Comparative Antibiotic Dose-Effect Relations at Several Dosing Intervals in Murine Pneumonitis and Thigh-Infection Models

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Abstract
Animal studies that compare antibiotics have used only a limited number of doses administered at intervals chosen without regard for their pharmacodynamic effects or pharmacokinetic profiles. We compared the relative efficacy and potency of three β-lactams and two aminoglycosides in lung and thigh-infection models in neutropenic mice by defining the maximum attainable antimicrobial effect at 24 h (Emax) and the total dose required to reach 50% of maximum effect (P50) at several dosing intervals. For β-lactams, Emaxs were similar, whereas Psos increased 10- to 50-fold with longer intervals in both models. Aminoglycosides were significantly more bactericidal in the lung than in the thigh, and dosing interval had little impact on Psos in either model. Recognizing the variable impact of dosing interval on efficacy for different classes of antibiotics is mandatory for the proper design and interpretation of comparative trials.

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