Resistance to antibiotics among bacterial pathogens is rapidly spreading and therapeutic options against multidrug-resistant bacteria are limited. There is an urgent need for new drugs, especially those that can circumvent the broad array of resistance pathways that bacteria have evolved. In this study, we assessed the pharmacokinetic/pharmacodynamic relationship of the novel β-lactamase inhibitor relebactam (MK-7655; REL) in a hollow fiber infection model. REL is intended for use with the carbapenem β-lactam antibiotic imipenem for the treatment of Gram-negative bacterial infections. In this study, we used an in vitro hollow fiber infection model to confirm the efficacy of human exposures associated with the Phase 2 doses (imipenem 500 mg + REL 125 or 250 mg administered intravenously every 6 hours as a 30-minute infusion) against imipenem-resistant strains of Pseudomonas aeruginosa and Klebsiella pneumoniae. Dose fractionation experiments confirmed that the pharmacokinetic parameter best correlated with REL activity is the area under the concentration-time curve, consistent with findings in a murine pharmacokinetic/pharmacodynamic model. Determination of the pharmacokinetic/pharmacodynamic relationship between β-lactam antibiotics and β-lactamase inhibitors is complex as there is an interdependence between their respective exposure-response relationships. Here, we show that this interdependence could be captured by treating the minimum inhibitory concentration (MIC) of imipenem as dynamic: it changes with time and this change is directly related to REL levels. For the strains tested, the percentage of time above dynamic MIC for imipenem was maintained at the carbapenem target of 30-40%, required for maximum efficacy, for imipenem 500 mg plus REL 250 mg.
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