Worldwide emergence of fluconazole-resistant Candida parapsilosis: current framework and future research roadmap

Abstract

Candida parapsilosis is one of the most commen causes of life-threatening candidaemia, particularly in premature neonates, individuals with cancer of the haematopoietic system, and recipients of organ transplants. Historically, drug-susceptible strains have been linked to clonal outbreaks. However, worldwide studies started since 2018 have reported severe outbreaks among adults caused by fluconazole-resistant strains. Outbreaks caused by fluconazole-resistant strains are associated with high mortality rates and can persist despite strict infection control strategies. The emergence of resistance threatens the efficacy of azoles, which is the most widely used class of antifungals and the only available oral treatment option for candidaemia. The fact that most patients infected with fluconazole-resistant strains are azole-naive underscores the high potential adaptability of fluconazole-resistant strains to diverse hosts, environmental niches, and reservoirs. Another concern is the multidrug-resistant and echinocandin-tolerant C parapsilosis isolates, which emerged in 2020. Raising awareness, establishing effective clinical interventions, and understanding the biology and pathogenesis of fluconazole-resistant C parapsilosis are urgently needed to improve treatment strategies and outcomes.

Figure 1:. Burden and epidemiology of C parapsilosis worldwide.

(A) The worldwide epidemiology of C parapsilosis. (B) The burden of fluconazole resistant isolates. More details available in the appendix (pp 13–43). (C) Countries reporting C parapsilosis bloodstream isolates with fluconazole resistance more than 10% sharply increased during the COVID-19 pandemic, including some outbreaks with clonal dissemination of resistant isolates (appendix pp 39–43).

Figure 2:. Mechanisms of azole and echinocandin resistance in C parapsilosis

(A) Drug target modulation through acquisition of amino acid substitutions in ERG11—a key enzyme involved in the ergosterol biosynthetic pathway—as well as overexpression of ERG11 and efflux pumps are the main mechanisms underpinning azole resistance in Candida species. ERG11 amino acid substitutions, such as Y132F and K143R, are the most prevalent cause of fluconazole resistance in C parapsilosis. (B) Echinocandin-resistant C parapsilosis isolates mostly harbour mutations in short stretches of the catalytic subunit of the β-glucan synthase, known as hot-spots of FKS1. !=presence of a mutation in the catalytic subunit.

Figure 3:. Heteroresistant C parapsilosis isolates are a small subpopulation that tolerate high concentrations of echinocandins.

Echinocandin heteroresistance is a novel concept describing a phenotypically resistant subpopulation that could actively proliferate at a high concentration of a drug and potentially lead to prophylaxis inefficacy. During echinocandin treatment, the susceptible, clonal kins perished, whereas the phenotypically resistant cells survived, replicated, translocated to deeper tissues, and caused systemic infection. The overgrowth of the fungus in the colonisation sites in tandem with virulence and host-related attributes might result in translocation into deeper tissues and result in the failure of antifungal prophylaxis (adapted from references 27 and 38). CFU=colony forming unit.