3.1.1 Digestive physiology

Digestive physiology affects the absorption and metabolism of drugs given orally. Substances can be absorbed from the stomach and small intestine into the portal system to be metabolized in the liver before entering the general circulation. This is known as the ‘first-pass’ effect that can alter the activity of therapeutic agents. The first-pass effect has been demonstrated in rabbits (Huang et al., 1981). Conversely, substances absorbed across the buccal mucosa avoid the portal circulation and hepatic metabolism. It is not always possible to extrapolate dosages and effects of an orally administered drug in a rabbit from another species. There are differences between a carnivore, such as a dog, that swallows food without mastication and whose stomach empties completely and a herbivore, such as a rabbit, that chews the food thoroughly and has a stomach that is never empty. The acid pH of the rabbit’s stomach can affect ionization and absorption of drugs.

Caecotrophy effectively recycles ingested material and prolongs the length of time that substances are retained in the gut. Fluids and small particles are retained in the caecum, whereas substances that bind with large particles will be excreted rapidly. The absorption of certain drugs may be affected by increased retention time in the caecum (Guillot et al., 1988). The dual production of hard and soft faeces in the rabbit is a complex process controlled by the fusus coli, which is highly innervated and vascular. The fusus coli is affected by hormones, such as aldosterone and prostaglandins, as well as the autonomic nervous system. Pharmacological preparations can affect digestive function through their effect on the fusus coli. For example, non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, inhibit endogenous prostaglandin formation and inhibit soft faeces production (Pairet et al., 1986). The ingestion of soft faeces from the anus is triggered by a number of factors including odour, which can be affected by medication. Some drugs, e.g. ampicillin, inhibit normal caecotrophy (Escoula et al., 1981).

3.1.2 Microflora of caecum and digestive tract

The caecum is inhabited by a variety of micro-organisms including protozoa and anaerobic bacteria (see Section 1.3.6). The balance of micro-organisms in the digestive tract, especially in the caecum, is influenced by many factors including antibiotics and other medications. Physiological processes alter caecal pH throughout the day in response to the digestion of food and passage of digesta. Diet affects both the composition of digesta that reaches the caecum and its rate of passage through the gut. Low fibre diets reduce gastrointestinal motility and prolong retention time of digesta in the caecum. Diets high in indigestible fibre promote optimal gastrointestinal motility and a healthy caecal microflora. Therefore rabbits fed on high fibre diets may be less susceptible to disruption of the caecal microflora than those fed on an exclusively cereal diet. Stress or pain increases circulating catecholamines or cortisol, which can have an effect on the balance of gut bacteria. Increased glucocorticoid levels increase coliform counts and alter the aerobic-to-anaerobic bacteria ratio in the gut (Straw, 1988). ‘Dysbiosis’ is the condition that results when the natural flora of the gut are thrown out of balance.

3.1.3 Antibiotic toxicity in rabbits

In rabbits, antibiotics can alter the gut flora with potentially lethal effects, yet rabbits are prone to bacterial infections that require antibiotics to effect a cure. There are many areas of confusion over the use of antibiotics to treat clinical disease in pet rabbits. Their use should be limited to cases where a bacterial infection has been identified.

Some antibiotics have the potential to cause enteritis in rabbits by selectively killing certain bacteria within the gut and allowing pathogenic species to proliferate. Clostridium spp., in particular, can proliferate in the caecum or small intestine and cause rapid death due to the effects of enterotoxins. Clostridium spiroforme is the major pathogen in rabbit enterotoxaemia, although Clostridium difficile and Clostridium perfringens may also be involved on rare occasions (Perkins et al., 1995). A particular strain of C. spiroforme is pathogenic to rabbits and produces an iota toxin. Clostridium perfringens type E also produces iota toxin. Antibodies against either organism will neutralize the other’s iota toxin. This cross-reactivity led people to believe that C. perfringens type E was the pathogen in antibiotic-related diarrhoea in rabbits until C. spiroforme was identified in 1983 (Carman, 1993). For antibiotic-associated enterotoxaemia to develop in rabbits, both the antibiotic and the clostridium need to be present. Clostridium spiroforme is not a normal inhabitant of the rabbit gut flora and normal intestinal ecology of the adult must be disrupted before C. spiroforme will colonize (Carman and Borriello, 1984). Glucose is required as a substrate for iota toxin production (Jenkins, 1997) and it is thought that undigested starch in the hindgut of young rabbits fed on cereal diets may increase susceptibility to enterotoxaemia. In young rabbits intestinal absorption of starch is not as efficient as in adults and residual amounts of carbohydrate may reach the caecum to act as a substrate for bacterial fermentation. Adult rabbits appear to digest starch more efficiently, with only small amounts reaching the caecocolic segment unabsorbed (Blas and Gidenne, 1998). Therefore high carbohydrate diets are less likely to predispose to enterotoxaemia in adults.

In addition to Clostridium spp. there are other pathogenic bacteria that can cause intestinal inflammation, enteritis and diarrhoea. Escherichia coli can produce toxins. In a study of the effects of ampicillin and gentamicin on the bacterial flora of the caecum, a strain of Enterobacter aerogenes predominated in rabbits treated with ampicillin, 40% of which died (Escoula et al., 1981).

Most of the information about antibiotic-associated diarrhoea in rabbits has been gained from experimental studies rather than from the treatment of clinical cases. Healthy rabbits are used for experimental investigations rather than those suffering from disease. Usually young rabbits are used in experimental studies rather than adults, which have a different population of caecal microflora and a varying ability to digest starch. The effect of diet, particularly indigestible fibre, on experimental results is largely overlooked. In some studies, the effects of antibiotic administration is an incidental finding during the treatment of a disease such as osteomyelitis or lung abscesses, in which rabbits are used as experimental models. For example, ampicillin and clindamycin are considered to be high-risk antibiotics that will readily induce diarrhoea. Yet in one study (Norden and Budinsky, 1990), rabbits were given high doses of ampicillin (200 mg/kg) three times daily. Half the rabbits died with diarrhoea and inanition but the other half survived. In another study, Mader et al. (1989) compared cefazolin (5 or 15 mg/kg) and clindamycin (70 mg/kg) in the treatment of osteomyelitis. The antibiotics were given by subcutaneous injection every 6 h for 28 days. Seven out of 20 rabbits in the clindamycin group died, 4 with diarrhoea, whereas all the 24 rabbits in the two cefazolin groups survived and none developed diarrhoea.

Experimental investigations of the effects of antibiotics on gut flora in rabbits have given confusing results. For example, Milhaud et al. (1976) and Escoula et al. (1981) reported a high incidence of antibiotic-associated diarrhoea in rabbits given ampicillin, in contrast to Hara-Kudo et al. (1996), who reported a low incidence of diarrhoea in rabbits injected with ampicillin in comparison with other antibiotics. Differences in the route of administration and dosages may explain some of these discrepancies but, in many cases, the overall picture is still inconsistent.

3.1.4 Legislation

In the UK, the Veterinary Medicines Regulations govern the authorization, manufacture, distribution and administration of veterinary medicines (http://www.vmd.defra.gov.uk). These regulations prohibit the administration of veterinary medicinal products (POM-Vs) without the authorization of a veterinary surgeon. Veterinary medicinal products are authorized for use for a specific condition in a particular species of animal. There are exemptions to this rule that can permit the use of alternative products. These exemptions are known collectively as the prescribing cascade.

With the limited amount of authorized drugs available, clearly, many of the drugs prescribed for rabbits are done under the cascade. ‘Off-label’ drug usage may be necessary for a variety of reasons and the responsibility for the use of a medicine in this way lies wholly with the prescribing veterinary surgeon. Because the safeguards ensuring safety and efficacy in place for authorized medications have not been implemented, use of ‘off-label’ medicines can pose a potential risk. Sufficient information should be given to the rabbit’s owner to allow informed consent to the use of the chosen medication; this should include other therapeutic options and use of the cascade to choose the medication suitable for the case. A non-authorized drug should show a clinical advantage compared with the authorized product in the specific circumstances under consideration. All information should be included in the clinical notes, and an ‘off-label’ consent form signed.

The exemptions are different for food-producing animals and those kept as companions. In food-producing animals, to ensure that tissue residue implications have been evaluated, only products authorized for other food-producing animals may be used. In companion animals, products authorized for use in any another species or for a different use in the same species may be used. If there is not a suitable veterinary medicine available, then the use of human preparations is acceptable.

Rabbits are kept as both food-producing and companion animals, so their place in the prescribing cascade is ambiguous. The Veterinary Medicines Directorate takes the view that rabbits should be regarded as food-producing animals

unless the veterinarian in whose care they have been placed can be satisfied that neither the particular animal(s) being treated nor their produce will enter the food chain. Where the veterinarian is satisfied that the animal(s) concerned are being kept solely as pets and will not be used for food production then those particular animals may be regarded as companion animals for the purposes of the prescribing cascade. (Veterinary Medicines Directorate, personal communication).

There are people who keep rabbits both as companions and for meat. Exhibition rabbit breeders especially will kill and eat surplus stock. Rabbit breeders seldom present an animal to a veterinary surgeon for clinical examination. Instead, they treat their rabbits themselves with a variety of home remedies and medications obtained from the Internet. Magazines and textbooks on rabbit care often describe the use of medicines such as antibiotics, parasiticides and motility stimulants that are only available on prescription. As a result, rabbit breeders expect veterinary surgeons to supply these medicines on demand, without consultation, and are unaware of the stringent legislation governing the use of veterinary medicines for rabbits. At the time of writing it is possible for rabbit breeders and owners of pet rabbits to obtain prescription medications illegally over the Internet, often by importation from other countries where the regulations on prescribing are different. These medications may not be what they purport to be and their effects are at best unpredictable if not dangerous, and their use should be strongly discouraged. The prescribing cascade severely limits the choice of medicines available for the treatment of rabbits destined to be eaten as meat.

3.2.1 Antibiotics

There is a temptation to prescribe antibiotics in any situation where there is an ill rabbit and no specific diagnosis. In view of the risk of antibiotic-associated diarrhoea, it is preferable to reserve antibiotic therapy for situations where there is a definite indication for their use. Antibiotics are most successful for the treatment of primary bacterial infections and for preventing secondary bacterial invasion of tissues damaged by viruses, surgery or other disease. Any antibiotic therapy carries a risk of life-threatening diarrhoea and enterotoxaemia in rabbits. This risk is influenced by diet, choice of antibiotic, dose rate, route of administration, presence of pathogenic clostridial species, age, stress, concurrent corticosteroid therapy and fate. The risk of antibiotic therapy needs to be weighed against the risk of not prescribing antibiotics.

Consideration should be given to the causative pathogen and the efficacy of a particular antibiotic against that organism. The goal of treatment is to achieve an effective concentration of the drug at the site of infection for as long as possible in order to kill the bacteria that is present or likely to be present. Concentrations in excess of the mean inhibitory concentration (MIC) are required. MIC depends on the pharmacokinetics of the antibiotic and the micro-organism at which it is directed. Ideally, culture and sensitivity identify the causal organism and aid antibiotic selection, but this option is not always available in the clinical setting. Infections may be in inaccessible sites such as the tympanic bulla or anterior chamber of the eye. Pasteurella multocida and Staphylococcus spp. are frequently isolated from infected sites. In vitro rabbit isolates of P. multocida are generally sensitive to penicillin, chloramphenicol, tetracycline, erythromycin, novobiocin and nitrofurans with varying susceptibility to streptomycin, kanamycin, neomycin and sulphonamides. They are usually resistant to clindamycin and lincomycin (Manning et al., 1989).

It is important to give therapeutic dosages for an antibiotic to be effective. Medicating the drinking water with antibiotics is unsatisfactory because it is difficult to ensure correct dosages as water intake can vary significantly and the taste of antibiotic can deter the rabbit from drinking the water. Equally, many antibiotics deteriorate in the presence of sunlight. Sweetening the water with sucrose or fruit juices and covering the water bottle can help overcome these problems, but this is still an inaccurate method for providing medication, particularly in pet rabbits.

In a study by Okerman et al. (1990), antibiotics were given to rabbits in the drinking water prior to infecting them with pathogenic P. multocida. In vitro sensitivity of the pathogen was confirmed and trimethoprim sulpha, spiramycin, tetracycline, erythromycin, chloramphenicol and enrofloxacin were tested at typical dose rates. Enrofloxacin was given at three different dosages: 25, 50 and 100 mg/L. Only enrofloxacin at 100 mg/L was effective in preventing infection. Enrofloxacin at 50 mg/L and chloramphenicol prevented rabbits dying but some of the survivors were not in good health. All the rabbits treated with the other antibiotics succumbed to acute pasteurellosis. This study not only highlighted the shortcomings of administering medication in the drinking water but also the importance of giving the correct dose of antibiotic.

It is possible to use potentially toxic antibiotics in a manner that gives high local tissue levels without producing harmful effects. For example, gentamicin, which is known to be nephrotoxic in rabbits, can be injected into abscess capsules or sutured into wounds in the form of antibiotic-impregnated beads with no harmful effect on the kidneys.

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