In Vitro Activity of MK-7655, a Novel β-Lactamase Inhibitor, in Combination with Imipenem against Carbapenem-Resistant Gram-Negative Bacteria

Abstract

c Carbapenem-resistant bacteria represent a significant treatment challenge due to the lack of active antimicrobials available. MK-7655 is a novel ␤-lactamase inhibitor under clinical development. We investigated the combined killing activity of imipenem and MK-7655 against four imipenem-resistant bacterial strains, using a mathematical model previously evaluated in our laboratory. Time-kill studies (TKS) were conducted with imipenem and MK-7655 against a KPC-2-producing Klebsiella pneumoniae isolate (KP6339) as well as 3 Pseudomonas aeruginosa isolates (PA24226, PA24227, and PA24228) with OprD porin deletions and overexpression of AmpC. TKS were performed using 25 clinically achievable concentration combinations in a 5-by-5 array. Bacterial burden at 24 h was determined in triplicate by quantitative culture and mathematically modeled using a three-dimensional response surface. Mathematical model assessments were evaluated experimentally using clinically relevant dosing regimens of imipenem, with or without MK-7655, in a hollow-fiber infection model (HFIM). The combination of imipenem and MK-7655 was synergistic for all strains. Interaction indices were as follows: for KP6339, 0.50 (95% confidence interval [CI], 0.42 to 0.58); for PA24226, 0.60 (95% CI, 0.58 to 0.62); for PA24227, 0.70 (95% CI, 0.66 to 0.74); and for PA24228, 0.55 (95% CI, 0.49 to 0.61). In the HFIM, imipenem plus MK-7655 considerably reduced the bacterial burden at 24 h, while failure with imipenem alone was seen against all isolates. Sustained suppression of bacterial growth at 72 h was achieved with simulated doses of 500 mg imipenem plus 500 mg MK-7655 in 2 (KP6339 and PA24227) strains, and it was achieved in an additional strain (PA24228) when the imipenem dose was increased to 1,000 mg. Additional studies are being conducted to determine the optimal dose and combinations to be used in clinical investigations.

Clinical management of infections caused by multidrug-resistant Enterobacteriaceae

“…The combination of ceftolozanetazobactam has demonstrated synergistic activity in vitro against many ESBL producers and AmpC producers; unfortunately, it is not active against KPC-producing enterobacteria [Titelman et al 2011;Sader et al 2011]. MK-7655 in combination with imipenem has been shown to be effective in vitro against a variety of AmpC-and KPC-producing isolates [Hirsch et al 2012].…”

Investigational Antimicrobial Agents of 2013

“…Time-kill studies demonstrated synergy between MK-7655 and imipenem (Fig. 4, compound 9) when tested against KPC-producing K. pneumoniae and carbapenem-resistant strains of P. aeruginosa strains with OprD porin deletions and overexpression of AmpC (160). Pharmacodynamic studies have helped to guide the clinical dosing of the inhibitor combination based on a new modeling index of fluctuating susceptibility over time, defined as time above instantaneous MIC (TϾMIC i ) (161).…”

New Polymyxin B Dosing Strategies To Fortify Old Allies in the War against KPC-2-Producing Klebsiella pneumoniae

“…Previous dynamic in vitro experiments (HFIM and one-compartment model) examining regimens against KPC-Kp have not described pharmacodynamic activity past 72 h (13,(37)(38)(39)(40). Therefore, it is remarkable that in the present study, the triple combination that included a polymyxin B burst, meropenem, and rifampin was bactericidal until at least 78 h for KPC-Kp 9A and 30 h for KPC-Kp 27A despite combatting a starting inoculum that was 10 to 1,000ϫ higher than those previously investigated.…”