title: 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 fAUC/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 < or =0.25 microg/ml but only 0.59 or 0.27 if MICs were 0.5 or 1 microg/ml, respectively. Predicted cure rates in these MIC categories were significantly higher at 0.72 and 0.40 with the high dose and 0.91 and 0.72 with the PD-targeted regimen(P < 0.0001). Analyses based on the local susceptibility profile produced PTA and POC estimates of 0.44 and 0.74 with the standard ciprofloxacin dose, 0.58 and 0.81 with the high dose, and 0.84 and 0.93 with the PD-targeted regimen, respectively. In conclusion, as demonstrated by clinical outcome-based MCSs, the highest recommended ciprofloxacin dose of 400 mg i.v. q8h should be used in the treatment of P. aeruginosa infection to improve PD target attainment and clinical cure. However, even this appears ineffective if pathogen MICs are 1 mug/ml, warranting the consideration of a lower MIC breakpoint, < or =0.5 microg/ml.
authors.affiliation: Faculty of Pharmacy, University of Manitoba, Winnipeg, Canada. zelenits@ms.umanitoba.ca
authors.forename: Sheryl
authors.initials: S
authors.lastname: Zelenitsky
authors.forename: Robert
authors.initials: R
authors.lastname: Ariano
authors.forename: Godfrey
authors.initials: G
authors.lastname: Harding
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
mesh_terms: D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D019540:Area Under Curve; D002939:Ciprofloxacin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D003198:Computer Simulation; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000890:Anti-Infective Agents; D002939:Ciprofloxacin