Drug Resistance Updates
Volume 12, Issue 6 , Pages 141-147 , December 2009

Azole-resistance in Aspergillus: Proposed nomenclature and breakpoints

  • Paul E. Verweij

      Affiliations

    • Department of Medical Microbiology, Radboud University, Nijmegen Medical Centre, The Netherlands
    • ,
  • Susan J. Howard

      Affiliations

    • The National Aspergillosis Centre, The University of Manchester and University Hospital of South Manchester, Manchester, United Kingdom
    • ,
  • Willem J.G. Melchers

      Affiliations

    • Department of Medical Microbiology, Radboud University, Nijmegen Medical Centre, The Netherlands
    • ,
  • David W. Denning

      Affiliations

    • The National Aspergillosis Centre, The University of Manchester and University Hospital of South Manchester, Manchester, United Kingdom
    • Corresponding Author InformationCorresponding author at: 2nd Floor Education & Research Centre, University Hospital of South Manchester, Southmoor Road, Manchester, M23 9LT, United Kingdom. Tel.: +44 161 291 5811; fax: +44 161 291 5806.

Received 18 April 2009 ,Accepted 8 June 2009.

References 

  1. Arendrup MC, Perkhofer S, Howard SJ, Garcia-Effron G, Vishukumar A, Perlin D, et al. Establishing in vitro–in vivo correlations for Aspergillus fumigatus: the challenge of azoles vs. echinocandins. Antimicrob. Agents Chemother. 2008;52:3504–3511
  2. Balajee SA, Gribskov JL, Hanley E, Nickle D, Marr KA. Aspergillus lentulus sp. nov., a new sibling species of A. fumigatus. Eukaryot. Cell. 2005;4:625–632
  3. 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;55:31–37
  4. 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;29:509–512
  5. Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N. Engl. J. Med. 2007;356:348–359
  6. Cuenca-Estrella M, Moore CB, Barchiesi F, Bille J, Chryssanthou E, Denning DW, et al. Multicenter evaluation of the reproducibility of the proposed antifungal susceptibility testing method for fermentative yeasts of the Antifungal Susceptibility Testing Subcommittee of the European Committee on Antimicrobial Susceptibility Testing (AFST-EUCAST). Clin. Microbiol. Infect. 2003;9:467–474
  7. Cuenca-Estrella M, Arendrup MC, Chryssanthou E, Dannaoui E, Lass-Florl C, Sandven P, et al. Multicentre determination of quality control strains and quality control ranges for antifungal susceptibility testing of yeasts and filamentous fungi using the methods of the Antifungal Susceptibility Testing Subcommittee of the European Committee on Antimicrobial Susceptibility Testing (AFST-EUCAST). Clin. Microbiol. Infect. 2007;13:1018–1022
  8. Dannaoui E, Borel E, Monier MF, Piens MA, Picot S, Persat F. Acquired itraconazole resistance in Aspergillus fumigatus. J. Antimicrob. Chemother. 2001;47:333–340
  9. 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;40:401–414
  10. Denning DW, Venkateswarlu K, Oakley KL, Anderson MJ, Manning NJ, Stevens DA, et al. Itraconazole resistance in Aspergillus fumigatus. Antimicrob. Agents Chemother. 1997;41:1364–1368
  11. Denning DW, Riniotis K, Dobrashian R, Sambatakou H. Chronic cavitary and fibrosing pulmonary and pleural aspergillosis: case series, proposed nomenclature change, and review. Clin. Infect. Dis. 2003;37(Suppl. 3):S265–S280
  12. 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;47:1120–1124
  13. Guinea J, Recio S, Peláez T, Torres-Narbona M, Bouza E. Clinical isolates of Aspergillus species remain fully susceptible to voriconazole in the post-voriconazole era. Antimicrob. Agents Chemother. 2008;52:3444–3446
  14. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N. Engl. J. Med. 2002;347:408–415
  15. Hodiamont CJ, Dolman KM, ten Berge RJM, Melchers WJG, Verweij PE, et al. Multiple-azole-resistant Aspergillus fumigatus osteomyelitis in a patient with chronic granulomatous disease successfully treated with longterm oral posaconazole and surgery. Med. Mycol. 2009;47:217–220
  16. Hope WW, Warn PA, Sharp A, Howard S, Kasai M, Louie A, et al. Derivation of an in vivo drug exposure breakpoint for flucytosine against Candida albicans and impact of the MIC, growth rate, and resistance genotype on the antifungal effect. Antimicrob. Agents Chemother. 2006;50:3680–3688
  17. Howard SJ, Moore CB, Denning DW . Azole resistance in Aspergillus niger. In: 2nd Advances Against Aspergillosis. Athens, Greece. 2006;
  18. Howard SJ, Webster I, Moore CB, Gardiner RE, Park S, Perlin DS, et al. Multi-azole resistance in Aspergillus fumigatus. Int. J. Antimicrob. Agents. 2006;28:450–453
  19. Howard SJ, Albarrag A, Anderson MJ, Gardiner RE, Park S, Perlin D, et al. Azole resistance in clinical Aspergillus fumigatus strains. In: 46th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, USA. 2006;
  20. Howard SJ, Harrison E, Bowyer P, Denning DW . Molecular identification of clinical black Aspergillus isolates and azole resistance. In: 3rd Advances Against Aspergillosis. Miami, USA. 2008;
  21. Howard SJ, Cesar D, Anderson MJ, Albarrag AM, Fisher M, Pasqualotto AC, et al. Frequency and evolution of azole resistance in Aspergillus fumigatus associated with treatment failure. Emerg. Infect. Dis. 2009;15:1068–1076
  22. Howard SJ, Pasqualotto AC, Denning DW. 2009b. Azole resistance in ABPA and Aspergillus bronchitis. Clin Microbiol. Infect. 2009, in press.
  23. Johnson E, Oakley KL, Radford S, Moore CB, Warn P, Warnock DW, et al. Lack of correlation of in vitro amphotericin B susceptibility testing with outcome of in a murine model of Aspergillus infection. J. Antimicrob. Chemother. 1999;45:85–93
  24. Kontoyiannis DP, Lewis RE, May GS, Osherov N, Rinaldi MG. Aspergillus nidulans is frequently resistant to amphotericin B. Mycoses. 2002;45:406–407
  25. Krishnan PU, Miles K, Shetty N. Detection of methicillin and mupirocin resistance in Staphylococcus aureus isolates using conventional and molecular methods: a descriptive study from a burns unit with high prevalence of MRSA. J. Clin. Pathol. 2002;55:745–748
  26. Lagrou K, De Vleeschouwer J, Meerseman W, et al. Triazole resistance among 229 clinical Aspergillus fumigatus isolates. In: 3rd Advances Against Aspergillosis. Miami 230, USA. 2008;Abstract 33
  27. Lass-Florl C, Perkhofer S. In vitro susceptibility-testing in Aspergillus species. Mycoses. 2008;51:437–446
  28. Manavathu EK, Cutright J, Chandrasekar PH. Comparative study of susceptibilities of germinated and ungerminated conidia of Aspergillus fumigatus to various antifungal agents. J. Clin. Microbiol. 1999;37:858–861
  29. Manavathu EK, Baskaran I, Krishnan S, Alangaden G, Chandrasekar PH . Cytochrome P450 14-alpha-sterol demethylase mutation dependent triazole cross-resistance in Aspergillus fumigatus. In: 43rd Interscience Conference on Antimicrobial Agents and ChemotherapyPC Chicago, USA. 2003;
  30. Mann PA, Parmegiani RM, Wei SQ, et al. Mutations in Aspergillus fumigatus resulting in reduced susceptibility to posaconazole appear to be restricted to a single amino acid in the cytochrome P450 14alpha-demethylase. Antimicrob. Agents Chemother. 2003;47:577–581
  31. Mavridou E, Mouton JW, Brüggemann RJ, Melchers WJG, Verweij PE. Efficacy of posaconazole against clinical aspergillus fumigatus isolates with mutations in the cyp51a gene. In: 48th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, USA. 2008;abstract M-2171
  32. 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;48:2747–2750
  33. Mellado E, Garcia-Effron G, Alcázar-Fuoli L, Melchers WJ, Verweij PE, Cuenca-Estrella M, et al. A new Aspergillus fumigatus resistance mechanism conferring in vitro cross-resistance to azole antifungals involves a combination of cyp51A alterations. Antimicrob. Agents Chemother. 2007;51:1897–1904
  34. Mosquera J, Denning DW. Azole cross-resistance in Aspergillus fumigatus. Antimicrob. Agents Chemother. 2002;46:556–557
  35. Mosquera J, Warn PA, Morrissey J, Moore CB, Gil-Lamaignere C, Denning DW. Susceptibility testing of Aspergillus flavus: inoculum dependence with itraconazole and lack of correlation between susceptibility to amphotericin B in vitro and outcome in vivo. Antimicrob. Agents Chemother. 2001;45:1456–1462
  36. Nascimento AM, Goldman GH, Park S, et al. Multiple resistance mechanisms among Aspergillus fumigatus mutants with high-level resistance to itraconazole. Antimicrob. Agents Chemother. 2003;47:1719–1726
  37. National Committee for Clinical Laboratory Standards . Reference method for broth dilution antifungal susceptibility testing of filamentous fungi. Wayne, PA: National Committee for Clinical Laboratory Standards; 2002;Approved standard M38-A
  38. Oakley KL, Morrissey G, Denning DW. Efficacy of SCH-56592 in a temporarily neutropenic murine model of invasive aspergillosis with an itraconazole-susceptible and an itraconazole-resistant isolate of Aspergillus fumigatus. Antimicrob. Agents Chemother. 1997;41:1504–1507
  39. Pfaller MA, Messer SA, Boyken L, Rice C, Tendolkar S, Hollis RJ, et al. In Vitro survey of triazole cross-resistance among more than 700 clinical isolates of Aspergillus species. J. Clin. Microbiol. 2008;46:2568–2572
  40. Rambali B, Fernandez JA, Van Nuffel L, Woestenborghs F, Baert L, Massart DL, et al. Susceptibility testing of pathogenic fungi with itraconazole: a process analysis of test variables. J. Antimicrob. Chemother. 2001;48:163–177
  41. Rex JH, Pfaller MA, Galgiani JN, Bartlett MS, Espinel-Ingroff A, Ghannoum MA, et al. Development of interpretive breakpoints for antifungal susceptibility testing: conceptual framework and analysis of in vitro–in vivo correlation data for fluconazole, itraconazole, and Candida infections. Subcommittee on Antifungal Susceptibility Testing of the National Committee for Clinical Laboratory Standards. Clin. Infect. Dis. 1997;24:235–247
  42. Rodríguez-Tudela JL, Almirante B, Rodríguez-Pardo D, Laguna F, Donnelly JP, Mouton JW, et al. Correlation of the MIC and dose/MIC ratio of fluconazole to the therapeutic response of patients with mucosal candidiasis and candidemia. Antimicrob. Agents Chemother. 2007;51:3599–3604
  43. Subcommittee of Antifungal Susceptibility Testing of the European Committee for Antimicrobial Susceptibility Testing of the European Society of Clinical Microbiology and Infectious Diseases . Method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for conidia forming moulds. 2007;
  44. Slaven JW, Anderson MJ, Sanglard D, et al. Increased expression of a novel Aspergillus fumigatus ABC transporter gene, atrF, in the presence of itraconazole in an itraconazole resistant clinical isolate. Fungal Genet. Biol. 2002;36:199–206
  45. Snelders E, van der Lee HAL, Kuijpers J, Rijs AJMM, Varga J, Samson RA, et al. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLoS Med. 2008;5:e219
  46. Snelders E, Huis In ‘t Veld RA, Rijs AJ, Kema GH, Melchers WJ, Verweij PE. Possible environmental origin of resistance of Aspergillus fumigatus to medical triazoles. Appl. Environ. Microbiol. 2009;75:4053–4057
  47. Steinbach WJ, Benjamin DK, Kontoyiannis DP, Perfect JR, Lutsar I, Marr KA, et al. Infections due to Aspergillus terreus: a multicenter retrospective analysis of 83 cases. Clin. Infect. Dis. 2004;39:192–198
  48. Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N. Engl. J. Med. 2007;356:335–347
  49. Varga J, Houbraken J, Van Der Lee HA, Verweij PE, Samson RA. Aspergillus calidoustus sp. nov., causative agent of human infections previously assigned to Aspergillus ustus. Eukaryot. Cell. 2008;7:630–638
  50. Van der Linden JWM, Snelders E, Debets Y, Kampinga GA, Kuijper E, Mattson E, et al. Prospective study of the prevalence of azole resistance in aspergillus species in the Netherlands. In: 48th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington. 2008;abstract M-1718
  51. Van der Linden JWM, Jansen RR, Bresters D, Visser CE, Geerlings SE, Kuijper EJ, et al. Azole resistant central nervous system aspergillosis. Clin. Infect. Dis. 2009;48:1441–1458
  52. Verweij PE, Mellado E, Melchers WJ. Multiple-triazole-resistant aspergillosis. N. Engl. J. Med. 2007;356:1481–1483
  53. Walsh TJ, Petraitis V, Petraitiene R, Field-Ridley A, Sutton D, Ghannoum M, et al. Experimental pulmonary aspergillosis due to Aspergillus terreus: pathogenesis and treatment of an emerging fungal pathogen resistant to amphotericin B. J. Infect. Dis. 2003;188:305–319
  54. Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, et al. Infectious Diseases Society of America. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin. Infect. Dis. 2008;46:327–360
  55. Warris A, Weemaes CM, Verweij PE. Multidrug resistance in Aspergillus fumigatus. N. Engl. J. Med. 2002;347:2173–2174
  56. Xiao L, Madison V, Chau AS, Loebenberg D, Palermo RE, McNicholas PM. Three-dimensional models of wild-type and mutated forms of cytochrome P450 14α-sterol demethylases from Aspergillus fumigatus and Candida albicans provide insights into posaconazole binding. Antimicrob. Agents Chemother. 2004;48:568–574

PII: S1368-7646(09)00062-4

doi: 10.1016/j.drup.2009.09.002

Drug Resistance Updates
Volume 12, Issue 6 , Pages 141-147 , December 2009

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