First Reported Case of Azole-Resistant Aspergillus fumigatus Due to the TR/L98H Mutation in Germany

LETTER

Aspergillus fumigatus is clinically the most relevant mold in immunocompromised patients. Azoles are the drugs of choice for treatment of invasive infections (13). Recently, an increasing number of azole-resistant A. fumigatus isolates in the environment, as well as in patient specimens, have been described in the Netherlands (9, 11), France (2), Denmark (7, 8), China (6), India, and Great Britain (3–5). In a nationwide study from the Netherlands, the case fatality rate of patients with azole-resistant invasive aspergillosis was 88% (11). The isolates are azole resistant in part due to a point mutation in the 14alpha-sterol demethylase gene (cyp51A) and increased expression of this gene due to a tandem repeat promoter alteration (TR/L98H mutation). It has been speculated that the appearance of this new mutation is correlated with the use of azoles in agriculture that are structurally similar to those in human medicine (12), because environmental and clinical resistant isolates clustered apart from nonresistant isolates (9). In a study performed in Austria, Denmark, and Spain in 2009, environmental A. fumigatus isolates with this genetic alteration were found in Denmark but not in the other two countries (7).

Here, we describe a clinical azole-resistant A. fumigatus isolate carrying the TR/L98H mutation in the cyp51A gene in Germany. The patient, a 48-year-old male heroin addict, suffered from an aspergilloma, and treatment with oral voriconazole (400 mg) was initiated in May 2011 and continued until his admission to the University Hospital, Essen, Germany, in February 2012 for excision of a destroyed lobe, indicating treatment failure. A. fumigatus was found in a sputum culture from 6 February 2012, showing resistance to itraconazole (MIC, ≥16 mg/liter) and to voriconazole (MIC, 4.0 mg/liter) and intermediate susceptibility to posaconazole (MIC, 0.5 mg/liter) using broth microdilution (3a). The phenotypic species identification was verified by sequencing of the ITS1-5.8s-ITS2 region. The isolate was further analyzed for the genetic basis of this resistance phenotype (10). It was shown that the TR/L98H mutation was the cause of azole resistance. Treatment was reassessed and changed to liposomal amphotericin B. Three weeks later, the patient was discharged in good clinical condition.

To date, it seems that the prevalence of azole-resistant A. fumigatus isolates is higher in some geographic areas than in others. For example, in the Netherlands, 5.3% of patients' isolates were azole resistant (11), a rate similar to data for isolates from cystic fibrosis patients in France (4.6%) (2). In contrast, azole-resistant A. fumigatus was detected in only 1 of 118 isolates from 89 French patients with hematological malignancies (1). In the current guidelines of the IDSA, routine susceptibility testing of A. fumigatus isolates is generally not recommended (13). However, clinicians and laboratories should be aware of the increasing phenomenon of azole-resistant A. fumigatus. Itraconazole might be a sensitive marker for suggesting azole resistance.

This study constitutes the first report of an azole-resistant A. fumigatus isolate with the TR/L98H mutation in Germany and underlines the emergence of such isolates in Western Europe. Further epidemiological and clinical studies are necessary to determine the prevalence of azole resistance in Germany and its impact on antifungal therapy in patients' outcomes.