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

• Published in: PLoS neglected tropical diseases Vol. 14; no. 3; p. e0008137
• Main Authors: Naicker, Serisha D, Mpembe, Ruth S, Maphanga, Tsidiso G, Zulu, Thokozile G, Desanto, Daniel, Wadula, Jeannette, Mvelase, Nomonde, Maluleka, Caroline, Reddy, Kessendri, Dawood, Halima, Maloba, Motlatji, Govender, Nelesh P
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.03.2020; Public Library of Science (PLoS)
• Subjects: Adult; Amphotericin B; Antifungal agents; Antifungal Agents - pharmacology; Antimicrobial agents; Biology and Life Sciences; Breakpoints; Cryptococcosis; Cryptococcosis - microbiology; Cryptococcus neoformans; Cryptococcus neoformans - drug effects; Cryptococcus neoformans - isolation & purification; Disease; Drug resistance; Drug Resistance, Fungal; Drug therapy; Female; Fluconazole; Fluconazole - pharmacology; Fungal infections; Fungi; Fungicides; Health sciences; Health services; Hospitals; Humans; Infections; Inoculation; Itraconazole; Laboratories; Male; Medicine and Health Sciences; Meningitis; Methods; Microbial drug resistance; Microbial Sensitivity Tests; Minimum inhibitory concentration; Pathology; Patient outcomes; Pesticides; Physical Sciences; Population studies; Posaconazole; Prospective Studies; South Africa; Statistics; Surveillance; Tropical diseases; Voriconazole; South Africa
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0008137

Fluconazole is used in combination with amphotericin B for induction treatment of cryptococcal meningitis and as monotherapy for consolidation and maintenance treatment. More than 90% of isolates from first episodes of cryptococcal disease had a fluconazole minimum inhibitory concentration (MIC) ≤4 μg/ml in a Gauteng population-based surveillance study of Cryptococcus neoformans in 2007-2008. We assessed whether fluconazole resistance had emerged in clinical cryptococcal isolates over a decade. We prospectively collected C. neoformans isolates from 1 January through 31 March 2017 from persons with a first episode of culture-confirmed cryptococcal disease at 37 South African hospitals. Isolates were phenotypically confirmed to C. neoformans species-complex level. We determined fluconazole MICs (range: 0.125 μg/ml to 64 μg/ml) of 229 C. neoformans isolates using custom-made broth microdilution panels prepared, inoculated and read according to Clinical and Laboratory Standards Institute M27-A3 and M60 recommendations. These MIC values were compared to MICs of 249 isolates from earlier surveillance (2007-2008). Clinical data were collected from patients during both surveillance periods. There were more males (61% vs 39%) and more participants on combination induction antifungal treatment (92% vs 32%) in 2017 compared to 2007-2008. The fluconazole MIC50, MIC90 and geometric mean MIC was 4 μg/ml, 8 μg/ml and 4.11 μg/ml in 2017 (n = 229) compared to 1 μg/ml, 2 μg/ml and 2.08 μg/ml in 2007-2008 (n = 249) respectively. Voriconazole, itraconazole and posaconazole Etests were performed on 16 of 229 (7%) C. neoformans isolates with a fluconazole MIC value of ≥16 μg/ml; only one had MIC values of >32 μg/ml for these three antifungal agents. Fluconazole MIC50 and MIC90 values were two-fold higher in 2017 compared to 2007-2008. Although there are no breakpoints, higher fluconazole doses may be required to maintain efficacy of standard treatment regimens for cryptococcal meningitis.