Comparative Pharmacodynamics and Antimutant Potentials of Doripenem and Imipenem with Ciprofloxacin-Resistant Pseudomonas aeruginosa in an In Vitro Model

Abstract

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 g/ml; MICs of imipenem, 1, 2, and 2 g/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. Pseudomonas aeruginosa remains an important cause of nosocomial infections of the lung, urinary tract, and bloodstream, especially within intensive care units (13,19). This organism is particularly problematic for critically ill, neutropenic, immunocompromised, and mechanically ventilated patients (21). Over the past decade, fluoroquinolone resistance among these organisms has increased, often requiring other antibiotics for successful treatment (20). Recent studies have suggested that beta-lactam monotherapy for serious pseudomonal infections is probably as effective as combination therapy, even though in vitro synergism can sometimes be demonstrated with the combinations (4, 15).Doripenem is a new carbapenem antibiotic active against Pseudomonas aeruginosa. The pharmacodynamics of doripenem have been studied in vivo using a murine thigh model of infection with 10 Gram-negative organisms (1) and a rabbit model of pseudomonal pneumonia (3). A species-independent relationship between changes in the logarithm of the number of CFU of Gramnegative organisms per thigh and the cumulative percentages of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (T ϾMIC ) was established in the former study, and similar efficacies of doripenem, imipenem, and meropenem were reported in the latter. T ϾMIC relationships of doripenem and imipenem antipseudomonal effects were also observed with each of three isogenic strains in an in vitro study using a dynamic model (14). Because the simulated ranges of the T ϾMIC s and the ratios of carbapene...

The Efficacy and Safety of Doripenem in the Treatment of Acute Bacterial Infections—A Systemic Review and Meta-Analysis of Randomized Controlled Trials

“…Finally, doripenem was comparable to other carbapenems, including imipenem and meropenem, in terms of microbiological eradication rate in the subgroup analysis. All these findings may be well explained by previous in vitro studies [3,4,19,20,21] that showed doripenem had a greater or similar in vitro activity against bacteria, including multi-drug resistant organisms. In this meta-analysis, we did not assess we did not evaluate the association between in vitro activity and the in vivo response of different organisms, especially for antibiotic-resistant pathogens, because the associated information was limited.…”

Use of antimicrobial agents in livestock

“…The other important criticism of the conventional PKPD indices is that each of the PK components (T, C max and AUC) are dependent covariates (73) and it has been suggested that it is pointless to search for the best predictive index if all are related.…”

Pseudomonas aeruginosa Susceptibility in Spain: Antimicrobial Activity and Resistance Suppression Evaluation by PK/PD Analysis

“…As a final point, PK/PD analysis based on the MIC distributions of the Spanish national survey was applied to estimate the probability of the suppression of the emergence of resistance to the different antimicrobial dosage regimens. Different works have reported the required antimicrobial PK/PD indices to suppress the emergence of P. aeruginosa an-tibiotic resistance [53][54][55][56][57][58][59], although no standardized methods are currently established to determine the antibiotic exposure for the attainment of resistance suppression. In our study, none of the dosage regimens commonly used in ICU patients were able to attain high probabilities of resistance suppression, although ceftazidime/avibactam and ceftolozane/tazobactam 2/1 g q 8 h provide moderate probabilities (>80-90%).…”