Extending the utility and durability of antifungal agents via innovative treatment regimens that minimise drug resistance

A type of fungus called Candida, that lives on and in the human body, can sometimes cause fatal infections in humans, usually in patients who have suffered from a physical trauma or have weakened immunity.

When a Candida infection of the bloodstream or other normally sterile body site (invasive candidiasis) is detected, rapid treatment with antifungal drugs can be a lifesaving measure. Unfortunately, there are a limited number of effective drugs, and Candida species are becoming more resistant to them. This dilemma has recently been highlighted by the World Health Organisation as a public health crisis of growing concern.

Invasive candidiasis is the most common invasive fungal infection in the UK, with an estimated 5,000 cases each year. Critically ill patients in intensive care units are particularly vulnerable, with an estimated 30-40% of all infections occurring in this setting.
Unfortunately, even with the use of antifungal drugs, up to 50% of patients will not survive. Treatment options are limited with just four antifungal drug classes available; azoles; echinocandins; polyenes; nucleoside analogues. Preserving the effectiveness of these drugs is vital for ensuring we have viable treatment options to manage invasive candidiasis in the future. This is the overarching aim of this study.

There are several approaches that can be used to preserve the effectiveness of available antifungal drugs. One is to change the way in which they are used, preferably by reducing the frequency of use or the amount of drug needed to achieve an effect. Another is to combine different drug classes (called combination therapy). The best modifications of antifungal use will maintain antifungal activity but reduce the rate of emergence of drug resistance. To achieve this, we need a thorough understanding of how antifungal resistance (AFR) develops.

AFR can be defined as the ability of fungal cells to grow in the presence of high concentrations of antifungal drug. This behaviour can be readily studied in the lab since fungal cells can be grown very quickly (overnight) and we have many methods for observing their responses to antifungal drugs, such as microscopy and growth tests.

In this programme of work, we will connect three world class research centres in Liverpool, London and Exeter to discover new drugs and drug combinations that prevent fungal growth, and limit AFR. The first step will be to measure the growth of five different Candida species in the presence of various antifungal drugs and drug combinations, including new antifungal drugs that will soon come to market. The most effective drug treatments will then be progressed to study their effectiveness in a mouse model of invasive candidiasis.

By learning about the way that Candida species adapt to fungal drugs in the laboratory setting, in mice and in critically ill patients, we can develop new tests to recognise AFR early when this happens during an infection. By working as a team of scientists and clinicians we can share important knowledge and, informed by current practices, develop better tests for AFR. In turn this will help clinicians to detect AFR as it emerges during treatment, and to modify patients' treatment for a better outcome.

Fungal diseases kill over one million people annually, but therapy is constrained to four drug classes, almost always used clinically as monotherapies. The utility of each drug class is being progressively compromised by the widespread emergence of antifungal resistance (AFR), contributing to recent declarations by the WHO and CDC that fungal infections have become a global health emergency. The WHO report highlighted five Candida species including C. auris, a new and commonly multidrug resistant species, C. albicans, C. glabrata, C. parapsilosis and C. tropicalis. In this programme we will work with all five species.

Antifungal regimens are optimised for antifungal efficacy, not resistance emergence. We hypothesise that:
a) Antifungal resistance (AFR) is not inevitable. The evolution and dissemination of drug-resistant phenotypes can be minimised given a better understanding of the pharmacological and pathophysiological mechanisms leading to the emergence of AFR
b) The utility and durability of antifungal agents can be extended using approaches that simultaneously optimise antifungal killing and mitigate antifungal resistance (AFR)

The major questions that we address are:
How do resistance trajectories of clinical Candida isolates become impacted by different types and durations of antifungal drug exposure?
How can antifungal regimens be optimised to best suppress this?

Using extant and soon-to-market antifungal drugs, we will define and parameterise via in vitro (WP1) and in vivo (WP2) analyses the antifungal efficacy and resistance liabilities of antifungal monotherapy, coupled to underlying mechanisms that are the most robustly indicative of resistance emergence and tractable to clinical monitoring (WP3). Against this baseline of new understanding, and with the guidance of a scientific advisory board (SAB), we will pursue regimen modifications, including novel combination therapies, that most effectively mitigate resistance emergence.