Systemic Antifolate Chemotherapy Does Not Select for Fluconazole-Resistant Candida: A Multicenter Clinical Study

Area of Science:

• Medical Mycology
• Antifungal Resistance
• Cancer Therapeutics

Background:

• Previous in vitro studies show folic acid antagonists like methotrexate can induce multidrug resistance in Candida species to azole antifungals.
• Antineoplastic antifolates, such as methotrexate and pemetrexed, are used in cancer therapy.
• The clinical significance of in vitro observed antifungal resistance in vivo remains unclear.

Purpose of the Study:

• To investigate if systemic antifolate therapy (methotrexate or pemetrexed) is a risk factor for fluconazole-resistant yeast colonization or infection.
• To evaluate the in vivo impact of antifolate treatment on the development of azole resistance in endogenous yeasts.

Main Methods:

• A case-control study involving 44 cancer patients receiving high-dose antifolate therapy and 48 controls not exposed to antifolates.
• Collection of oral swabs and clinical data from all participants.
• Isolation, identification, and fluconazole susceptibility testing of 109 fungal strains from 13 species.

Main Results:

• Fluconazole-resistant yeast isolates were found in 9.1% of antifolate-treated patients and 6.3% of control patients.
• No statistically significant difference in the prevalence of fluconazole-resistant yeasts between the two groups.
• The study identified 13 different fungal species across all isolates.

Conclusions:

• Systemic antineoplastic antifolate therapy does not appear to induce azole resistance in endogenous yeast species in vivo.
• The in vitro phenomenon of antifolate-induced azole cross-resistance does not translate to a clinically significant increased risk of fluconazole-resistant yeast infections in cancer patients.