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Antibiotic Therapeutics in Laboratory Animals

Antibiotic Therapeutics in Laboratory Animals

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Published by: Keith Giomeer Petrola on Apr 10, 2012
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REVIEW ARTICLE
Antibiotic therapeutics in laboratory animals
T. H. Morris
Department of Laboratory Animal Science, Smith Kline Beecham Pharmaceuticals, New Frontiers SciencePark, Third Avenue, Harlow, EssexCM19 SAW, UK
Summary
Information on antibiotic therapeutics in laboratory species, especially in rodents andrabbits, is reviewed. A number of areas are considered: interference by antibiotics with anexperiment, antibiotic toxicity, routes of administration, effects of formulation on bioavailability, antibiotic prophylaxis, use of combinations of antibiotics, misuse of antibiotics, regulatory approval for antibiotic use in animals, sources of information onantibiotic indications and dose, and extrapolation of dose information from other species.
Keywords
Antibiotics; laboratoryanimals; therapyThe purpose of this review is to highlightsome specific questions and problemsconcerning the use of antibiotics in thecommon laboratory species. Although dogs,cats, horses and domestic species are usedin research, they will not be discussed hereas there is a large volume of informationon the clinical use of antibiotics in thesespecies, and as many of these antibioticsare approved by regulatory authorities for use in these species, clear indications for their rational use are provided (NationalOffice of Animal Health 1992, VPD 1991).This review deals principally withrodents and rabbits since they make upover 90% of the animals used in research.There is no uniform source of informationon rational use of antibiotics comparable tothat available for the common companionand domesticated species. The situation issummarized well by Latt (1976) '...dosages of therapeutic agents for laboratoryanimals are scattered throughout thescientific literature or are extrapolated fromdosages recommended for other species'.Other non-mammalian species are usedas laboratory animals in smaller quantities,for example birds and poikilotherms suchas reptiles, fish and amphibians and thesespecies will not be discussed as there can
Accepted 17 May 1994
 be major differences in pharmacokinetics.An introduction to antibiotic therapeuticsfor these species can be found inspecialized medical texts (BSAVA, Jacobsen
et al. 1991).
A number of areas will be considered:interference by antibiotics with anexperiment, antibiotic toxicity, routes of administration, effects of formulation on bioavailability, antibiotic prophylaxis, useof combinations of antibiotics, misuse of antibiotics, regulatory approval for antibiotic use in animals, sources of information on antibiotic indications anddose, and extrapolation of dose informationfrom other species.
Interference by antibiotics withexperimental studies
Bacterial infections in animals used for experimental studies are undesirable. Atthe most basic level the morbidity produced by an infection increases animaldiscomfort and experimental variation.More specific interactions can also occur,for example, studies on enteric pathogensor enteric diseases such as malabsorptionmay be compromised by concurrent enteric bacterial infection and the associated
Laboratory Animals (1995) 29, 16-36
 
Antibiotic therapeutics in laboratory animals
 pathology. However, it should also berecognized that use of an antibiotic to'solve' the problem of a concurrent bacterial infection may itself interfere withthe experiment. The adverse effects of theaminoglycosides on renal function or thefluoroquinolones on juvenile cartilageformation may produce relatively obvious problems. However, the effects may be lessovert. If a compound is undeinvestigation, and concurrently anantibiotic with pharmacokinetic disposition by the same mechanism is alsoadministered to the animal, then thekinetics of this compound undeinvestigation may be affected. As a specificexample the concurrent administration of chloramphenicol prolonged the duration of xylazine-ketamine anaesthesia in rats butnot dogs (Nossmann et
al. 1990).
Concurrent administration of chloramphenicol to dogs and catsundergoing pentobarbital anaesthesiasignificantly increased the duration of anaesthesia (Adams
&
Dixit 1970). Theseresults suggest a competitive interaction atthe level of biotransformation.Chloramphenicol may competitivelyenhance the activity of bioinactivatedcompounds and decrease the activity of  bioactivated compounds metabolizedthrough the same family of cytochromesrequired for the metabolism of many drugs(Burns & Conney 1965). Direct druginteractions may also occur, fluoroquinolonescompete for gamma-amino butyric acid(CABA) receptor sites in the centralnervous system, and thus their use would be contraindicated in certain neurologicalstudies (Bahri
&
Blouin
1991J.
It is alsoclear from the examples cited above thatinterfering effects differ between species,making prediction more difficult. Studies of antimicrobial efficacy may be compromisedwhere toxic antibiotics are used, such asclindamycin in the rabbit [Sande
&
Johnson 1975) without concurrent controls
treated with antibiotic but no bacterialchallenge. The confounding effects of antibiotics can be even more subtle. When bacitracin, gentamicin and the antifungalnystatin were given to rats to reduce their 
17
intestinal microflora, caecocolonic motilitywas altered and there was increased faecalexcretion of dry matter and water (Cherbutet
01.
1991).
In a study that models a morecommon clinical situation, intestinalmotility was altered when amoxycillin-clavunate was given to human patients(Caron et
01.
1991J.
These changes couldinfluence not only absorption and excretionof a test compound, depending on the sitesof drug absorption, but also studies of theintestinal tract itself. Antibiotic use shouldtherefore be very critically reviewed if given during the course of an experimentalstudy.
Antibiotic toxicity
In all species even drugs with ahigh therapeuticindex can cause toxicity at very high dosesor when the usual dose is not adjusted totake account of the age and condition of the animal (Table 1). Studies with new-bornmice and guineapigs show that a varietyof liver enzyme systems are essentiallyabsent at birth and only begin to appear atthe end of the first week of life [Jondorf et
01.
1958). Renal excretion mechanismssuch as glomerular filtration and proximaltubular secretion may be absent at birthand develop over days or weeks dependingon species (Prescott
&
Baggott
1988).
Inadult life impairment of renal or hepaticfunction, whether by disease or experimentalmanipulation, may alter the requiredantibiotic dose. As an example Table 1documents the adjustments on dosagerequired when using tetracycline inanimals with renal dysfunction. It mayeven be important to consider theanimals's diurnal rhythm (Heinze
et al.
1992).
Mice are nocturnally active animals,and barbiturate sleep time can be up totwice as long when given during the dayrather than at night (Davis
1962).
Biotransformation of some antibiotics may be by hepatic mechanisms similar to pentobarbitone. It is possible that doses for a particular antibiotic might be extrapolatedfrom animals active during the day to themouse. When these agents are administeredto a mouse during the light phase they
 
18
Table
1
Modification of antibiotic dosage with reduced renal or hepatobiliary functionMorrisSystem affectedHepatic function reducedBiliary obstructionRenal function reducedRenal function reducedRenal function reducedRenal function reduced Antibiotic affectedErythromycin, chloramphenicol, metronidazole,c1indamycin, lincomycin Ampicillin, fluoroquinolonesErythromycin, chloramphenicol, doxycyclineMost penicillins and cephalosporins,c1indamycin, lincomycin, trimethorpim,sulphonamides Aminoglycosides, carbenicillin, ticarcillin,vancomycin, metronidazole, fluoroquinolonesTetracyclines, cephaloridine. nitrofurantoin,polymixinEffect on doseReduce doseNormally excreted in the bile,biliary obstruction may reduceaccessto site of infectionGive usual doseConsider minor dose reductionConsider major dose reduction Avoid using these antibiotics Adapted from Prescott
&
Baggot
1988,
Sande
1990b
could be metabolized to a different extentthan if given during the active dark phase,leading to differences in antibiotic plasmaconcentrations. This potential for differencesin plasma concentrations and even ineffectivetherapy would be increased if extrapolationof dose quantity or frequency was alsoinaccurate (see section below 'Extrapolationof antibiotic dose information betweenspecies'). In addition, antibacterials thatare eliminated via the kidney may have blood levels that vary depending on thetime of day of administration. For examplesulphonamides given during the active phase in chickens and calves are eliminatedtwice as fast compared to when givenduring the animal's resting phase [Heinze
et al.
1992). There is also evidence of strain differences within laboratory specieswith respect to the toxic effects of antibiotics. Tobramycin is more toxic inFischer rats than in Sprague-Dawley rats[Reinhard
et al. 1991).
Many species have adverse reactions to particular antibiotics at doses that arenormally safe therapeutic doses in othespecies. In rodents and rabbits this is oneof the most important considerations inantibiotic therapeutics (Tables 2 and 3). Itshould be emphasized that the single mostimportant mechanism of antibiotic toxicityin rodents and rabbits is the secondaryeffects from the disruption of the normalenteric flora. In the guinea pig and hamstethe specific cause of death is often thetoxin produced by overgrowing
Clostridiwn
difficile
[Richard 1990, Fekety 1986,Manning
et al.
1984). In one study inguineapigs, aureomycin caused overgrowthof 
Listeria monocytogenes
which then ledto septicaemia and widely distributednecrotic lesions (Roine et
al.
1953). In therabbit the toxins produced by C.
perfringens
and C.
spiroforme
have been implicated inlincomycin [Rehg
&
Pakes 1982) andclindamycin (Katz
et al.
1978) inducedenteritis.The hamster is particularly sensitive totoxigenic C.
difficile
overgrowth caused bya very wide range of antibiotics (Bartlett
et al.
1978, Fekety 1986, Fekety
et al.
1979) and it has been suggested thattreatment of hamsters with any antibioticsshould be undertaken with caution sincemortality is high (Richard 1990).Tetracycline, metronidazole and to a lesser extent chloramphenicol are relatively poor inducers of enterocolitis in hamsters (seeTable 2) but the high incidence of renaldysfunction in older hamsters (Hubbard &Schmidt 1987) may even make tetracyclineadministration hazardous (see Table 1).Apart from severe enterocolitis caused byother antibiotics even the 'classical' guineapigtoxicity to penicillin most probably is notdue to 'allergy' (Anon 1992). Newborn andgerm-free guineapigs are not susceptibleto penicillin toxicity (Manning
et al.
1984), so deaths in normal animals afte penicillin may simply be another example

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