In Vitro Acquisition of Secondary Azole Resistance in Aspergillus fumigatus Isolates after Prolonged Exposure to Itraconazole: Presence of Heteroresistant Populations
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Secondary resistance to azoles in Aspergillus fumigatus isolates from patients taking long-term itraconazole therapy has been described. We studied the acquisition of secondary azole resistance in 20 A. fumigatus isolates with no mutations at codon 54, 98, 138, 220, 432, or 448 in the cyp51A gene. Adjusted conidium inocula (3 × 10 7 CFU/ml) of each isolate were prepared and progressively or directly exposed to increasing itraconazole concentrations, ranging from 0.5 μg/ml to 16 μg/ml. Itraconazole, voriconazole, and posaconazole MICs were determined using the CLSI M38-A2 procedure before (MIC initial ) and after (MIC final ) exposure to itraconazole. In both procedures, the MIC final was significantly higher than the MIC initial . However, after progressive exposure to itraconazole, the MICs of the three azoles were higher than after direct exposure. No mutations were found at codon 54, 98, 138, 220, 432, or 448 in the cyp51A gene of isolates growing at the highest concentration of itraconazole. More concentrated conidium inocula (2 × 10 9 CFU/ml) plated in itraconazole at 4 μg/ml revealed the presence of heteroresistant populations in two initially wild-type isolates. These isolates became resistant to itraconazole and posaconazole only after use of the concentrated inoculum. These heteroresistant isolates harbored a mutation at codon G54, and the MICs of itraconazole and posaconazole were >16 μg/ml. In all procedures, A. fumigatus short tandem repeat (STR Af ) typing was used to demonstrate that the genotype did not change before or after exposure to itraconazole.
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Progressive itraconazole exposure in vitro can reproduce decreased susceptibility in A. fumigatus independent of mutation in cyp51A gene.
“Progressive itraconazole exposure in vitro can reproduce such phenomena, independent of the mutation in cyp51A gene [162].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [162]
Secondary resistance in A. fumigatus suggests existence of heteroresistance.
“This is called secondary resistance, suggesting the existence of heteroresistance.”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [162]
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Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance
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“Progressive itraconazole exposure in vitro can reproduce such phenomena, independent of the mutation in cyp51A gene [162].”
- Authors
- Escribano, P., Recio, S., Peláez, T., González-Rivera, M., Bouza, E., & Guinea, J.
- Affiliations
- Universidad Complutense de Madrid (ES)
- Instituto de Investigación Sanitaria del Hospital Gregorio Marañón, Madrid, Spain
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2012-01
- Volume
- 56
- Issue
- 1
- Pages
- 174-178
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC3256017
- OpenAlex
- W2053956395
- Cited by
- 48
- References
- 31
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 5 · 2015: 6 · 2014: 3 · 2013: 3 · 2012: 4
- FWCI
- 2.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Instituto de Salud Carlos III
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- Aspergillus fumigatus, itraconazole, heteroresistance, cyp51A mutations, voriconazole, posaconazole, antifungal resistance, long-term antifungal therapy, in vitro exposure, short tandem repeat typing
- MeSH terms
- Antifungal Agents, Aspergillosis, Aspergillus fumigatus, Codon, Culture Media, Cytochrome P-450 Enzyme System, DNA Mutational Analysis, Fungal Proteins, Humans, Microbial Sensitivity Tests, Mutation, Pyrimidines, Time Factors, Triazoles, Mycological Typing Techniques, Itraconazole, Drug Resistance, Fungal, Voriconazole
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