Heteroresistance of Cryptococcus gattii to Fluconazole
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We analyzed 71 clinical and environmental Cryptococcus gattii strains that had been isolated before or after the advent of azole antifungals to determine their level of heteroresistance to fluconazole (LHF). All strains of C. gattii manifested heteroresistance, with LHFs that ranged between 4 μg/ml and 32 μg/ml. A considerably higher proportion of the C. gattii strains (86%) than Cryptococcus neoformans strains (46%) exhibited LHFs that were ≥16 μg/ml. No significant correlation was observed between the molecular type or serotypes of strains and their respective LHF. The strains which expressed a higher LHF were also more resistant to xenobiotics than the strains with a low LHF, and the level of resistance to xenobiotics was significantly higher than that reported for C. neoformans . The heteroresistant subpopulation, whose level of drug resistance had been raised in a stepwise manner to 64 μg/ml, reverted to the original LHF upon daily transfers in drug-free medium. Importantly, the strains with high LHFs were significantly more virulent than those with low LHFs. Since all the clinical isolates that had not been exposed to azole drugs as well as the environmental strains manifested heteroresistance to fluconazole, heteroresistance of C. gattii to azoles is an intrinsic mechanism as in C. neoformans and is associated with the strain's virulence.
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Antifungal heteroresistance refers to the coexistence of a small population of resistant cells, usually much less than 1%, and a large population of susceptible fungal cells.
“Antifungal heteroresistance refers to the coexistence of a small population of resistant cells (usually <<1%) and a large population of susceptible fungal cells (Fig 1).”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [26]
The paper describes fluconazole heteroresistance as a minor resistant subpopulation emerging within a susceptible colony. It does not establish that the resistant population is usually much less than 1%; Table 2 reports resistant-subpopulation percentages both below and above 1% at the tested fluconazole concentrations. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAntifungal heteroresistance was first found in C. neoformans and Cryptococcus gattii and is considered an intrinsic property of these species, associated with disomic chromosomes.
“Antifungal heteroresistance was first been found in C. neoformans and Cryptococcus gattii, and was considered as an intrinsic property of these species, associating with disomic chromosomes [24–27].”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [26]
The Introduction describes an earlier report of fluconazole heteroresistance in C. neoformans, and the Results and Discussion describe it as innate in both C. neoformans and C. gattii. The Discussion reports an association between chromosomal gain and azole resistance in C. neoformans, but does not establish disomic chromosomes as the mechanism of heteroresistance in both species; it says that mechanism remains to be elucidated. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredC. gattii shows a higher level of heteroresistance to fluconazole than C. neoformans.
“A comparative study showed that C. gattii showed a higher level of heteroresistance to fluconazole than C. neoformans [159].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [159]
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References 38 · Cited by 103
Research works printed but not linked: 5
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- Authors
- Varma, A., & Kwon-Chung, K. J.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Kwon-Chung, K. J.
- ORCID
- Kwon-Chung, K. J.
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2010-06
- Volume
- 54
- Issue
- 6
- Pages
- 2303-2311
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC2876399
- OpenAlex
- W2084612493
- Cited by
- 103
- References
- 38
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 3 · 2023: 6 · 2022: 6 · 2021: 4 · 2020: 3 · 2019: 2 · 2018: 6 · 2017: 9 · 2016: 9 · 2015: 4 · 2014: 6 · 2013: 8 · 2012: 13
- FWCI
- 8.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pfizer
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases
- 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
- Cryptococcus gattii, fluconazole, heteroresistance, azole resistance, intrinsic drug resistance, xenobiotic resistance, virulence, Cryptococcus neoformans, molecular typing, serotypes, clinical and environmental isolates
- MeSH terms
- Animals, Antifungal Agents, Cryptococcosis, Cryptococcus neoformans, Environmental Microbiology, Female, Humans, Mice, Inbred BALB C, Microbial Sensitivity Tests, Serotyping, Species Specificity, Virulence, Fluconazole, Drug Resistance, Fungal, Mice, Cryptococcus gattii
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