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

被引：264

作者：

van der Linden, Jan W. M. ^{[1
,2
]}

Camps, Simone M. T. ^{[1
,2
]}

Kampinga, Greetje A. ^{[3
]}

Arends, Jan P. A. ^{[3
]}

Debets-Ossenkopp, Yvette J. ^{[4
]}

Haas, Pieter J. A. ^{[5
]}

Rijnders, Bart J. A. ^{[6
]}

Kuijper, Ed J. ^{[7
]}

van Tiel, Frank H. ^{[8
]}

Varga, Janos ^{[9
]}

Karawajczyk, Anna ^{[10
]}

Zoll, J. ^{[1
,2
]}

Melchers, Willem J. G. ^{[1
,2
]}

Verweij, Paul E. ^{[1
,2
]}

机构：

[1] Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, NL-6500 HB Nijmegen, Netherlands

[2] Radboud Univ Nijmegen, Med Ctr, Nijmegen Inst Infect Inflammat & Immun N4I, NL-6500 HB Nijmegen, Netherlands

[3] Univ Groningen, Univ Med Ctr Groningen, Dept Med Microbiol, NL-9700 AB Groningen, Netherlands

[4] Vrije Univ Amsterdam Med Ctr, Dept Med Microbiol, Amsterdam, Netherlands

[5] Univ Med Ctr Utrecht, Dept Med Microbiol, Utrecht, Netherlands

[6] Erasmus MC, Dept Internal Med, Div Infect Dis, Rotterdam, Netherlands

[7] Leiden Univ, Med Ctr, Dept Med Microbiol, NL-2300 RA Leiden, Netherlands

[8] Univ Med Ctr Maastricht, Dept Med Microbiol, Maastricht, Netherlands

[9] Univ Szeged, Dept Microbiol, Szeged, Hungary

[10] LeadParma Med BV, Nijmegen, Netherlands

来源：

CLINICAL INFECTIOUS DISEASES | 2013年 / 57卷 / 04期

关键词：

Aspergillus fumigatus; azole resistance; voriconazole; prevalence; invasive aspergillosis; AZOLE RESISTANCE; CROSS-RESISTANCE; TR/L98H MUTATION; PHARMACODYNAMICS; ANIDULAFUNGIN; ITRACONAZOLE; PREVALENCE; MECHANISM; FREQUENCY; DISEASE;

D O I：

10.1093/cid/cit320

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：513 / 520

页数：8

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