Comparative pharmacodynamics and antimutant potentials of doripenem and imipenem with ciprofloxacin-resistant Pseudomonas aeruginosa in an in vitro model.
To compare the antipseudomonal efficacy of doripenem and imipenem as well as their abilities to restrict the enrichment of resistant Pseudomonas 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 (AUC(24)) to the MIC. Three clinical isolates of ciprofloxacin-resistant P. 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 AUC(24)/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 (I(E)s) and areas under the bacterial mutant concentration curves (AUBC(M)s), respectively. With each antibiotic, the I(E) and AUBC(M) versus log AUC(24)/MIC relationships were bacterial strain independent. At similar AUC(24)/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 AUC(24)s related to the means of the MICs for the three studied strains and had higher antimutant potentials for two of the three strains.
Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, Moscow, Russia. firsov@dol.ru
Alexander A
AA
Firsov
Deborah
D
Gilbert
Kenneth
K
Greer
Yury A
YA
Portnoy
Stephen H
SH
Zinner
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D019540:Area Under Curve; D015780:Carbapenems / Q000494:pharmacology*; D002939:Ciprofloxacin / Q000494:pharmacology*; D000077726:Doripenem; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial; D006801:Humans; D015378:Imipenem / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009154:Mutation; D011237:Predictive Value of Tests; D011552:Pseudomonas Infections / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D002939:Ciprofloxacin; D015378:Imipenem; D000077726:Doripenem