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 (REL; MK-7655) 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 at 500 mg plus REL
at 125 or 250 mg administered intravenously every 6 h as a 30-min infusion) against
imipenem-resistant strains of Pseudomonas aeruginosa and Klebsiella pneumoniae Dose fractionation experiments confirmed that the pharmacokinetic parameter that 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 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 the dosing interval time that the concentration remains above the dynamic MIC for
imipenem was maintained at the
carbapenem target of 30 to 40%, required for maximum efficacy, for
imipenem at 500 mg plus REL at 250 mg.