Abstract
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.
Highlights
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The search for optimal predictors of clinical outcome and antibacterial effects remains important to optimize treatment. From this point of view, a previously described approach to determining MICs of antibiotics in combinations using pharmacokinetically based (PK-based) concentration ratios seems promising [11,12,13,14,15]. According to this PK-based approach, to predict antibacterial effects of antibiotics used in combination in an in vitro dynamic model by their MICs in the presence of each other, antibiotic-to-antibiotic concentration ratios during MIC determinations should be equal to respective antibiotic-to-antibiotic area under the concentration-time curve (AUC) ratios when simulated in pharmacodynamic experiments
To explore whether this alternative, PK-based approach to antibiotic MIC estimation in the presence of inhibitor is predictive of the efficacy of carbapenem/carbapenemase inhibitor combinations, the antibacterial effects of imipenem and doripenem alone and in combination with relebactam were studied in time-kill experiments against high-level carbapenem-resistant KPC-producing K. pneumoniae
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. As recommended by CLSI, the antibacterial activity of imipenem/relebactam, as estimated by the MIC (minimal inhibitory concentration), is usually determined by varying imipenem concentrations in the presence of a fixed concentration of relebactam [10] This traditional approach to MIC determinations for antibiotic/inhibitor combinations might be inadequate, as it does not consider the actual antibiotic-to-inhibitor concentration ratios achieved in humans. No correlation with the effect of ampicillin plus sulbactam was found when antibiotic MICs were determined at a fixed sulbactam concentration (traditional approach to MIC determination) To explore whether this alternative, PK-based approach to antibiotic MIC estimation in the presence of inhibitor is predictive of the efficacy of carbapenem/carbapenemase inhibitor combinations, the antibacterial effects of imipenem and doripenem alone and in combination with relebactam were studied in time-kill experiments against high-level carbapenem-resistant KPC-producing K. pneumoniae. In all time-kill experiments this constant 1.5/1 concentration ratio was realized
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