COMBAT Candida - COMBination Antifungal Therapy for Candida Bloodstream Infections

Candida species make up 5 of the 11 WHO-listed high and critical priority fungal pathogens due to rising incidence, high mortality (~30%) and increasing antifungal resistance. Combination antifungal therapy with micafungin and flucytosine has potential to improve clinical outcomes, while mitigating resistance emergence, yielding benefit to public health as well as the individual. This approach will be tested in a phase 2b randomised controlled trial in South Africa, a high burden setting for antifungal resistance, for safety and efficacy in the treatment of Candida bloodstream infections. An innovative trial design will select the appropriate dose of flucytosine for this indication, and incorporate resistance, as well as mortality and fungal clearance as components of a hierarchical composite primary endpoint for Win Ratio analysis. A programme of work garnering evidence around Candida epidemiology, transmission dynamics, and resistance mechanisms induced by antifungal exposure in patients, and using a murine model of South African clade Candida auris will complement trial findings. A health economics analysis will assess cost-effectiveness of the intervention. If safe and effective for improving clinical, mycological and resistance outcomes in this high burden setting, this combination regimen will be readily implementable to optimise candidaemia treatment and prevent antifungal resistance emergence globally.