Pharmacodynamic Analysis of Ceftriaxone, Gatifloxacin, and Levofloxacin Against Streptococcus pneumoniae with the Use of Monte Carlo Simulation

Abstract

To evaluate the pharmacodynamics of four intravenous antimicrobial regimens-ceftriaxone 1 g, gatifloxacin 400 mg, levofloxacin 500 mg, and levofloxacin 750 mg, each every 24 hours-against recent Streptococcus pneumoniae isolates. Pharmacodynamic analysis using Monte Carlo simulation. The Surveillance Network (TSN) 2002 database. Streptococcus pneumoniae isolates (7866 isolates) were stratified according to penicillin susceptibilities as follows: susceptible (4593), intermediate (1986), and resistant (1287). Risk analysis software was used to simulate 10,000 patients by integrating published pharmacokinetic parameters, their variability, and minimum inhibitory concentration (MIC) distributions from the TSN database. Probability of target attainment was determined for percentage of time above the MIC (%T > MIC) from 0-100% for ceftriaxone and area under the concentration-time curve (AUC):MIC ratio from 0-150 for the fluoroquinolones. For ceftriaxone, probability of target attainment remained 90% or greater against the three isolate groups until a %T > MIC of 70% or greater, and it remained 90% or greater against susceptible and intermediate isolates over the entire interval (%T > MIC 0-100%). For levofloxacin 500 mg, probability of target attainment was 90% at an AUC:MIC < or = 30, but the curve declined sharply with further increases in pharmacodynamic target. Levofloxacin 750 mg achieved a probability of target attainment of 99% at an AUC:MIC ratio < or = 30; the probability remained approximately 90% until a target of 70 or greater, when it declined steeply. Gatifloxacin demonstrated a high probability (99%) of target attainment at an AUC:MIC ratio < or = 30, and it remained above 90% until a target of 70. Ceftriaxone maintained high probability of target attainment over a broad range of pharmacodynamic targets regardless of penicillin susceptibility (%T > MIC 0-60%). Levofloxacin 500 mg maintained high probability of target attainment for AUC:MIC ratios 0-30; whereas, levofloxacin 750 mg and gatifloxacin maintained high probability of target attainment for AUC:MIC ratios 0-60. Rate of decline in the pharmacodynamic curve was most pronounced for the two levofloxacin regimens and more gradual for gatifloxacin and ceftriaxone.