The FDA has approved Allecra Therapeutics’s novel antibiotic combination, Exblifep (cefepime/enmetazobactam), to treat complicated urinary tract infections (cUTIs), including acute pyelonephritis (AP), in patients 18 years of age and older caused by the following gram-negative bacteria: Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis, and Enterobacter cloacae complex. Exblifep, a combination of the novel β-lactamase inhibitor, enmetazobactam, with the fourth generation cephalosporine, cefepime, was specifically designed to fight extended-spectrum β-lactamase (ESBL)-mediated resistance and represents an important new therapeutic option in the battle against antimicrobial resistance (AMR).

The current standard of care (SOC) for treating cUTIs, piperacillin/tazobactam (TZP), is under threat from the growing prevalence of ESBL-mediated resistance. ESBL-producing pathogens are often resistant to most fluoroquinolone, aminoglycoside, and β-lactam antibiotics. This led to the use of carbapenem antibiotics to treat drug-resistant cUTIs. Carbapenems are highly effective against MDR pathogens and are typically reserved as last-resort treatment options to limit the growth of carbapenem-resistant bacterial strains. However, the increased use of cUTIs resulted in the emergence of carbapenem-resistant Enterobacterales (CRE). Therefore, a critical need exists for “carbapenem-sparing” options, such as EXBLIFEP, to treat cUTIs caused by ESBL-producing bacteria and other resistant infections.

The FDA’s approval of Exblifep was highly influenced by positive clinical data from Allecra’s Phase III ALLIUM trial that demonstrated its efficacy against ESBL-mediated AMR in gram-negative bacteria. In the patients with an ESBL-producing baseline pathogen (n=142), 73.7% of patients in the cefepime/enmetazobactam group achieved the composite outcome of overall treatment success compared to 51.5% of those in the piperacillin/tazobactam group. Exblifep further demonstrated non-inferiority, as well as superiority to piperacillin/tazobactam concerning the trial’s primary endpoints of clinical cure and microbiological eradication in cUTI patients.

In addition to the FDA approval, Exblifep has also been submitted for marketing approval in the EU and received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in January 2024. The CHMP’s positive opinion included treatment of cUTIs, AP, hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and bacteremia associated with any of those infections. The EMA is expected to make a final decision in March this year.

ESBL-mediated AMR is an urgent global threat. Exblifep has the potential to serve as a replacement for piperacillin/tazobactam in treating cUTIs and an alternative to carbapenem use. Monitoring for the emergence of enmetazobactam-resistant bacterial strains should be prioritised to ensure continued efficacy against ESBL pathogens. However, it is unlikely that Exblifep can solve this issue alone. A significant need remains for the continued development of novel therapeutic options to effectively treat drug-resistant infections and address the serious threat of increasing ESBL prevalence in the long term.

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