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Frequency and evolution of Azole resistance in Aspergillus fumigatus associated with treatment failure.

Howard SJ, Cerar D, Anderson MJ, Albarrag A, Fisher MC, Pasqualotto AC, Laverdiere M, Arendrup MC, Perlin DS, Denning DW - Emerging Infect. Dis. (2009)

Bottom Line: 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.Azole resistance in A. fumigatus is an emerging problem and may develop during azole therapy.

View Article: PubMed Central - PubMed

Affiliation: Regional Mycology Laboratory, Manchester, UK.

ABSTRACT
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.

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Related in: MedlinePlus

Unrooted phylogenetic tree showing the genetic relationship of isolates from 7 patients.The genetic relationship of these isolates is shown in relation to each other and to 18 other isolates. AF numbers belong to a collection of >200 isolates, held in Manchester, UK. ATCC, American Type Culture Collection; CBS, Centraalbureau voor Schimmelcultures; FGSC, Fungal Genetics Stock Center. Bootstrap values >90 only are shown. Scale bar indicates nucleotide substitutions per site.
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Figure 2: Unrooted phylogenetic tree showing the genetic relationship of isolates from 7 patients.The genetic relationship of these isolates is shown in relation to each other and to 18 other isolates. AF numbers belong to a collection of >200 isolates, held in Manchester, UK. ATCC, American Type Culture Collection; CBS, Centraalbureau voor Schimmelcultures; FGSC, Fungal Genetics Stock Center. Bootstrap values >90 only are shown. Scale bar indicates nucleotide substitutions per site.

Mentions: The relatedness of isolates obtained from patients 3, 4, 5, 6, 8, 9, and 13 were compared by microsatellite typing (Figure 2). The isolates from 5 patients consisted of a susceptible/resistant pair, whereas an overlapping group of 4 patients had more than 1 cyp51A mutation. All isolates were from the lower respiratory tract, except the resistant isolate from patient 5, which was from a cerebral lesion.


Frequency and evolution of Azole resistance in Aspergillus fumigatus associated with treatment failure.

Howard SJ, Cerar D, Anderson MJ, Albarrag A, Fisher MC, Pasqualotto AC, Laverdiere M, Arendrup MC, Perlin DS, Denning DW - Emerging Infect. Dis. (2009)

Unrooted phylogenetic tree showing the genetic relationship of isolates from 7 patients.The genetic relationship of these isolates is shown in relation to each other and to 18 other isolates. AF numbers belong to a collection of >200 isolates, held in Manchester, UK. ATCC, American Type Culture Collection; CBS, Centraalbureau voor Schimmelcultures; FGSC, Fungal Genetics Stock Center. Bootstrap values >90 only are shown. Scale bar indicates nucleotide substitutions per site.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2744247&req=5

Figure 2: Unrooted phylogenetic tree showing the genetic relationship of isolates from 7 patients.The genetic relationship of these isolates is shown in relation to each other and to 18 other isolates. AF numbers belong to a collection of >200 isolates, held in Manchester, UK. ATCC, American Type Culture Collection; CBS, Centraalbureau voor Schimmelcultures; FGSC, Fungal Genetics Stock Center. Bootstrap values >90 only are shown. Scale bar indicates nucleotide substitutions per site.
Mentions: The relatedness of isolates obtained from patients 3, 4, 5, 6, 8, 9, and 13 were compared by microsatellite typing (Figure 2). The isolates from 5 patients consisted of a susceptible/resistant pair, whereas an overlapping group of 4 patients had more than 1 cyp51A mutation. All isolates were from the lower respiratory tract, except the resistant isolate from patient 5, which was from a cerebral lesion.

Bottom Line: 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.Azole resistance in A. fumigatus is an emerging problem and may develop during azole therapy.

View Article: PubMed Central - PubMed

Affiliation: Regional Mycology Laboratory, Manchester, UK.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus