for rabbits, rodents, and ferrets, very few pharmacokinetic studies or clinical trials have been performed specifically for these animals; rather, they are carried out primarily to establish information for human trials. Because of this, antimicrobial dosages for these patients are generally based on extrapolations from other species and/or clinical experience. Lack of scientifically derived dosages, combined with the extra‐label use of most antimicrobials, are daily challenges of veterinarians who care for small mammal patients. Clients should be informed of this, and give written consent for treatment of their animals. Extrapolation of drug dosages from one species to another can be done in several ways. Straightforward linear extrapolations based on body weight alone tend to result in overdosing of larger animals and underdosing of smaller ones. This method is only appropriate with drugs that have large margins of safety and wide therapeutic margins, or if the two animals are similar in taxonomy, body size, and physiology. Metabolic scaling is a method popular in zoological medicine, and uses a formula based on body weight, a constant based on the energy group of the animal, and the known pharmacokinetic data of the drug in one species to calculate the dosage of the drug in other species. Allometric scaling uses mathematical equations to analyze differences in anatomy, physiology, biochemistry, and pharmacokinetics in animals of different sizes. Known pharmacokinetic parameters in several species are used in the equations to estimate the pharmacokinetic parameter in an unknown species, and thus predict drug dosage. Allometric scaling is commonly used in the pharmaceutical industry to determine the first dosage in human trials. There are several reports in the literature validating the use of allometric scaling to predict pharamacokinetic parameters in small mammal species for several drugs, including some fluoroquinolone antimicrobials. Tables 36.1–36.3 present drug dosages for the treatment of common microbial diseases. Tables 36.4–36.11 present clinical signs and suggested drugs for common bacterial diseases. Rabbits and rodents are prey species, and are generally less tolerant of handling and other manipulations than predator species such as ferrets, dogs, and cats, especially when debilitated. Administration of antimicrobials in these prey species must be performed in a way that allows for the entire dose to be given without unduly stressing the patient. The method of administration must also be achievable for the client, otherwise frustration and noncompliance may result. Available antimicrobial formulations are often too large and/or too concentrated for small mammals and need to be split up or diluted for accurate dosing. Routes of antimicrobial administration in rabbits, rodents, and ferrets include oral (liquid, pill, or capsule), subcutaneous (usually in the loose skin over the shoulders), intraperitoneal (generally reserved for very small rodents), intramuscular (generally avoided in very small animals), topical, and less commonly, via intravenous or intraosseous catheter, nebulization, gavage, nasoesophageal or esophagostomy tube (rabbits, ferrets), or antimicrobial‐impregnated implants. Injections are more commonly used in clinic than at home; however, some clients are willing to master the procedure, particularly if the pet objects excessively to being medicated orally, or if it has a sore mouth, or tends to nip. Self‐administration, where the animal willingly takes the entire dose on its own, preferably with minimal or no restraint, is the best and least stressful method of medication (for both the animal and the administrator). Flavored antimicrobial preparations, such as trimethoprim/sulfa or chloramphenicol palmitate suspensions, are willingly consumed by some of these patients. Crushed pills, liquids, or capsule contents can be mixed with small amounts of palatable liquids, gels, or food to encourage consumption. Small rodents, such as rats and mice, willingly take vanilla‐flavored human nutritional supplements, such as Boost® or Ensure®, directly from a syringe or small dish. Hamsters favor rice‐based baby cereal, rabbits like bananas, chinchillas are partial to raisins, and ferrets enjoy malt‐flavored cat laxatives or pet nutritional supplements such as Nutri‐Cal® . The internet abounds with suggestions from clients and veterinarians alike, and these include Cool Whip®, maple syrup, V.A.L. syrup, canned pumpkin, cooked sweet potato, coconut milk, raspberry‐flavored gelatin, etc. The availability of a suitable vehicle, compatible with both the antimicrobial and the patient, is limited only by the imagination of the veterinarian. Table 36.1 Reported antimicrobial drug dosages in rabbits, guinea pigs, and chinchillas. Caution: most uses and dosages are extra‐label. a Observe correct withdrawal time in meat rabbits. b Do not use in meat rabbits. PO, per os; SC, subcutaneous; IM, intramuscular; IV, intravenous; dw, drinking water. Table 36.2 Reported antimicrobial dosages in hamsters, gerbils, rats, and mice. Caution: most uses and dosages are extra‐label. PO, per os; SC, subcutaneous; IM, intramuscular; dw, drinking water. Table 36.3 Reported antimicrobial dosages in ferrets, hedgehogs, and sugar gliders. Caution: most uses and dosages are extra‐label.
36
Antimicrobial Therapy in Rabbits, Rodents, and Ferrets
Introduction
Antimicrobial Use and Resistance
Antimicrobial Toxicity
Extra‐label Use, Compounding, and Importation
Drug Dosages
Drug Administration
Drug
Rabbita
Guinea pig
Chinchilla
Amikacin
2–5 mg/kg q 8–12 h; SC, IM
2–5 mg/kg q 8–12 h; SC, IM
2–5 mg/kg q 8–12 h; SC, IM, IV
Azithromycin
5 mg/kg q 48 h; IM OR 15–30 mg/kg q 24 h; PO
15–30 mg/kg q 12–24 h; PO
15–30 mg/kg q 24 h; PO
Captan powder
–
–
5 ml/475 ml bathing dust
Cephalexin
11–22 mg/kg q 8–12 h; SC
50 mg/kg q 24 h; IM
–
Chloramphenicol
30 mg/kg q 8–12 h; PO, SC, IM, IVb
20–50 mg/kg q 6–12 h; PO, SC, IM, IV
30–50 mg/kg q 12 h; PO,SC,IM, IV
Chlortetracycline
50 mg/kg q 24 h; PO
–
50 mg/kg q 12 h; PO
Ciprofloxacin
5–20 mg/kg q 12 h; PO
5–20 mg/kg q 12 h; PO
5–20 mg/kg q 12 h; PO
Clindamycin
Do not use
7.5 mg/kg q 12 h; SC; Do not use PO
7.5 mg/kg q 12 h; SC; Do not use PO
Doxycycline
2.5 mg/kg q 12 h; PO
2.5 mg/kg q 12 h; PO
2.5 mg/kg q 12 h; PO
Enrofloxacin
5–10 mg/kg q 12 h; PO, SC, IM OR 200 mg/L dw q 24 h
0.05–0.2 mg/mL dw q 24 h OR 5–15 mg/kg q 12 h; PO, SC, IM
5–15 mg/kg q 12 h; PO, SC, IM
Fenbendazole
20–50 mg/kg q 24 h; PO
Fluconazole
38 mg/kg q 12 h; PO
16–20 mg/kg q 24 h × 14 d; PO
16 mg/kg q 24 h × 14 d; PO
Gentamicin
1.5–2.5 mg/kg q 8 h; SC, IM, IV
2–4 mg/kg q 8–12 h; SC, IM
2 mg/kg q 12 h; SC, IM, IV
Griseofulvin (avoid in pregnant animals)
25 mg/kg q 24 h × 30–45d; PO
25–50 mg/kg q 12 h × 14–60d; PO OR 1.5% in DMSO for 5–7 d; topically
25 mg/kg q 24 h × 30–60d; PO
Itraconazole
20–40 mg/kg q 24 h; PO
5–10 mg/kg q 24 h; PO
5 mg/kg q 24 h; PO
Ketoconazole
10–40 mg/kg q 24 h; PO
10–40 mg/kg q 24 h; PO
10–40 mg/kg q 24 h; PO
Lime sulfur dip
Dilute 1:40 with water, dip q 7d for 4–6 wk
Dilute 1:40 with water, dip q 7d for 4–6 wk
Dilute 1:40 with water, dip q 7d for 4–6 wk
Marbofloxacin
2 mg/kg q 24 h; IM, IV OR 5 mg/kg q 24 h; PO
4 mg/kg q 24 h; PO, SC
4 mg/kg q 2 h4; PO, SC
Metronidazole
20 mg/kg q 12 h; PO
25 mg/kg q 12 h; PO
10–20 mg/kg q 12 h; PO; use with caution
Oxytetracycline
50 mg/kg q 12 h; PO OR 1 mg/mL dw
–
50 mg/kg q 12 h; PO
Penicillin G, benzathine
42,000–60,000 IU/kg q 48 h; SC, IM
Toxic
Avoid
Penicillin G, procaine
42,000–84,000 IU/kg q 24 h; SC, IM
Toxic
Avoid
Sulfadimethoxine
10–15 mg/kg q 12 h × 10d; PO
10–15 mg/kg q 12 h; PO
25–50 mg/kg q 24 h × 10–14d; PO
Sulfamethazine
1 mg/mL dw
1 mg/mL dw
1 mg/mL dw
Sulfaquinoxaline
1 mg/mL dw
1 mg/mL dw
–
Terbinafine
100 mg/kg q 12–24 h; PO
10–40 mg/kg q 24 h × 4–6 wk; PO
10–30 mg/kg q 24 h × 4–6 wk; PO
Tetracycline
50 mg/kg q 8–12 h; PO OR 250–1000 mg/L dw q 24 h
10–40 mg/kg q 24 h; PO
0.3–2 mg/mL dw q 24 h OR 10–20 mg/kg q 8–12 h; PO
Trimethoprim‐sulfa
30 mg/kg q 12–24 h; PO, SC, IM
15–30 mg/kg q 12 h; PO, SC
15–30 mg/kg q 12 h; PO, SC
Tylosin
10 mg/kg q 12 h; PO, SC
10 mg/kg q 24 h; PO, SC; use with caution
10 mg/kg q 24 h; PO, SC
Drug
Hamster
Gerbil
Rat
Mouse
Amikacin
2–5 mg/kg q 8–12 h; SC
2–5 mg/kg q 8–12 h; SC
10 mg/kg q 12 h; SC
10 mg/kg q 8–12 h; SC
Ampicillin
Toxic
6–30 mg/kg q 8 h; PO
20–100 mg/kg q 12 h; PO, SC
20–100 mg/kg q 12 h; PO, SC OR 500 mg/L dw
Azithromycin
30 mg/kg q 24 h; PO
Cephalexin
–
25 mg/kg q 24 h; SC
15 mg/kg q 12 h; SC
60 mg/kg q 12 h; PO
Cephaloridine
10–25 mg/kg q 24 h; SC
30 mg/kg q 12 h; IM
10–25 mg/kg q 24 h; SC
10–25 mg/kg q 24 h; SC
Cephalosporin
–
–
–
30 mg/kg q 12 h; SC
Chloramphenicol palmitate
50–200 mg/kg q 8 h; PO
50–200 mg/kg q 8 h; PO
50–200 mg/kg q 8 h; PO
0.5 mg/mL dw OR 50–200 mg/kg q 8 h; PO
Chloramphenicol succinate
20–50 mg/kg q 12 h; SC
20–50 mg/kg q 12 h; SC
30–50 mg/kg q 12 h; SC
30–50 mg/kg q 12 h; SC
Chlortetracycline
20 mg/kg q 12 h; PO, SC
–
–
25 mg/kg q 12 h; PO, SC
Ciprofloxacin
7–20 mg/kg q 12 h; PO
7–20 mg/kg q 12 h; PO
7–20 mg/kg q 12 h; PO
7–20 mg/kg q 12 h; PO
Doxycycline
2.5–5 mg/kg q 12 h; PO; do not use in young or pregnant animals
2.5–5 mg/kg q 12 h; PO; do not use in young or pregnant animals
5 mg/kg q 12 h; PO
2.5 –5 mg/kg q 12 h; PO
Enrofloxacin
0.05–0.2 mg/mL dw × 14d OR 5–10 mg/kg q 12 h; PO, SC
0.05–0.2 mg/mL dw × 14d OR 5–10 mg/kg q 12 h; PO, SC
0.05–0.2 mg/mL dw × 14d OR 5–10 mg/kg q 12 h; PO, SC
0.05–0.2 mg/mL dw × 14d OR 5–10 mg/ kg q 12 h; PO, SC
Erythromycin
–
–
20 mg/kg q 12 h; PO
20 mg/kg q 12 h; PO
Gentamicin
5 mg/kg q 24 h; SC
2–4 mg/kg q 8 h; SC
5–10 mg/kg divided q 8–12 h; SC
2–4 mg/kg q 8–12 h; SC
Griseofulvin (avoid in pregnant animals)
25–50 mg/kg q 12 h × 14–60d; PO OR 1.5% in DMSO for 5–7 d; topically
25–50 mg/kg q 12 h × 14–60d; PO OR 1.5% in DMSO for 5–7 d; topically
25–50 mg/kg q 12 h × 14–60d; PO OR 1.5% in DMSO for 5–7 d; topically
25–50 mg/kg q 12 h × 14–60d; PO OR 1.5% in DMSO for 5–7 d; topically
Ketoconazole
10–40 mg/kg q 24 h × 14d; PO
10–40 mg/kg q 24 h × 14d; PO
10–40 mg/kg q 24 h × 14d; PO
10–40 mg/kg q 24 h × 14d; PO
Metronidazole
7.5 mg/70–90gm animal q 8 h
7.5 mg/70–90gm animal q 8 h
10–40 mg/kg q 24 h; PO
2.5 mg/mL dw × 5 d OR 20–60 mg/kg q 8–12 h; PO
Neomycin
0.5 mg/mL dw OR 100 mg/kg q 24 h; PO
2 g/L dw OR 100 mg/kg q 24 h; PO
2 g/L dw OR 25 mg/kg q 12 h; PO
2 g/L dw
Oxytetracycline
0.25–1 mg/mL dw or 16 mg/kg q 24 h; SC
0.8 mg/mL dw or 10 mg/kg q 8 h; PO or 20 mg/kg q 24 h; SC
500 mg/L dw or 10–20 mg/kg q 8 h; PO
500 mg/L dw OR 10–20 mg/kg q 8 h; PO
Sulfadimethoxine
10–15 mg/kg q 12 h; PO
10–15 mg/kg q 12 h; PO
10–15 mg/kg q 12 h; PO
10–15 mg/kg q 12 h; PO
Sulfamerazine
1 mg/mL dw q 24 h
0.8 mg/mL dw q 24 h
1 mg/mL dw
1 mg/mL dw OR 500 mg/L dw
Sulfamethazine
1 mg/mL dw q 24 h
0.8 mg/mL dw q 24 h
1 mg/mL dw
1 mg/mL dw
Sulfaquinoxaline
1 mg/ml dw q 24 h
1 mg/ml dw q 24 h
Tetracycline
0.4 mg/mL dw q 24 h OR 10–20 mg/kg q 8–12 h; PO
2–5 mg/mL dw q 24 h OR 10–20 mg/ kg q 8–12 h; PO
2–5 mg/mL dw OR 10–20 mg/kg q 8 h; PO
2–5 mg/mL dw OR 10–20 mg/kg q 8 h; PO
Trimethoprim‐sulfa
15–30 mg/kg q 12–24 h; PO, SC
30 mg/kg q 12–24 h; PO, SC
15–30 mg/kg q 12 h; PO, SC
30 mg/kg q 12 h; PO, SC
Tylosin
2–8 mg/kg q 12 h; SC, PO OR 500 mg/mL dw
0.5 mg/mL dw q 24 h OR 10 mg/kg q 24 h; PO, SC
0.5 mg/mL dw OR 10 mg/kg q 24 h; PO, SC
0.5 mg/mL dw OR 10 mg/kg q 24 h; PO, SC
Drug
Ferrets
Hedgehogs
Sugar gliders
Amikacin
10–15 mg/kg q 12 h; SC, IM
2–5 mg/kg q 8–12 h; SC, IM
10 mg/kg q 12 h; IM
Amoxicillin
20–30 mg/kg q 8–12 h; PO
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