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Cited by 22Fungal Infections and StudiesAntifungal resistance and susceptibilityFungal Plant Pathogen Control

Investigation of fluconazole heteroresistance in clinical and environmental isolates of Cryptococcus neoformans complex and Cryptococcus gattii complex in the state of Amazonas, Brazil

Moreira, Izabela de Mesquita Bárcia, Cortez, Ana Cláudia Alves, de Souza, Érica Simplício, Pinheiro, Silviane Bezerra, de Souza Oliveira, Juliana Gomes, Sadahiro, Aya, Cruz, Katia Santana, Matsuura, Ani Beatriz Jackisch +3 more·2022·Medical Mycology
DOI 10.1093/mmy/myac005
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Abstract

Heteroresistance, defined as the occurrence of apparently homogeneous subpopulations of microbial cells showing different levels of antimicrobial susceptibility is a problem that has been associated with therapeutical failure in cryptococcosis. The purpose of the study was an investigation on the level of heteroresistance to fluconazole (LHF) as observed in clinical and environmental C. neoformans/C. gattii complex species isolates from Amazonas State (AM), Brazil. A total of 45 isolates and 9 type strains were analyzed. The assessments comprised testing for minimal inhibitory concentrations (MICs), for LHFs, for the strains’ capacity of adaptation to high fluconazole (FLC) concentrations above the LHF, and for the stability of the heteroresistance phenomenon. The mean MICs for clinical isolates of C. gattii (6.4 µg/ml) were higher than those observed for environmental C. gattii strains (1.7 µg/ml) and clinical (3.7 µg/ml) as well as environmental (1.5 µg/ml) C. neoformans isolates. The phenomenon of heteroresistance to FLC was recorded for all isolates. On average, the LHF (8–256 µg/ml) of the isolates was 16 times higher than the FLC MICs (0.5–16 µg/ml) and a proportion of 85% isolates showed LHFs ≥ 16 µg/ml, 40% even ≥ 32 µg/ml. According to the adaptation assay, a considerable number of isolates (58%) showed the capacity of adaptation to MICs even higher than the initially recorded LHF. After the adaptation experiment, the adaptative-LHF values (8–512 µg/ml) were about 60 times higher than the original MIC values. After nine subsequent passages in drug-free broth, the isolates had their adaptative-LHF reduced. However, the LHF did not revert to the initially measured level. Our findings challenge the clinical interpretation of the antifungal MIC testing and motivate future studies correlating the levels of heteroresistance and parameters like LHF and adaptative-LHF with cryptococcosis-associated morbidity and mortality. Lay summary: Cryptococcosis affects many people and is caused by fungi of the Cryptococcus neoformans/Cryptococcus gattii complexes. These agents appear to become more resistant to antifungals when exposed to increasing concentrations of antifungals due to a phenomenon called heteroresistance.

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Crossref · 10.1093/mmy/myac005

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  • Increased emergence of heteroresistance in clinical versus environmental isolates supports the induction effect of antifungal exposure.

    “Several studies have confirmed the increased emergence of heteroresistance in clinical, compared with environmental, isolates, supporting the induction effect of antifungal exposure [101,158].”

    From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [158]

  • Several studies have confirmed increased emergence of heteroresistance in clinical compared with environmental isolates.

    “Several studies have confirmed the increased emergence of heteroresistance in clinical, compared with environmental, isolates, supporting the induction effect of antifungal exposure [101,158].”

    From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [158]

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Authors
Moreira, I. D. M. B., Cortez, A. C. A., de Souza, É. S., Pinheiro, S. B., de Souza Oliveira, J. G., Sadahiro, A., Cruz, K. S., Matsuura, A. B. J., Melhem, M. D. S. C., Frickmann, H., & de Souza, J. V. B.
Affiliations
  • Universidade Federal do Amazonas (BR)
  • Instituto Nacional de Pesquisas da Amazônia (BR)
  • Superior School of Technology, Amazon State University- UEA, 69050-020, Manaus, Brazil
  • Collection of Microorganisms of Medical Interest, Coordination of Society, Environment and Health, National Institute for Amazonian Research- INPA, 69060-001, Manaus, Brazil
  • Laboratory of Mycology, Tropical Medicine Foundation Dr. Heitor Vieira Dourado- FMT- HVD, 69040-000, Manaus, Brazil
  • Fiocruz Amazônia (BR)
  • Universidade Federal de Mato Grosso do Sul (BR)
  • Bundeswehrkrankenhaus (DE)
  • Laboratory of Mycology, Coordination of Society, Environment and Health, National Institute for Amazonian Research-INPA, 69060-001, Manaus, Brazil
ORCID
Venue
Medical Mycology
Publisher
Oxford University Press (OUP)
Published
2022-01-27
Volume
60
Issue
3
ISSN
  • 0268-1218 (ISSN-L)
  • 1369-3786
  • 1460-2709
DOI
10.1093/mmy/myac005
OpenAlex
W4206998595
Cited by
22
References
29
Citations by year
2026: 2 · 2025: 8 · 2024: 6 · 2023: 4 · 2022: 2
FWCI
3.61
Type
journal article
Language
en
Open access
closed
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Medical Mycology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Fundação de Amparo à Pesquisa do Estado do Amazonas (001/2017)
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
Topics
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
Keywords
cryptococcosis, antifungal susceptibility, minimum inhibitory concentration, clinical isolates, environmental isolates, Amazonas, type strain
MeSH terms
Animals, Antifungal Agents, Brazil, Cryptococcosis, Cryptococcus neoformans, Microbial Sensitivity Tests, Fluconazole, Drug Resistance, Fungal, Cryptococcus gattii

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