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Published on: December 28, 2017
Aspergillus fumigatus variant with decreased susceptibility to multiple antifungals
S Arunmozhi Balajee1, Molly Weaver, Alexander Imhof
1Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Abstract:
Isolates of Aspergillus fumigatus that demonstrate resistance to itraconazole (ITZ) have been described previously; however, the prevalence and clinical significance of ITZ resistance are not completely understood. In this study we assessed the ITZ susceptibilities of 128 A. fumigatus isolates that caused invasive infection in 82 stem cell transplant patients before and after the use of ITZ in our institution (study period, 1991 to 2000). The MICs for 10 isolates obtained from seven patients were high, > or 1 microg/ml. The average ITZ MIC increased after institutional use of the drug began in 1995. The majority of the isolates for which MICs were high (6 of 10) and one isolate for which the MIC was low (0.06 microg/ml) demonstrated an unusual phenotype, appearing as predominantly white colonies. For all seven atypical isolates, voriconazole MICs were high (> or = 2 microg/ml), and minimal effective concentrations of caspofungin were high (> or 4 microg/ml). For two of the seven atypical isolates, amphotericin B MICs were high (> or 2 microg/ml). The isolates appeared white due to slow sporulation; however, after prolonged incubations, the isolates sporulated with no difference in conidial color or conidiophore morphology compared with typical isolates. Randomly amplified polymorphic DNA-PCR patterns of these isolates were distinct compared with those of other A. fumigatus isolates. Sequencing of 18S rRNA genes confirmed that all were A. fumigatus; however, the mitochondrial cytochrome b gene sequences of all the atypical isolates were unique. These data suggest the potential presence of a genetically unique, poorly sporulating variant of A. fumigatus that demonstrates decreased susceptibilities to several antifungals.
Insights
Antifungal resistance in Aspergillus fumigatus is a growing concern. This study identified a unique, poorly sporulating A. fumigatus variant with reduced susceptibility to multiple antifungals, including itraconazole.
Area of Science:
- Medical Mycology
- Infectious Diseases
- Antimicrobial Resistance
Background:
- Itraconazole (ITZ) resistance in Aspergillus fumigatus is known but not fully understood.
- Invasive fungal infections pose significant risks, especially in immunocompromised patients like stem cell transplant recipients.
Purpose of the Study:
- To assess the prevalence and clinical significance of ITZ resistance in A. fumigatus isolates from stem cell transplant patients.
- To characterize unusual A. fumigatus isolates exhibiting reduced antifungal susceptibility.
Main Methods:
- Antifungal susceptibility testing (MICs) for ITZ, voriconazole, caspofungin, and amphotericin B.
- Phenotypic characterization including colony morphology and sporulation.
- Molecular typing using randomly amplified polymorphic DNA-PCR and gene sequencing (18S rRNA, mitochondrial cytochrome b).
Main Results:
- 10 of 128 A. fumigatus isolates showed high ITZ MICs (>1 µg/ml).
- Seven atypical isolates with high ITZ MICs displayed a distinct white colony phenotype due to slow sporulation.
- These atypical isolates also exhibited high MICs for voriconazole and caspofungin, and in some cases, amphotericin B.
- Molecular analysis revealed unique mitochondrial cytochrome b gene sequences in the atypical isolates, suggesting a distinct genetic variant.
Conclusions:
- A genetically unique, poorly sporulating variant of A. fumigatus may be emerging.
- This variant demonstrates decreased susceptibility to multiple antifungal agents.
- Further research is needed to understand the prevalence and clinical impact of this antifungal-resistant A. fumigatus variant.
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