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Animal Models of Infection for the Study of Antibiotic Pharmacodynamics 99The rigor of the selected breakpoint can be further evaluated using simulation.The availability of population PK parameters and their variability in targetpatient groups can be used to determine the probability of individual patientsattaining a PK–PD target parameter using a selected breakpoint. The simulationcan be even further developed by incorporating the distribution of MICs inorganisms of interest and serum concentration data for individual patients for thepopulation means and variances (60). This corresponds to the equivalent of asimulated clinical trial.An alternative approach employs direct simulation of human PKs in theanimal and testing of strains with varying MICs to the test agent. One wouldexpect to see a graded response according to MIC and ultimately a “no effect” at athreshold MIC value. This approach is shown in Figure 8.Human dosage regimens of amoxicillin were simulated in neutropenic mice,whose thighs were then infected with several strains of S. pneumoniae with varyinglevels of susceptibility to the drug. For strains with MICs exceeding 2 mg/L, littleor no effect was seen on bacterial counts recovered from mice at 24 hours, thussupporting a susceptibility breakpoint of 2 mg/L or less.CONCLUSIONSAnimal models of infection are a pivotal tool in the study of PK–PD properties ofanti-infectives. Consideration of PK–PD issues in the design and interpretation ofexperiments in animals have strengthened the usefulness of these models for thestudy of human infection. Animal experimentation has been greatly improvedbecause of recognition of the importance of these issues. In addition, many of therecognized limitations of animal models for application to treatment of humaninfections have been overcome by recognition of the importance of PKs in theoutcome of infection. These principles are routinely applied in the study of newdrugs in all phases of drug discovery and development as well as in the optimizationof dosage in the pre- and postmarketing evaluation of agents.ACKNOWLEDGMENTSWe acknowledge the excellent assistance of scientists and animal care personnel inDiscovery and Preclinical Pharmacology at Microcide Pharmaceuticals, who contributedto generating data for some of the examples provided.REFERENCES1. Eagle H, Fleishman R, Levy M. “Continuous” vs. “discontinuous” therapy withpenicillin. N Engl J Med 1953; 248:481–488.2. Eagle H, Fleishman R, Levy M. On the duration of penicillin action in relation to itsconcentration in the serum. J Lab Clin Med 1953; 40:122–132.3. Eagle H, Fleishman R, Musselman A. Effect of schedule of administration on thetherapeutic efficacy of penicillin. Am J Med 1950; 9:280–299.4. Collins H, Cross A, Dobek A, Opal S, McClain J, Sadoff J. Oral ciprofloxacin and amonoclonal antibody to lipopolysaccharide protect leukopenic rats from lethal infectionwith Pseudomonas aeruginosa. J Infect Dis 1989; 159:1073–1082.5. Tisdale J, Pasko M, Mylotte J. Antipseudomonal activity of simulated infusion ofgentamycin alone or with piperacillin assessed by serum bactericidal rate and areaunder the killing curve. Antimicrob Agents Chemother 1989; 33(9):1500–1505.