Cefepime–Zidebactam for Infections Caused by Carbapenem-Resistant Gram-Negative Bacteria, Including Metallo-β-Lactamase Producers: A Phase 2, Open-Label, Single-Arm, Multicenter Study
Rajiv Karthik Krishnaswami, Dilip Kumar Dubey, Rahul Vasantrao Sonawane, Prashant Raghunath Potdar, Deepak Kumar, Pratikshit Madhav Mahajan, Deepesh Gokulchand Aggarwal, Vishnu Rao Polati, Venkatasubramanian Ramasubramanian, Dorairajan Suresh Kumar, Umang Agrawal, Praveen Kumar Tirlangi, Nitin Gupta, Vasant Chandrakant Nagvekar, Subramanian Swaminathan, Mukesh Kalla, Abi Manesh S, Balaji Veeraraghavan, Thomas L Holland, Adrian J Brink, Souha S Kanj, Nicholas A Turner, Carlos Roberto Veiga Kiffer, Robert A Bonomo, Parikshit Prayag, Thomas P LodiseAbstract
Background
Infections caused by carbapenem-resistant (CR) Gram-negative bacteria, particularly metallo-β-lactamase (MBL)-producers, have limited treatment options. Cefepime–zidebactam retains activity against these pathogens, but clinical data are limited.
Methods
This prospective, open-label, single-arm, multicenter phase 2 trial enrolled adults with CR Gram-negative infections. Participants received intravenous cefepime–zidebactam for 7–21 days with renal dose adjustment. The Micro-ITT population included participants with a confirmed qualifying CR Gram-negative pathogen, and the CME population included those meeting prespecified evaluability criteria. The primary endpoint was investigator-assessed clinical cure at TOC in the CME population. Outcomes were also reviewed by an external adjudication committee.
Results
Seventy-two participants received treatment; 68 were included in the Micro-ITT population and 60 in the CME population. Among 68 qualifying isolates, 56 (82.4%) were MBL producers, predominantly NDM-β-lactamase producers. Investigator-assessed clinical cure at test-of-cure in the CME population was 91.7% (95% confidence interval, 81.6%–97.2%), and favorable microbiological outcome at TOC was 90.0%. Among participants in the CME population with MBL-producing pathogens, clinical cure was 93.9% and favorable microbiological outcome was 91.8%. External adjudication in the CME population yielded clinical cure of 86.7% and favorable microbiological outcome of 85.0%. Twenty-eight-day mortality was 2.8%. Treatment-related adverse events occurred in 15.3%, and serious treatment-related adverse events occurred in 2.8%.
Conclusions
In 60 evaluable adults with carbapenem-resistant Gram-negative infections, predominantly MBL-producing (81.7%) and cUTI/AP (58.3%), investigator-assessed TOC clinical cure was 91.7%; post hoc adjudicated cure was 86.7%. Day 28 all-cause mortality was 2.8%, and cefepime zidebactam was well tolerated.