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Animal Models of Infection for the Study of Antibiotic Pharmacodynamics 81TABLE 1 Summary of Advantages and Disadvantages of Various Endpoints in AnimalModels of InfectionEndpoint Advantages DisadvantagesDeath/moribundconditionQuantitation ofpathogens inbody tissuesand fluidsTissue damageand inflammationClear endpoint (death)Comparable endpoint in humansRepresents a difficult test ofantibiotic/dosage regimenCan determine static/cidal activityof agentCan assess emergence of drugresistance during treatment totest agentsMeasure postantibiotic,subinhibitory effects andcorrelate with in vitro propertiesMay test strains that are avirulentin other models (e.g., sepsis)Assess relationship between drugconcentrations in infectedcompartment with bacterialeradication (e.g., drugconcentrations incerebrospinal fluid)Considers impact of bothbacterial growth and resultanteffects of antibioticsAnimal stress and sufferingShort-term models requireoverwhelming inoculum that maytrigger cytokine responsesirrelevant to that seen in humansNonspecific effects of drugs(bacterial killing vs. otherpharmacological effects)Cannot differentiate between cidaland static effects in vivoDifficult to assess emergence of drugresistance during therapyOutcomes can be very dependent oninoculum and other adjuvants andcan obscure PK–PD analysisUnanticipated changes in drugpharmacokinetics due to alteredphysiology during severe infectionRelevance of tissue burden to clinicalsetting in humans often notestablished (“fuzzy test-tube”)Unrealistic introduction of pathogensinto sterile body sitesNeed to control for possible antibioticcarryover in processing specimensfor quantitative cultureRelevance to human infectionuncertainPK CONSIDERATIONS IN ANIMAL MODELS OF INFECTIONAs described in earlier chapters, one objective of PD modeling is to relate the invivo exposure of an anti-infective to the observed effects listed above. Thisrequires careful study of antimicrobial PKs in the test species.Our approach is to measure the PK properties of readily available drugs inthe infected animals. Although literature data are often available, the results in apreclinical PK study (where the goal is to carefully measure PK properties) maydiffer from the values obtained in sick animals or with multiple doses. For novelcompounds, the PKs are not known, and studies in both infected and uninfectedanimals are needed to characterize the PK properties of the agent as well as todetermine the actual exposure to drug in the experimental model. Nonlinear