Monte Carlo Simulation To Estimate In Vitro Susceptibility Breakpoints For Moxifloxacin, Gatifloxacin, And Levofloxacin Against Staphylococcus Aureus

Authors: Meagher AK, Craig WA, Jones RN, Dalhoff A, Stass H, Ambrose PG
Conference: ICAAC
Keywords: anti-infectives, AUC:MIC ratio, CFU, gram-positive, infectious disease, MIC, mice, murine, non compartmental, noncompartmental, nonlinear, oral, PK/PD, quinolone, resistance, T>MIC
Division: Cognigen

Abstract

Background: Emerging resistance with staphylococci has called for a change in treatment paradigms and review of breakpoints. Current NCCLS breakpoints for gatifloxacin and levofloxacin against Staphylococcus spp. are ≤ 2 μg/mL for susceptible; breakpoints for moxifloxacin have not been established. Breakpoints can be evaluated using PK-PD models to predict in vivo efficacy.

Methods: Monte Carlo simulation was used to identify the probability of attaining PK-PD targets associated with efficacy using standard dosing regimens: moxifloxacin 400 mg QD, gatifloxacin 400 mg QD, and levofloxacin 500 mg QD. Single oral dose Phase I AUC0-∞ data for moxifloxacin was obtained (n=374), FDA submitted PK data were used for gatifloxacin and levofloxacin; all were adjusted for protein binding. PK-PD target was derived from a neutropenic murine-thigh model that identified a static AUC:MIC for reference quinolones. A target free-drug (f) 24hr AUC:MIC value of 30 was evaluated. Clinical isolate MIC distributions, including MSSA and MRSA, were obtained from surveillance studies. 5000 subject simulations were performed using fixed and continuous MIC data.

Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Washington, DC, October 2004

By AK Meagher, WA Craig, RN Jones, A Dalhoff, H Stass, PG Ambrose