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Allecra is focused on the treatment of Gram-negative multi drug-resistant infections

Third-generation cephalosporin (3GC)-resistant Enterobacteriaceae have been categorized as critical priority pathogens by the World Health Organization. Escherichia coli and Klebsiella pneumoniae are amongst the most frequently isolated pathogens in healthcare-associated infections across diverse geographies and the number of attributable deaths rank highest for those species. The CTX-M family of extended-spectrum β-lactamases (ESBLs) has become the dominant mechanism of 3GC-resistance in K. pneumoniae and E. coli. The rapid spread of CTX-M-producing Enterobacteriaceae has contributed to an increase in carbapenem consumption, which in turn promotes selection of carbapenem-resistance. KPC and OXA carbapenemases are spreading and have become endemic in certain areas of the world.   
Enmetazobactam (formerly known as AAI101) is a novel extended-spectrum β-lactamase inhibitor belonging to the penicillanic acid sulfone class. It exerts potent inhibitory activity towards CTX-M, TEM, SHV, and other class A β-lactamases through a different mechanism of action than tazobactam. Cefepime is a 4th-generation oxyimino cephalosporin with well-documented efficacy in complicated urinary tract infections (cUTI) or acute pyelonephritis (AP), pneumonia, intra-abdominal infections (IAI), and febrile neutropenia. Although cefepime is subject to hydrolysis by class A ESBLs and carbapenemases, and by MBLs, it generally remains active against class C AmpC and class D OXA-48 producers.

Cefepime-enmetazobactam is currently investigated in a phase 3, multicenter, randomized, double-blind, non-inferiority study comparing cefepime 2 g combined with enmetazobactam 500 mg to piperacillin 4 g combined with tazobactam 500 mg administered every 8 h in adults with cUTI or AP.

Cefepime-enmetazobactam is intended as a therapy for infections caused by ESBL-, AmpC-, and OXA-48-producing strains of Enterobacteriaceae, and by P. aeruginosa. This combination is expected to provide an empiric option in settings with a high incidence of ESBL-producing Enterobacteriaceae that pursue carbapenem-sparing strategies.

Allecra’s lead combination candidate cefepime-enmetazobactam has been granted Qualified Infectious Disease Product and Fast Track Designation by the US Food and Drug Administration (FDA).

References
• Cassini A, et al. 2019. Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis. The Lancet Infectious Diseases 19:56-66.
• Belley A, et al. 2019. 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. J Clin Microbiol accepted for publication.
• Morrissey I, et al. 2019. In vitro activity of cefepime-enmetazobactam against Gram-negative isolates collected from United States and European hospitals during 2014-2015. Antimicrob Agents Chemother doi:10.1128/AAC.00514-19.
• Papp-Wallace KM, et al. 2019. Beyond Piperacillin-Tazobactam: Cefepime and AAI101 as a Potent β-Lactam−β-Lactamase Inhibitor Combination. Antimicrobial Agents and Chemotherapy 63:e00105-19.
• Bush K, Bradford PA. 2019. Interplay between beta-lactamases and new beta-lactamase inhibitors. Nat Rev Microbiol 17:295-306.
• Tacconelli E, et al. 2018. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 18:318-327.
• Temkin E, et al. 2018. Estimating the number of infections caused by antibiotic-resistant Escherichia coli and Klebsiella pneumoniae in 2014: a modelling study. Lancet Glob Health 6:e969-e979.
• Bush K. 2018. Past and Present Perspectives on beta-Lactamases. Antimicrob Agents Chemother 62:e01076-18.
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