Decreasing fluconazole susceptibility of clinical South African Cryptococcus neoformans isolates over a decade

摘要

Cryptococcus neoformans, a pathogenic fungal species-complex with an environmental niche, is the most common cause of meningitis among HIV-seropositive adults in sub-Saharan Africa. Fluconazole is recommended in combination with amphotericin B for induction treatment of cryptococcal meningitis and as monotherapy for consolidation and maintenance treatment. Fluconazole is also commonly prescribed to HIV-seropositive individuals for other indications; fluconazole exposure may result in secondary resistance if patients have concurrent active cryptococcal disease. Azole fungicides used in agriculture may potentially drive primary cryptococcal resistance when the fungus is exposed to these fungicides in the environment. We aimed to determine fluconazole MICs in 2017 and compare these values to those obtained in a 2007 2008 South African survey to assess whether fluconazole resistance had emerged in C. neoformans over a decade. We found that the proportion of isolates with an MIC of 16 ug/ml increased from 0% in 2007 2008 to 7% in 2017. MIC50 and MIC90 values were also two-fold higher in 2017 compared to 2007 2008. These study findings provided evidence for higher fluconazole dose recommendations (in combination with amphotericin B for the induction phase and as monotherapy for consolidation and maintenance phases) in the 2019 Southern African guideline for HIV-associated cryptococcosis.