In Vivo Efficacy of Meropenem with a Novel Non-β-Lactam–β-Lactamase Inhibitor, Nacubactam, against Gram-Negative Organisms Exhibiting Various Resistance Mechanisms in a Murine Complicated Urinary Tract Infection Model

Abstract

Urinary tract infections (UTIs) are a tremendous burden on the health care system due to the vast number of infections resulting in antibiotic therapy and/or hospitalization. Additionally, these infections are frequently caused by multidrug-resistant (MDR) organisms, limiting the availability of effective antimicrobials. Nacubactam is a novel non-β-lactam-β-lactamase inhibitor with activity against class A and class C β-lactamases. Nacubactam is being developed in combination with meropenem, providing broad-spectrum activity in addition to improved stability against common β-lactamases. Here, we utilized a neutropenic murine complicated UTI (cUTI) model to determine the potential clinical utility of meropenem-nacubactam compared with meropenem or nacubactam alone against 10, , and isolates with diverse genotypic and phenotypic profiles, including NDM, KPC, OXA, CTX-M, SHV, and TEM enzyme-producing isolates. Selected isolates had meropenem-nacubactam MICs between 1 and 8 μg/ml. Meropenem-nacubactam demonstrated the greatest efficacy against 9 of 10 isolates, achieving a ≥3 log reduction from the 48-h control in all isolates tested, including isolates prepared as high inoculums. Nacubactam alone confirmed antibacterial properties, achieving a>1 log reduction against the majority of isolates. The combination of meropenem-nacubactam further enhanced the activity of either agent alone, notably against meropenem-resistant isolates. Against ceftazidime-avibactam-resistant isolates, meropenem-nacubactam demonstrated increased antibacterial kill upwards of 6 log CFU in comparison to the 48-h control. Our data support the potential clinical utility of meropenem-nacubactam for cUTI in humans against MDR , although further clinical data supporting meropenem-nacubactam efficacy are needed.

Efficacy of Human-Simulated Epithelial Lining Fluid Exposure of Meropenem-Nacubactam Combination against Class A Serine β-Lactamase-Producing Enterobacteriaceae in the Neutropenic Murine Lung Infection Model

“…Against contemporary clinical Enterobacteriaceae isolates (n ϭ 317), meropenem and meropenem-nacubactam MIC 90 values were 8 mg/liter and 0.25 mg/liter, respectively, while cefepime and cefepime-nacubactam MIC 90 values were Ͼ64 mg/liter and 0.5 mg/ liter, respectively (26). In addition, our observations are in agreement with the recent findings of Monogue and colleagues (27). Utilizing a murine urinary tract infection model, the authors demonstrated that human-simulated meropenem-nacubactam plasma exposure had potent activity against meropenem-and ceftazidime-avibactamresistant Enterobacteriaceae strains.…”

“…Utilizing a murine urinary tract infection model, the authors demonstrated that human-simulated meropenem-nacubactam plasma exposure had potent activity against meropenem-and ceftazidime-avibactamresistant Enterobacteriaceae strains. Isolates in that study harbored a range of ␤lactamases, including ESBL, KPC, OXA, and NDM enzymes (27).…”

New β-Lactamase Inhibitors Nacubactam and Zidebactam Improve the In Vitro Activity of β-Lactam Antibiotics Against Mycobacterium abscessus Complex Clinical Isolates

“…Although such targets are not established for β-lactams against MABC organisms, target %fT >MIC values against other bacteria are ≈40% for carbapenems and ≈40-60% for cephalosporins (19, 20). Monogue et al showed that nacubactam plasma concentrations exceed 8 μg/mL for about 60% of the dosing interval when dosed intravenously at 1.5 grams every 8 hours (0.5 hr infusion) (13), suggesting that β-lactam MICs in the presence of nacubactam 8 μg/mL may predict clinical efficacy if the β-lactam dosing regimen meets the %fT >MIC target for MIC in the presence of the BLI. Likewise, susceptibility breakpoints based on such targets should be predictive of clinical efficacy.…”

“…However, ceftazidime has poor intrinsic activity against MABC organisms, as evidenced by high MICs despite combination with avibactam or relebactam (10, 12), while imipenem has relatively high intrinsic activity and MICs are only modestly lower in the presence of these BLIs (8, 10). Newer diazabicyclooctane-based BLIs being developed for treatment of challenging Gram-negative infections, including nacubactam and zidebactam (13, 14), may offer advantages over avibactam and relebactam. Both nacubactam (OP0595, RG6080) co-formulated with meropenem and zidebactam (WCK 5107) co-formulated with cefepime (co-formulation is WCK 5222) have completed clinical safety, tolerability, pharmacokinetics and lung penetration studies (ClinicalTrials.gov identifiers: NCT02972255, NCT03182504, NCT02674347, NCT03630094) and received Fast Track and Qualified Infectious Disease Product (QIDP) designations from the U.S. Food and Drug Administration (15, 16).…”

Nacubactam Enhances Meropenem Activity against Carbapenem-Resistant Klebsiella pneumoniae Producing KPC

“…In vivo, nacubactam combined with cefepime was effective in a murine pneumonia model infected with K. pneumoniae and murine thigh infection models using CTX-M-15-containing E. coli, KPC-2-positive K. pneumoniae, or AmpC-depressed P. aeruginosa (26)(27)(28). A meropenem-nacubactam combination was also effective in Enterobacteriaceaeinfected murine models of complicated urinary tract infections (cUTI) (29). Herein, we set out to determine the efficiency of the meropenem-nacubactam combination against a panel of Klebsiella pneumoniae clinical isolates and to conduct in-depth biochemical and mechanistic studies with nacubactam, namely, to determine the structure-activity relationships (SAR) and efficacy of the DBO against the clinically significant class A carbapenemase KPC.…”