Azole Resistance in Moulds—Approach to Detection in a Clinical Laboratory

Abstract

The multitude of factors has contributed to the increasing number of fungal infections caused by species of difficult-to-treat opportunistic moulds, such as Fusarium, Scedosporium, and cryptic Aspergilli. Also, rare fungi sporadically encountered, such as Rasamsonia argillacea, Penicillium oxalicum, and melanized fungi, are now well recognized. The high mortality associated with these rare and uncommon fungi is primarily linked to the difficulty in diagnosis and limited therapeutic options, as many of them exhibit resistance to antifungals including azoles. Azole resistance in Aspergillus fumigatus has been increasingly reported because standardized methods for susceptibility testing and associated clinical breakpoints and epidemiological cutoff values became available. However, such advances in antifungal susceptibility testing (AFST) in non-Aspergillus moulds barring mucorales have been lacking. Notwithstanding the fact that the true incidence of these non-Aspergillus filamentous moulds in clinical settings is hitherto unknown, also data on AFST by standardized methods is largely lacking. Determination of minimum inhibitory concentration (MIC) by reference techniques is the gold standard to detect azole resistance in filamentous fungi. In recent years, some progress has been made toward the description of resistance mechanisms at molecular level especially in Aspergillus. This paper reviews the present state of azole resistance in Aspergillus and other filamentous mould species and discusses their relevance to clinical practice.

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References

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

  1. 1.

    Neblett Fanfair R, Benedict K, Bos J, Bennett SD, Lo YC, Adebanjo T, et al. Necrotizing cutaneous mucormycosis after a tornado in Joplin, Missouri, in 2011. N Engl J Med. 2012;367:2214–25.

    Article  PubMed  Google Scholar 

  2. 2.

    Brandt ME, Park BJ. Think fungus—prevention and control of fungal infections. Emerg Infect Dis. 2013;19:1688–9.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.••

    Chowdhary A, Kathuria S, Xu J, Meis JF. Emergence of azole-resistant Aspergillus fumigatus strains due to agricultural azole use creates an increasing threat to human health. PLoS Pathog. 2013;9:e1003633. Highlights the role of fungicides in emergence of azole resistance in A. fumigatus strains.

  4. 4.

    Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC. Hidden killers: human fungal infections. Sci Transl Med. 2012;4:165rv13.

    Article  PubMed  Google Scholar 

  5. 5.

    Steinbach WJ, Marr KA, Anaissie EJ, Azie N, Quan SP, Meier-Kriesche HU, et al. Clinical epidemiology of 960 patients with invasive aspergillosis from the PATH Alliance registry. J Infect. 2012;65:453–64.

    Article  PubMed  Google Scholar 

  6. 6.

    Lanternier F, Dannaoui E, Morizot G, Elie C, Garcia-Hermoso D, Huerre M, et al. A global analysis of mucormycosis in France: the RetroZygo Study (2005–2007). Clin Infect Dis. 2012;54:S35–43.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Muhammed M, Coleman JJ, Carneiro HA, Mylonakis E. The challenge of managing fusariosis. Virulence. 2011;2:91–6.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Cortez KJ, Roilides E, Quiroz-Telles F, Meletiadis J, Antachopoulos C, Knudsen T, et al. Infections caused by Scedosporium spp. Clin Microbiol Rev. 2008;21:157–97.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Doyon JB, Sutton DA, Theodore P, Dhillon G, Jones KD, Thompson EH, et al. Rasamsonia argillacea pulmonary and aortic graft infection in an immune-competent patient. J Clin Microbiol. 2013;51:719–22.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Chowdhary A, Kathuria S, Agarwal K, Sachdeva N, Singh PK, Jain S et al, Voriconazole resistant Penicillium oxalicum: an emerging pathogen in immunocompromised hosts. Open Forum Infect Dis. 2014; doi:10.1093/ofid/ofu029

  11. 11.

    Singh PK, Kathuria S, Agarwal K, Gaur SN, Meis JF, Chowdhary A. Clinical significance and molecular characterization of nonsporulating molds isolated from the respiratory tracts of bronchopulmonary mycosis patients with special reference to basidiomycetes. J Clin Microbiol. 2013;51:3331–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.••

    Sleiman S, Halliday CL, Chapman B, Brown M, Nitschke J, Lau AF, et al. Performance of matrix-assisted laser desorption ionization-time of flight mass spectrometry for the identification of Aspergillus, Scedosporium, and Fusarium spp. in the Australian clinical setting. J Clin Microbiol. 2016. A database was prepared for the identification of Aspergillus, Scedosporium , and Fusarium species using MALDI-TOF MS by combining in-house database with Bruker Fungal library, thereby improving the species identification significantly.

  13. 13.

    Roemer T, Krysan DJ. Antifungal drug development: challenges, unmet clinical needs, and new approaches. Cold Spring Harb Perspect Med. 2014;4

  14. 14.

    Kontoyiannis DP, Marr KA, Park BJ, Alexander BD, Anaissie EJ, Walsh TJ, et al. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001–2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database. Clin Infect Dis. 2010;50:1091–100.

    Article  PubMed  Google Scholar 

  15. 15.

    Peterson SW. Phylogenetic analysis of Aspergillus species using DNA sequences from four loci. Mycologia. 2008;100:205–26.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Balajee SA, Baddley JW, Peterson SW, Nickle D, Varga J, Boey A, et al. Aspergillus alabamensis, a new clinically relevant species in the section Terrei. Eukaryot Cell. 2009;8:713–22.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Balajee SA, Kano R, Baddley JW, Moser SA, Marr KA, Alexander BD, et al. Molecular identification of Aspergillus species collected for the Transplant-Associated Infection Surveillance Network. J Clin Microbiol. 2009;47:3138–41.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Alastruey-Izquierdo A, Mellado E, Peláez T, Pemán J, Zapico S, Alvarez M, et al. Population-based survey of filamentous fungi and antifungal resistance in Spain (FILPOP Study). Antimicrob Agents Chemother. 2013;57:3380–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Alcazar-Fuoli L, Mellado E, Alastruey-Izquierdo A, Cuenca-Estrella M, Rodriguez-Tudela JL. Aspergillus section Fumigati: antifungal susceptibility patterns and sequence-based identification. Antimicrob Agents Chemother. 2008;52:1244–51.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Alastruey-Izquierdo A, Alcazar-Fuoli L, Cuenca-Estrella M. Antifungal susceptibility profile of cryptic species of Aspergillus. Mycopathologia. 2014;178:427–33.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Denning DW, Cadranel J, Beigelman-Aubry C, Ader F, Chakrabarti A, Blot S, et al. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Eur Respir J. 2016;47:45–68.

    Article  PubMed  Google Scholar 

  22. 22.

    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.

  23. 23.

    Maertens JA, Raad II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016;387:760–9.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Arendrup MC, Mavridou E, Mortensen KL, Snelders E, Frimodt-Møller N, Khan H, et al. Development of azole resistance in Aspergillus fumigatus during azole therapy associated with change in virulence. PLoS One. 2010;5:e10080.

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.•

    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 Med. 2008;5:e219. Investigated the prevalence and spread of azole resistance in A. fumigatus isolates collected over a period of 14 years.

  27. 27.

    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;65:2116–8.

    CAS  Article  PubMed  Google Scholar 

  28. 28.••

    Bader O, Tünnermann J, Dudakova A, Tangwattanachuleeporn M, Weig M, Groß U. Environmental isolates of azole-resistant Aspergillus fumigatus in Germany. Antimicrob Agents Chemother. 2015;59:4356–9. The article describes that 12 % of the soil samples were positive for resistant A. fumigatus and harbored TR 34 /L98H and TR 46 /Y121F/T289A alleles, dispersed along a corridor across northern Germany.

  29. 29.••

    Sharma C, Hagen F, Moroti R, Meis JF, Chowdhary A. Triazole-resistant Aspergillus fumigatus harbouring G54 mutation: is it de novo or environmentally acquired? J Global Antimicrob Resist. 2015;3:69–73. The authors describe the genetic heterogeneity of resistant A. fumigatus strains harboring the G54E mutation in the environment of India, Romania, and Tanzania anticipating that long-term exposure of A. fumigatus to fungicides may induce selection of G54 mutants in the environment.

  30. 30.

    Verweij PE, Chowdhary A, Melchers WJ, Meis JF. Azole resistance in Aspergillus fumigatus: can we retain the clinical use of mold-active antifungal azoles? Clin Infect Dis. 2016;62:362–8.

    Article  PubMed  Google Scholar 

  31. 31.

    Chowdhary A, Sharma C, Hagen F, Meis JF. Exploring azole antifungal drug resistance in Aspergillus fumigatus with special reference to resistance mechanisms. Future Microbiol. 2014;9:697–711.

    CAS  Article  PubMed  Google Scholar 

  32. 32.••

    Snelders E, Karawajczyk A, 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;54:2425–30. The authors gave an insight into the mutations in the cyp51A gene and correlated the mutations with the phenotype regarding their susceptibility to azole compounds.

  33. 33.

    Arabatzis M, Kambouris M, Kyprianou M, Chrysaki A, Foustoukou M, Kanellopoulou M, et al. Polyphasic identification and susceptibility to seven antifungals of 102 Aspergillus isolates recovered from immunocompromised hosts in Greece. Antimicrob Agents Chemother. 2011;55:3025–30.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Masih A, Singh PK, Kathuria K, Agarwal K, Meis JF, Chowdhary A. Identification by molecular methods and Matrix-assistedlaser desorption ionization–time of flight mass spectrometry and antifungal susceptibility profiles of clinically significant rare Aspergillus species in a referral chest hospital in Delhi, India. J Clin Microbiol. 2016, pii: JCM.00962-16.

  35. 35.

    Arendrup MC, Cuenca-Estrella M, Lass-Flörl C, Hope WW. Breakpoints for antifungal agents: an update from EUCAST focusing on echinocandins against Candida spp. and triazoles against Aspergillus spp. Drug Resist Updat. 2013;16:81–95.

    Article  PubMed  Google Scholar 

  36. 36.

    Espinel-Ingroff A, Fothergill A, Fuller J, Johnson E, Pelaez T, Turnidge J. Wild-type MIC distributions and epidemiological cutoff values for caspofungin and Aspergillus spp. for the CLSI broth microdilution method (M38-A2 document). Antimicrob Agents Chemother. 2011;55:2855–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Espinel-Ingroff A, Chowdhary A, Gonzalez GM, Lass-Flörl C, Martin-Mazuelos E, Meis J, et al. Multicenter study of isavuconazole MIC distributions and epidemiological cutoff values for Aspergillus spp. for the CLSIM38-A2 broth microdilution method. Antimicrob Agents Chemother. 2013;57:3823–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Howard SJ, Lass-Flörl C, Cuenca-Estrella M, Gomez-Lopez A, Arendrup MC. Determination of isavuconazole susceptibility of Aspergillus and Candida species by the EUCAST method. Antimicrob Agents Chemother. 2013;57:5426–31.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Verweij PE, Ananda-Rajah M, Andes D, Arendrup MC, Brüggemann RJ, Chowdhary A, et al. International expert opinion on the management of infection caused by azole-resistant Aspergillus fumigatus. Drug Resist. 2015;21-22:30–40.

    Article  Google Scholar 

  40. 40.

    Van der Linden JWM, Arendrup MC, van der Lee HAL, Verweij PE. Azole containing agar plates as a screening tool for azole resistance of Aspergillus fumigatus. Mycoses. 2009;52 Suppl 1:19.

    Google Scholar 

  41. 41.

    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;52:1123–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    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;68:1497–504.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    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;52:868–74.

    Article  Google Scholar 

  44. 44.

    Snelders E, Karawajczyk A, Verhoeven RJ, Venselaar H, Schaftenaar G, Verweij PE, et al. The structure-function relationship of the Aspergillus fumigatus cyp51A L98H conversion by site-directed mutagenesis: the mechanism of L98H azole resistance. Fungal Genet Biol. 2011;48:1062–70.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    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;48:2747–50.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Mellado E, Garcia-Effron G, Alcázar-fouli 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;51:1897–904.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.•

    van der Linden JW, Camps SM, Kampinga GA, Arends JP, Debets-Ossenkopp YJ, Haas PJ, et al. Aspergillosis due to voriconazole highly resistant Aspergillus fumigatus and recovery of genetically related resistant isolates from domiciles. Clin Infect Dis. 2013;57:513–20. The article describes the emergence of a new environmental resistance mechanism in A. fumigatus isolates from patients and their environment.

  48. 48.•

    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:e50034. The article reports a new non-cyp51A-mediated resistance mechanism using whole-genome sequencing in the A. fumigatus.

  49. 49.

    Albarrag AM, Anderson MJ, Howard SJ, Robson GD, Warn PA, Sanglard D, et al. Interrogation of related clinical pan-azole-resistant Aspergillus fumigatus strains: G138C, Y431C, and G434C single nucleotide polymorphisms in cyp51A, upregulation of cyp51A, and integration and activation of transposon Atf1 in the cyp51A promoter. Antimicrob Agents Chemother. 2011;55:5113–21.

  50. 50.

    Howard SJ, Harrison E, Bowyer P, Varga J, Denning DW. Cryptic species and azole resistance in the Aspergillus niger complex. Antimicrob Agents Chemother. 2011;55:4802–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Tortorano AM, Prigitano A, Esposto MC, Arsic Arsenijevic V, Kolarovic J, Ivanovic D, et al. European Confederation of Medical Mycology (ECMM) epidemiological survey on invasive infections due to Fusarium species in Europe. Eur J Clin Microbiol Infect Dis. 2014;33:1623–30.

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Al-Hatmi AM, Van Den Ende AH, Stielow JB, Van Diepeningen AD, Seifert KA, Mc Cormick W, et al. Evaluation of two novel barcodes for species recognition of opportunistic pathogens in Fusarium. Fungal Biol. 2016;120:231–45.

    Article  PubMed  Google Scholar 

  53. 53.

    Guarro J. Fusariosis, a complex infection caused by a high diversity of fungal species refractory to treatment. Eur J Clin Microbiol Infect Dis. 2013;32:1491–500.

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Muhammed M, Anagnostou T, Desalermos A, Kourkoumpetis TK, Carneiro HA, Glavis-Bloom J, et al. Fusarium infection: report of 26 cases and review of 97 cases from the literature. Medicine (Baltimore). 2013;92:305–16.

    Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Scheel CM, Hurst SF, Barreiros G, Akiti T, Nucci M, Balajee SA. Molecular analysis of Fusarium isolates recovered from a cluster of invasive mold infections in a Brazilian hospital. BMC Infect Dis. 2013;13:49.

    Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    van Diepeningen AD, Al-Hatmi AMS, Brankovics B, de Hoog GS. Taxonomy and clinical spectra of Fusarium species: where do we stand in 2014? Curr Clin Micro Rpt. 2014;1:10–8.

    Article  Google Scholar 

  57. 57.

    Garnica M, da Cunha MO, Portugal R, Maiolino A, Colombo AL, Nucci M. Risk factors for invasive fusariosis in patients with acute myeloid leukemia and in hematopoietic cell transplant recipients. Clin Infect Dis. 2015;60:875–80.

    Article  PubMed  Google Scholar 

  58. 58.

    Vazquez JA, Miceli MH, Alangade G. Invasive fungal infections in transplant recipients. Ther Adv Infect Dis. 2013;3:85–105.

    Google Scholar 

  59. 59.

    Stempel JM, Hammond SP, Sutton DA, Weiser LM, Marty FM. Invasive fusariosis in the voriconazole era: single-center 13-year experience. Open Forum Infect Dis. 2015;2:ofv099.

    Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Al-Hatmi AM, van Diepeningen AD, Curfs-Breuker I, de Hoog GS, Meis JF. Specific antifungal susceptibility profiles of opportunists in the Fusarium fujikuroi complex. J Antimicrob Chemother. 2015;70:1068–71.

    CAS  PubMed  Google Scholar 

  61. 61.

    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. 2015;60:1079–84.

    Article  PubMed  Google Scholar 

  62. 62.

    Abuhelwa AY, Foster DJR, Mudge S, Hayes D, Upton RN. Population pharmacokinetic modelling of itraconazole and hydroxyl-itraconazole for oral SUBA™-itraconazole and Sporanox® capsule formulations in healthy subjects in fed and fasted states. Antimicrob Agents Chemother. 2015;59:5681–96.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Fan J, Urban M, Parker JE, Brewer HC, Kelly SL, Hammond-Kosack KE, et al. Characterization of the sterol 14α-demethylases of Fusarium graminearum identifies a novel genus specific CYP51 function. New Phytol. 2013;198:821–35.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Harun A, Gilgado F, Chen SC, Meyer W. Abundance of Pseudallescheria/Scedosporium species in the Australian urban environment suggests a possible source for scedosporiosis including the colonization of airways in cystic fibrosis. Med Mycol. 2010;48:S70–6.

  65. 65.

    Subedi S, Chen SCA. Epidemiology of scedosporiosis. Curr Fungal Infect Rep. 2015;9:275–84.

    Article  Google Scholar 

  66. 66.

    Gilgado F, Cano J, Gene J, Sutton DA, Guarro J. Molecular and phenotypic data supporting distinct species statuses for Scedosporium apiospermum and Pseudallescheria boydii and the proposed new species Scedosporium dehoogii. J Clin Microbiol. 2008;46:766–71.

    Article  PubMed  Google Scholar 

  67. 67.

    Troke P, Aguirrebengoa K, Arteaga C, Ellis D, Heath CH, Lutsar I, et al. Treatment of scedosporiosis with voriconazole: clinical experience with 107 patients. Antimicrob Agents Chemother. 2008;52:1743–50.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Heath CH, Slavin MA, Sorrell TC, Handke R, Harun A, Phillips M, et al. Population-based surveillance for scedosporiosis in Australia: epidemiology, disease manifestations and emergence of Scedosporium aurantiacum infection. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2009;15:689–93.

    CAS  Google Scholar 

  69. 69.

    Rodriguez-Tudela JL, Berenguer J, Guarro J, Kantarcioglu AS, Horre R, de Hoog GS, et al. Epidemiology and outcome of Scedosporium prolificans infection, a review of 162 cases. Med Mycol. 2009;47:359–70.

    Article  PubMed  Google Scholar 

  70. 70.•

    Ramsperger M, Duan S, Sorrell TC, Meyer W, Chen SC-A. The genus Scedosporium and Pseudallescheria: current challenges in laboratory diagnosis. Curr Clin Microbiol Rep. 2014;1:27–36. The review abridges the methods currently used to enable an informed choice of detection and/or identification techniques in the clinical mycology laboratory.

  71. 71.••

    Lackner M, de Hoog GS, Verweij PE, Najafzadeh MJ, Curfs-Breuker I, Klaassen CH, et al. Species-specific antifungal susceptibility patterns of Scedosporium and Pseudallescheria species. Antimicrob Agents Chemother. 2012;56:2635–42. The article reports species-specific susceptibility patterns of Pseudallescheria boydii and P. apiosperma and found only voriconazole exhibited low MIC values for P. apiosperma and P. boydii.

  72. 72.

    Gosbell IB, Toumasatos V, Yong J, Kuo RS, Ellis DH, Perrie RC. Cure of orthopaedic infection with Scedosporium prolificans, using voriconazole plus terbinafine, without the need for radical surgery. Mycoses. 2003;46:233–6.

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Machouart M, Garcia-Hermoso D, Rivier A, Hassouni N, Catherinot E, Salmon A, et al. Emergence of disseminated infections due to Geosmithia argillacea in patients with chronic granulomatous disease receiving long-term azole antifungal prophylaxis. J Clin Microbiol. 2011;49:1681–3.

    Article  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Valentin T, Neumeister P, Pichler M, Rohn A, Koidl C, Haas D, et al. Disseminated Geosmithia argillacea infection in a patient with gastrointestinal GvHD. Bone Marrow Transplant. 2012;47:734–6.

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Houbraken J, Spierenburg H, Frisvad JC. Rasamsonia, a new genus comprising thermotolerant and thermophilic Talaromyces and Geosmithia species. Antonie Van Leeuwenhoek. 2012;101:403–21.

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    Houbraken J, Verweij PE, Rijs AJ, Borman AM, Samson RA. Identification of Paecilomyces variotii in clinical samples and settings. J Clin Microbiol. 2010;48:2754–61.

    Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Cohen-Abbo A, Edwards KM. Multifocal osteomyelitis caused by Paecilomyces variotii in a patient with chronic granulomatous disease. Infection. 1995;23:55–7.

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Eloy P, Bertrand B, Rombeaux P, Delos M, Trigaux JP. Mycotic sinusitis. Acta Otorhinolaryngol Belg. 1997;51:339–52.

    CAS  PubMed  Google Scholar 

  79. 79.•

    Salle VE, Lecuyer T, Chouaki F, Lescure X, Smail A, Vaidie A, et al. Paecilomyces variotii fungemia in a patient with multiple myeloma: case report and literature review. J Infect. 2005;51:e93–5. The authors report the first case of P. variotii fungemia along with review of literature suggesting substantial morbidity due to this fungus.

  80. 80.

    De Hoog GS, Guarro J, Gené J, Figueras MJ. Atlas of clinical fungi. 2nd ed. Utrecht, Netherlands/ University Rovira i Virgili, Reus, Spain: Centraalbureau voor Schimmelcultures; 2000.

    Google Scholar 

  81. 81.

    Summerbell RC. Aspergillus, Fusarium, Sporothrix, Piedraia, and their relatives. In: Howard DH, editor. Pathogenic fungi in humans and animals. 2nd ed. New York: Marcel Dekker; 2003. p. 237–498.

    Google Scholar 

  82. 82.••

    Perdomo H, Sutton DA, García D, Fothergill AW, Cano J, Gené J, et al. Spectrum of clinically relevant Acremonium species in the United States. J Clin Microbiol. 2011;49:243–56. The study identified a large number of clinical isolates belonging to Acremonium species morphologically and confirmed the identifications by internal transcribed spacer region of the rRNA gene sequencing.

  83. 83.

    Pfaller M, Boyken L, Hollis R, Kroeger J, Messer S, Tendolkar S, et al. Use of epidemiological cutoff values to examine 9-year trends in susceptibility of Aspergillus species to the triazoles. J Clin Microbiol. 2011;49:586–90.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Revankar SG, Sutton DA. Melanized fungi in human disease. Clin Microbiol Rev. 2010;23:884–928.

    Article  PubMed  PubMed Central  Google Scholar 

  85. 85.••

    Chowdhary A, Perfect J, de Hoog GS. Black molds and melanized yeasts pathogenic to humans. Cold Spring Harb Perspect Med. 2014;5:a019570. A comprehensive review describing melanized fungi involved in human infection.

    Article  PubMed  Google Scholar 

  86. 86.

    Chowdhary A, Meis JF, Guarro J, de Hoog GS, Kathuria S, Arendrup MC, et al. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of systemic phaeohyphomycosis: diseases caused by black fungi. Clin Microbiol Infect. 2014;20 Suppl 3:47–75.

    CAS  Article  PubMed  Google Scholar 

  87. 87.••

    Sitterlé E, Giraud S, Leto J, Bouchara JP, Rougeron A, Morio F, et al. Matrix-assisted laser desorption ionization-time of flight mass spectrometry for fast and accurate identification of Pseudallescheria/Scedosporium species. Clin Microbiol Infect. 2014;20:929–35. The authors investigated the potential of MALDI-TOF MS to discriminate Pseudallescheria/Scedosporium species that cannot be currently identified by morphological examination in the clinical setting by building a reference database library.

  88. 88.

    Escribano P, Peláez T, Muñoz P, Bouza E, Guinea J. Is azole resistance in Aspergillus fumigatus a problem in Spain? Antimicrob Agents Chemother. 2013;57:2815–20.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Peláez T, Alvarez-Pérez S, Mellado E, Serrano D, Valerio M, Blanco JL, et al. Invasive aspergillosis caused by cryptic Aspergillus species: a report of two consecutive episodes in a patient with leukaemia. J Med Microbiol. 2013;62:474–8.

    Article  PubMed  Google Scholar 

  90. 90.

    Negri CE, Gonçalves SS, Xafranski H, Bergamasco MD, Aquino VR, Castro PT, et al. Cryptic and rare Aspergillus species in Brazil: prevalence in clinical samples and in vitro susceptibility to triazoles. J Clin Microbiol. 2014;52:3633–40.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Balajee SA, Gribskov J, Brandt M, Ito J, Fothergill A, Marr KA. Mistaken identity: Neosartorya pseudofischeri and its anamorph masquerading as Aspergillus fumigatus. J Clin Microbiol. 2005;43:5996–9.

  92. 92.

    Vinh DC, Shea YR, Sugui JA, Parrilla-Castellar ER, Freeman AF, Campbell JW, et al. Invasive aspergillosis due to Neosartorya udagawae. Clin Infect Dis. 2009;49:102–11.

    Article  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Gonçalves SS, Stchigel AM, Cano J, Guarro J, Colombo AL. In vitro antifungal susceptibility of clinically relevant species belonging to Aspergillus section Flavi. Antimicrob Agents Chemother. 2013;57:1944–7.

  94. 94.

    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;7:630–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Panackal AA, Imhof A, Hanley EW, Marr KA. Aspergillus ustus infections among transplant recipients. Emerg Infect Dis. 2006;12:403–8.

    Article  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Arendrup MC, Jensen RH, Grif K, Skov M, Pressler T, Johansen HK, et al. In vivo emergence of Aspergillus terreus with reduced azole susceptibility and a Cyp51a M217I alteration. J Infect Dis. 2012;206:981–5.

    CAS  Article  PubMed  Google Scholar 

  97. 97.

    Wang H, Xiao M, Kong F, Chen S, Dou HT, Sorrell T, et al. Accurate and practical identification of 20 Fusarium species by seven-locus sequence analysis and reverse line blot hybridization, and an in vitro antifungal susceptibility study. J Clin Microbiol. 2011;49:1890–8.

    Article  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Dalyan Cilo B, Al-Hatmi AM, Seyedmousavi S, Rijs AJ, Verweij PE, Ener B, et al. Emergence of fusarioses in a university hospital in Turkey during a 20-year period. Eur J Clin Microbiol Infect Dis. 2015;34:1683–91.

    CAS  Article  PubMed  Google Scholar 

  99. 99.

    Ricna D, Lengerova M, Palackova M, Hadrabova M, Kocmanova I, Weinbergerova B, et al. Disseminated fusariosis by Fusarium proliferatum in a patient with aplastic anaemia receiving primary posaconazole prophylaxis—case report and review of the literature. Mycoses. 2016;59:48–55.

    Article  PubMed  Google Scholar 

  100. 100.

    Nishimori M, Takahashi T, Suzuki E, Kodaka T, Hiramoto N, Itoh K, et al. Fatal fungemia with Scedosporium prolificans in a patient with acute myeloid leukemia. Med Mycol J. 2014;55:E63–70.

    Article  PubMed  Google Scholar 

  101. 101.

    Lackner M, Rezusta A, Villuendas MC, Palacian MP, Meis JF, Klaassen CH. Infection and colonisation due to Scedosporium in Northern Spain. An in vitro antifungal susceptibility and molecular epidemiology study of 60 isolates. Mycoses. 2011;54 Suppl 3:12–21.

    Article  PubMed  Google Scholar 

  102. 102.

    Homa M, Galgóczy L, Tóth E, Tóth L, Papp T, Chandrasekaran M, et al. In vitro antifungal activity of antipsychotic drugs and their combinations with conventional antifungals against Scedosporium and Pseudallescheria isolates. Med Mycol. 2015;5:890–5.

    Article  Google Scholar 

  103. 103.

    Bernhardt A, Seibold M, Rickerts V, Tintelnot K. Cluster analysis of Scedosporium boydii infections in a single hospital. Int J Med Microbiol. 2015;305:724–8.

    Article  PubMed  Google Scholar 

  104. 104.

    Júnior MC, de Moraes AA, Silva HM, Costa CR, Silva MR. Acremonium kiliense: case report and review of published studies. Mycopathologia. 2013;176:417–21.

    Article  PubMed  Google Scholar 

  105. 105.

    Herbrecht R, Letscher-Bru V, Fohrer C, Campos F, Natarajan-Ame S, Zamfir A, et al. Acremonium strictum pulmonary infection in a leukemic patient successfully treated with posaconazole after failure of amphotericin B. Eur J Clin Microbiol Infect Dis. 2002;21:814–7.

    CAS  Article  PubMed  Google Scholar 

  106. 106.

    Houbraken J, Giraud S, Meijer M, Bertout S, Frisvad JC, Meis JF, et al. Taxonomy and antifungal susceptibility of clinically important Rasamsonia species. J Clin Microbiol. 2013;51:22–30.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Giraud S, Pihet M, Razafimandimby B, Carrère J, Degand N, Mely L, et al. Geosmithia argillacea: an emerging pathogen in patients with cystic fibrosis. J Clin Microbiol. 2010;48:2381–6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. 108.

    De Ravin SS, Challipalli M, Anderson V, Shea YR, Marciano B, Hilligoss D, et al. Geosmithia argillacea: an emerging cause of invasive mycosis in human chronic granulomatous disease. Clin Infect Dis. 2011;52:e136–43.

    Article  PubMed  PubMed Central  Google Scholar 

  109. 109.

    da Cunha KC, Sutton DA, Fothergill AW, Gené J, Cano J, Madrid H, et al. In vitro antifungal susceptibility and molecular identity of 99 clinical isolates of the opportunistic fungal genus Curvularia. Diagn Microbiol Infect Dis. 2013;76:168–74.

    Article  PubMed  Google Scholar 

  110. 110.

    Giraldo A, Sutton DA, Samerpitak K, de Hoog GS, Wiederhold NP, Guarro J, et al. Occurrence of Ochroconis and Verruconis species in clinical specimens from the United States. J Clin Microbiol. 2014;52:4189–201.

    Article  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Badali H, Chander J, Gulati N, Attri A, Chopra R, Najafzadeh MJ, et al. Subcutaneous phaeohyphomycotic cyst caused by Pyrenochaeta romeroi. Med Mycol. 2010;48:763–8.

    CAS  Article  PubMed  Google Scholar 

  112. 112.

    Cerar D, Malallah YM, Howard SJ, Bowyer P, Denning DW. Isolation, identification and susceptibility of Pyrenochaeta romeroi in a case of eumycetoma of the foot in the UK. Int J Antimicrob Agents. 2009;34:617–8.

    Article  PubMed  Google Scholar 

  113. 113.

    Badali H, Yazdanparast SA, Bonifaz A, Mousavi B, de Hoog GS, Klaassen CH, et al. Veronaea botryosa: molecular identification with amplified fragment length polymorphism (AFLP) and in vitro antifungal susceptibility. Mycopathologia. 2013;175:505–13.

    CAS  Article  PubMed  Google Scholar 

  114. 114.

    Sang H, Zheng XE, Kong QT, Zhou WQ, He W, Lv GX, et al. A rare complication of ear piercing: a case of subcutaneous phaeohyphomycosis caused by Veronaea botryosa in China. Med Mycol. 2011;49:296–302.

    CAS  Article  PubMed  Google Scholar 

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Correspondence to Anuradha Chowdhary.

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Anuradha Chowdhary, Aradhana Masih, Cheshta Sharma declare that they have no conflict of interest. Cheshta Sharma was supported by a research grant from University Grants Commission Research Fellowship, India (F.2-15/2003 SA-I).

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This article is part of the Topical Collection on Advances in Diagnosis of Invasive Fungal Infections

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Chowdhary, A., Masih, A. & Sharma, C. Azole Resistance in Moulds—Approach to Detection in a Clinical Laboratory. Curr Fungal Infect Rep 10, 96–106 (2016). https://doi.org/10.1007/s12281-016-0265-2

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Keywords

  • Azole resistance
  • Resistance mechanism
  • EUCAST
  • CLSI
  • Aspergillus fumigatus
  • Fusarium species
  • Scedosporium species