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Volume 15, Number 7—July 2009

Research

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

Susan J. Howard, Dasa Cerar, Michael J. Anderson, Ahmed Albarrag, Matthew C. Fisher, Alessandro C. Pasqualotto, Michel Laverdiere, Maiken C. Arendrup, David S. Perlin, and David W. DenningComments to Author 
Author affiliations: Regional Mycology Laboratory, Manchester, UK (S.J. Howard, D.W. Denning); University of Manchester, Manchester Academic Health Science Centre, Manchester (S.J. Howard, M.J. Anderson, A. Albarrag, D.W. Denning); University Medical Centre, Ljubljana, Slovenia (D. Cerar); Imperial College, London, UK (M.C. Fisher); Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (A.C. Pasqualotto); Hôpital Maisonneuve-Rosemont, Montreal, Québec, Canada (M. Laverdiere); Statens Serum Institut, Copenhagen, Denmark (M.C. Ardendrup); Public Health Research Institute, Newark, NJ, USA (D.S. Perlin)

Main Article

Table 3

Cyp51A amino acid substitutions and associated cross-resistance patterns in azole-resistant RMLM Aspergillus fumigatus isolates*

Cyp51A codon No. patients No. isolates Amino acid substitutions MIC, mg/L†
Itraconazole Voriconazole Posaconazole
F46‡ 3 4‡ Y >8 2–4 0.125–0.5
G54 4 5 E, R, V >8 0.125–1 1–>8
L98+TR 2 2 H >8 8 1–2
G138 1 10 C >8 8–>8 2–>8
H147§ 1 Y >8 >8 0.5
M172‡ 3 4‡ V >8 2–4 0.125–0.5
P216 1 1 L >8 1 1
M220 3 4 K, T >8 1–4 0.5–>8
N248‡ 1 1 T >8 2 0.25
D255‡ 1 1 E >8 2 0.25
E427‡ 4 5‡ G, K >8 2–4 0.125–0.5
Y431 1 1 C >8 4 1
G434 1 1 C >8 4 1
G448 2 2 S >8 >8 0.5–1
No substitutions 2 3 NA >8 2–8 0.25–1

*RMLM, Regional Mycology Laboratory Manchester; TR, tandem repeat in cyp51A promoter; NA, not applicable. Synonymous mutations not shown. Some mutations are associated with resistance but may not be causal (see text).
†Putative cut-off values for resistance are itraconazole and voriconazole >2 mg/L and posaconazole >0.5 mg/L.
‡F46Y found with M172V and E427K in 4 isolates along with 3 silent mutations. E427G seen alone in 1 isolate. N248 and D255 found in combination with 46/172/427 in 1 isolate.
§Found with G448S in 1 of 2 isolates.

Main Article

1These data were presented in part at the 2nd Advances Against Aspergillosis meeting, February 22–26, 2006, Athens, Greece; and 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 27–30, 2006, San Francisco, CA, USA.

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