Observational studyThe Journal of clinical investigation2019
Dynamic ploidy changes drive fluconazole resistance in human cryptococcal meningitis.
Observational study in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 116 papers, 2 of them syntheses that pooled it.
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Who cites it
116 citing papers in PubMed, 2 syntheses or guidelines pooled it, 163 citations in OpenAlex.
- Geographical distribution of the Cryptococcus gattii species complex: a systematic review.The Lancet. Microbe · 2024Pooled it
- Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM.The Lancet. Infectious diseases · 2024Guideline
- Adjunctive sertraline for asymptomatic cryptococcal antigenemia: A randomized clinical trial.Medical mycology · 2020Trial
- FKS1/2-variant independent mechanisms underlying the emergence of resistance in echinocandin-refractory Candida auris infections.Nature communications · 2026Article
- A multiplex droplet digital PCR assay for chromosome copy-number determination in Candida albicans.G3 (Bethesda, Md.) · 2026Article
- Beyond antifungal susceptibility: molecular mechanisms, detection, and clinical implications of fungal heteroresistance.Molecular biology reports · 2026Review
- Structural genome variation drives adaptation of the xylose-fermenting yeast Scheffersomyces stipitis to lignocellulosic hydrolysates.Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology · 2026Article
- Dynamics associated with the efflux pumps in biofilms and persister cells ofMicrobiology spectrum · 2026Article
- Variable ectopic heterochromatin islands provide an alternative route to antifungal heteroresistance inbioRxiv : the preprint server for biology · 2026Article
- Primary Cryptococcal Cellulitis With High Antigenemia in an Immunocompromised Host: A Case Report and Laboratory Investigation of the CausativeOpen forum infectious diseases · 2026Article
- Antifungal-induced DNA dynamics and chitin remodelling across Cryptococcus spp. and the novel broad-spectrum anti-cryptococcal candidate CPTH2.Scientific reports · 2026Article
- Instability and Subpopulation Dynamics of Azole Trailing Phenotypes in Clinical Candida tropicalis Isolates.Mycopathologia · 2026Article
- Profound cell wall remodeling inMicrobiology spectrum · 2026Article
- Review
- Article
- Heterochromatin epimutations impose mitochondrial dysfunction to confer antifungal resistance.The EMBO journal · 2026Article
- Advances in cryptococcal infections-associated immunopathology and potential therapeutic strategies.Frontiers in pharmacology · 2026Review
- Riboflavin inhibits growth and reduces virulence ofVirulence · 2025Article
- Pathogenicity and virulence of Cryptococcus neoformans from an environmental perspective.Virulence · 2025Review
- Effectiveness of voriconazole therapy for pulmonary cryptococcosis in fluconazole treatment failure: a multicenter real-world study.BMC infectious diseases · 2025Article
56 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
14 authors at 8 institutions in 5 countries.
Funding
Abstract
backgroundCryptococcal meningitis (CM) causes an estimated 180,000 deaths annually, predominantly in sub-Saharan Africa, where most patients receive fluconazole (FLC) monotherapy. While relapse after FLC monotherapy with resistant strains is frequently observed, the mechanisms and impact of emergence of FLC resistance in human CM are poorly understood. Heteroresistance (HetR) - a resistant subpopulation within a susceptible strain - is a recently described phenomenon in Cryptococcus neoformans (Cn) and Cryptococcus gattii (Cg), the significance of which has not previously been studied in humans.
methodsA cohort of 20 patients with HIV-associated CM in Tanzania was prospectively observed during therapy with either FLC monotherapy or in combination with flucytosine (5FC). Total and resistant subpopulations of Cryptococcus spp. were quantified directly from patient cerebrospinal fluid (CSF). Stored isolates underwent whole genome sequencing and phenotypic characterization.
resultsHeteroresistance was detectable in Cryptococcus spp. in the CSF of all patients at baseline (i.e., prior to initiation of therapy). During FLC monotherapy, the proportion of resistant colonies in the CSF increased during the first 2 weeks of treatment. In contrast, no resistant subpopulation was detectable in CSF by day 14 in those receiving a combination of FLC and 5FC. Genomic analysis revealed high rates of aneuploidy in heteroresistant colonies as well as in relapse isolates, with chromosome 1 (Chr1) disomy predominating. This is apparently due to the presence on Chr1 of ERG11, which is the FLC drug target, and AFR1, which encodes a drug efflux pump. In vitro efflux levels positively correlated with the level of heteroresistance.
conclusionOur findings demonstrate for what we believe is the first time the presence and emergence of aneuploidy-driven FLC heteroresistance in human CM, association of efflux levels with heteroresistance, and the successful suppression of heteroresistance with 5FC/FLC combination therapy.
fundingThis work was supported by the Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377/Z/11/Z and the Daniel Turnberg Travel Fellowship.
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