Evaluating Ciprofloxacin Dosing for Pseudomonas aeruginosa Infection by Using Clinical Outcome-Based Monte Carlo Simulations

Abstract

Pseudomonas aeruginosa causes serious infections whose outcome is highly dependent on antimicrobial therapy. The goal of this study was to predict the relative efficacies of three ciprofloxacin dosing regimens for P. aeruginosa infection using clinical outcome-based Monte Carlo simulations (MCS) with "real patient" demographics, pharmacokinetics, MICs, and pharmacodynamics (PDs). Each cohort consisted of 1,000 simulated study subjects. Three ciprofloxacin dosing regimens were studied, including (i) the recommended standard dose of 400 mg given intravenously (i.v.) every 12 h (q12h), (ii) the recommended high dose of 400 mg i.v. q8h, and (iii) a novel, PD-targeted regimen to attain a ƒAUC/MIC value of >86. Probability of target attainment (PTA) and probability of cure (POC) were determined for each regimen. POC with the standard dose was at least 0.90 if pathogen MICs were <0.25 g/ml but only 0.59 or 0.27 if MICs were 0.5 or 1 g/ml, respectively. Predicted cure rates in these MIC categories were significantly higher at 0. Pseudomonas aeruginosa infection is associated with significant patient morbidity and mortality. Clinical outcome is influenced by patient-and infection-related factors and is highly dependent on antimicrobial therapy. Several studies have demonstrated the association between appropriate antimicrobial selection based on sensitive MICs and patient outcome including survival (6)(7)(8)29). More recent work has elucidated the influence of antimicrobial dosing and pharmacodynamics (PDs) on treatment response. In our previous study of P. aeruginosa bloodstream infection, C max /MIC and AUC/MIC for ciprofloxacin and gentamicin were significantly associated with clinical cure (30) and demonstrated PD relationships consistent with those observed in the treatment of other serious gram-negative infections (20,22).PD targets may be difficult to attain in cases involving antimicrobials with dose-dependent toxicity, variable pharmacokinetics (PKs), or high MICs. For example, standard ciprofloxacin dosing falls within a relatively narrow range, is not adjusted for body weight, and only moderately increased from 400 mg given intravenously (i.v.) every 12 h (q12h) to q8h for severe infections. Furthermore, P. aeruginosa is generally less susceptible, with MICs for sensitive isolates more often approaching the Clinical and Laboratory Standards Institute (CLSI) (formerly known as NCCLS) breakpoint of 1 g/ml. Such factors render ciprofloxacin dosing critical in attaining adequate PD targets and treatment response. As a result, the goal was to predict the relative efficacies of three ciprofloxacin dosing regimens for P. aeruginosa infection using clinical outcome-based Monte Carlo simulations (MCS) with "real patient" demographics, PKs, MICs, and PDs. MATERIALS AND METHODSSimulated study subjects. MCSs were generated according to the algorithm in Fig. 1 using SYSTAT version 10 (2000; SPSS Inc.). Each cohort consisted of 1,000 simulated study subjects using "real patient" demographics from the prior study of P. aerug...

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