Combination Antifungals for Candida auris : using the hollow fibre model to study an azole/5FC combination for a WHO priority pathogen

Resistance to antibiotics is a major global health problem. The main focus has been on antibiotic resistance in bacteria, but drug resistance in fungal infections is a growing part of this problem.
This is typified by the emergence of a new species of pathogenic fungus. Called Candida auris, a type of harmful yeast discovered as recently as 2009 and has since spread around the world. It is extremely resistant to most of the antifungal drugs currently available. It also spreads quickly within hospital environments, and outbreaks can be very difficult to control- it has resulted in whole intensive care units (ICUs) having to be completely shut down, including in the UK.
If it gets into the bloodstream, it has a very high mortality of up to 70%. There is therefore an urgent need to find better treatments for this infection. The World Health Organization (WHO) have designated this a pathogen of "critical" public health importance.
This project will investigate a combination of antifungal drugs as a potential treatment for Candida auris. We will test flucytosine (also known as 5FC) in combination with an antifungal in the azole class (isavuconazole or posaconazole). Using a single antifungal drug, resistance is likely to emerge, but combination therapy may prevent this. Combination antifungal therapy has proved effective in other serious fungal infections.
Clinical trials in patients are ultimately needed to test the best treatments but pre clinical laboratory data is needed to choose the best candidate treatments to go forward for clinical trial. To generate this information we will use a laboratory model known as the Hollow Fibre Infection Model. This is an experimental laboratory system mimics the way drugs circulate in the human body and then act against microbes. It has been successfully used to test a variety of antibiotics for different pathogens. This model has significant advantage over animal experiments. It is cheaper to run and has fewer ethical challenges, yet has been proven to provide reliable data on the effect of drugs against pathogens. Samples taken from the system can also be used to understand the mechanisms for drug resistance emerging at a molecular and genomic level.
If we find this drug combination effective, it can be taken forward to clinical trials for the treatment of severe Candida auris infections, with the ultimate goal of finding the best possible treatment for this infection.