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Antimicrobial Agents and Chemotherapy, October 2005, p. 4009-4014, Vol. 49, No. 10
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.10.4009-4014.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Sheryl Zelenitsky,^1,2,3* Robert Ariano,^1,2,3 Godfrey Harding,^2,3 and Alan Forrest⁴

Faculties of Pharmacy,¹ Medicine, University of Manitoba,² St. Boniface General Hospital, Winnipeg, Manitoba, Canada,³ School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York⁴

Received 14 February 2005/ Returned for modification 1 May 2005/ Accepted 22 July 2005

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 AUC/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 µg/ml but only 0.59 or 0.27 if MICs were 0.5 or 1 µg/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 µg/ml, warranting the consideration of a lower MIC breakpoint, 0.5 µg/ml.

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* Corresponding author. Mailing address: Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2. Phone: (204) 474-8414. Fax: (204) 474-7617. E-mail: zelenits{at}ms.umanitoba.ca.

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Antimicrobial Agents and Chemotherapy, October 2005, p. 4009-4014, Vol. 49, No. 10
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.10.4009-4014.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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