Comparative Pharmacodynamics and Antimutant Potentials of Doripenem and Imipenem with Ciprofloxacin-Resistant Pseudomonas aeruginosa in anIn VitroModel

Abstract

ABSTRACTTo compare the antipseudomonal efficacy of doripenem and imipenem as well as their abilities to restrict the enrichment of resistantPseudomonas aeruginosa, multiple-dosing regimens of each drug were simulated at comparable values of the cumulative percentages of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (T>MIC) and ratios of the 24-hour area under the curve (AUC24) to the MIC. Three clinical isolates of ciprofloxacin-resistantP. aeruginosa(MIC of doripenem, 1 μg/ml; MICs of imipenem, 1, 2, and 2 μg/ml) were exposed to thrice-daily doripenem or imipenem for 3 days at AUC24/MIC ratios of from 50 to 170 h (doripenem) and from 30 to 140 h (imipenem). The antimicrobial effects for susceptible and resistant subpopulations of bacteria were expressed by the areas between control growth and time-kill curves (IEs) and areas under the bacterial mutant concentration curves (AUBCMs), respectively. With each antibiotic, theIEand AUBCMversus log AUC24/MIC relationships were bacterial strain independent. At similar AUC24/MIC ratios, doripenem was slightly less efficient than imipenem against susceptible and resistant subpopulations of bacteria. However, doripenem appeared to be somewhat more efficient than imipenem at clinically achievable AUC24s related to the means of the MICs for the three studied strains and had higher antimutant potentials for two of the three strains.