Skip to main content

Advertisement

SpringerLink
Log in

Antifungal Resistance Testing and Implications for Management

  • Advances in Diagnosis of Invasive Fungal Infections (O Morrissey, Section Editor)
  • Published:
Current Fungal Infection Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Antifungal agents are the mainstay in the management of patients with invasive fungal disease. However, resistance to current antifungal agents can develop with clinical use, which may negatively impact clinical outcomes. We review the strengths and weaknesses of antifungal susceptibility testing and how the detection of resistance, either phenotypically or molecularly, correlates with clinical outcomes.

Recent Findings

Phenotypic resistance is associated with worse outcomes, although this must be taken in context with other patient factors. Newer molecular assays have been developed that have shown promising results for the detection of resistance mechanisms, including azole resistance in Aspergillus fumigatus and echinocandin resistance in different Candida species. Further work is needed to improve the clinical utility of these assays for faster turn-around-time and direct use on specimens.

Summary

Detection of antifungal resistance may provide useful information for the treatment of invasive fungal disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. WHO. Antimicrobial resistance: global report on surveillance: World Health Organization; 2014 [Available from: http://www.who.int/drugresistance/documents/surveillancereport/en/].

  2. Lockhart SR, Etienne KA, Vallabhaneni S, Farooqi J, Chowdhary A, Govender NP, et al. Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses. Clin Infect Dis. 2017;64(2):134–40. https://doi.org/10.1093/cid/ciw691.

    Article  CAS  PubMed  Google Scholar 

  3. Chow NA, Gade L, Tsay SV, Forsberg K, Greenko JA, Southwick KL, et al. Multiple introductions and subsequent transmission of multidrug-resistant Candida auris in the USA: a molecular epidemiological survey. Lancet Infect Dis. 2018. https://doi.org/10.1016/S1473-3099(18)30597-8.

    Article  Google Scholar 

  4. Chowdhary A, Sharma C, Meis JF. Candida auris: A rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally. PLoS Pathog. 2017;13(5):e1006290. https://doi.org/10.1371/journal.ppat.1006290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. • Meis JF, Chowdhary A, Rhodes JL, Fisher MC, Verweij PE. Clinical implications of globally emerging azole resistance in Aspergillus fumigatus. Philos Trans R Soc Lond B Biol Sci. 2016;371(1709). https://doi.org/10.1098/rstb.2015.0460Comprehensive review of azole resistance inA. fumigatus.

    Article  Google Scholar 

  6. Bueid A, Howard SJ, Moore CB, Richardson MD, Harrison E, Bowyer P, et al. Azole antifungal resistance in Aspergillus fumigatus: 2008 and 2009. J Antimicrob Chemother. 2010;65(10):2116–8. https://doi.org/10.1093/jac/dkq279.

    Article  CAS  PubMed  Google Scholar 

  7. Howard SJ, Cerar D, Anderson MJ, Albarrag A, Fisher MC, Pasqualotto AC, et al. Frequency and evolution of azole resistance in Aspergillus fumigatus associated with treatment failure. Emerg Infect Dis. 2009;15(7):1068–76. https://doi.org/10.3201/eid1507.090043.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Snelders E, van der Lee HA, Kuijpers J, Rijs AJ, Varga J, Samson RA, et al. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLoS medicine. 2008;5(11):e219. https://doi.org/10.1371/journal.pmed.0050219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Pfaller MA, Diekema DJ, Andes D, Arendrup MC, Brown SD, Lockhart SR, et al. Clinical breakpoints for the echinocandins and Candida revisited: integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy. 2011;14(3):164–76. https://doi.org/10.1016/j.drup.2011.01.004.

    Article  CAS  Google Scholar 

  10. Pfaller MA, Rex JH, Rinaldi MG. Antifungal susceptibility testing: technical advances and potential clinical applications. Clin Infect Dis. 1997;24(5):776–84. https://doi.org/10.1093/clinids/24.5.776.

    Article  CAS  PubMed  Google Scholar 

  11. Rex JH, Pfaller MA. Has antifungal susceptibility testing come of age? Clin Infect Dis. 2002;35(8):982–9. https://doi.org/10.1086/342384.

    Article  CAS  PubMed  Google Scholar 

  12. Arendrup MC, Cuenca-Estrella M, Lass-Florl C, Hope W, Eucast A. EUCAST technical note on the EUCAST definitive document EDef 7.2: method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for yeasts EDef 7.2 (EUCAST-AFST). Clin Microbiol Infect. 2012;18(7):E246–7. https://doi.org/10.1111/j.1469-0691.2012.03880.x.

    Article  CAS  PubMed  Google Scholar 

  13. CLSI. Reference method for broth dilution antifungal susceptibility testing of yeasts; Approved standard - Fourth Edition. Clinical and Laboratory Standards Institute: Wayne, PA; 2017.

    Google Scholar 

  14. CLSI. Reference method for broth dilution antifungal susceptibility testing of filamentous fungi, third edition. Clinical and Laboratory Standards Institute: Wayne, PA; 2017.

    Google Scholar 

  15. CLSI. Method for antifungal disk diffusion susceptibility testing of yeasts, third edition. Clinical and Laboratory Standards Institute: Wayne, PA; 2018.

    Google Scholar 

  16. Pfaller MA, Andes D, Diekema DJ, Espinel-Ingroff A, Sheehan D. Testing CSfAS. Wild-type MIC distributions, epidemiological cutoff values and species-specific clinical breakpoints for fluconazole and Candida: time for harmonization of CLSI and EUCAST broth microdilution methods. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy. 2010;13(6):180–95. https://doi.org/10.1016/j.drup.2010.09.002.

    Article  CAS  Google Scholar 

  17. Garey KW, Rege M, Pai MP, Mingo DE, Suda KJ, Turpin RS, et al. Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis. 2006;43(1):25–31. https://doi.org/10.1086/504810.

    Article  CAS  PubMed  Google Scholar 

  18. CLSI. Performance standards for antifungal susceptibility testing of yeasts, first edition. Clinical and Laboratory Standards Institute: Wayne, PA; 2017.

    Google Scholar 

  19. EUCAST. EUCAST Antifungal agents breapoint tables for interpretation of MICs 2018 [Available from: http://www.eucast.org/astoffungi/clinicalbreakpointsforantifungals/].

  20. Pfaller MA, Diekema DJ. Progress in antifungal susceptibility testing of Candida spp. by use of Clinical and Laboratory Standards Institute broth microdilution methods, 2010 to 2012. J Clin Microbiol. 2012;50(9):2846–56. https://doi.org/10.1128/JCM.00937-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Turnidge J, Paterson DL. Setting and revising antibacterial susceptibility breakpoints. Clin Microbiol Rev. 2007;20(3):391–408, table of contents. https://doi.org/10.1128/CMR.00047-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. •• Patel TS, Carver PL, Eschenauer GA. Are in vitro susceptibilities to azole antifungals predictive of clinical outcome in the treatment of candidemia? J Clin Microbiol. 2018;56(12). https://doi.org/10.1128/JCM.01072-18Comprehensive review of azole phenotypic susceptibility testing and correlations with outcomes in patients with candidemia.

  23. CLSI. Epidemiological cutoff values for antiufngal susceptibility testing, second edition. Clinical and Laboratory Standards Institute: Wayne, PA; 2018.

    Google Scholar 

  24. Espinel-Ingroff A, Arendrup M, Canton E, Cordoba S, Dannaoui E, Garcia-Rodriguez J, et al. Multicenter study of method-dependent epidemiological cutoff values for detection of resistance in Candida spp. and Aspergillus spp. to amphotericin B and echinocandins for the Etest Agar Diffusion Method. Antimicrob Agents Chemother. 2017;61(1). https://doi.org/10.1128/AAC.01792-16.

  25. Espinel-Ingroff A, Colombo AL, Cordoba S, Dufresne PJ, Fuller J, Ghannoum M, et al. International evaluation of mic distributions and epidemiological cutoff value (ECV) definitions for Fusarium species identified by molecular methods for the CLSI broth microdilution method. Antimicrob Agents Chemother. 2016;60(2):1079–84. https://doi.org/10.1128/AAC.02456-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Espinel-Ingroff A, Turnidge J, Alastruey-Izquierdo A, Botterel F, Canton E, Castro C, et al. Method-dependent epidemiological cutoff values for detection of triazole resistance in Candida and Aspergillus species for the Sensititre YeastOne colorimetric broth and Etest agar diffusion methods. Antimicrob Agents Chemother. 2019;63(1). https://doi.org/10.1128/AAC.01651-18.

  27. 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(2):235–47. https://doi.org/10.1093/clinids/24.2.235.

    Article  CAS  PubMed  Google Scholar 

  28. Baddley JW, Patel M, Bhavnani SM, Moser SA, Andes DR. Association of fluconazole pharmacodynamics with mortality in patients with candidemia. Antimicrob Agents Chemother. 2008;52(9):3022–8. https://doi.org/10.1128/AAC.00116-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Clancy CJ, Yu VL, Morris AJ, Snydman DR, Nguyen MH. Fluconazole MIC and the fluconazole dose/MIC ratio correlate with therapeutic response among patients with candidemia. Antimicrob Agents Chemother. 2005;49(8):3171–7. https://doi.org/10.1128/AAC.49.8.3171-3177.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lee SC, Fung CP, Huang JS, Tsai CJ, Chen KS, Chen HY, et al. Clinical correlates of antifungal macrodilution susceptibility test results for non-AIDS patients with severe Candida infections treated with fluconazole. Antimicrob Agents Chemother. 2000;44(10):2715–8. https://doi.org/10.1128/aac.44.10.2715-2718.2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pai MP, Turpin RS, Garey KW. Association of fluconazole area under the concentration-time curve/MIC and dose/MIC ratios with mortality in nonneutropenic patients with candidemia. Antimicrob Agents Chemother. 2007;51(1):35–9. https://doi.org/10.1128/AAC.00474-06.

    Article  CAS  PubMed  Google Scholar 

  32. Rodriguez-Tudela JL, Almirante B, Rodriguez-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(10):3599–604. https://doi.org/10.1128/AAC.00296-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Clancy CJ, Staley B, Nguyen MH. In vitro susceptibility of breakthrough Candida bloodstream isolates correlates with daily and cumulative doses of fluconazole. Antimicrob Agents Chemother. 2006;50(10):3496–8. https://doi.org/10.1128/AAC.00741-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Eschenauer GA, Carver PL, Lin SW, Klinker KP, Chen YC, Potoski BA, et al. Fluconazole versus an echinocandin for Candida glabrata fungaemia: a retrospective cohort study. J Antimicrob Chemother. 2013;68(4):922–6. https://doi.org/10.1093/jac/dks482.

    Article  CAS  PubMed  Google Scholar 

  35. Brosh-Nissimov T, Ben-Ami R. Differential association of fluconazole dose and dose/MIC ratio with mortality in patients with Candida albicans and non-albicans bloodstream infection. Clin Microbiol Infect. 2015;21(11):1011–7. https://doi.org/10.1016/j.cmi.2015.07.005.

    Article  CAS  PubMed  Google Scholar 

  36. Fernandez-Ruiz M, Guinea J, Lora-Pablos D, Zaragoza O, Puig-Asensio M, Almirante B, et al. Impact of fluconazole susceptibility on the outcome of patients with candidaemia: data from a population-based surveillance. Clin Microbiol Infect. 2017;23(9):672 e1- e11. https://doi.org/10.1016/j.cmi.2017.01.014.

    Article  CAS  Google Scholar 

  37. Eschenauer GA, Carver PL, Patel TS, Lin SW, Klinker KP, Pai MP, et al. Survival in patients with Candida glabrata bloodstream infection is associated with fluconazole dose. Antimicrob Agents Chemother. 2018;62(6). https://doi.org/10.1128/AAC.02566-17.

  38. Pfaller MA, Diekema DJ, Rex JH, Espinel-Ingroff A, Johnson EM, Andes D, et al. Correlation of MIC with outcome for Candida species tested against voriconazole: analysis and proposal for interpretive breakpoints. J Clin Microbiol. 2006;44(3):819–26. https://doi.org/10.1128/JCM.44.3.819-826.2006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Testing ECoAS. Voriconazole: rationale for the clinical breakpoints, version 2.0 2010 [Available from: http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Rationale_documents/Voriconazole_Rationale_Document_version_2.0_March_2010.pdf].

  40. Dannaoui E, Abdul M, Arpin M, Michel-Nguyen A, Piens MA, Favel A, et al. Results obtained with various antifungal susceptibility testing methods do not predict early clinical outcome in patients with cryptococcosis. Antimicrob Agents Chemother. 2006;50(7):2464–70. https://doi.org/10.1128/AAC.01520-05.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Vena A, Munoz P, Guinea J, Escribano P, Pelaez T, Valerio M, et al. Fluconazole resistance is not a predictor of poor outcome in patients with cryptococcosis. Mycoses. 2019;62(5):441–9. https://doi.org/10.1111/myc.12847.

    Article  CAS  PubMed  Google Scholar 

  42. Lee CH, Chang TY, Liu JW, Chen FJ, Chien CC, Tang YF, et al. Correlation of anti-fungal susceptibility with clinical outcomes in patients with cryptococcal meningitis. BMC Infect Dis. 2012;12:361. https://doi.org/10.1186/1471-2334-12-361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Aller AI, Martin-Mazuelos E, Lozano F, Gomez-Mateos J, Steele-Moore L, Holloway WJ, et al. Correlation of fluconazole MICs with clinical outcome in cryptococcal infection. Antimicrob Agents Chemother. 2000;44(6):1544–8. https://doi.org/10.1128/aac.44.6.1544-1548.2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kartsonis N, Killar J, Mixson L, Hoe CM, Sable C, Bartizal K, et al. Caspofungin susceptibility testing of isolates from patients with esophageal candidiasis or invasive candidiasis: relationship of MIC to treatment outcome. Antimicrob Agents Chemother. 2005;49(9):3616–23. https://doi.org/10.1128/AAC.49.9.3616-3623.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Laverdiere M, Lalonde RG, Baril JG, Sheppard DC, Park S, Perlin DS. Progressive loss of echinocandin activity following prolonged use for treatment of Candida albicans oesophagitis. J Antimicrob Chemother. 2006;57(4):705–8. https://doi.org/10.1093/jac/dkl022.

    Article  CAS  PubMed  Google Scholar 

  46. Thompson GR 3rd, Wiederhold NP, Vallor AC, Villareal NC, Lewis JS 2nd, Patterson TF. Development of caspofungin resistance following prolonged therapy for invasive candidiasis secondary to Candida glabrata infection. Antimicrob Agents Chemother. 2008;52(10):3783–5. https://doi.org/10.1128/AAC.00473-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lewis JS 2nd, Wiederhold NP, Wickes BL, Patterson TF, Jorgensen JH. Rapid emergence of echinocandin resistance in Candida glabrata resulting in clinical and microbiologic failure. Antimicrob Agents Chemother. 2013;57(9):4559–61. https://doi.org/10.1128/AAC.01144-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hernandez S, Lopez-Ribot JL, Najvar LK, McCarthy DI, Bocanegra R, Graybill JR. Caspofungin resistance in Candida albicans: correlating clinical outcome with laboratory susceptibility testing of three isogenic isolates serially obtained from a patient with progressive Candida esophagitis. Antimicrob Agents Chemother. 2004;48(4):1382–3. https://doi.org/10.1128/aac.48.4.1382-1383.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Miller CD, Lomaestro BW, Park S, Perlin DS. Progressive esophagitis caused by Candida albicans with reduced susceptibility to caspofungin. Pharmacotherapy. 2006;26(6):877–80. https://doi.org/10.1592/phco.26.6.877.

    Article  PubMed  Google Scholar 

  50. Cleary JD, Garcia-Effron G, Chapman SW, Perlin DS. Reduced Candida glabrata susceptibility secondary to an FKS1 mutation developed during candidemia treatment. Antimicrob Agents Chemother. 2008;52(6):2263–5. https://doi.org/10.1128/AAC.01568-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hakki M, Staab JF, Marr KA. Emergence of a Candida krusei isolate with reduced susceptibility to caspofungin during therapy. Antimicrob Agents Chemother. 2006;50(7):2522–4. https://doi.org/10.1128/AAC.00148-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Krogh-Madsen M, Arendrup MC, Heslet L, Knudsen JD. Amphotericin B and caspofungin resistance in Candida glabrata isolates recovered from a critically ill patient. Clin Infect Dis. 2006;42(7):938–44. https://doi.org/10.1086/500939.

    Article  CAS  PubMed  Google Scholar 

  53. Wiederhold NP, Najvar LK, Bocanegra RA, Kirkpatrick WR, Patterson TF. Caspofungin dose escalation for invasive candidiasis due to resistant Candida albicans. Antimicrob Agents Chemother. 2011;55(7):3254–60. https://doi.org/10.1128/AAC.01750-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lackner M, Tscherner M, Schaller M, Kuchler K, Mair C, Sartori B, et al. Positions and numbers of FKS mutations in Candida albicans selectively influence in vitro and in vivo susceptibilities to echinocandin treatment. Antimicrob Agents Chemother. 2014;58(7):3626–35. https://doi.org/10.1128/AAC.00123-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Alexander BD, Johnson MD, Pfeiffer CD, Jimenez-Ortigosa C, Catania J, Booker R, et al. Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis. 2013;56(12):1724–32. https://doi.org/10.1093/cid/cit136.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Beyda ND, John J, Kilic A, Alam MJ, Lasco TM, Garey KW. FKS mutant Candida glabrata: risk factors and outcomes in patients with candidemia. Clin Infect Dis. 2014;59(6):819–25. https://doi.org/10.1093/cid/ciu407.

    Article  CAS  PubMed  Google Scholar 

  57. Shields RK, Nguyen MH, Press EG, Kwa AL, Cheng S, Du C, et al. The presence of an FKS mutation rather than MIC is an independent risk factor for failure of echinocandin therapy among patients with invasive candidiasis due to Candida glabrata. Antimicrob Agents Chemother. 2012;56(9):4862–9. https://doi.org/10.1128/AAC.00027-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Shields RK, Nguyen MH, Press EG, Updike CL, Clancy CJ. Anidulafungin and micafungin MIC breakpoints are superior to that of caspofungin for identifying FKS mutant Candida glabrata strains and Echinocandin resistance. Antimicrob Agents Chemother. 2013;57(12):6361–5. https://doi.org/10.1128/AAC.01451-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Espinel-Ingroff A, Arendrup MC, Pfaller MA, Bonfietti LX, Bustamante B, Canton E, et al. Interlaboratory variability of Caspofungin MICs for Candida spp. Using CLSI and EUCAST methods: should the clinical laboratory be testing this agent? Antimicrob Agents Chemother. 2013;57(12):5836–42. https://doi.org/10.1128/AAC.01519-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Eschenauer GA, Nguyen MH, Shoham S, Vazquez JA, Morris AJ, Pasculle WA, et al. Real-world experience with echinocandin MICs against Candida species in a multicenter study of hospitals that routinely perform susceptibility testing of bloodstream isolates. Antimicrob Agents Chemother. 2014;58(4):1897–906. https://doi.org/10.1128/AAC.02163-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Arendrup MC, Rodriguez-Tudela JL, Lass-Florl C, Cuenca-Estrella M, Donnelly JP, Hope W, et al. EUCAST technical note on anidulafungin. Clin Microbiol Infect. 2011;17(11):E18–20. https://doi.org/10.1111/j.1469-0691.2011.03647.x.

    Article  CAS  PubMed  Google Scholar 

  62. Arendrup MC, Perlin DS, Jensen RH, Howard SJ, Goodwin J, Hope W. Differential in vivo activities of anidulafungin, caspofungin, and micafungin against Candida glabrata isolates with and without FKS resistance mutations. Antimicrob Agents Chemother. 2012;56(5):2435–42. https://doi.org/10.1128/AAC.06369-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Pfaller MA, Diekema DJ, Jones RN, Castanheira M. Use of anidulafungin as a surrogate marker to predict susceptibility and resistance to caspofungin among 4,290 clinical isolates of Candida by using CLSI methods and interpretive criteria. J Clin Microbiol. 2014;52(9):3223–9. https://doi.org/10.1128/JCM.00782-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Pfaller MA, Messer SA, Diekema DJ, Jones RN, Castanheira M. Use of micafungin as a surrogate marker to predict susceptibility and resistance to caspofungin among 3,764 clinical isolates of Candida by use of CLSI methods and interpretive criteria. J Clin Microbiol. 2014;52(1):108–14. https://doi.org/10.1128/JCM.02481-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ullmann AJ, Aguado JM, Arikan-Akdagli S, Denning DW, Groll AH, Lagrou K, et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect. 2018;24(Suppl 1):e1–e38. https://doi.org/10.1016/j.cmi.2018.01.002.

    Article  PubMed  Google Scholar 

  66. Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious diseases society of America. Clin Infect Dis. 2016;63(4):e1–e60. https://doi.org/10.1093/cid/ciw326.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Verweij PE, Mellado E, Melchers WJ. Multiple-triazole-resistant aspergillosis. N Engl J Med. 2007;356(14):1481–3. https://doi.org/10.1056/NEJMc061720.

    Article  CAS  PubMed  Google Scholar 

  68. Denning DW, Venkateswarlu K, Oakley KL, Anderson MJ, Manning NJ, Stevens DA, et al. Itraconazole resistance in Aspergillus fumigatus. Antimicrob Agents Chemother. 1997;41(6):1364–8.

    Article  CAS  Google Scholar 

  69. 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(5):509–12.

    Article  CAS  Google Scholar 

  70. 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(3):401–14. https://doi.org/10.1093/jac/40.3.401.

    Article  CAS  PubMed  Google Scholar 

  71. Seyedmousavi S, Bruggemann RJ, Meis JF, Melchers WJ, Verweij PE, Mouton JW. Pharmacodynamics of isavuconazole in an Aspergillus fumigatus mouse infection model. Antimicrob Agents Chemother. 2015;59(5):2855–66. https://doi.org/10.1128/AAC.04907-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. •• Heo ST, Tatara AM, Jimenez-Ortigosa C, Jiang Y, Lewis RE, Tarrand J, et al. Changes in in vitro susceptibility patterns of Aspergillus to triazoles and correlation with aspergillosis outcome in a tertiary care cancer center, 1999-2015. Clin Infect Dis. 2017;65(2):216–25. https://doi.org/10.1093/cid/cix297Large single-center study in hematology and/or stem cell transplant receipients with invasive aspergillosis that found no correlation between phenotypic azole resistance and mortality, and also reported no mutations withinCYP51A.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Steinmann J, Hamprecht A, Vehreschild MJ, Cornely OA, Buchheidt D, Spiess B, et al. Emergence of azole-resistant invasive aspergillosis in HSCT recipients in Germany. J Antimicrob Chemother. 2015;70(5):1522–6. https://doi.org/10.1093/jac/dku566.

    Article  CAS  PubMed  Google Scholar 

  74. Wiederhold NP, Gil VG, Gutierrez F, Lindner JR, Albataineh MT, McCarthy DI, et al. First Detection of TR34 L98H and TR46 Y121F T289A Cyp51 Mutations in Aspergillus fumigatus Isolates in the United States. J Clin Microbiol. 2016;54(1):168–71. https://doi.org/10.1128/JCM.02478-15.

    Article  CAS  PubMed  Google Scholar 

  75. Ahmad S, Khan Z, Hagen F, Meis JF. Simple, low-cost molecular assays for TR34/L98H mutations in the cyp51A gene for rapid detection of triazole-resistant Aspergillus fumigatus isolates. J Clin Microbiol. 2014;52(6):2223–7. https://doi.org/10.1128/JCM.00408-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Mahmoudi S, Badali H, Rezaie S, Azarnezhad A, Barac A, Kord M, et al. A simple and low cost tetra-primer ARMS-PCR method for detection triazole-resistant Aspergillus fumigatus. Mol Biol Rep. 2019;46(4):4537–43. https://doi.org/10.1007/s11033-019-04909-1.

    Article  CAS  PubMed  Google Scholar 

  77. Trama JP, Mordechai E, Adelson ME. Detection of Aspergillus fumigatus and a mutation that confers reduced susceptibility to itraconazole and posaconazole by real-time PCR and pyrosequencing. J Clin Microbiol. 2005;43(2):906–8. https://doi.org/10.1128/JCM.43.2.906-908.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wiederhold NP, Grabinski JL, Garcia-Effron G, Perlin DS, Lee SA. Pyrosequencing to detect mutations in FKS1 that confer reduced echinocandin susceptibility in Candida albicans. Antimicrob Agents Chemother. 2008;52(11):4145–8. https://doi.org/10.1128/AAC.00959-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhao Y, Nagasaki Y, Kordalewska M, Press EG, Shields RK, Nguyen MH, et al. Rapid detection of FKS-associated echinocandin resistance in Candida glabrata. Antimicrob Agents Chemother. 2016;60(11):6573–7. https://doi.org/10.1128/AAC.01574-16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Bernal-Martinez L, Gil H, Rivero-Menendez O, Gago S, Cuenca-Estrella M, Mellado E, et al. Development and validation of a high-resolution melting assay to detect azole resistance in Aspergillus fumigatus. Antimicrob Agents Chemother. 2017;61(12). https://doi.org/10.1128/AAC.01083-17.

  81. Balashov SV, Park S, Perlin DS. Assessing resistance to the echinocandin antifungal drug caspofungin in Candida albicans by profiling mutations in FKS1. Antimicrob Agents Chemother. 2006;50(6):2058–63. https://doi.org/10.1128/AAC.01653-05.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Pham CD, Bolden CB, Kuykendall RJ, Lockhart SR. Development of a Luminex-based multiplex assay for detection of mutations conferring resistance to Echinocandins in Candida glabrata. J Clin Microbiol. 2014;52(3):790–5. https://doi.org/10.1128/JCM.03378-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Gygax SE, Vermitsky JP, Chadwick SG, Self MJ, Zimmerman JA, Mordechai E, et al. Antifungal resistance of Candida glabrata vaginal isolates and development of a quantitative reverse transcription-PCR-based azole susceptibility assay. Antimicrob Agents Chemother. 2008;52(9):3424–6. https://doi.org/10.1128/AAC.00462-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang H, Kong F, Sorrell TC, Wang B, McNicholas P, Pantarat N, et al. Rapid detection of ERG11 gene mutations in clinical Candida albicans isolates with reduced susceptibility to fluconazole by rolling circle amplification and DNA sequencing. BMC Microbiol. 2009;9:167. https://doi.org/10.1186/1471-2180-9-167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Perlin DS, Wiederhold NP. Culture-independent molecular methods for detection of antifungal resistance mechanisms and fungal identification. J Infect Dis. 2017;216(suppl_3):S458–S65. https://doi.org/10.1093/infdis/jix121.

    Article  CAS  PubMed  Google Scholar 

  86. Douglas CM, D'Ippolito JA, Shei GJ, Meinz M, Onishi J, Marrinan JA, et al. Identification of the FKS1 gene of Candida albicans as the essential target of 1,3-beta-D-glucan synthase inhibitors. Antimicrob Agents Chemother. 1997;41(11):2471–9.

    Article  CAS  Google Scholar 

  87. Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS. Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint. Antimicrob Agents Chemother. 2009;53(9):3690–9. https://doi.org/10.1128/AAC.00443-09.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Garcia-Effron G, Park S, Perlin DS. Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints. Antimicrob Agents Chemother. 2009;53(1):112–22. https://doi.org/10.1128/AAC.01162-08.

    Article  CAS  PubMed  Google Scholar 

  89. Baixench MT, Aoun N, Desnos-Ollivier M, Garcia-Hermoso D, Bretagne S, Ramires S, et al. Acquired resistance to echinocandins in Candida albicans: case report and review. J Antimicrob Chemother. 2007;59(6):1076–83. https://doi.org/10.1093/jac/dkm095.

    Article  CAS  PubMed  Google Scholar 

  90. Perlin DS. Echinocandin resistance in Candida. Clin Infect Dis. 2015;61(Suppl 6):S612–7. https://doi.org/10.1093/cid/civ791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Dudiuk C, Gamarra S, Leonardeli F, Jimenez-Ortigosa C, Vitale RG, Afeltra J, et al. Set of classical PCRs for detection of mutations in Candida glabrata FKS genes linked with echinocandin resistance. J Clin Microbiol. 2014;52(7):2609–14. https://doi.org/10.1128/JCM.01038-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Garcia-Effron G, Dilger A, Alcazar-Fuoli L, Park S, Mellado E, Perlin DS. Rapid detection of triazole antifungal resistance in Aspergillus fumigatus. J Clin Microbiol. 2008;46(4):1200–6. https://doi.org/10.1128/JCM.02330-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Xu H, Chen W, Li L, Wan Z, Li R, Liu W. Clinical itraconazole-resistant strains of Aspergillus fumigatus, isolated serially from a lung aspergilloma patient with pulmonary tuberculosis, can be detected with real-time PCR method. Mycopathologia. 2010;169(3):193–9. https://doi.org/10.1007/s11046-009-9249-x.

    Article  CAS  PubMed  Google Scholar 

  94. Denning DW, Park S, Lass-Florl C, Fraczek MG, Kirwan M, Gore R, et al. High-frequency triazole resistance found In nonculturable Aspergillus fumigatus from lungs of patients with chronic fungal disease. Clin Infect Dis. 2011;52(9):1123–9. https://doi.org/10.1093/cid/cir179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Zhao Y, Stensvold CR, Perlin DS, Arendrup MC. Azole resistance in Aspergillus fumigatus from bronchoalveolar lavage fluid samples of patients with chronic diseases. J Antimicrob Chemother. 2013;68(7):1497–504. https://doi.org/10.1093/jac/dkt071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Dudakova A, Spiess B, Tangwattanachuleeporn M, Sasse C, Buchheidt D, Weig M, et al. Molecular tools for the detection and deduction of azole antifungal drug resistance phenotypes in Aspergillus species. Clin Microbiol Rev. 2017;30(4):1065–91. https://doi.org/10.1128/CMR.00095-16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Chong GL, van de Sande WW, Dingemans GJ, Gaajetaan GR, Vonk AG, Hayette MP, et al. Validation of a new Aspergillus real-time PCR assay for direct detection of Aspergillus and azole resistance of Aspergillus fumigatus on bronchoalveolar lavage fluid. J Clin Microbiol. 2015;53(3):868–74. https://doi.org/10.1128/JCM.03216-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Chong GM, van der Beek MT, von dem Borne PA, Boelens J, Steel E, Kampinga GA, et al. PCR-based detection of Aspergillus fumigatus Cyp51A mutations on bronchoalveolar lavage: a multicentre validation of the AsperGenius assay(R) in 201 patients with haematological disease suspected for invasive aspergillosis. J Antimicrob Chemother. 2016;71(12):3528–35. https://doi.org/10.1093/jac/dkw323.

    Article  CAS  PubMed  Google Scholar 

  99. Slaven JW, Anderson MJ, Sanglard D, Dixon GK, Bille J, Roberts IS, 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(3):199–206.

    Article  CAS  Google Scholar 

  100. Fraczek MG, Bromley M, Buied A, Moore CB, Rajendran R, Rautemaa R, et al. The cdr1B efflux transporter is associated with non-cyp51a-mediated itraconazole resistance in Aspergillus fumigatus. J Antimicrob Chemother. 2013;68(7):1486–96. https://doi.org/10.1093/jac/dkt075.

    Article  CAS  PubMed  Google Scholar 

  101. Camps SM, Dutilh BE, Arendrup MC, Rijs AJ, Snelders E, Huynen MA, et al. Discovery of a HapE mutation that causes azole resistance in Aspergillus fumigatus through whole genome sequencing and sexual crossing. PloS one. 2012;7(11):e50034. https://doi.org/10.1371/journal.pone.0050034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Willger SD, Puttikamonkul S, Kim KH, Burritt JB, Grahl N, Metzler LJ, et al. A sterol-regulatory element binding protein is required for cell polarity, hypoxia adaptation, azole drug resistance, and virulence in Aspergillus fumigatus. PLoS Pathog. 2008;4(11):e1000200. https://doi.org/10.1371/journal.ppat.1000200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Rybak JM, Ge W, Wiederhold NP, Parker JE, Kelly SL, Rogers PD, et al. Mutations in hmg1, challenging the paradigm of clinical triazole resistance in Aspergillus fumigatus. MBio. 2019;10(2). https://doi.org/10.1128/mBio.00437-19.

  104. Cowen LE, Sanglard D, Howard SJ, Rogers PD, Perlin DS. Mechanisms of antifungal drug resistance. Cold Spring Harbor perspectives in medicine. 2014. https://doi.org/10.1101/cshperspect.a019752.

    Article  Google Scholar 

  105. Selmecki A, Forche A, Berman J. Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science. 2006;313(5785):367–70. https://doi.org/10.1126/science.1128242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Fungus Testing Laboratory, Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA

    Hamid Badali & Nathan P. Wiederhold

  2. Invasive Fungi Research Center, Mazandaran University of Medical Sciences, Sari, Iran

    Hamid Badali

Authors
  1. Hamid Badali
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nathan P. Wiederhold
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nathan P. Wiederhold.

Ethics declarations

Conflict of Interest

Nathan Wiederhold reports grants from Astellas, grants from Cepheid, grants from Cidara, grants from bioMerieux, grants from F2G, grants from Viamet, personal fees from Mayne Pharmaceuticals, and personal fees from Gilead outside the submitted work. Hamid Badali declares no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Topical Collection on Advances in Diagnosis of Invasive Fungal Infections

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Badali, H., Wiederhold, N.P. Antifungal Resistance Testing and Implications for Management. Curr Fungal Infect Rep 13, 274–283 (2019). https://doi.org/10.1007/s12281-019-00354-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12281-019-00354-6

Keywords

Search

Navigation