Skip directly to site content Skip directly to page options Skip directly to A-Z link Skip directly to A-Z link Skip directly to A-Z link
Volume 17, Number 10—October 2011
CME ACTIVITY - Research

Clinical Implications of Azole Resistance in Aspergillus fumigatus, the Netherlands, 2007–2009

Jan W.M. van der LindenComments to Author , Eveline Snelders, Greetje A. Kampinga, Bart J.A. Rijnders, Eva Mattsson, Yvette J. Debets-Ossenkopp, Ed J. Kuijper, Frank H. Van Tiel, Willem J.G. Melchers, Paul E. Verweij, and Kuijper

Author affiliations: Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands (J.W.M. van der Linden, E. Snelders, W.J.G. Melchers, P.E. Verweij); Groningen University Medical Centre, Groningen, the Netherlands (G.A. Kampinga); Erasmus Medical Centre, Rotterdam, the Netherlands (B.J.A. Rijnders); Utrecht University Medical Centre, Utrecht, the Netherlands (E. Mattsson); Vrije University Medical Centre, Amsterdam, the Netherlands (Y.J. Debets-Ossenkopp); Leiden University Medical Centre, Leiden, the Netherlands (E.J. Kuijper); Maastricht University Medical Centre, Maastricht, the Netherlands (F.H. van Tiel)

Main Article

Table 2

Characteristics of itraconazole-positive Aspergillus fumigatus isolates, the Netherlands, 2007–2009*

No. isolates Mutations in the Cyp51A gene Median MIC, mg/L (range)
Itraconazole Voriconazole Posaconazole
74 TR/L98H† >16 (16–>16) 8 (1–16) 0.5 (0.25–2)
1 G54W† >16 0.5 >16
1 P216L† 16 2 0.5
1 F219I† >16 0.25 0.25
1 Series‡ >16 >16 1
4 None >16 (16–>16) 4 (0.5–4) 0.2 (0.125–1)

*In vitro susceptibility testing was performed according to the Clinical and Laboratory Standards Institute M38A2 method (32).
†Mutations that have previously been shown to be associated with azole resistance in A. fumigatus (7,20,21).
‡Series of mutations in Cyp51A-gene: F46Y, G89G, M172V, N248T, D255E, L358L, E427K, and C454C (8).

*In vitro susceptibility testing was performed according to the Clinical and Laboratory Standards Institute M38A2 method (32).
†Mutations that have previously been shown to be associated with azole resistance in A. fumigatus (7,20,21).
‡Series of mutations in Cyp51A-gene: F46Y, G89G, M172V, N248T, D255E, L358L, E427K, and C454C (8).

*In vitro susceptibility testing was performed according to the Clinical and Laboratory Standards Institute M38A2 method (32).
†Mutations that have previously been shown to be associated with azole resistance in A. fumigatus (7,20,21).
‡Series of mutations in Cyp51A-gene: F46Y, G89G, M172V, N248T, D255E, L358L, E427K, and C454C (8).

Main Article

References
  1. Walsh  TJ, Anaissie  EJ, Denning  DW, Herbrecht  R, Kontoyiannis  DP, Marr  KA, Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46:32760. DOIPubMedGoogle Scholar
  2. Herbrecht  R, Denning  DW, Patterson  TF, Bennett  JE, Greene  RE, Oestmann  JW, Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347:40815. DOIPubMedGoogle Scholar
  3. Walsh  TJ, Pappas  P, Winston  DJ, Lazarus  HM, Petersen  F, Raffalli  J, Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med. 2002;346:22534. DOIPubMedGoogle Scholar
  4. Schwartz  S, Ruhnke  M, Ribaud  P, Corey  L, Driscoll  T, Cornely  OA, Improved outcome in central nervous system aspergillosis, using voriconazole treatment. Blood. 2005;106:26415. DOIPubMedGoogle Scholar
  5. Slobbe  L, Polinder  S, Doorduijn  JK, Lugtenburg  PJ, el Barzouhi  A, Steyerberg  EW, Outcome and medical costs of patients with invasive aspergillosis and acute myelogenous leukemia-myelodysplastic syndrome treated with intensive chemotherapy: an observational study. Clin Infect Dis. 2008;47:150712. DOIPubMedGoogle Scholar
  6. Snelders  E, van der Lee  HAL, Kuijpers  J, Rijs  AJMM, Varga  J, Samson  RA, Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLoS Med. 2008;5:e219. DOIPubMedGoogle Scholar
  7. Howard  SJ, Cerar  D, Anderson  MJ, Albarrag  A, Fisher  MC, Pasqualotto  AC, Frequency and evolution of azole resistance in Aspergillus fumigatus associated with treatment failure. Emerg Infect Dis. 2009;15:106876. DOIPubMedGoogle Scholar
  8. Bueid  A, Howard  SJ, Moore  CB, Richardson  MD, Harrison  E, Bowyer  P, Azole antifungal resistance in Aspergillus fumigatus: 2008 and 2009. J Antimicrob Chemother. 2010;65:21168. DOIPubMedGoogle Scholar
  9. Warris  A, Weemaes  CM, Verweij  PE. Multidrug resistance in Aspergillus fumigatus. N Engl J Med. 2002;347:21734. DOIPubMedGoogle Scholar
  10. Verweij  PE, Mellado  E, Melchers  WJ. Multiple-triazole-resistant aspergillosis. N Engl J Med. 2007;356:14813. DOIPubMedGoogle Scholar
  11. Mellado  E, Garcia-Effron  G, Alcázar-Fuoli  L, Melchers  WJ, Verweij  PE, Cuenca-Estrella  M, A new Aspergillus fumigatus resistance mechanism conferring in vitro cross-resistance to azole antifungals involves a combination of cyp51A alterations. Antimicrob Agents Chemother. 2007;51:1897904. DOIPubMedGoogle Scholar
  12. Lagrou  K, De Vleeschouwer  J, Meerseman  W, Dupont  L, Verleden  G, Melchers  WJG, Triazole resistance among 229 clinical Aspergillus fumigatus isolates. Presented at: 3rd Advances Against Aspergillosis Conference; Miami, Florida, USA; January 16–19, 2008. Abstract 33.
  13. Arendrup  MC, Perkhofer  S, Howard  SJ, Garcia-Effron  G, Vishukumar  A, Perlin  D, Establishing in vitro–in vivo correlations for Aspergillus fumigatus: the challenge of azoles versus echinocandins. Antimicrob Agents Chemother. 2008;52:350411. DOIPubMedGoogle Scholar
  14. Chryssanthou  E. In vitro susceptibility of respiratory isolates of Aspergillus species to itraconazole and amphotericin B acquired resistance to itraconazole. Scand J Infect Dis. 1997;29:50912. DOIPubMedGoogle Scholar
  15. Dannaoui  E, Borel  E, Monier  MF, Piens  MA, Picot  S, Persat  F. Acquired itraconazole resistance in Aspergillus fumigatus. J Antimicrob Chemother. 2001;47:33340. DOIPubMedGoogle Scholar
  16. Denning  DW, Radford  SA, Oakley  KL, Hall  L, Johnson  EM, Warnock  DW. Correlation between in-vitro susceptibility testing to itraconazole and in-vivo outcome of Aspergillus fumigatus infection. J Antimicrob Chemother. 1997;40:40114. DOIPubMedGoogle Scholar
  17. Chen  J, Li  H, Li  R, Bu  D, Wan  Z. Mutations in the cyp51A gene and susceptibility to itraconazole in Aspergillus fumigatus serially isolated from a patient with lung aspergilloma. J Antimicrob Chemother. 2005;55:317. DOIPubMedGoogle Scholar
  18. Mellado  E, Garcia-Effron  G, Alcazar-Fuoli  L, Cuenca-Estrella  M, Rodriguez-Tudela  JL. Substitutions at methionine 220 in the 14alpha-sterol demethylase (Cyp51A) of Aspergillus fumigatus are responsible for resistance in vitro to azole antifungal drugs. Antimicrob Agents Chemother. 2004;48:274750. DOIPubMedGoogle Scholar
  19. Diaz-Guerra  TM, Mellado  E, Cuenca-Estrella  M, Rodriguez-Tudela  JL. A point mutation in the 14alpha-sterol demethylase gene cyp51A contributes to itraconazole resistance in Aspergillus fumigatus. Antimicrob Agents Chemother. 2003;47:11204. DOIPubMedGoogle Scholar
  20. Verweij  PE, Howard  SJ, Melchers  WJG, Denning  DW. Azole resistance in Aspergillus: proposed nomenclature and breakpoints. Drug Resist Updat. 2009;12:1417. DOIPubMedGoogle Scholar
  21. Snelders  E. Karawajczyk, Schaftenaar G, Verweij PE, Melchers WJ. Azole resistance profile of amino acid changes in Aspergillus fumigatus cyp51A based on protein homology modeling. Antimicrob Agents Chemother. 2010;54:242530. DOIPubMedGoogle Scholar
  22. van Leer-Buter  C, Takes  RP, Hebeda  KM, Melchers  WJ, Verweij  PE. Aspergillosis–and a misleading sensitivity result. Lancet. 2007;370:102. DOIPubMedGoogle Scholar
  23. van der Linden  JW, Jansen  RR, Bresters  D, Visser  CE, Geerlings  SE, Kuijper  EJ, Azole resistant central nervous system aspergillosis. Clin Infect Dis. 2009;48:11113. DOIPubMedGoogle Scholar
  24. Hodiamont  CJ, Dolman  KM, ten Berge  RJM, Melchers  WJ, Verweij  PE, Pajkrt  D. Multiple-azole-resistant Aspergillus fumigatus osteomyelitis in a patient with chronic granulomatous disease successfully treated with long-term oral posaconazole and surgery. Med Mycol. 2009;47:21720. DOIPubMedGoogle Scholar
  25. Mavridou  E, Brüggemann  RJ, Melchers  WJ, Verweij  PE, Mouton  JW. Impact of cyp51A mutations on the pharmacokinetic and pharmacodynamic properties of voriconazole in a murine model of disseminated aspergillosis. Antimicrob Agents Chemother. 2010;54:475864. DOIPubMedGoogle Scholar
  26. Mavridou  E, Brüggemann  RJ, Melchers  WJ, Mouton  JW, Verweij  PE. Efficacy of posaconazole against three clinical Aspergillus fumigatus isolates with mutations in the cyp51A gene. Antimicrob Agents Chemother. 2010;54:8605. DOIPubMedGoogle Scholar
  27. Verweij  PE, Snelders  E, Kema  GH, Mellado  E, Melchers  WJ. Azole resistance in Aspergillus fumigatus: a side-effect of environmental fungicide use? Lancet Infect Dis. 2009;9:78995. DOIPubMedGoogle Scholar
  28. Snelders  E, Huis in ‘t Veld  RAG, Rijs  AJJM, Kema  GHJ, Melchers  WJ, Verweij  PE. Possible environmental origin of resistance of Aspergillus fumigatus to medical triazoles. Appl Environ Microbiol. 2009;75:40537. DOIPubMedGoogle Scholar
  29. Mortensen  KL, Mellado  E, Lass-Flörl  C, Rodriguez-Tudela  JL, Johansen  HK, Arendrup  MC. Environmental study of azole-resistant Aspergillus fumigatus and other aspergilli in Austria, Denmark, and Spain. Antimicrob Agents Chemother. 2010;54:45459. DOIPubMedGoogle Scholar
  30. Verweij  PE, Te Dorsthorst  DT, Rijs  AJ, De Vries-Hospers  HG, Meis  JF. Nationwide survey of in vitro activities of itraconazole and voriconazole against clinical Aspergillus fumigatus isolates cultured between 1945 and 1998. J Clin Microbiol. 2002;40:264850. DOIPubMedGoogle Scholar
  31. Klaassen  CH, de Valk  HA, Curfs-Breuker  IM, Meis  JF. Novel mixed-format real-time PCR assay to detect mutations conferring resistance to triazoles in Aspergillus fumigatus and prevalence of multi-triazole resistance among clinical isolates in the Netherlands. J Antimicrob Chemother. 2010;65:9015. DOIPubMedGoogle Scholar
  32. Clinical and Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing of filamentous fungi; approved standard, 2nd ed. CLSI document M38–A2. Wayne (PA): The Institute; 2008.
  33. De Pauw  B, Walsh  TJ, Donnelly  JP, Stevens  DA, Edwards  JE, Calandra  T, Revised definitions of invasive fungal disease from the EORTC/MSG. Clin Infect Dis. 2008;46:181321. DOIPubMedGoogle Scholar
  34. Landis  JR, Koch  GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33:15974. DOIPubMedGoogle Scholar
  35. Baddley  JW, Marr  KA, Andes  DR, Walsh  TJ, Kauffman  CA, Kontoyiannis  DP, Patterns of susceptibility of Aspergillus isolates recovered from patients enrolled in the Transplant-Associated Infection Surveillance Network. J Clin Microbiol. 2009;47:32715. DOIPubMedGoogle Scholar
  36. van der Linden  JW, Snelders  E, Arends  JP, Daenen  SM, Melchers  WJ, Verweij  PE. Rapid diagnosis of azole-resistant aspergillosis by direct PCR using tissue specimens. J Clin Microbiol. 2010;48:147880. DOIPubMedGoogle Scholar
  37. Denning  DW, Park  S, Lass-Florl  C, Fraczek  MG, Kirwan  M, Gore  R, High-frequency triazole resistance found in nonculturable Aspergillus fumigatus from lungs of patients with chronic fungal disease. Clin Infect Dis. 2011;52:11239. DOIPubMedGoogle Scholar

Main Article

Page created: September 22, 2011
Page updated: September 22, 2011
Page reviewed: September 22, 2011
The conclusions, findings, and opinions expressed by authors contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.
file_external