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

TLDR

Animal studies comparing antibiotics have used only a limited number of doses at intervals chosen without regard to pharmacodynamic or pharmacokinetic effects. The study compared the relative efficacy and potency of three beta‑lactams and two aminoglycosides in lung and thigh infection models in neutropenic mice. The authors defined 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. Beta‑lactams showed similar maximum effects but required 10‑ to 50‑fold higher doses (P50) at longer intervals in both lung and thigh models, whereas aminoglycosides were more bactericidal in the lung than thigh and their P50s were largely unaffected by interval, underscoring the need to account for interval effects when designing comparative trials.

Abstract

Animal studies that compare antibiotics have used only a limited number of doses administered at intervals chosen without regard for their pharmacodynamic effects of pharmacokinetic profiles. We compared the relative efficacy and potency of three beta-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 beta-lactams, Emaxs were similar, whereas P50s 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 P50s 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.