Limits...
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.

Show MeSH

Related in: MedlinePlus

Azole resistance in clinical Aspergillus fumigatus isolates received in the Regional Mycology Laboratory Manchester, UK, 1997–2007. Overall azole resistance for each year is shown above each column as a percentage. Data do not include sequential isolates from the same patient.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2744247&req=5

Figure 1: Azole resistance in clinical Aspergillus fumigatus isolates received in the Regional Mycology Laboratory Manchester, UK, 1997–2007. Overall azole resistance for each year is shown above each column as a percentage. Data do not include sequential isolates from the same patient.

Mentions: Five percent of 400 isolates were resistant to itraconazole (when duplicate isolates from the same patient with similar susceptibility profiles were removed from the analysis). The overall frequency of itraconazole resistance in this collection (with repeat specimens included) was 7% (n = 519). The first case of azole resistance in this collection was seen in 1999. The frequency of resistance since 2004 (8%) has increased significantly (Fisher exact test, p<0.001), compared with the period prior to 2004 (Figure 1).


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)

Azole resistance in clinical Aspergillus fumigatus isolates received in the Regional Mycology Laboratory Manchester, UK, 1997–2007. Overall azole resistance for each year is shown above each column as a percentage. Data do not include sequential isolates from the same patient.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Azole resistance in clinical Aspergillus fumigatus isolates received in the Regional Mycology Laboratory Manchester, UK, 1997–2007. Overall azole resistance for each year is shown above each column as a percentage. Data do not include sequential isolates from the same patient.
Mentions: Five percent of 400 isolates were resistant to itraconazole (when duplicate isolates from the same patient with similar susceptibility profiles were removed from the analysis). The overall frequency of itraconazole resistance in this collection (with repeat specimens included) was 7% (n = 519). The first case of azole resistance in this collection was seen in 1999. The frequency of resistance since 2004 (8%) has increased significantly (Fisher exact test, p<0.001), compared with the period prior to 2004 (Figure 1).

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