Cefepime-enmetazobactam tops piperacillin-tazobactam for complicated UTI, acute pyelonephritis

The investigational combination drug comprising the fourth-generation cephalosporin cefepime and the novel, potent extended-spectrum β-lactamase (ESBL) inhibitor enmetazobactam (FPE) demonstrated superiority to the piperacillin-tazobactam (PTZ) regimen in patients with complicated* urinary tract infection/acute pyelonephritis (cUTI/AP) caused by ESBL-producing Enterobacterales, according to the results of the ALLIUM trial.

“FPE demonstrated superiority [to] PTZ in the primary endpoint** at test of cure (TOC),” said presenting author Professor Keith Kaye from the University of Michigan Medical School, Ann Arbor, Michigan, US. “[The] superiority of FPE was also demonstrated in subgroups of patients with cUTI/AP caused by ESBL-producing isolates.”

Carbapenems are typically used as first-line agents for treating ESBLs. [www.idsociety.org/practice-guideline/amr-guidance, accessed November 12, 2020] However, the increasing carbapenem-resistance due to increasing carbapenem consumption underscores the “critical need for carbapenem-sparing therapies for infections caused by ESBL-producing Enterobacterales,” said Kaye.

Moreover, Kaye noted in a previous press release that the development of new treatment alternatives for these infections has been categorized as ‘critical priority’ by the WHO, owing to the controversy surrounding PTZ use. “FPE may provide a novel therapeutic option addressing this serious threat,” he said.

The team thus sought to compare FPE against PTZ in 1,034 hospitalized cUTI/AP patients. Participants were randomized 1:1 to receive FPE or PTZ*** via 2-hour IV infusions Q8H for 7–14 days. Apart from the primary analysis performed in the microbiological modified intention-to-treat (mMITT; n=678) cohort at TOC, subgroup analyses were conducted on patients with ESBL baseline uropathogens that were either resistant (mMITTr; n=172) or nonresistant (mMITTnr; n=142) to either combination regimen. [ID Week 2020, abstract LB-4]

In terms of overall response of success, FPE was superior to PTZ in the mMITT cohort (79 percent vs 59 percent) and the two subgroups evaluated (74 percent vs 51 percent [mMITTr] and 74 percent vs 52 percent [mMITTnr]) at TOC.

When the composite endpoints were assessed individually, there appeared to be no difference between the FPE and PTZ arms in terms of clinical cure (93 percent vs 89 percent [mMITT] and 88 percent vs 91 percent [mMITTnr]). However, microbiological eradication rates were higher with FEP vs PTZ (83 percent vs 65 percent [mMITT] and 78 percent vs 56 percent [mMITTnr]), which might have driven the superiority of FPE to PTZ in the primary analysis, noted Kaye.

“These results support the development of FPE as an alternative to PTZ for gram-negative infections in hospital settings where ESBL involvement is prevalent or suspected, [or where] carbapenem-sparing regimens are desirable,” said Kaye.

“[Taken together,] FPE may represent a new empiric carbapenem-sparing option in settings where ESBLs are endemic,” he concluded.