Azole-resistance in Aspergillus terreus and related species: An emerging problem or a rare Phenomenon?

Tamara Zoran; Bettina Sartori; Laura Sappl; Maria Aigner; Ferran Sánchez-Reus; Antonio Rezusta; Anuradha Chowdhary; Saad J. Taj-Aldeen; Maiken C. Arendrup; Salvatore Oliveri; Dimitrios P. Kontoyiannis; Ana Alastruey-Izquierdo; Katrien Lagrou; Giuliana Lo Cascio; Jacques F. Meis; Walter Buzina; Claudio Farina; Miranda Drogari-Apiranthitou; Anna Grancini; Anna M. Tortorano; Birgit Willinger; Axel Hamprecht; Elizabeth Johnson; Lena Klingspor; Valentina Arsic-Arsenijevic; Oliver A. Cornely; Joseph Meletiadis; Wolfgang Prammer; Vivian Tullio; Jörg Janne Vehreschild; Laura Trovato; Russell E. Lewis; Esther Segal; Peter Michael Rath; Petr Hamal; Manuel Rodriguez-Iglesias; Emmanuel Roilides; Sevtap Arikan-Akdagli; Arunaloke Chakrabarti; Arnaldo L. Colombo; Mariana S. Fernández; M. Teresa Martin-Gomez; Hamid Badali; Georgios Petrikkos; Nikolai Klimko; Sebastian M. Heimann; Omrum Uzun; Maryam Roudbary; Sonia de la Fuente; Jos Houbraken; Brigitte Risslegger; Cornelia Lass-Flörl; Michaela Lackner

doi:10.3389/fmicb.2018.00516

Azole-resistance in Aspergillus terreus and related species: An emerging problem or a rare Phenomenon?

Tamara Zoran, Bettina Sartori, Laura Sappl, Maria Aigner, Ferran Sánchez-Reus, Antonio Rezusta, Anuradha Chowdhary, Saad J. Taj-Aldeen, Maiken C. Arendrup, Salvatore Oliveri, Dimitrios P. Kontoyiannis, Ana Alastruey-Izquierdo, Katrien Lagrou, Giuliana Lo Cascio, Jacques F. Meis, Walter Buzina, Claudio Farina, Miranda Drogari-Apiranthitou, Anna Grancini, Anna M. TortoranoBirgit Willinger, Axel Hamprecht, Elizabeth Johnson, Lena Klingspor, Valentina Arsic-Arsenijevic, Oliver A. Cornely, Joseph Meletiadis, Wolfgang Prammer, Vivian Tullio, Jörg Janne Vehreschild, Laura Trovato, Russell E. Lewis, Esther Segal, Peter Michael Rath, Petr Hamal, Manuel Rodriguez-Iglesias, Emmanuel Roilides, Sevtap Arikan-Akdagli, Arunaloke Chakrabarti, Arnaldo L. Colombo, Mariana S. Fernández, M. Teresa Martin-Gomez, Hamid Badali, Georgios Petrikkos, Nikolai Klimko, Sebastian M. Heimann, Omrum Uzun, Maryam Roudbary, Sonia de la Fuente, Jos Houbraken, Brigitte Risslegger, Cornelia Lass-Flörl^*, Michaela Lackner

^*Corresponding author for this work

Department of Clinical Medicine

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Abstract

Objectives: Invasive mold infections associated with Aspergillus species are a significant cause of mortality in immunocompromised patients. The most frequently occurring aetiological pathogens are members of the Aspergillus section Fumigati followed by members of the section Terrei. The frequency of Aspergillus terreus and related (cryptic) species in clinical specimens, as well as the percentage of azole-resistant strains remains to be studied.

Methods: A global set (n = 498) of A. terreus and phenotypically related isolates was molecularly identified (beta-tubulin), tested for antifungal susceptibility against posaconazole, voriconazole, and itraconazole, and resistant phenotypes were correlated with point mutations in the cyp51A gene.

Results: The majority of isolates was identified as A. terreus (86.8%), followed by A. citrinoterreus (8.4%), A. hortai (2.6%), A. alabamensis (1.6%), A. neoafricanus (0.2%), and A. floccosus (0.2%). One isolate failed to match a known Aspergillus sp., but was found most closely related to A. alabamensis. According to EUCAST clinical breakpoints azole resistance was detected in 5.4% of all tested isolates, 6.2% of A. terreus sensu stricto (s.s.) were posaconazole-resistant. Posaconazole resistance differed geographically and ranged from 0% in the Czech Republic, Greece, and Turkey to 13.7% in Germany. In contrast, azole resistance among cryptic species was rare 2 out of 66 isolates and was observed only in one A. citrinoterreus and one A. alabamensis isolate. The most affected amino acid position of the Cyp51A gene correlating with the posaconazole resistant phenotype was M217, which was found in the variation M217T and M217V.

Conclusions: Aspergillus terreus was most prevalent, followed by A. citrinoterreus. Posaconazole was the most potent drug against A. terreus, but 5.4% of A. terreus sensu stricto showed resistance against this azole. In Austria, Germany, and the United Kingdom posaconazole-resistance in all A. terreus isolates was higher than 10%, resistance against voriconazole was rare and absent for itraconazole.

Original language	English
Article number	516
Journal	Frontiers in Microbiology
Volume	9
Issue number	MAR
Number of pages	9
ISSN	1664-302X
DOIs	https://doi.org/10.3389/fmicb.2018.00516
Publication status	Published - 2018

Keywords

Aspergillus section Terrei
Azoles
Cryptic species
Cyp51A alterations
Susceptibility profiles

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Azole-Resistance in Aspergillus terreus and Related Species: An Emerging Problem or a Rare Phenomenon?Final published version, 1.29 MBLicence: CC BY

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Zoran, T., Sartori, B., Sappl, L., Aigner, M., Sánchez-Reus, F., Rezusta, A., Chowdhary, A., Taj-Aldeen, S. J., Arendrup, M. C., Oliveri, S., Kontoyiannis, D. P., Alastruey-Izquierdo, A., Lagrou, K., Cascio, G. L., Meis, J. F., Buzina, W., Farina, C., Drogari-Apiranthitou, M., Grancini, A., ... Lackner, M. (2018). Azole-resistance in Aspergillus terreus and related species: An emerging problem or a rare Phenomenon? Frontiers in Microbiology, 9(MAR), [516]. https://doi.org/10.3389/fmicb.2018.00516

Zoran, T, Sartori, B, Sappl, L, Aigner, M, Sánchez-Reus, F, Rezusta, A, Chowdhary, A, Taj-Aldeen, SJ, Arendrup, MC, Oliveri, S, Kontoyiannis, DP, Alastruey-Izquierdo, A, Lagrou, K, Cascio, GL, Meis, JF, Buzina, W, Farina, C, Drogari-Apiranthitou, M, Grancini, A, Tortorano, AM, Willinger, B, Hamprecht, A, Johnson, E, Klingspor, L, Arsic-Arsenijevic, V, Cornely, OA, Meletiadis, J, Prammer, W, Tullio, V, Vehreschild, JJ, Trovato, L, Lewis, RE, Segal, E, Rath, PM, Hamal, P, Rodriguez-Iglesias, M, Roilides, E, Arikan-Akdagli, S, Chakrabarti, A, Colombo, AL, Fernández, MS, Martin-Gomez, MT, Badali, H, Petrikkos, G, Klimko, N, Heimann, SM, Uzun, O, Roudbary, M, de la Fuente, S, Houbraken, J, Risslegger, B, Lass-Flörl, C & Lackner, M 2018, 'Azole-resistance in Aspergillus terreus and related species: An emerging problem or a rare Phenomenon?', Frontiers in Microbiology, vol. 9, no. MAR, 516. https://doi.org/10.3389/fmicb.2018.00516

@article{44e14400bc0043b9b09902b0bd583b90,

title = "Azole-resistance in Aspergillus terreus and related species: An emerging problem or a rare Phenomenon?",

abstract = "Objectives: Invasive mold infections associated with Aspergillus species are a significant cause of mortality in immunocompromised patients. The most frequently occurring aetiological pathogens are members of the Aspergillus section Fumigati followed by members of the section Terrei. The frequency of Aspergillus terreus and related (cryptic) species in clinical specimens, as well as the percentage of azole-resistant strains remains to be studied. Methods: A global set (n = 498) of A. terreus and phenotypically related isolates was molecularly identified (beta-tubulin), tested for antifungal susceptibility against posaconazole, voriconazole, and itraconazole, and resistant phenotypes were correlated with point mutations in the cyp51A gene. Results: The majority of isolates was identified as A. terreus (86.8%), followed by A. citrinoterreus (8.4%), A. hortai (2.6%), A. alabamensis (1.6%), A. neoafricanus (0.2%), and A. floccosus (0.2%). One isolate failed to match a known Aspergillus sp., but was found most closely related to A. alabamensis. According to EUCAST clinical breakpoints azole resistance was detected in 5.4% of all tested isolates, 6.2% of A. terreus sensu stricto (s.s.) were posaconazole-resistant. Posaconazole resistance differed geographically and ranged from 0% in the Czech Republic, Greece, and Turkey to 13.7% in Germany. In contrast, azole resistance among cryptic species was rare 2 out of 66 isolates and was observed only in one A. citrinoterreus and one A. alabamensis isolate. The most affected amino acid position of the Cyp51A gene correlating with the posaconazole resistant phenotype was M217, which was found in the variation M217T and M217V. Conclusions: Aspergillus terreus was most prevalent, followed by A. citrinoterreus. Posaconazole was the most potent drug against A. terreus, but 5.4% of A. terreus sensu stricto showed resistance against this azole. In Austria, Germany, and the United Kingdom posaconazole-resistance in all A. terreus isolates was higher than 10%, resistance against voriconazole was rare and absent for itraconazole.",

keywords = "Aspergillus section Terrei, Azoles, Cryptic species, Cyp51A alterations, Susceptibility profiles",

author = "Tamara Zoran and Bettina Sartori and Laura Sappl and Maria Aigner and Ferran S{\'a}nchez-Reus and Antonio Rezusta and Anuradha Chowdhary and Taj-Aldeen, {Saad J.} and Arendrup, {Maiken C.} and Salvatore Oliveri and Kontoyiannis, {Dimitrios P.} and Ana Alastruey-Izquierdo and Katrien Lagrou and Cascio, {Giuliana Lo} and Meis, {Jacques F.} and Walter Buzina and Claudio Farina and Miranda Drogari-Apiranthitou and Anna Grancini and Tortorano, {Anna M.} and Birgit Willinger and Axel Hamprecht and Elizabeth Johnson and Lena Klingspor and Valentina Arsic-Arsenijevic and Cornely, {Oliver A.} and Joseph Meletiadis and Wolfgang Prammer and Vivian Tullio and Vehreschild, {J{\"o}rg Janne} and Laura Trovato and Lewis, {Russell E.} and Esther Segal and Rath, {Peter Michael} and Petr Hamal and Manuel Rodriguez-Iglesias and Emmanuel Roilides and Sevtap Arikan-Akdagli and Arunaloke Chakrabarti and Colombo, {Arnaldo L.} and Fern{\'a}ndez, {Mariana S.} and Martin-Gomez, {M. Teresa} and Hamid Badali and Georgios Petrikkos and Nikolai Klimko and Heimann, {Sebastian M.} and Omrum Uzun and Maryam Roudbary and {de la Fuente}, Sonia and Jos Houbraken and Brigitte Risslegger and Cornelia Lass-Fl{\"o}rl and Michaela Lackner",

year = "2018",

doi = "10.3389/fmicb.2018.00516",

language = "English",

volume = "9",

journal = "Frontiers in Microbiology",

issn = "1664-302X",

publisher = "Frontiers Media S.A.",

number = "MAR",

}

TY - JOUR

T1 - Azole-resistance in Aspergillus terreus and related species

T2 - An emerging problem or a rare Phenomenon?

AU - Zoran, Tamara

AU - Sartori, Bettina

AU - Sappl, Laura

AU - Aigner, Maria

AU - Sánchez-Reus, Ferran

AU - Rezusta, Antonio

AU - Chowdhary, Anuradha

AU - Taj-Aldeen, Saad J.

AU - Arendrup, Maiken C.

AU - Oliveri, Salvatore

AU - Kontoyiannis, Dimitrios P.

AU - Alastruey-Izquierdo, Ana

AU - Lagrou, Katrien

AU - Cascio, Giuliana Lo

AU - Meis, Jacques F.

AU - Buzina, Walter

AU - Farina, Claudio

AU - Drogari-Apiranthitou, Miranda

AU - Grancini, Anna

AU - Tortorano, Anna M.

AU - Willinger, Birgit

AU - Hamprecht, Axel

AU - Johnson, Elizabeth

AU - Klingspor, Lena

AU - Arsic-Arsenijevic, Valentina

AU - Cornely, Oliver A.

AU - Meletiadis, Joseph

AU - Prammer, Wolfgang

AU - Tullio, Vivian

AU - Vehreschild, Jörg Janne

AU - Trovato, Laura

AU - Lewis, Russell E.

AU - Segal, Esther

AU - Rath, Peter Michael

AU - Hamal, Petr

AU - Rodriguez-Iglesias, Manuel

AU - Roilides, Emmanuel

AU - Arikan-Akdagli, Sevtap

AU - Chakrabarti, Arunaloke

AU - Colombo, Arnaldo L.

AU - Fernández, Mariana S.

AU - Martin-Gomez, M. Teresa

AU - Badali, Hamid

AU - Petrikkos, Georgios

AU - Klimko, Nikolai

AU - Heimann, Sebastian M.

AU - Uzun, Omrum

AU - Roudbary, Maryam

AU - de la Fuente, Sonia

AU - Houbraken, Jos

AU - Risslegger, Brigitte

AU - Lass-Flörl, Cornelia

AU - Lackner, Michaela

PY - 2018

Y1 - 2018

N2 - Objectives: Invasive mold infections associated with Aspergillus species are a significant cause of mortality in immunocompromised patients. The most frequently occurring aetiological pathogens are members of the Aspergillus section Fumigati followed by members of the section Terrei. The frequency of Aspergillus terreus and related (cryptic) species in clinical specimens, as well as the percentage of azole-resistant strains remains to be studied. Methods: A global set (n = 498) of A. terreus and phenotypically related isolates was molecularly identified (beta-tubulin), tested for antifungal susceptibility against posaconazole, voriconazole, and itraconazole, and resistant phenotypes were correlated with point mutations in the cyp51A gene. Results: The majority of isolates was identified as A. terreus (86.8%), followed by A. citrinoterreus (8.4%), A. hortai (2.6%), A. alabamensis (1.6%), A. neoafricanus (0.2%), and A. floccosus (0.2%). One isolate failed to match a known Aspergillus sp., but was found most closely related to A. alabamensis. According to EUCAST clinical breakpoints azole resistance was detected in 5.4% of all tested isolates, 6.2% of A. terreus sensu stricto (s.s.) were posaconazole-resistant. Posaconazole resistance differed geographically and ranged from 0% in the Czech Republic, Greece, and Turkey to 13.7% in Germany. In contrast, azole resistance among cryptic species was rare 2 out of 66 isolates and was observed only in one A. citrinoterreus and one A. alabamensis isolate. The most affected amino acid position of the Cyp51A gene correlating with the posaconazole resistant phenotype was M217, which was found in the variation M217T and M217V. Conclusions: Aspergillus terreus was most prevalent, followed by A. citrinoterreus. Posaconazole was the most potent drug against A. terreus, but 5.4% of A. terreus sensu stricto showed resistance against this azole. In Austria, Germany, and the United Kingdom posaconazole-resistance in all A. terreus isolates was higher than 10%, resistance against voriconazole was rare and absent for itraconazole.

AB - Objectives: Invasive mold infections associated with Aspergillus species are a significant cause of mortality in immunocompromised patients. The most frequently occurring aetiological pathogens are members of the Aspergillus section Fumigati followed by members of the section Terrei. The frequency of Aspergillus terreus and related (cryptic) species in clinical specimens, as well as the percentage of azole-resistant strains remains to be studied. Methods: A global set (n = 498) of A. terreus and phenotypically related isolates was molecularly identified (beta-tubulin), tested for antifungal susceptibility against posaconazole, voriconazole, and itraconazole, and resistant phenotypes were correlated with point mutations in the cyp51A gene. Results: The majority of isolates was identified as A. terreus (86.8%), followed by A. citrinoterreus (8.4%), A. hortai (2.6%), A. alabamensis (1.6%), A. neoafricanus (0.2%), and A. floccosus (0.2%). One isolate failed to match a known Aspergillus sp., but was found most closely related to A. alabamensis. According to EUCAST clinical breakpoints azole resistance was detected in 5.4% of all tested isolates, 6.2% of A. terreus sensu stricto (s.s.) were posaconazole-resistant. Posaconazole resistance differed geographically and ranged from 0% in the Czech Republic, Greece, and Turkey to 13.7% in Germany. In contrast, azole resistance among cryptic species was rare 2 out of 66 isolates and was observed only in one A. citrinoterreus and one A. alabamensis isolate. The most affected amino acid position of the Cyp51A gene correlating with the posaconazole resistant phenotype was M217, which was found in the variation M217T and M217V. Conclusions: Aspergillus terreus was most prevalent, followed by A. citrinoterreus. Posaconazole was the most potent drug against A. terreus, but 5.4% of A. terreus sensu stricto showed resistance against this azole. In Austria, Germany, and the United Kingdom posaconazole-resistance in all A. terreus isolates was higher than 10%, resistance against voriconazole was rare and absent for itraconazole.

KW - Aspergillus section Terrei

KW - Azoles

KW - Cryptic species

KW - Cyp51A alterations

KW - Susceptibility profiles

U2 - 10.3389/fmicb.2018.00516

DO - 10.3389/fmicb.2018.00516

M3 - Journal article

C2 - 29643840

AN - SCOPUS:85044825355

SN - 1664-302X

VL - 9

JO - Frontiers in Microbiology

JF - Frontiers in Microbiology

IS - MAR

M1 - 516

ER -

Azole-resistance in Aspergillus terreus and related species: An emerging problem or a rare Phenomenon?

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Keywords

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