Frequency and Evolution of Azole Resistance in Aspergillus fumigatus Associated with Treatment Failure1
Published Date:Jul 2009
Source:Emerg Infect Dis. 15(7):1068-1076.
Keywords:Amino Acid Substitution
Antifungal Drug Resistance
Cytochrome P-450 Enzyme System
Drug Resistance, Fungal
Sterol 14-alpha Demethylase CYP51A
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.
image/gif image/jpeg image/gif image/jpeg application/pdf text/plain text/plain
You May Also Like: