Introduction
(Article introduction authored by ICU Editorial Team)
Invasive candidiasis poses a growing global health threat, with rising incidence and high mortality rates despite limited treatment options. Antifungal resistance is rapidly spreading, particularly among multidrug-resistant species. Antifungal stewardship and infection control are crucial, but the role of antifungal monotherapy in driving resistance warrants examination.
Combination therapy shows promise in preventing resistance emergence, improving drug penetration, expediting fungal clearance, and reducing toxicity. Laboratory evidence suggests synergistic activity against Candida spp, including the multidrug-resistant Candida auris. Clinical trials are needed to validate these combinations with resistance endpoints.
Candida bloodstream infections affect around 750,000 individuals annually, with mortality rates ranging from 10-47%. Limited treatment options exist, with rising resistance against available drugs. New agents are forthcoming, but environmental use and single-agent clinical use risk hastening resistance. Innovations in pharmaceutical approaches are crucial to preserve the effectiveness of current and future antifungals.
The scope of the problem – Antifungal-Resistant Candida spp
The widespread use of antifungals has led to a global epidemiological shift towards Candida spp. with reduced susceptibility to azoles, resulting in rising secondary resistance and the emergence of multi-drug resistant strains like C. auris and C. glabrata (Nakaseomyces glabrata). Non-albicans species, including C. krusei and C. glabrata, are becoming more prevalent globally and now account for over half of invasive cases in SENTRY surveillance.
Azole-resistant C. parapsilosis has become a global threat, with increasing fluconazole resistance observed globally. C. auris is highly concerning due to its widespread azole resistance and emerging resistance to other antifungal classes.
Echinocandin resistance remains rare but is increasing, posing a threat to the final useful drug class. Outbreaks of C. auris continue globally, with it becoming a dominant pathogen in some regions. With azole resistance rising, there’s a growing reliance on echinocandins, which is jeopardizing their effectiveness as well.
The Role of Antifungal Monotherapy
Prior antifungal exposure increases the risk of azole and echinocandin resistance in Candida bloodstream infections. Monotherapy, commonly used for treatment and prophylaxis, promotes resistance selection and stress adaptation, leading to treatment failure. Resistance emergence during antifungal exposure has been observed, such as echinocandin resistance associated with FKS hotspot mutations in C. auris infections.
Heteroresistance, where a resistant subpopulation grows despite drug exposure, and antifungal tolerance, where susceptible cells persist at high drug concentrations, are also concerning adaptive mechanisms.
These phenomena highlight the importance of judicious antifungal use and the potential benefits of combination therapy to combat resistance.
The role of combination antifungal therapy
While stringent antifungal stewardship and infection, prevention and control measures are key, combination antifungal regimens have potential to prevent resistance whilst optimising the treatment of invasive candidiasis.
Combinationantifungals may enhance fungal clearance, potentially allow lower doses with reduced toxicity risk, optimise antifungal penetration to sanctuary sites whereCandida persist, and mitigate the evolution of resistance and stress responses observed during antifungal monotherapy.
Although theoretically lower doses could be used, risk of cumulative toxicity, and increased cost of drug combinations must be weighed against potential benefit.
Current research
Most research has focused on the nature of interactions of drug combinations against Candida using in vitro or animal experiments, with very limited study of resistance mitigation.
Antifungal interactions vary between synergy, indifference and antagonism depending on the combination, concentration species/ isolate (C albicans predominant) and model used. Findings are not always consistent across in vitro-in vivo studies : the single randomised trial of fluconazole+/-AmB reported improved mycological clearance and higher success rates with combination, despite in vitro and murine studies frequently reporting antagonism.
Flucytosine (5-fc) combination therapy
Flucytosine (5-FC) shows promise for combination therapy in invasive candidiasis, with in vitro studies demonstrating synergy, including against C. auris. Animal studies also support its efficacy in combination with AmB, showing improved survival. Flucytosine has good oral bioavailability and penetration into infected tissues, making it a valuable option.
While clinical data is limited, guidelines recommend flucytosine combination therapy for complicated candidiasis. However, caution is advised due to emerging resistance, especially in multidrug-resistant C. auris cases where flucytosine may be the only effective drug.
Early combination therapy may help mitigate resistance evolution, as seen in cryptococcal meningitis. Comprehensive evaluation of drug combinations is crucial for guiding future management guidelines.
Novel antifungal agents There are promising new antifungal drugs in the pipeline for candidiasis including fosmanogepix, ibrexafungerp, and the long-acting echinocandin, rezafungin28.
The concern, as new agents reach clinical use, is that exposure to similar molecules both in the environment, and as monotherapy in patients, will see similar resistance emerge, limiting future utility.
Our In vitro study revealed manogepix (active compound of fosmanogepix) to be the most synergistic of four agents tested in combination with anidulafungin against 15 C. auris isolates (clades I and III)24. Future drug development research must investigate combinations to optimise and future-proof novel agents.
Future research
Although evidence that particular drug combinations can enhance Candida clearance is mounting, very little is known regarding impact on antifungal resistance. Future research will be enhanced by collaborations to survey and study antifungal resistance, collate diverse isolate banks and build clinical networks. In vitro studies, must investigate whether exposure to two drugs can suppress resistance.
Conclusion
Invasive candidiasis is a rising global health threat. Emergence and spread of resistant Candida spp demands an urgent and innovative response. Combination treatment mustbe explored for combating on-treatment resistance evolution whilst enhancing efficacy.
Pre-clinical studies have identified promising combinations. It is now time to take these approaches to the bedside to evaluate whether combination treatment can improve clinical and resistance outcomes for patients, particularly in settings harboring a high burden of antifungal resistance.
Source: R M Wake, P E Allebone-Salt, L L H John, B A Caswall, N P Govender, R Ben-Ami, L W Murray, C Logan, T S Harrison, T A Bicanic, Optimising the Treatment of Invasive Candidiasis – A Case for Combination Therapy, Open Forum Infectious Diseases, 2024;, ofae072, https://doi.org/10.1093/ofid/ofae072