Abstract

Background

The EnACT trial was a phase 2 randomized clinical trial conducted in Uganda, which evaluated a novel orally delivered lipid nanocrystal (LNC) amphotericin B in combination with flucytosine for the treatment of cryptococcal meningitis. When flucytosine (5FC) is used as monotherapy in cryptococcosis, 5FC can induce resistant Cryptococcus mutants. Oral amphotericin B uses a novel drug delivery mechanism, and we assessed whether resistance to 5FC develops during oral LNC–amphotericin B therapy.

Methods

We enrolled Ugandans with HIV diagnosed with cryptococcal meningitis and who were randomized to receive 5FC and either standard intravenous (IV) amphotericin B or oral LNC–amphotericin B. We used broth microdilution to measure the minimum inhibitory concentration (MIC) of the first and last cryptococcal isolates in each participant. Breakpoints are inferred from 5FC in Candida albicans. We measured cerebral spinal fluid (CSF) 5FC concentrations by liquid chromatography and tandem mass spectrometry.

Results

Cryptococcus 5FC MIC50 was 4 µg/mL, and MIC90 was 8 µg/mL. After 2 weeks of therapy, there was no evidence of 5FC resistance developing, defined as a >4-fold change in susceptibility in any Cryptococcus isolate tested. The median CSF 5FC concentration to MIC ratio (interquartile range) was 3.0 (1.7–5.5) µg/mL. There was no association between 5FC/MIC ratio and early fungicidal activity of the quantitative rate of CSF yeast clearance (R2 = 0.004; P = .63).

Conclusions

There is no evidence of baseline resistance to 5FC or incident resistance during combination therapy with oral or IV amphotericin B in Uganda. Oral amphotericin B can safely be used in combination with 5FC.

Details

Title
5-Flucytosine Longitudinal Antifungal Susceptibility Testing of Cryptococcus neoformans: A Substudy of the EnACT Trial Testing Oral Amphotericin
Author
McHale, Thomas C 1   VIAFID ORCID Logo  ; Akampurira, Andrew 2 ; Gerlach, Elliot S 3 ; Mucunguzi, Atukunda 2 ; Nicol, Melanie R 4   VIAFID ORCID Logo  ; Williams, Darlisha A 1 ; Nielsen, Kirsten 3 ; Bicanic, Tihana 5   VIAFID ORCID Logo  ; Fieberg, Ann 6 ; Dai, Biyue 6 ; Meya, David B 1   VIAFID ORCID Logo  ; Boulware, David R 1 ; Enock Kagimu; Musubire, Abdu K; Tugume, Lillian; Ssebambulidde, Kenneth; Kasibante, John; Nsangi, Laura; Mugabi, Timothy; Gakuru, Jane; Kimuda, Sarah; Kasozi, Derrick; Namombwe, Suzan; Turyasingura, Isaac; Rutakingirwa, Morris K; Mpoza, Edward; Enos Kigozi; Muzoora, Conrad; Ellis, Jayne; Skipper, Caleb P; Hullsiek, Kathy H; Abassi, Mahsa; Asmus Tukundane; Ndyetukira, Jane F; Ahimbisibwe, Cynthia; Sadiq, Alisat; Kugonza, Florence; Nabbale, Shifa; Kiiza, Tadeo; Namudde, Alice; Luggya, Tony; Kwizera, Richard; Okiror, Michael; Babirye, Dora; Nanteza, Catherine; Mulwana, Susan; Muyise, Rhona; Kisembo, John; Luswata, Andrew; Namujju, Carol; Laker, Eva; Stewart Walukaga; Liu, Minda; Engen, Nicole; Wele, Abduljewad; Rwomushana, Irene; Kabahubya, Mable; Ssemusu, Michael; Mwesigye, James; Rukundo, Joan; Jjunju, Samuel

1  Department of Medicine, University of Minnesota , Minneapolis, Minnesota , USA 
2  Infectious Diseases Institute, Makerere University , Kampala , Uganda 
3  Department of Microbiology & Immunology, University of Minnesota , Minneapolis, Minnesota , USA 
4  Department of Experimental and Clinical Pharmacology, University of Minnesota , Minneapolis, Minnesota , USA 
5  Institute of Infection and Immunity, St Georges, University of London , London , UK 
6  Division of Biostatistics, School of Public Health, University of Minnesota , Minneapolis, Minnesota , USA 
Publication year
2023
Publication date
Dec 2023
Publisher
Oxford University Press
e-ISSN
23288957
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1093/ofid/ofad596
ProQuest document ID
3170919098
Copyright
© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.