Efficacy and safety of novel carbapenem-β-lactamase inhibitor combinations: Results from phase II and III trials.

Objectives: The addition of novel β-lactamase inhibitors to carbapenems restores the activity against multidrug-resistant Gram-negative bacteria. The aim of this study was to summarize the evidence on the efficacy and safety of novel carbapenem-β-lactamase inhibitor combinations.

Methods: We conducted a meta-analysis of clinical trials comparing novel carbapenem-β-lactamase inhibitor combinations with comparators to assess the clinical and microbiological responses, mortality, and adverse events (AEs).

Results: A total of 1,984 patients were included. The pooled risk ratios (RRs) of clinical cure, microbiological eradication, all-cause mortality, and 28-day mortality were 1.11 (95% CI: 0.98-1.26), 0.98 (95% CI: 0.82-1.16), 0.90 (95% CI: 0.49-0.94), and 0.68 (95% CI: 0.49-0.94) between the novel carbapenem-β-lactamase inhibitor combinations and control groups. Sensitivity analysis revealed that the phase II trial of imipenem-cilastatin/relebactam (ICR) against complicated urinary tract infections could be the most important factor of heterogeneity for the microbiological response. The therapeutic effect of novel carbapenem-β-lactamase inhibitor combinations was better in meropenem-vaborbactam (MEV), phase III trials, and number of patients less than 200. The RRs of AEs from any cause and serious adverse events (SAEs) for patients receiving novel carbapenem-β-lactamase inhibitor combinations were 0.98 (95% CI: 0.93-1.04) and 1.01 (95% CI: 0.75-1.36), respectively.

Conclusions: ICR and MEV were superior to comparators for clinical cure and survival rate in the treatment of complicated infections, and both were as tolerable as the comparators.