Introduction

Antimicrobial resistance (AMR) represents an escalating global health crisis. In 2019, an estimated 4.95 million deaths were associated with AMR pathogens worldwide, including 1.27 million deaths directly attributable to resistant infections. Projections suggest that, without effective intervention, AMR could result in up to 10 million deaths annually by 2050.

This document provides suggestions on the treatment of infections caused by extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E), AmpC β-lactamase-producing Enterobacterales (AmpC-E), carbapenem-resistant Enterobacterales (CRE), Pseudomonas aeruginosa with difficult-to-treat resistance (DTR P. aeruginosa), carbapenem-resistant Acinetobacter baumannii (CRAB) and Stenotrophomonas maltophilia.;

Following is the summary of the suggestions on the use of Cefepime-Enmetazobactam in management of antimicrobial resistant gram-negative infections

ESBL-Producing Enterobacterales (ESBL-E)

Complicated Urinary Tract Infection (cUTI)

Suggestion

• TMP-SMX, ciprofloxacin, or levofloxacin are preferred agents when susceptibility is demonstrated.
• Cefepime-enmetazobactam or carbapenems are preferred when resistance, intolerance, or toxicities preclude the use of TMP-SMX or fluoroquinolones. IV fosfomycin, aminoglycosides, and piperacillin-tazobactam, are alternative options for ESBL-E cUTI.

Rationale

• Enmetazobactam restores cefepime activity against almost all ESBL-E isolates in surveillance studies.
• In a randomized cUTI trial, treatment success occurred in:
  1. 74% (56/76) receiving cefepime-enmetazobactam
  2. 52% (34/66) receiving piperacillin-tazobactam
• In the absence of direct comparisons with carbapenems, the guideline panel considers cefepime-enmetazobactam and carbapenems equally effective options for ESBL-E cUTI. 

ESBL-E Infections Outside the Urinary Tract

Suggestion

• The guideline states that ertapenem, imipenem, and meropenem are preferred agents.
• Cefepime-enmetazobactam is an alternative option for ESBL-E infections outside the urinary tract.

Rationale

The document notes

• Extensive clinical experience exists with cefepime for invasive infections.
• Enmetazobactam provides inhibitory activity against ESBLs.
• PK/PD modeling demonstrates adequate intrapulmonary penetration and a high probability of target attainment against Enterobacterales isolates with MICs ≤8/8 µg/mL.
• Compared with tazobactam, enmetazobactam contains a methyl substitution that confers a neutral charge and zwitterionic structure, enhancing bacterial cell penetration and increasing periplasmic concentrations.
• Clinical data for non-urinary tract ESBL-E infections remain limited.
• Additional evidence is needed before cefepime-enmetazobactam can be suggested as a preferred therapy. 

AmpC β-Lactamase-Producing Enterobacterales (AmpC-E)

The guideline states: Because cefepime is generally active against AmpC-E, cefepime-enmetazobactam is also anticipated to retain activity; however, its use is preferentially reserved for infections caused by ESBL-E or organisms co-producing AmpC and ESBL enzymes. 

Summary

Strongest clinical evidence in the guideline comes from cUTI studies, while evidence for invasive non-UTI infections remains limited and additional data are needed.

Reference

IDSA 2026 Guidelines -https://www.idsociety.org/practice-guideline/amr-guidance/