Search

The effects of supratherapeutic doses of intravenous (IV) relebactam on duration of ventricular depolarization and subsequent repolarization were assessed in a thorough QT/corrected QT study. This was a single‐dose, double‐blind (relebactam only), randomized, placebo‐ and positive‐controlled, 3‐period, balanced crossover study in healthy participants. Participants received in randomized order, and separated by a washout (≥4 days), a single dose of IV relebactam 1150 mg, oral moxifloxacin 400 mg (open‐label positive control), and IV placebo. Least squares mean and 2‐sided 90% confidence interval for change from baseline in population‐derived corrected QT intervals for relebactam, moxifloxacin, and placebo were estimated for 24 hours. The upper limit of the 90% confidence interval of all least squares mean population‐derived corrected QT treatment differences from placebo was not >10 milliseconds at any time point for 24 hours. Corrected QT assay sensitivity was confirmed with moxifloxacin treatment. Analysis of electrocardiogram parameters resulted in no additional cardiac safety concerns. Overall, a supratherapeutic dose of relebactam yielded no cardiac safety events; the 1150‐mg supratherapeutic dose (4.6‐fold above the 250‐mg therapeutic dose) was not associated with QT prolongation or other abnormal cardiodynamic parameters. This study lends additional support to relebactam's use as a β‐lactamase inhibitor in antimicrobial therapy.

Background:

ABSTRACTThe scarcity of new antibiotics against drug-resistant bacteria has led to the development of inhibitors targeting specific resistance mechanisms, which aim to restore the effectiveness of existing agents. However, there are few guidelines for the optimal dosing of inhibitors. Extending the utility of mathematical modeling, which has been used as a decision support tool for antibiotic dosing regimen design, we developed a novel mathematical modeling framework to guide optimal dosing strategies for a beta-lactamase inhibitor. To illustrate our approach, MK-7655 was used in combination with imipenem against a clinical isolate of Klebsiella pneumoniaeknown to produce KPC-2. A theoretical concept capturing fluctuating susceptibility over time was used to define a novel pharmacodynamic index (time above instantaneous MIC [T>MICi]). The MK-7655 concentration-dependent MIC reduction was characterized by using a modified sigmoid maximum effect (Emax)-type model. Various dosing regimens of MK-7655 were simulated to achieve escalating T>MICivalues in the presence of a clinical dose of imipenem (500 mg every 6 h). The effectiveness of these dosing exposures was subsequently validated by using a hollow-fiber infection model (HFIM). An apparent trend in the bacterial response was observed in the HFIM with increasing T>MICivalues. In addition, different dosing regimens of MK-7655 achieving a similar T>MICi(69%) resulted in comparable bacterial killing over 48 h. The proposed framework was reasonable in predicting the in vitroactivity of a novel beta-lactamase inhibitor, and its utility warrants further investigations.

ABSTRACTKilling by beta-lactams is well known to be reduced against a dense bacterial population, commonly known as the inoculum effect. However, the underlying mechanism of this phenomenon is not well understood. We proposed a semimechanistic mathematical model to account for the reduced in vitrokilling observed. Time-kill studies were performed with 4 baseline inocula (ranging from approximately 1 × 105to 1 × 108CFU/ml) of Escherichia coliATCC 25922 (MIC, 2 mg/liter). Constant but escalating piperacillin concentrations used ranged from 0.25× to 256× MIC. Serial samples were taken over 24 h to quantify viable bacterial burden, and all the killing profiles were mathematically modeled. The inoculum effect was attributed to a reduction of effective drug concentration available for bacterial killing, which was expressed as a function of the baseline inoculum. Biomasses associated with different inocula were examined using a colorimetric method. Despite identical drug-pathogen combinations, the baseline inoculum had a significant impact on bacterial killing. Our proposed mathematical model was unbiased and reasonable in capturing all 28 killing profiles collectively (r2= 0.88). Biomass was found to be significantly more after 24 h with a baseline inoculum of 1 × 108CFU/ml, compared to one where the initial inoculum was 1 × 105CFU/ml (P= 0.002). Our results corroborated previous observations that in vitrokilling by piperacillin was significantly reduced against a dense bacterial inoculum. This phenomenon can be reasonably captured by our proposed mathematical model, and it may improve prediction of bacterial response to various drug exposures in future investigations.

Relebactam is a novel class A and C β-lactamase inhibitor that is being developed in combination with imipenem-cilastatin for the treatment of serious infections with Gram-negative bacteria. Here we report on two phase 1 randomized, double-blind, placebo-controlled pharmacokinetics, safety, and tolerability studies of relebactam administered with or without imipenem-cilastatin to healthy participants: (i) a single-dose (25 to 1,150 mg) and multiple-dose (50 to 625 mg every 6 h [q6h] for 7 to 14 days) escalation study with men and (ii) a single-dose (125 mg) study with women and elderly individuals.

ABSTRACTResistance 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 vitrohollow-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 aeruginosaand 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.