Project Overview

Background: 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 III randomised controlled trial in Johannesburg, 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.

1. SCARS: Surveillance of Candida Antifungal Resistance in the Southern African Region
This study is nested within a multi-centre, prospective cohort study, which aims to explore the relationship between antifungal use and the development of resistance in Candida species. The primary hypothesis is that systemic fungal use in the ICU setting influences local fungal ecology, and drives resistance development. Additionally, the study investigates whether invasive candidiasis arises from the colonizing flora, particularly focusing on how skin and gut mycobiota serve as reservoirs for invasive infection. The study enrols ICU patients from 4 major hospitals in Johannesburg, as well as collaborations with Mozambique.

The study comprises three key components:

SCARS was awarded a Failsafe Grant.

2. CombAT Candida – Combination Antifungal Therapy against Candida Blood Stream Infections
This project is divided into 3 work packages, each with its own study design and objectives.

Work Package 1: A multi-site prospective cohort study of Candida invasive infection, colonisation and environmental contamination in South African ICUs. This observational study aims to understand antifungal resistance dynamics in ICUs in South Africa. It runs synergistically with the aforementioned ‘SCARS’ study, aiming to generate setting specific comprehensive data, and exploring the relationship between antifungal drug exposure and resistance ecology.

Work Package 2: An animal study using a murine model of C. auris to provide insight of the impact of single- and combination drug exposure on resistance evolution, in a complex biological organism. It also allows exploration of the implication of immune function on pathogenesis and antifungal resistance.

Work Package 3: Clinical Trial (ISRCTN56596656) – comparing combination (micafungin + 5-FC) and monotherapy (micafungin) for safety and efficacy in improving clinical, mycological and resistance endpoints for participants with candida blood stream infections. It also explores antifungal pharmacokinetics and pharmacodynamics. Finally, cost-effectiveness of this intervention is explored.

CombAT Candida was awarded a Wellcome Trust Grant.

Overall Purpose: This program of work informs evidence on Candida epidemiology, transmission dynamics, and resistance mechanisms induced by antifungal exposure in patients. Through this, the study will help develop guidelines for management of Invasive Candida infections in South Africa.