When might we consider using the newer β-lactam agents as empirical therapy against presumed carbapenem-resistant...

Carbapenem-resistant Gram-negative (CRGN) pathogens-including Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii-are a major global health threat. Newer β-lactam agents including novel β-lactam/β-lactamase inhibitor combinations and other recently introduced β-lactam agents have expanded treatment options. However, although current guidelines focus on their use as targeted therapy, their role in empirical treatment of suspected bacterial sepsis remains unclear.

In this review we evaluate epidemiological studies, randomized trials, comparative observational studies, international guidelines, microbiological surveillance data on CRGN infections and clinical factors supporting consideration of empirical use of newer β-lactam agents in patients with sepsis at risk for CRGN infection.

Carbapenem resistance epidemiology varies substantially across regions and strongly affects the likelihood of CRGN infection. Key risk factors include prior CRGN colonization or infection, recent broad-spectrum antibiotic exposure, prolonged hospitalization and healthcare contact in high-prevalence settings. In sepsis, delayed effective antimicrobial therapy-particularly in septic shock or severe immunosuppression-is associated with poorer outcomes. However, indiscriminate empirical use of newer β-lactam agents may promote resistance and compromise stewardship efforts. Direct evidence supporting empirical use of these agents remains limited and is based largely on observational data and extrapolation from targeted-therapy studies. Empirical use of newer agents may be appropriate for carefully selected patients with a high probability of CRGN infection and clinical scenarios where delayed active therapy could have serious consequences.

A risk-stratified, stewardship-integrated approach incorporating local epidemiology, patient-level risk factors, illness severity and rapid diagnostics may optimize timely effective therapy while preserving the long-term utility of these agents.