In vitro activity of MK-7655, a novel β-lactamase inhibitor, in combination with imipenem against carbapenem-resistant Gram-negative bacteria

Abstract

Carbapenem-resistant bacteria represent a significant treatment challenge due to the lack of active antimicrobials available. MK-7655 is a novel β-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.

Fig 1

Comparison of expected and observed killing activities of imipenem plus MK-7655 for each tested isolate. The red mesh surface shows the expected killing activity of the combination, while the black dots show the observed killing. When a black dot is below the mesh, observed killing is more than expected killing (synergism). Conversely, a black dot above the mesh signifies antagonism (observed killing is less than expected killing). Synergism and antagonism are defined by interactive indices (VUP_observed/VUP_expected) of <1 and >1, respectively.

Fig 2

Observed microbiologic responses in infection models for the following isolates and drug exposures: KP6339 (A), PA24226 with low-dose exposure(s) (B), PA24226 with high-dose exposure(s) (C), PA24227 with low-dose exposure(s) (D), PA24227 with high-dose exposure(s) (E), PA24228 with low-dose exposure(s) (F), and PA24228 with high-dose exposure(s) (G). Data shown are mean values ± standard deviations. IPM, imipenem; MK, MK-7655.