Aspergillosis due to Voriconazole Highly Resistant Aspergillus fumigatus and Recovery of Genetically Related Resistant Isolates From Domiciles

Jan W. M. van der Linden; Simone M. T. Camps; Greetje A. Kampinga; Jan P. A. Arends; Yvette J. Debets-Ossenkopp; Pieter J. A. Haas; Bart J. A. Rijnders; Ed J. Kuijper; Frank H. van Tiel; Janos Varga; Anna Karawajczyk; J. Zoll; Willem J. G. Melchers; Paul E. Verweij

doi:10.1093/cid/cit320

Aspergillosis due to Voriconazole Highly Resistant Aspergillus fumigatus and Recovery of Genetically Related Resistant Isolates From Domiciles

Jan W. M. van der Linden, Simone M. T. Camps, Greetje A. Kampinga, Jan P. A. Arends, Yvette J. Debets-Ossenkopp, Pieter J. A. Haas, Bart J. A. Rijnders, Ed J. Kuijper, Frank H. van Tiel, Janos Varga, Anna Karawajczyk, J. Zoll, Willem J. G. Melchers, Paul E. Verweij^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background. Azole resistance is an emerging problem in Aspergillus fumigatus and complicates the management of patients with Aspergillus-related diseases. Selection of azole resistance may occur through exposure to azole fungicides in the environment. In the Netherlands a surveillance network was used to investigate the epidemiology of resistance selection in A. fumigatus. Methods. Clinical A. fumigatus isolates were screened for azole resistance in 8 university hospitals using azole agar dilution plates. Patient information was collected using an online questionnaire and azole-resistant A. fumigatus isolates were analyzed using gene sequencing, susceptibility testing, and genotyping. Air sampling was performed to investigate the presence of resistant isolates in hospitals and domiciles. Results. Between December 2009 and January 2011, 1315 A. fumigatus isolates from 921 patients were screened. A new cyp51A-mediated resistance mechanism (TR46/Y121F/T289A) was observed in 21 azole-resistant isolates from 15 patients in 6 hospitals. TR46/Y121F/T289A isolates were highly resistant to voriconazole (minimum inhibitory concentration >= 16 mg/L). Eight patients presented with invasive aspergillosis due to TR46/Y121F/T289A, and treatment failed in all 5 patients receiving primary therapy with voriconazole. TR46/Y121F/T289A Aspergillus fumigatus was recovered from 6 of 10 sampled environmental sites. Conclusions. We describe the emergence and geographical migration of a voriconazole highly resistant A. fumigatus that was associated with voriconazole treatment failure in patients with invasive aspergillosis. Recovery of TR46/Y121F/T289A from the environment suggests an environmental route of resistance selection. Exposure of A. fumigatus to azole fungicides may facilitate the emergence of new resistance mechanisms over time, thereby compromising the use of azoles in the management of Aspergillus-related diseases.

Original language	English
Pages (from-to)	513-520
Journal	Clinical Infectious Diseases
Volume	57
Issue number	4
DOIs	https://doi.org/10.1093/cid/cit320
Publication status	Published - 15 Aug 2013

Keywords

Aspergillus fumigatus
azole resistance
voriconazole
prevalence
invasive aspergillosis

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10.1093/cid/cit320

Cite this

van der Linden, J. W. M., Camps, S. M. T., Kampinga, G. A., Arends, J. P. A., Debets-Ossenkopp, Y. J., Haas, P. J. A., Rijnders, B. J. A., Kuijper, E. J., van Tiel, F. H., Varga, J., Karawajczyk, A., Zoll, J., Melchers, W. J. G., & Verweij, P. E. (2013). Aspergillosis due to Voriconazole Highly Resistant Aspergillus fumigatus and Recovery of Genetically Related Resistant Isolates From Domiciles. Clinical Infectious Diseases, 57(4), 513-520. https://doi.org/10.1093/cid/cit320

@article{91f82322d15447d094778947f55fa2d7,

title = "Aspergillosis due to Voriconazole Highly Resistant Aspergillus fumigatus and Recovery of Genetically Related Resistant Isolates From Domiciles",

abstract = "Background. Azole resistance is an emerging problem in Aspergillus fumigatus and complicates the management of patients with Aspergillus-related diseases. Selection of azole resistance may occur through exposure to azole fungicides in the environment. In the Netherlands a surveillance network was used to investigate the epidemiology of resistance selection in A. fumigatus. Methods. Clinical A. fumigatus isolates were screened for azole resistance in 8 university hospitals using azole agar dilution plates. Patient information was collected using an online questionnaire and azole-resistant A. fumigatus isolates were analyzed using gene sequencing, susceptibility testing, and genotyping. Air sampling was performed to investigate the presence of resistant isolates in hospitals and domiciles. Results. Between December 2009 and January 2011, 1315 A. fumigatus isolates from 921 patients were screened. A new cyp51A-mediated resistance mechanism (TR46/Y121F/T289A) was observed in 21 azole-resistant isolates from 15 patients in 6 hospitals. TR46/Y121F/T289A isolates were highly resistant to voriconazole (minimum inhibitory concentration >= 16 mg/L). Eight patients presented with invasive aspergillosis due to TR46/Y121F/T289A, and treatment failed in all 5 patients receiving primary therapy with voriconazole. TR46/Y121F/T289A Aspergillus fumigatus was recovered from 6 of 10 sampled environmental sites. Conclusions. We describe the emergence and geographical migration of a voriconazole highly resistant A. fumigatus that was associated with voriconazole treatment failure in patients with invasive aspergillosis. Recovery of TR46/Y121F/T289A from the environment suggests an environmental route of resistance selection. Exposure of A. fumigatus to azole fungicides may facilitate the emergence of new resistance mechanisms over time, thereby compromising the use of azoles in the management of Aspergillus-related diseases.",

keywords = "Aspergillus fumigatus, azole resistance, voriconazole, prevalence, invasive aspergillosis",

author = "{van der Linden}, {Jan W. M.} and Camps, {Simone M. T.} and Kampinga, {Greetje A.} and Arends, {Jan P. A.} and Debets-Ossenkopp, {Yvette J.} and Haas, {Pieter J. A.} and Rijnders, {Bart J. A.} and Kuijper, {Ed J.} and {van Tiel}, {Frank H.} and Janos Varga and Anna Karawajczyk and J. Zoll and Melchers, {Willem J. G.} and Verweij, {Paul E.}",

year = "2013",

month = aug,

day = "15",

doi = "10.1093/cid/cit320",

language = "English",

volume = "57",

pages = "513--520",

journal = "Clinical Infectious Diseases",

issn = "1058-4838",

publisher = "Oxford University Press",

number = "4",

}

van der Linden, JWM, Camps, SMT, Kampinga, GA, Arends, JPA, Debets-Ossenkopp, YJ, Haas, PJA, Rijnders, BJA, Kuijper, EJ, van Tiel, FH, Varga, J, Karawajczyk, A, Zoll, J, Melchers, WJG & Verweij, PE 2013, 'Aspergillosis due to Voriconazole Highly Resistant Aspergillus fumigatus and Recovery of Genetically Related Resistant Isolates From Domiciles', Clinical Infectious Diseases, vol. 57, no. 4, pp. 513-520. https://doi.org/10.1093/cid/cit320

Aspergillosis due to Voriconazole Highly Resistant Aspergillus fumigatus and Recovery of Genetically Related Resistant Isolates From Domiciles. / van der Linden, Jan W. M.; Camps, Simone M. T.; Kampinga, Greetje A. et al.
In: Clinical Infectious Diseases, Vol. 57, No. 4, 15.08.2013, p. 513-520.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Aspergillosis due to Voriconazole Highly Resistant Aspergillus fumigatus and Recovery of Genetically Related Resistant Isolates From Domiciles

AU - van der Linden, Jan W. M.

AU - Camps, Simone M. T.

AU - Kampinga, Greetje A.

AU - Arends, Jan P. A.

AU - Debets-Ossenkopp, Yvette J.

AU - Haas, Pieter J. A.

AU - Rijnders, Bart J. A.

AU - Kuijper, Ed J.

AU - van Tiel, Frank H.

AU - Varga, Janos

AU - Karawajczyk, Anna

AU - Zoll, J.

AU - Melchers, Willem J. G.

AU - Verweij, Paul E.

PY - 2013/8/15

Y1 - 2013/8/15

N2 - Background. Azole resistance is an emerging problem in Aspergillus fumigatus and complicates the management of patients with Aspergillus-related diseases. Selection of azole resistance may occur through exposure to azole fungicides in the environment. In the Netherlands a surveillance network was used to investigate the epidemiology of resistance selection in A. fumigatus. Methods. Clinical A. fumigatus isolates were screened for azole resistance in 8 university hospitals using azole agar dilution plates. Patient information was collected using an online questionnaire and azole-resistant A. fumigatus isolates were analyzed using gene sequencing, susceptibility testing, and genotyping. Air sampling was performed to investigate the presence of resistant isolates in hospitals and domiciles. Results. Between December 2009 and January 2011, 1315 A. fumigatus isolates from 921 patients were screened. A new cyp51A-mediated resistance mechanism (TR46/Y121F/T289A) was observed in 21 azole-resistant isolates from 15 patients in 6 hospitals. TR46/Y121F/T289A isolates were highly resistant to voriconazole (minimum inhibitory concentration >= 16 mg/L). Eight patients presented with invasive aspergillosis due to TR46/Y121F/T289A, and treatment failed in all 5 patients receiving primary therapy with voriconazole. TR46/Y121F/T289A Aspergillus fumigatus was recovered from 6 of 10 sampled environmental sites. Conclusions. We describe the emergence and geographical migration of a voriconazole highly resistant A. fumigatus that was associated with voriconazole treatment failure in patients with invasive aspergillosis. Recovery of TR46/Y121F/T289A from the environment suggests an environmental route of resistance selection. Exposure of A. fumigatus to azole fungicides may facilitate the emergence of new resistance mechanisms over time, thereby compromising the use of azoles in the management of Aspergillus-related diseases.

AB - Background. Azole resistance is an emerging problem in Aspergillus fumigatus and complicates the management of patients with Aspergillus-related diseases. Selection of azole resistance may occur through exposure to azole fungicides in the environment. In the Netherlands a surveillance network was used to investigate the epidemiology of resistance selection in A. fumigatus. Methods. Clinical A. fumigatus isolates were screened for azole resistance in 8 university hospitals using azole agar dilution plates. Patient information was collected using an online questionnaire and azole-resistant A. fumigatus isolates were analyzed using gene sequencing, susceptibility testing, and genotyping. Air sampling was performed to investigate the presence of resistant isolates in hospitals and domiciles. Results. Between December 2009 and January 2011, 1315 A. fumigatus isolates from 921 patients were screened. A new cyp51A-mediated resistance mechanism (TR46/Y121F/T289A) was observed in 21 azole-resistant isolates from 15 patients in 6 hospitals. TR46/Y121F/T289A isolates were highly resistant to voriconazole (minimum inhibitory concentration >= 16 mg/L). Eight patients presented with invasive aspergillosis due to TR46/Y121F/T289A, and treatment failed in all 5 patients receiving primary therapy with voriconazole. TR46/Y121F/T289A Aspergillus fumigatus was recovered from 6 of 10 sampled environmental sites. Conclusions. We describe the emergence and geographical migration of a voriconazole highly resistant A. fumigatus that was associated with voriconazole treatment failure in patients with invasive aspergillosis. Recovery of TR46/Y121F/T289A from the environment suggests an environmental route of resistance selection. Exposure of A. fumigatus to azole fungicides may facilitate the emergence of new resistance mechanisms over time, thereby compromising the use of azoles in the management of Aspergillus-related diseases.

KW - Aspergillus fumigatus

KW - azole resistance

KW - voriconazole

KW - prevalence

KW - invasive aspergillosis

U2 - 10.1093/cid/cit320

DO - 10.1093/cid/cit320

M3 - Article

C2 - 23667263

SN - 1058-4838

VL - 57

SP - 513

EP - 520

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

IS - 4

ER -