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Erschienen in: Current Fungal Infection Reports 3/2019

20.06.2019 | Hot Topics

(New) Methods for Detection of Aspergillus fumigatus Resistance in Clinical Samples

verfasst von: Jeffrey D. Jenks, Birgit Spiess, Dieter Buchheidt, Martin Hoenigl

Erschienen in: Current Fungal Infection Reports | Ausgabe 3/2019

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Abstract

Purpose of Review

The incidence of invasive aspergillosis has increased substantially over the past few decades, accompanied by a change in susceptibility patterns of Aspergillus fumigatus with increasing resistance observed against triazole antifungals, including voriconazole and isavuconazole, the most commonly used antifungal agents for the disease. Culture-based methods for determining triazole resistance are still the gold standard but are time consuming and lack sensitivity. We sought to provide an update on non-culture-based methods for detecting resistance patterns to Aspergillus.

Recent Findings

New molecular-based approaches for detecting triazole resistance to Aspergillus, real-time polymerase chain reaction (PCR) to detect mutations to the Cyp51A protein, have been developed which are able to detect most triazole-resistant A. fumigatus strains in patients with invasive aspergillosis.

Summary

Over the last few years, a number of non-culture-based methods for molecular detection of Aspergillus triazole resistance have been developed that may overcome some of the limitations of culture. These molecular methods are therefore of high epidemiological and clinical relevance, mainly in immunocompromised patients with hematological malignancies, where culture has particularly limited sensitivity. These assays are now able to detect most triazole-resistant Aspergillus fumigatus strains. Given that resistance rates vary, clinical utility for these assays still depends on regional resistance patterns.
Literatur
1.
Zurück zum Zitat •• Hoenigl M, Gangneux JP, Segal E, Alanio A, Chakrabarti A, Chen SC, et al. Global guidelines and initiatives from the European Confederation of Medical Mycology to improve patient care and research worldwide: new leadership is about working together. Mycoses. 2018;61(11):885–94. https://doi.org/10.1111/myc.12836 Describes global guidelines and optimal collaboration strategies to optimize clinical care in resource-rich and resource-limited settings. CrossRefPubMed •• Hoenigl M, Gangneux JP, Segal E, Alanio A, Chakrabarti A, Chen SC, et al. Global guidelines and initiatives from the European Confederation of Medical Mycology to improve patient care and research worldwide: new leadership is about working together. Mycoses. 2018;61(11):885–94. https://​doi.​org/​10.​1111/​myc.​12836 Describes global guidelines and optimal collaboration strategies to optimize clinical care in resource-rich and resource-limited settings. CrossRefPubMed
2.
Zurück zum Zitat •• Jenks JD, Mehta SR, Taplitz R, Aslam S, Reed SL, Hoenigl M. Point-of-care diagnosis of invasive aspergillosis in non-neutropenic patients: Aspergillus galactomannan lateral flow assay versus Aspergillus-specific lateral flow device test in bronchoalveolar lavage. Mycoses. 2019;62(3):230–6. https://doi.org/10.1111/myc.12881 Paper highlights the difficulties of defining, categorizing, and diagnosing Invasive aspergillosis in non-neutropenic hosts. CrossRefPubMed •• Jenks JD, Mehta SR, Taplitz R, Aslam S, Reed SL, Hoenigl M. Point-of-care diagnosis of invasive aspergillosis in non-neutropenic patients: Aspergillus galactomannan lateral flow assay versus Aspergillus-specific lateral flow device test in bronchoalveolar lavage. Mycoses. 2019;62(3):230–6. https://​doi.​org/​10.​1111/​myc.​12881 Paper highlights the difficulties of defining, categorizing, and diagnosing Invasive aspergillosis in non-neutropenic hosts. CrossRefPubMed
6.
Zurück zum Zitat Jenks JD, Mehta SR, Taplitz R, Law N, Reed SL, Hoenigl M. Bronchoalveolar lavage Aspergillus galactomannan lateral flow assay versus Aspergillus-specific lateral flow device test for diagnosis of invasive pulmonary aspergillosis in patients with hematological malignancies. The Journal of infection. 2019;78(3):249–59. https://doi.org/10.1016/j.jinf.2018.10.014.CrossRefPubMed Jenks JD, Mehta SR, Taplitz R, Law N, Reed SL, Hoenigl M. Bronchoalveolar lavage Aspergillus galactomannan lateral flow assay versus Aspergillus-specific lateral flow device test for diagnosis of invasive pulmonary aspergillosis in patients with hematological malignancies. The Journal of infection. 2019;78(3):249–59. https://​doi.​org/​10.​1016/​j.​jinf.​2018.​10.​014.CrossRefPubMed
7.
Zurück zum Zitat • Jenks JD, Salzer HJF, Hoenigl M. Improving the rates of Aspergillus detection: an update on current diagnostic strategies. Expert Rev Anti-Infect Ther. 2019;17(1):39–50. https://doi.org/10.1080/14787210.2018.1558054 Diagnosis of fungal infections is a major issue in the treatment of immunocompromised patients. This review provides an important overview on the current status of diagnostic strategies. CrossRefPubMed • Jenks JD, Salzer HJF, Hoenigl M. Improving the rates of Aspergillus detection: an update on current diagnostic strategies. Expert Rev Anti-Infect Ther. 2019;17(1):39–50. https://​doi.​org/​10.​1080/​14787210.​2018.​1558054 Diagnosis of fungal infections is a major issue in the treatment of immunocompromised patients. This review provides an important overview on the current status of diagnostic strategies. CrossRefPubMed
10.
Zurück zum Zitat •• Schauwvlieghe A, de Jonge N, van Dijk K, Verweij PE, Bruggemann RJ, Biemond BJ, et al. The diagnosis and treatment of invasive aspergillosis in Dutch haematology units facing a rapidly increasing prevalence of azole-resistance. A nationwide survey and rationale for the DB-MSG 002 study protocol. Mycoses. 2018;61(9):656–64. https://doi.org/10.1111/myc.12788 This paper describes the increasing incidence of azole resistance in the Netherlands, an increasing problem globally.CrossRefPubMed •• Schauwvlieghe A, de Jonge N, van Dijk K, Verweij PE, Bruggemann RJ, Biemond BJ, et al. The diagnosis and treatment of invasive aspergillosis in Dutch haematology units facing a rapidly increasing prevalence of azole-resistance. A nationwide survey and rationale for the DB-MSG 002 study protocol. Mycoses. 2018;61(9):656–64. https://​doi.​org/​10.​1111/​myc.​12788 This paper describes the increasing incidence of azole resistance in the Netherlands, an increasing problem globally.CrossRefPubMed
17.
19.
Zurück zum Zitat Huttner A, Emonet S, Harbarth S, Renzi G, Kaiser L, Schrenzel J. Polymerase-chain reaction/electrospray ionization-mass spectrometry for the detection of bacteria and fungi in bronchoalveolar lavage fluids: a prospective observational study. Clin Microbiol Infect. 2014;20(12):O1059–66. https://doi.org/10.1111/1469-0691.12749.CrossRefPubMed Huttner A, Emonet S, Harbarth S, Renzi G, Kaiser L, Schrenzel J. Polymerase-chain reaction/electrospray ionization-mass spectrometry for the detection of bacteria and fungi in bronchoalveolar lavage fluids: a prospective observational study. Clin Microbiol Infect. 2014;20(12):O1059–66. https://​doi.​org/​10.​1111/​1469-0691.​12749.CrossRefPubMed
20.
Zurück zum Zitat Klaassen CH, de Valk HA, Curfs-Breuker IM, Meis JF. Novel mixed-format real-time PCR assay to detect mutations conferring resistance to triazoles in Aspergillus fumigatus and prevalence of multi-triazole resistance among clinical isolates in the Netherlands. J Antimicrob Chemother. 2010;65(5):901–5. https://doi.org/10.1093/jac/dkq041.CrossRefPubMed Klaassen CH, de Valk HA, Curfs-Breuker IM, Meis JF. Novel mixed-format real-time PCR assay to detect mutations conferring resistance to triazoles in Aspergillus fumigatus and prevalence of multi-triazole resistance among clinical isolates in the Netherlands. J Antimicrob Chemother. 2010;65(5):901–5. https://​doi.​org/​10.​1093/​jac/​dkq041.CrossRefPubMed
24.
Zurück zum Zitat Pfaller MA, Rhomberg PR, Wiederhold NP, Gibas C, Sanders C, Fan H, et al. In vitro activity of isavuconazole against opportunistic fungal pathogens from two mycology reference laboratories. Antimicrob Agents Chemother. 2018;62(10). https://doi.org/10.1128/aac.01230-18. Pfaller MA, Rhomberg PR, Wiederhold NP, Gibas C, Sanders C, Fan H, et al. In vitro activity of isavuconazole against opportunistic fungal pathogens from two mycology reference laboratories. Antimicrob Agents Chemother. 2018;62(10). https://​doi.​org/​10.​1128/​aac.​01230-18.
26.
Zurück zum Zitat Buil JB, Bruggemann RJM, Wasmann RE, Zoll J, Meis JF, Melchers WJG, et al. Isavuconazole susceptibility of clinical Aspergillus fumigatus isolates and feasibility of isavuconazole dose escalation to treat isolates with elevated MICs. J Antimicrob Chemother. 2018;73(1):134–42. https://doi.org/10.1093/jac/dkx354.CrossRefPubMed Buil JB, Bruggemann RJM, Wasmann RE, Zoll J, Meis JF, Melchers WJG, et al. Isavuconazole susceptibility of clinical Aspergillus fumigatus isolates and feasibility of isavuconazole dose escalation to treat isolates with elevated MICs. J Antimicrob Chemother. 2018;73(1):134–42. https://​doi.​org/​10.​1093/​jac/​dkx354.CrossRefPubMed
27.
Zurück zum Zitat Institute. CaLS. Reference method for broth dilution antifungal susceptibility testing of filamentous fungi.; Approved standard. In: CLSI document M38. 3rd ed. Wayne, PA: Clinical and Laboratory Standards Institute; 2017. Institute. CaLS. Reference method for broth dilution antifungal susceptibility testing of filamentous fungi.; Approved standard. In: CLSI document M38. 3rd ed. Wayne, PA: Clinical and Laboratory Standards Institute; 2017.
29.
Zurück zum Zitat Martin-Mazuelos E, Peman J, Valverde A, Chaves M, Serrano MC, Canton E. Comparison of the Sensititre YeastOne colorimetric antifungal panel and Etest with the NCCLS M38-A method to determine the activity of amphotericin B and itraconazole against clinical isolates of Aspergillus spp. J Antimicrob Chemother. 2003;52(3):365–70. https://doi.org/10.1093/jac/dkg384.CrossRefPubMed Martin-Mazuelos E, Peman J, Valverde A, Chaves M, Serrano MC, Canton E. Comparison of the Sensititre YeastOne colorimetric antifungal panel and Etest with the NCCLS M38-A method to determine the activity of amphotericin B and itraconazole against clinical isolates of Aspergillus spp. J Antimicrob Chemother. 2003;52(3):365–70. https://​doi.​org/​10.​1093/​jac/​dkg384.CrossRefPubMed
30.
Zurück zum Zitat Pfaller MA, Messer SA, Boyken L, Hollis RJ, Diekema DJ. In vitro susceptibility testing of filamentous fungi: comparison of Etest and reference M38-A microdilution methods for determining posaconazole MICs. Diagn Microbiol Infect Dis. 2003;45(4):241–4.CrossRef Pfaller MA, Messer SA, Boyken L, Hollis RJ, Diekema DJ. In vitro susceptibility testing of filamentous fungi: comparison of Etest and reference M38-A microdilution methods for determining posaconazole MICs. Diagn Microbiol Infect Dis. 2003;45(4):241–4.CrossRef
32.
34.
Zurück zum Zitat Espinel-Ingroff A, Rezusta A. E-test method for testing susceptibilities of Aspergillus spp. to the new triazoles voriconazole and posaconazole and to established antifungal agents: comparison with NCCLS broth microdilution method. J Clin Microbiol. 2002;40(6):2101–7.CrossRef Espinel-Ingroff A, Rezusta A. E-test method for testing susceptibilities of Aspergillus spp. to the new triazoles voriconazole and posaconazole and to established antifungal agents: comparison with NCCLS broth microdilution method. J Clin Microbiol. 2002;40(6):2101–7.CrossRef
36.
Zurück zum Zitat 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. 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.
37.
Zurück zum Zitat Guinea J, Verweij PE, Meletiadis J, Mouton JW, Barchiesi F, Arendrup MC. How to: EUCAST recommendations on the screening procedure E.Def 10.1 for the detection of azole resistance in Aspergillus fumigatus isolates using four-well azole-containing agar plates. Clin Microbiol Infect. 2018. https://doi.org/10.1016/j.cmi.2018.09.008. Guinea J, Verweij PE, Meletiadis J, Mouton JW, Barchiesi F, Arendrup MC. How to: EUCAST recommendations on the screening procedure E.Def 10.1 for the detection of azole resistance in Aspergillus fumigatus isolates using four-well azole-containing agar plates. Clin Microbiol Infect. 2018. https://​doi.​org/​10.​1016/​j.​cmi.​2018.​09.​008.
41.
Zurück zum Zitat Gitman MR, McTaggart L, Spinato J, Poopalarajah R, Lister E, Husain S, et al. Antifungal susceptibility testing of Aspergillus spp. by using a composite correlation index (CCI)-based matrix-assisted laser desorption ionization-time of flight mass spectrometry method appears to not offer benefit over traditional broth microdilution testing. J Clin Microbiol. 2017;55(7):2030–4. https://doi.org/10.1128/jcm.00254-17.CrossRefPubMedPubMedCentral Gitman MR, McTaggart L, Spinato J, Poopalarajah R, Lister E, Husain S, et al. Antifungal susceptibility testing of Aspergillus spp. by using a composite correlation index (CCI)-based matrix-assisted laser desorption ionization-time of flight mass spectrometry method appears to not offer benefit over traditional broth microdilution testing. J Clin Microbiol. 2017;55(7):2030–4. https://​doi.​org/​10.​1128/​jcm.​00254-17.CrossRefPubMedPubMedCentral
45.
Zurück zum Zitat Spiess B, Seifarth W, Merker N, Howard SJ, Reinwald M, Dietz A, et al. Development of novel PCR assays to detect azole resistance-mediating mutations of the Aspergillus fumigatus cyp51A gene in primary clinical samples from neutropenic patients. AntimicrobAgents Chemother. 2012;56(7):3905–10.CrossRef Spiess B, Seifarth W, Merker N, Howard SJ, Reinwald M, Dietz A, et al. Development of novel PCR assays to detect azole resistance-mediating mutations of the Aspergillus fumigatus cyp51A gene in primary clinical samples from neutropenic patients. AntimicrobAgents Chemother. 2012;56(7):3905–10.CrossRef
48.
Zurück zum Zitat 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;71:3528–35. https://doi.org/10.1093/jac/dkw323.CrossRefPubMed 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;71:3528–35. https://​doi.​org/​10.​1093/​jac/​dkw323.CrossRefPubMed
49.
Zurück zum Zitat •• Koehler P, Hamprecht A, Bader O, Bekeredjian-Ding I, Buchheidt D, Doelken G, et al. Epidemiology of invasive aspergillosis and azole resistance in patients with acute leukaemia: the SEPIA Study. Int J Antimicrob Agents. 2017;49(2):218–23. https://doi.org/10.1016/j.ijantimicag.2016.10.019 This very important study shows the clinical relevance of azole resistance in hematological patients on triazole therapy with azole-resistant A. fumigatus infections. CrossRefPubMed •• Koehler P, Hamprecht A, Bader O, Bekeredjian-Ding I, Buchheidt D, Doelken G, et al. Epidemiology of invasive aspergillosis and azole resistance in patients with acute leukaemia: the SEPIA Study. Int J Antimicrob Agents. 2017;49(2):218–23. https://​doi.​org/​10.​1016/​j.​ijantimicag.​2016.​10.​019 This very important study shows the clinical relevance of azole resistance in hematological patients on triazole therapy with azole-resistant A. fumigatus infections. CrossRefPubMed
51.
Zurück zum Zitat van der Linden JW, Snelders E, Arends JP, Daenen SM, Melchers WJ, Verweij PE. Rapid diagnosis of azole-resistant aspergillosis by direct PCR using tissue specimens. JClinMicrobiol. 2010;48(4):1478–80. van der Linden JW, Snelders E, Arends JP, Daenen SM, Melchers WJ, Verweij PE. Rapid diagnosis of azole-resistant aspergillosis by direct PCR using tissue specimens. JClinMicrobiol. 2010;48(4):1478–80.
52.
Zurück zum Zitat 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. ClinInfectDis. 2011;52(9):1123–9. 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. ClinInfectDis. 2011;52(9):1123–9.
Metadaten
Titel
(New) Methods for Detection of Aspergillus fumigatus Resistance in Clinical Samples
verfasst von
Jeffrey D. Jenks
Birgit Spiess
Dieter Buchheidt
Martin Hoenigl
Publikationsdatum
20.06.2019
Verlag
Springer US
Erschienen in
Current Fungal Infection Reports / Ausgabe 3/2019
Print ISSN: 1936-3761
Elektronische ISSN: 1936-377X
DOI
https://doi.org/10.1007/s12281-019-00342-w

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