Rajiv Karthik Krishnaswami

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.

We evaluated low-dose infliximab (5 mg/kg) as adjunctive therapy in 20 patients with severe central nervous system tuberculosis. At 3 months, 60% achieved disability-free survival (modified Rankin Scale ≤ 2), and 75% showed clinically meaningful improvement. Our outcomes matched reports of high-dose infliximab. Randomized trials to optimize dosing are needed.