title: Wild-type MIC distribution and epidemiological cutoff values for Aspergillus fumigatus and three triazoles as determined by the Clinical and Laboratory Standards Institute broth microdilution methods.
abstract: Antifungal susceptibility testing of Aspergillus species has been standardized by both the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Recent studies suggest the emergence of strains of Aspergillus fumigatus with acquired resistance to azoles. The mechanisms of resistance involve mutations in the cyp51A (sterol demethylase) gene, and patterns of azole cross-resistance have been linked to specific mutations. Studies using the EUCAST broth microdilution (BMD) method have defined wild-type (WT) MIC distributions, epidemiological cutoff values (ECVs), and cross-resistance among the azoles. We tested a collection of 637 clinical isolates of A. fumigatus for which itraconazole MICs were < or = 2 microg/ml against posaconazole and voriconazole using the CLSI BMD method. An ECV of < or = 1 microg/ml encompassed the WT population of A. fumigatus for itraconazole and voriconazole, whereas an ECV of < or = 0.25 microg/ml was established for posaconazole. Our results demonstrate that the WT distribution and ECVs for A. fumigatus and the mold-active triazoles were the same when determined by the CLSI or the EUCAST BMD method. A collection of 43 isolates for which itraconazole MICs fell outside of the ECV were used to assess cross-resistance. Cross-resistance between itraconazole and posaconazole was seen for 53.5% of the isolates, whereas cross-resistance between itraconazole and voriconazole was apparent in only 7% of the isolates. The establishment of the WT MIC distribution and ECVs for the azoles and A. fumigatus will be useful in resistance surveillance and is an important step toward the development of clinical breakpoints.
authors.affiliation: Medical Microbiology Division, Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA. michael-pfaller@uiowa.edu
authors.forename: M A
authors.initials: MA
authors.lastname: Pfaller
authors.forename: D J
authors.initials: DJ
authors.lastname: Diekema
authors.forename: M A
authors.initials: MA
authors.lastname: Ghannoum
authors.forename: J H
authors.initials: JH
authors.lastname: Rex
authors.forename: B D
authors.initials: BD
authors.lastname: Alexander
authors.forename: D
authors.initials: D
authors.lastname: Andes
authors.forename: S D
authors.initials: SD
authors.lastname: Brown
authors.forename: V
authors.initials: V
authors.lastname: Chaturvedi
authors.forename: A
authors.initials: A
authors.lastname: Espinel-Ingroff
authors.forename: C L
authors.initials: CL
authors.lastname: Fowler
authors.forename: E M
authors.initials: EM
authors.lastname: Johnson
authors.forename: C C
authors.initials: CC
authors.lastname: Knapp
authors.forename: M R
authors.initials: MR
authors.lastname: Motyl
authors.forename: L
authors.initials: L
authors.lastname: Ostrosky-Zeichner
authors.forename: D J
authors.initials: DJ
authors.lastname: Sheehan
authors.forename: T J
authors.initials: TJ
authors.lastname: Walsh
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001228:Aspergillosis / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000302:isolation & purification; D025141:Drug Resistance, Fungal; D008826:Microbial Sensitivity Tests; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D014230:Triazoles
references.citation: Antimicrob Agents Chemother. 2002 Feb;46(2):556-7
references.pmid: 11796377
references.citation: Med Mycol. 2006 Sep 1;44(Supplement_1):S319-S325
references.pmid: 30408924
references.citation: Clin Microbiol Rev. 2007 Jan;20(1):133-63
references.pmid: 17223626
references.citation: Clin Infect Dis. 2009 Feb 1;48(3):265-73
references.pmid: 19115967
references.citation: Clin Infect Dis. 2008 Feb 1;46(3):327-60
references.pmid: 18177225
references.citation: Diagn Microbiol Infect Dis. 2004 Mar;48(3):153-60
references.pmid: 15023422
references.citation: Antimicrob Agents Chemother. 2003 Mar;47(3):1120-4
references.pmid: 12604551
references.citation: Medicine (Baltimore). 2000 Jul;79(4):250-60
references.pmid: 10941354
references.citation: J Clin Microbiol. 2003 Aug;41(8):3623-6
references.pmid: 12904365
references.citation: Clin Microbiol Infect. 2006 May;12(5):418-25
references.pmid: 16643517
references.citation: Antimicrob Agents Chemother. 2007 Jun;51(6):1897-904
references.pmid: 17371828
references.citation: Clin Infect Dis. 2003 May 1;36(9):1122-31
references.pmid: 12715306
references.citation: J Antimicrob Chemother. 2005 Jan;55(1):31-7
references.pmid: 15563516
references.citation: J Clin Microbiol. 2008 Aug;46(8):2568-72
references.pmid: 18562581
references.citation: Rev Iberoam Micol. 2003 Dec;20(4):121-36
references.pmid: 15456349
references.citation: Antimicrob Agents Chemother. 2004 Jul;48(7):2747-50
references.pmid: 15215142
references.citation: Antimicrob Agents Chemother. 2008 Sep;52(9):3444-6
references.pmid: 18606840
references.citation: Int J Antimicrob Agents. 1999 Aug;12(3):213-9
references.pmid: 10461839
references.citation: Antimicrob Agents Chemother. 2005 Jun;49(6):2536-8
references.pmid: 15917566
references.citation: Curr Opin Infect Dis. 2006 Dec;19(6):538-43
references.pmid: 17075328
references.citation: N Engl J Med. 2007 Apr 5;356(14):1481-3
references.pmid: 17409336
references.citation: Clin Infect Dis. 2007 Jan 1;44(1):2-12
references.pmid: 17143808
references.citation: J Antimicrob Chemother. 2008 Jan;61 Suppl 1:i13-8
references.pmid: 18063599
references.citation: Diagn Microbiol Infect Dis. 2004 Oct;50(2):119-24
references.pmid: 15474321
references.citation: Clin Microbiol Rev. 2007 Jul;20(3):391-408, table of contents
references.pmid: 17630331
references.citation: N Engl J Med. 2002 Aug 8;347(6):408-15
references.pmid: 12167683
references.citation: Antimicrob Agents Chemother. 2004 Feb;48(2):568-74
references.pmid: 14742211
references.citation: Antimicrob Agents Chemother. 2008 Apr;52(4):1244-51
references.pmid: 18212093
references.citation: Antimicrob Agents Chemother. 2008 Oct;52(10):3504-11
references.pmid: 18644959
references.citation: J Clin Microbiol. 2007 Jun;45(6):1884-8
references.pmid: 17409208
references.citation: Antimicrob Agents Chemother. 2008 Jul;52(7):2468-72
references.pmid: 18474574
references.citation: Clin Infect Dis. 2008 Jan 1;46(1):120-8
references.pmid: 18171227
references.citation: Antimicrob Agents Chemother. 2003 May;47(5):1719-26
references.pmid: 12709346
references.citation: Blood. 2002 Dec 15;100(13):4358-66
references.pmid: 12393425
references.citation: J Med Microbiol. 2006 Oct;55(Pt 10):1457-1459
references.pmid: 17005798
references.citation: Int J Antimicrob Agents. 2006 Nov;28(5):450-3
references.pmid: 17034993
references.citation: Antimicrob Agents Chemother. 2005 May;49(5):2119-21
references.pmid: 15855543
references.citation: Infect Dis Clin North Am. 2006 Sep;20(3):545-61, vi
references.pmid: 16984868
references.citation: J Clin Microbiol. 2007 Jan;45(1):109-11
references.pmid: 17093015
references.citation: J Clin Microbiol. 2005 Jan;43(1):214-22
references.pmid: 15634974
references.citation: Antimicrob Agents Chemother. 2003 Feb;47(2):577-81
references.pmid: 12543662
references.citation: Antimicrob Agents Chemother. 2001 Jun;45(6):1828-35
references.pmid: 11353633
references.citation: Clin Infect Dis. 2008 Oct 15;47(8):1041-50
references.pmid: 18781877
references.citation: Clin Infect Dis. 2000 Dec;31(6):1524-8
references.pmid: 11096031
references.citation: Antimicrob Agents Chemother. 1997 Jun;41(6):1364-8
references.pmid: 9174200
references.citation: J Antimicrob Chemother. 2003 Aug;52(2):145-8
references.pmid: 12837738
references.citation: J Antimicrob Chemother. 2002 Feb;49(2):415-9
references.pmid: 11815592