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Exebacase for patients with Staphylococcus aureus bloodstream infection and endocarditis

2020; American Society for Clinical Investigation; Volume: 130; Issue: 7 Linguagem: Inglês

10.1172/jci136577

1558-8238

Vance G. Fowler, Anita Das, Joy Lipka-Diamond, Raymond Schuch, Roger J. Pomerantz, Luis Jáuregui-Peredo, Adam Bressler, David C. Evans, Gregory J. Moran, Mark E. Rupp, Robert A. Wise, G. Ralph Corey, Marcus Zervos, Pamela S. Douglas, Cara Cassino,

Bacterial Identification and Susceptibility Testing

BACKGROUNDNovel therapeutic approaches are critically needed for Staphylococcus aureus bloodstream infections (BSIs), particularly for methicillin-resistant S. aureus (MRSA). Exebacase, a first-in-class antistaphylococcal lysin, is a direct lytic agent that is rapidly bacteriolytic, eradicates biofilms, and synergizes with antibiotics.METHODSIn this superiority-design study, we randomly assigned 121 patients with S. aureus BSI/endocarditis to receive a single dose of exebacase or placebo. All patients received standard-of-care antibiotics. The primary efficacy endpoint was clinical outcome (responder rate) on day 14.RESULTSClinical responder rates on day 14 were 70.4% and 60.0% in the exebacase + antibiotics and antibiotics-alone groups, respectively (difference = 10.4, 90% CI [-6.3, 27.2], P = 0.31), and were 42.8 percentage points higher in the prespecified exploratory MRSA subgroup (74.1% vs. 31.3%, difference = 42.8, 90% CI [14.3, 71.4], ad hoc P = 0.01). Rates of adverse events (AEs) were similar in both groups. No AEs of hypersensitivity to exebacase were reported. Thirty-day all-cause mortality rates were 9.7% and 12.8% in the exebacase + antibiotics and antibiotics-alone groups, respectively, with a notable difference in MRSA patients (3.7% vs. 25.0%, difference = -21.3, 90% CI [-45.1, 2.5], ad hoc P = 0.06). Among MRSA patients in the United States, median length of stay was 4 days shorter and 30-day hospital readmission rates were 48% lower in the exebacase-treated group compared with antibiotics alone.CONCLUSIONThis study establishes proof of concept for exebacase and direct lytic agents as potential therapeutics and supports conduct of a confirmatory study focused on exebacase to treat MRSA BSIs.TRIAL REGISTRATIONClinicaltrials.gov NCT03163446.FUNDINGContraFect Corporation.