Increased antifungal drug resistance in clinical isolates of Cryptococcus neoformans in Uganda

Kyle D. Smith, Beatrice Achan, Kathy Huppler Hullsiek, Tami R. McDonald, Laura H. Okagaki, Ali A. Alhadab, Andrew Akampurira, Joshua R. Rhein, David B. Meya, David R. Boulware, Kirsten Nielsen, Abdu Musubire, Henry W. Nabeta, Darlisha A. Williams, Bozena Morawski, Melissa A. Rolfes, Jane Francis Ndyetukira, Cynthia Ahimbisibwe, Florence Kugonza, Alisat SadiqJonathan Dyal, Julie M. Neborak, Alexa M. King, Nathan Yueh, Sruti S. Velamakanni, Alice Namudde, Tadeo Kiiza Kandole, Julian Kaboggoza, Eva Laker, Tony Luggya, Liliane Tugume, Mahsa Abassi, Kate Birkenkamp, Elissa K. Butler, A. Wendy Fujita, Ryan Halupnick, Anna K. Strain, Priya Vedula, Radha Rajasingham, Andrew Kambugu, Paul R. Bohjanen, on behalf of the ASTRO-CM/COAT Team

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84 Scopus citations

Abstract

Cryptococcal antigen screening is recommended among people living with AIDS when entering HIV care with a CD4 count of <100 cells/μl, and preemptive fluconazole monotherapy treatment is recommended for those with subclinical cryptococcal antigenemia. Yet, knowledge is limited of current antimicrobial resistance in Africa. We examined antifungal drug susceptibility in 198 clinical isolates collected from Kampala, Uganda, between 2010 and 2014 using the CLSI broth microdilution assay. In comparison with two previous studies from 1998 to 1999 that reported an MIC50 of 4 μg/ml and an MIC90 of 8 μg/ml prior to widespread human fluconazole and agricultural azole fungicide usage, we report an upward shift in the fluconazole MIC50 to 8 μg/ml and an MIC90 value of 32 μg/ml, with 31% of isolates with a fluconazole MIC of ≥16 μg/ml. We observed an amphotericin B MIC50 of 0.5 μg/ml and an MIC90 of 1 μg/ml, of which 99.5% of isolates (197 of 198 isolates) were still susceptible. No correlation between MIC and clinical outcome was observed in the context of amphotericin B and fluconazole combination induction therapy. We also analyzed Cryptococcus susceptibility to sertraline, with an MIC50 of 4 μg/ml, suggesting that sertraline is a promising oral, low-cost, available, novel medication and a possible alternative to fluconazole. Although the CLSI broth microdilution assay is ideal to standardize results, limit human bias, and increase assay capacity, such assays are often inaccessible in low-income countries. Thus, we also developed and validated an assay that could easily be implemented in a resource-limited setting, with similar susceptibility results (P=0.52).

Original languageEnglish (US)
Pages (from-to)7197-7204
Number of pages8
JournalAntimicrobial agents and chemotherapy
Volume59
Issue number12
DOIs
StatePublished - Dec 1 2015

Bibliographical note

Funding Information:
We thank Henry Kajumbula for leadership of the Makerere University Microbiology Department. Additionally, we thank Benjamin Lueck and Joshua Kerkaert for their help with MIC assays. This work was supported by NIH grants U01AI089244, R01NS086312, T32AI055433, R24TW008886, and R25TW009345 and by Grand Challenges Canada grant S40296. ASTRO-CM and COAT team members are the following: Abdu Musubire, Henry W. Nabeta, Darlisha A. Williams, Bozena Morawski, Melissa A. Rolfes, Jane Francis Ndyetukira, Cynthia Ahimbisibwe, Florence Kugonza, Alisat Sadiq, Jonathan Dyal, Julie M. Neborak, Alexa M. King, Nathan Yueh, Sruti S. Velamakanni, Alice Namudde, Tadeo Kiiza Kandole, Julian Kaboggoza, Eva Laker, Tony Luggya, Liliane Tugume, Mahsa Abassi, Kate Birkenkamp, Elissa K. Butler, A. Wendy Fujita, Ryan Halupnick, Anna K. Strain, Priya Vedula, Radha Rajasingham, Andrew Kambugu, and Paul R. Bohjanen.

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