The DOI matches its Crossref record; 36 of the 36 references it cites were found in a registry or an index.
Heteroresistance to Fluconazole and Voriconazole in Cryptococcus neoformans
Open accessAbstract
Cryptococcus neoformans isolates that exhibited unusual patterns of resistance to fluconazole and voriconazole were isolated from seven isolates from two different geographical regions: one isolate from an Israeli non-AIDS patient and six serial isolates from an Italian AIDS patient who had suffered six recurrent episodes of cryptococcal meningitis. Each isolate produced cultures with heterogeneous compositions in which most of the cells were susceptible, but cells highly resistant to fluconazole (MICs, ≥64 μg/ml) were recovered at a variable frequency (7 × 10 −3 to 4.6 × 10 −2 ). Evidence showed that this type of resistance is innate and is unrelated to drug exposure since the Israeli patient had never been treated with azoles or any other antimycotic agents. Analysis of clonal subpopulations of these two strains showed that they exhibited heterogeneous patterns of resistance. The number of subpopulations which grew on fluconazole or voriconazole agar declined progressively with increasing azole concentration without a sharp cutoff point. For the Italian serial isolates, the number of clonal populations resistant to fluconazole (64 μg/ml) and voriconazole (1 μg/ml) increased steadily, yielding the highest number for the isolate from the last episode. Attempts to purify a sensitive subpopulation failed, but clones highly resistant to fluconazole (100 μg/ml) and moderately resistant to voriconazole (1 μg/ml) always produced a homogeneous population of resistant cells. Upon maintenance on drug-free medium, however, the majority of the homogeneously resistant cells of these subclones lost their resistance and returned to the stable initial heteroresistant phenotype. The pattern of heteroresistance was not affected by the pH or osmolarity of the medium but was influenced by temperature. The resistance appeared to be suppressed at 35°C and was completely abolished at 40°C. Although heterogeneity in azole resistance among subpopulations of single isolates has been reported for Candida species, the transient changes in expression of resistance under different growth conditions reported here have not been observed in fungal pathogens.
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“This phenomenon was first described in 1999, when researchers observed that a subset of Cryptococcus cells were able to grow at azole concentrations well above the inhibitory concentration in vitro21.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [21]
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Susceptibility testing of Cryptococcus neoformans: a microdilution technique
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Metadata
- Authors
- Mondon, P., Petter, R., Amalfitano, G., Luzzati, R., Concia, E., Polacheck, I., & Kwon-Chung, K. J.
- Affiliations
- National Institutes of Health (US)
- University of Verona (IT)
- Hadassah Medical Center (IL)
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 1999-08
- Volume
- 43
- Issue
- 8
- Pages
- 1856-1861
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC89380
- OpenAlex
- W2000804360
- Cited by
- 139
- References
- 36
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 3 · 2023: 6 · 2022: 11 · 2021: 5 · 2020: 9 · 2019: 7 · 2018: 3 · 2017: 5 · 2016: 3 · 2015: 2 · 2014: 10 · 2013: 7 · 2012: 12
- FWCI
- 3.27
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
- Funders
- Pfizer
- Topics
- Health Sciences › Medicine › Infectious Diseases › Fungal Infections and Studies
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Fungal Plant Pathogen Control
- Keywords
- Cryptococcus neoformans, azole resistance, fluconazole, voriconazole, heteroresistance, clonal subpopulations, cryptococcal meningitis, AIDS, temperature-dependent resistance, loss of resistance, serial isolates
- MeSH terms
- Acquired Immunodeficiency Syndrome, Adult, Amphotericin B, Antifungal Agents, Cryptococcus neoformans, Drug Resistance, Microbial, Humans, Hydrogen-Ion Concentration, Male, Microbial Sensitivity Tests, Osmolar Concentration, Phenotype, Pyrimidines, Staining and Labeling, Temperature, Triazoles, Fluconazole, Meningitis, Fungal, Itraconazole, Voriconazole
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