Beyond Piperacillin-Tazobactam: Cefepime and AAI101 as a Potent β-Lactam−β-Lactamase Inhibitor Combination

Abstract

Impeding, as well as reducing, the burden of antimicrobial resistance in Gram-negative pathogens is an urgent public health endeavor. Our current antibiotic armamentarium is dwindling, while major resistance determinants (e.g., extended-spectrum β-lactamases [ESBLs]) continue to evolve and disseminate around the world. One approach to attack this problem is to develop novel therapies that will protect our current agents. AAI101 is a novel penicillanic acid sulfone β-lactamase inhibitor similar in structure to tazobactam, with one important difference. AAI101 possesses a strategically placed methyl group that gives the inhibitor a net neutral charge, enhancing bacterial cell penetration. AAI101 paired with cefepime, also a zwitterion, is in phase III of clinical development for the treatment of serious Gram-negative infections. Here, AAI101 was found to restore the activity of cefepime against class A ESBLs (e.g., CTX-M-15) and demonstrated increased potency compared to that of piperacillin-tazobactam when tested against an established isogenic panel. The enzymological properties of AAI101 further revealed that AAI101 possessed a unique mechanism of β-lactamase inhibition compared to that of tazobactam. Additionally, upon reaction with AAI101, CTX-M-15 was modified to an inactive state. Notably, the in vivo efficacy of cefepime-AAI101 was demonstrated using a mouse septicemia model, indicating the ability of AAI101 to bolster significantly the therapeutic efficacy of cefepime in vivo. The combination of AAI101 with cefepime represents a potential carbapenem-sparing treatment regimen for infections suspected to be caused by Enterobacteriaceae expressing ESBLs.

Development of Broth Microdilution MIC and Disk Diffusion Antimicrobial Susceptibility Test Quality Control Ranges for the Combination of Cefepime and the Novel β-Lactamase Inhibitor Enmetazobactam

“…Whereas cefepime exhibits intrinsic activity against isolates expressing ␤-lactamases, AmpCs, and many OXAs, including OXA-48 (34), this fourth-generation cephalosporin remains susceptible to most ESBLs. Enmetazobactam inhibits a broad array of class A ␤-lactamases, including SHV, TEM, and CTX-M ESBLs (16), and cefepime-enmetazobactam exhibited similar potencies against both a collection of 1,696 recent clinical isolates of Enterobacteriaceae and a subset of 211 ESBL-producing Enterobacteriaceae, with an MIC 90 of 0.25 g/ml for both groups (17). That MIC QC ranges of cefepime-enmetazobactam (fixed enmetazobactam concentration of 8 g/ml) for CTX-M-15-producing E. coli NCTC 13353 and E. coli ATCC 25922 are identical indicates that ESBL activity was completely suppressed by enmetazobactam.…”

Critical analysis of antibacterial agents in clinical development

“…Finally, the penicillanic acid sulfone BLI enmeta zobactam is similar to tazobactam, with improved inhibitory activity of ESBL and OXA48 enzymes in Enterobacterales, and is being developed in combina tion with an optimized dosage regimen of cefepime 57 . Cefepime is easier to potentiate than piperacillin, therefore achieving lower MICs of the combination in wild type strains as well as in ESBL, and some KPC2 and KPC3, producers.…”

The latest advances in β-lactam/β-lactamase inhibitor combinations for the treatment of Gram-negative bacterial infections

“…Enmetazobactam is a penicillanic acid sulfone β-lactamase inhibitor, similar in structure to tazobactam ( Figure 2 and Table 2). However, enmetazobactam possesses a methyl group on the triazole moiety that gives the molecule a neutral charge and is predicted to enhance entry into the bacterial cell as well as interactions with β-lactamases [102]. Enmetazobactam inhibits class A βlactamases, including KPC carbapenemases with IC 50 values ≤ 0.52 μM [102].…”

“…However, enmetazobactam possesses a methyl group on the triazole moiety that gives the molecule a neutral charge and is predicted to enhance entry into the bacterial cell as well as interactions with β-lactamases [102]. Enmetazobactam inhibits class A βlactamases, including KPC carbapenemases with IC 50 values ≤ 0.52 μM [102]. In murine neutropenic thigh infection and immunocompetent septicemia models using cefepimeresistant Enterobacteriaceae, the cefepime-enmetazobactam combination significantly reduced bacterial burdens [102,103].…”