Frequency and Evolution of Azole Resistance in Aspergillus fumigatus Associated with Treatment Failure1

Howard, Susan J.; Cerar, Dasa; Anderson, Michael J.; Albarrag, Ahmed; Fisher, Matthew C.; Pasqualotto, Alessandro C.; Laverdiere, Michel; Arendrup, Maiken C.; Perlin, David S.; Denning, David W.

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Frequency and Evolution of Azole Resistance in Aspergillus fumigatus Associated with Treatment Failure1

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Jul 2009
By Howard, Susan J. ; Cerar, Dasa ; Anderson, Michael J. ; ...

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Alternative Title:

Emerg Infect Dis
Personal Author:

Howard, Susan J. ; Cerar, Dasa ; Anderson, Michael J. ; Albarrag, Ahmed ; Fisher, Matthew C. ; Pasqualotto, Alessandro C. ; Laverdiere, Michel ; Arendrup, Maiken C. ; Perlin, David S. ; Denning, David W.
Description:

Azoles are the mainstay of oral therapy for aspergillosis. Azole resistance in Aspergillus has been reported infrequently. The first resistant isolate was detected in 1999 in Manchester, UK. In a clinical collection of 519 A. fumigatus isolates, the frequency of itraconazole resistance was 5%, a significant increase since 2004 (p<0.001). Of the 34 itraconazole-resistant isolates we studied, 65% (22) were cross-resistant to voriconazole and 74% (25) were cross-resistant to posaconazole. Thirteen of 14 evaluable patients in our study had prior azole exposure; 8 infections failed therapy (progressed), and 5 failed to improve (remained stable). Eighteen amino acid alterations were found in the target enzyme, Cyp51A, 4 of which were novel. A population genetic analysis of microsatellites showed the existence of resistant mutants that evolved from originally susceptible strains, different cyp51A mutations in the same strain, and microalterations in microsatellite repeat number. Azole resistance in A. fumigatus is an emerging problem and may develop during azole therapy.
Subjects:

Amino Acid Substitution Antifungal Agents Antifungal Drug Resistance Aspergillosis Aspergillus Aspergillus Fumigatus Azoles Cytochrome P-450 Enzyme System Disease Progression Drug Resistance, Fungal Evolution, Molecular Fungal Proteins Humans Itraconazole Microsatellites Population Genetics Pyrimidines Research Sterol 14-alpha Demethylase CYP51A Treatment Failure Triazoles
Source:

Emerg Infect Dis. 15(7):1068-1076.
Document Type:

Journal Article
Volume:

15
Issue:

7
Collection(s):

Emerging Infectious Diseases
Main Document Checksum:

urn:sha256:2e377978c9e653933307113d365ce99e94f0c8873ae7d19e67ffa7217e72a627
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https://stacks.cdc.gov/view/cdc/17512/cdc_17512_DS1.pdf
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[PDF - 655.31 KB ]

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