The increasing identification of antibiotic-resistant pathogens that cause serious infections cannot be ignored. Although the future cannot be predicted with certainty, it is surely possible that an extensive epidemic of resistant bacterial infections could potentially harm millions of people. Given that it takes more than 10 years to establish the efficacy and safety of new compounds, there is an urgent need to restock the antibiotic pipeline. Only a few new antibacterial agents have received approval by the US Food and Drug Administration in the last 5 years, including linezolid in 2001, cefditoren, pivoxil and ertapenem in 2002, gemifloxacin and daptomycin in 2003, and telithromycin in 2004. Many of these agents are improved derivatives from established classes of antibiotics, and several are directed primarily at resistant Gram-positive bacteria (e.g., linezolid and daptomycin). One promising new addition is the recent approval of tigecycline (Tigacyl, Wyeth) in June 2005.

The minimal inhibitory concentration (MIC) is conventionally used to define in vitro levels of susceptibility or resistance of a specific bacterial strain to an antibiotic and to predict its clinical efficacy. Along with MIC, other measures of bacteria resistance exist: the MIC determined at high bacterial inocula (MIC_HI) that allow the estimation of the occurrence of inoculum effect (IE) and the mutant prevention concentration, MPC. Together, MIC, MIC_HI and MPC represent the bacterial “resistance profile”. In this paper, we provide a comprehensive analysis of such profiles of K. pneumoniae strains that differ by meropenem susceptibility, ability to produce carbapenemases and specific carbapenemase types. In addition, we have analyzed inter-relations between the MIC, MIC_HI and MPC for each tested K. pneumoniae strain. Low IE probability was detected with carbapenemase-non-producing K. pneumoniae, and high IE probability was detected with those that were carbapenemase-producing. MICs did not correlate with the MPCs; significant correlation was observed between the MIC_HIs and the MPCs, indicating that these bacteria/antibiotic characteristics display similar resistance properties of a given bacterial strain. To determine the possible resistance-related risk due to a given K. pneumoniae strain, we propose determining the MIC_HI. This can more or less predict the MPC value of the particular strain.

Since the introduction of antibiotics 6 decades ago, clinicians have taken comfort in the relative safety and exceptional efficacy of these drugs. Patients init

Traditionally, the antibacterial activity of β-lactam antibiotics in the presence of β-lactamase inhibitors is determined at the fixed inhibitor concentration. This traditional approach does not consider the ratio of antibiotic-to-inhibitor concentrations achieved in humans. To explore whether an alternative pharmacokinetically based approach to estimate MICs in combinations is predictive of antimicrobial efficacy, the effects of imipenem and doripenem alone and in combination with relebactam were studied in time-kill experiments against carbapenemase-producing Klebsiella pneumoniae. The carbapenem-to-relebactam concentration ratios in time-kill assays were equal to the therapeutic 24-h area under the concentration-time curve (AUC) ratios of the drugs (1.5/1). The simulated levels of carbapenem and relebactam were equal to their concentrations achieved in humans. When effects of combined regimens were plotted against respective C/MICs, a sigmoid relationship was obtained only with MICs determined by pharmacokinetically based method. The effectiveness of both carbapenems in the presence of relebactam was comparable by the results of time-kill experiments. These findings suggest that (1) antibiotic/inhibitor MICs determined at a pharmacokinetically based concentration ratio allow an adequate assessment of carbapenem susceptibility in carbapenemase-producing K. pneumoniae strains and can be used to predict antibacterial effects; (2) in time-kill experiments, the effects of imipenem and doripenem in the presence of relebactam are comparable.