Emergence of azole-resistant invasive aspergillosis in HSCT recipients in Germany

Steinmann, Joerg; Hamprecht, Axel; Vehreschild, Maria J. G. T.; Cornely, Oliver A.; Buchheidt, Dieter; Spieß, Birgit; Koldehoff, Michael; Buer, Jan; Meis, Jacques F.; Rath, Peter

doi:10.1093/jac/dku566

Cited by 165 publications

(129 citation statements)

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“…Nevertheless, a prevalence of approximately 5% is the most common in this population (28)(29)(30)(31)(32). In the present study, TR 34 /L98H was the most frequent mutation observed, as has been observed in other studies (4,(23)(24)(25)31). …”

Section: Discussionsupporting

confidence: 87%

“…Similarly, the prevalence of azole-resistant A. fumigatus in a Belgian multicenter prospective cohort of patients with Aspergillus disease was 5.5% (17). Higher prevalences (8 to 30%) have been reported in other surveillance studies and particularly in those involving hematological and intensive care unit patients (10,(23)(24)(25). The prevalence of resistance may vary between units, hospitals, and geographical regions.…”

Section: Discussionmentioning

confidence: 71%

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Culture-Based Methods and Molecular Tools for Azole-Resistant Aspergillus fumigatus Detection in a Belgian University Hospital

et al. 2017

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Azole-resistant Aspergillus fumigatus is an increasing worldwide problem with major clinical implications. Surveillance is warranted to guide clinicians to provide optimal treatment to patients. To investigate azole resistance in clinical Aspergillus isolates in our institution, a Belgian university hospital, we conducted a laboratory-based surveillance between June 2015 and October 2016. Two different approaches were used: a prospective culture-based surveillance using VIPcheck on unselected A. fumigatus (n ϭ 109 patients, including 19 patients with proven or probable invasive aspergillosis [IA]), followed by molecular detection of mutations conferring azole resistance, and a retrospective detection of azole-resistant A. fumigatus in bronchoalveolar lavage fluid using the commercially available AsperGenius PCR (n ϭ 100 patients, including 29 patients with proven or probable IA). By VIPcheck, 25 azole-resistant A. fumigatus specimens were isolated from 14 patients (12.8%). Of these 14 patients, only 2 had proven or probable IA (10.5%). Mutations at the cyp51A gene were observed in 23 of the 25 A. fumigatus isolates; TR 34 /L98H was the most prevalent mutation (46.7%), followed by TR 46 / Y121F/T289A (26.7%). Twenty-seven (27%) patients were positive for the presence of Aspergillus species by AsperGenius PCR. A. fumigatus was detected by AsperGenius in 20 patients, and 3 of these patients carried cyp51A mutations. Two patients had proven or probable IA and cyp51A mutation (11.7%). Our study has shown that the detection of azole-resistant A. fumigatus in clinical isolates was a frequent finding in our institution. Hence, a rapid method for resistance detection may be useful to improve patient management. Centers that care for immunocompromised patients should perform routine surveillance to determine their local epidemiology.KEYWORDS VIPcheck, AsperGenius, cyp51A, cyp51B, hapE A zole resistance in Aspergillus fumigatus is an emerging problem worldwide, with major epidemiological and clinical implications (1-6). Mold active triazoles are commonly used as first line treatment and prophylaxis of invasive aspergillosis (IA) (7). Mutations in the cyp51A gene, which encodes the target of azoles, the lanosterol 14␣-demethylase, represent the most commonly reported mechanism conferring azole resistance and consequently treatment failure in A. fumigatus (8-10). The most prevalent mutation (TR 34 /L98H) involves the insertion of a 34-bp tandem repeat (TR 34 ) in the promoter region of the cyp51A gene and a point mutation within the gene leading to an amino acid substitution (L98H). More recently, an additional cyp51A-mediated resistant genotype (TR 46 /Y121F/T289A) has been reported: a 46-bp tandem repeat (TR 46 ) in the promoter of cyp51A gene and two point mutations within the gene

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 71%

Culture-Based Methods and Molecular Tools for Azole-Resistant Aspergillus fumigatus Detection in a Belgian University Hospital

et al. 2017

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“…Evidence suggests that there is increasing resistance to azoles among Aspergillus species in centers outside the United States (16)(17)(18). Estimates of mortality attributable to azole-resistant aspergillosis range as high as 88% (19).…”

Section: Commentarymentioning

confidence: 99%

Updated guidelines for the diagnosis and management of aspergillosis

Misch¹,

Safdar²

2016

J. Thorac. Dis.

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“…These patients are frequently affected by invasive aspergillosis, a disease that can reach 30 to 100% of mortality and is mainly caused by Aspergillus fumigatus (Pfaller and Diekema, 2010;Steinbach et al, 2012;Steinmann et al, 2015;Lee and Sheppard, 2016).…”

Section: Introductionmentioning

confidence: 99%

SYBR safe<sup>TM</sup> efficiently replaces ethidium bromide in Aspergillus fumigatus gene disruption

Canela¹,

Takami²,

Ferreira³

2017

Genet. Mol. Res.

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ABSTRACT. Invasive aspergillosis is a disease responsible for high mortality rates, caused mainly by Aspergillus fumigatus. The available drugs are limited and this disease continues to occur at an unacceptable frequency. Gene disruption is essential in the search for new drug targets. An efficient protocol for A. fumigatus gene disruption was described but it requires ethidium bromide, a genotoxic agent, for DNA staining. Therefore, the present study tested SYBR safe TM , a non-genotoxic DNA stain, in A. fumigatus gene disruption protocol. The chosen gene was cipC, which has already been disrupted successfully in our laboratory. A deletion cassette was constructed in Saccharomyces cerevisiae and used in A. fumigatus transformation. There was no statistical difference between the tested DNA stains. The success rate of S. cerevisiae transformation was 63.3% for ethidium bromide and 70% for SYBR safe TM . For A. fumigatus gene disruption, the success rate for ethidium bromide was 100 and 97% for SYBR safe TM . In conclusion, SYBR safe TM efficiently replaced ethidium bromide, making this dye a safe and efficient alternative for DNA staining in A. fumigatus gene disruption.

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Emergence of azole-resistant invasive aspergillosis in HSCT recipients in Germany

Abstract: This report highlights the emergence of azole-resistant IA with TR34/L98H and TR46/Y121F/T289A mutations in HSCT patients in Germany and underscores the need for systematic antifungal susceptibility testing of A. fumigatus.

Cited by 165 publications

References 20 publications

Culture-Based Methods and Molecular Tools for Azole-Resistant Aspergillus fumigatus Detection in a Belgian University Hospital

Culture-Based Methods and Molecular Tools for Azole-Resistant Aspergillus fumigatus Detection in a Belgian University Hospital

Updated guidelines for the diagnosis and management of aspergillosis

SYBR safe<sup>TM</sup> efficiently replaces ethidium bromide in Aspergillus fumigatus gene disruption

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