Azole resistance in Aspergillus fumigatus

Vermeulen, Edith; Lagrou, Katrien; Verweij, Paul E.

doi:10.1097/qco.0000000000000005

Cited by 187 publications

(147 citation statements)

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“…Each was also at risk for invasive aspergillosis, and two had confirmed disease, including one with disseminated infection. It is not known if these isolates may have also been recovered from environmental sources, which has been reported in several studies, mainly in Europe, of A. fumigatus isolates with these mechanisms of azole resistance (9,14); however, this has not been a consistent finding (30). Of the 26 azole-resistant isolates included in this study, 6 did not contain mutations within the CYP51A gene.…”

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confidence: 41%

“…However, prolonged therapy may predispose patients to adverse effects and drug interactions associated with these agents and increase the potential for the development of drug-resistant organisms (8). Over the last several years, concern has been growing regarding azole resistance in Aspergillus fumigatus (9,10). Azole-resistant A. fumigatus isolates recovered from patients failing therapy have been reported in several countries around the world.…”

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confidence: 99%

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First Detection of TR34 L98H and TR46 Y121F T289A Cyp51 Mutations in Aspergillus fumigatus Isolates in the United States

et al. 2016

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dAzole resistance in Aspergillus fumigatus is an increasing problem. The TR34 L98H and TR46 Y121F T289A mutations that can occur in patients without previous azole exposure have been reported in Europe, Asia, the Middle East, Africa, and Australia. Here, we report the detection of both the TR34 L98H and TR46 Y121F T289A mutations in confirmed A. fumigatus isolates collected in institutions in the United States. These mutations, other mutations known to cause azole resistance, and azole MICs are reported here. Invasive aspergillosis remains a major problem in immunocompromised individuals, including solid organ transplant recipients, those undergoing hematopoietic stem cell transplant, and patients receiving highly immunosuppressive chemotherapies (1-3). In patients with structural damage to the lungs, such as those who have had tuberculosis or sarcoidosis, chronic pulmonary aspergillosis is also a significant problem, the prevalence of which has been estimated to be approximately 3 million patients worldwide (4-7). The azoles are a mainstay in the treatment of invasive aspergillosis, as the members of this class that have activity against Aspergillus species, itraconazole, posaconazole, voriconazole, and isavuconazole, may be given orally, and the treatment of this invasive fungal infection is often prolonged. However, prolonged therapy may predispose patients to adverse effects and drug interactions associated with these agents and increase the potential for the development of drug-resistant organisms (8). Over the last several years, concern has been growing regarding azole resistance in Aspergillus fumigatus (9, 10). Azole-resistant A. fumigatus isolates recovered from patients failing therapy have been reported in several countries around the world. Mutations in the CYP51A gene, which encodes the Cyp51 enzyme responsible for the last step in ergosterol biosynthesis, have been the resistance mechanism documented in clinical isolates, and these mutations have been found in isolates recovered from patients who have had long exposures to azoles (11, 12). However, resistant isolates harboring tandem repeats of various sizes in the promoter region of the CYP51A gene, along with nonsynonymous point mutations leading to amino acid changes in the Cyp51 enzyme, have been recovered from azole-naive patients with invasive aspergillosis (8, 12, 13). These resistance mechanisms, which include TR34 L98H and TR46 Y121F T289A, have been linked to the environmental use of azoles in agriculture and the preservation of various materials (14, 15), and they have been found in various countries, including many in Europe, India, China, Iran, Tanzania, and Australia (13, 16-21). However, these mutations have not yet been reported in isolates collected in the United States (22). Our objective was to evaluate the Cyp51-associated mechanisms of azole resistance in a collection of A. fumigatus isolates from institutions across the United States.The antifungal susceptibility database in the Fungus Testing Laboratory at the University of ...

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First Detection of TR34 L98H and TR46 Y121F T289A Cyp51 Mutations in Aspergillus fumigatus Isolates in the United States

et al. 2016

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“…However, there are several factors warranting the use of mycological culture. First, culture is necessary for susceptibility testing, which is of vital importance because azole resistance in Aspergillus species has emerged (50). Second, culture may also detect other molds (e.g., Mucorales) that give negative biomarker results.…”

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confidence: 99%

Novel Tests for Diagnosis of Invasive Aspergillosis in Patients with Underlying Respiratory Diseases

Prattes

Flick²,

Prüller

et al. 2014

Am J Respir Crit Care Med

119

114

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Rationale: Invasive pulmonary aspergillosis has been increasingly reported in nonneutropenic patients, including those with underlying respiratory diseases.Objectives: We compared the diagnostic performances of galactomannan, 1,3-b-D-glucan, and Aspergillus-specific lateralflow device tests with that of conventional culture by using bronchoalveolar lavage fluid samples from patients with underlying respiratory diseases.Methods: We analyzed 268 bronchoalveolar lavage samples from 221 patients with underlying respiratory diseases (and without hematologic malignancy or previous solid organ transplantation) that were collected for routine microbiological workup between February 2012 and May 2014 at the University Hospital of Graz, Austria. Invasive pulmonary aspergillosis was defined according to European Organization of Research and Treatment of Cancer/ Mycoses Study Group criteria modified for patients with respiratory diseases.Measurements and Main Results: Thirty-one patients (14%) had probable or proven, 25 possible, and the remaining 165 patients no invasive pulmonary aspergillosis. Probable/proven aspergillosis was associated with a significantly higher (P = 0.034) 30-day mortality rate of 32%. Sensitivities, specificities, and diagnostic odd ratios differed markedly between galactomannan (cut-off 0. Conclusions: Probable or proven invasive pulmonary aspergillosis was diagnosed in 14% of our study population and associated with significantly higher 30-day mortality rates. Although the performance of b-D-glucan was limited by low specificity and that of mycological culture by low sensitivity, the Aspergillus lateral-flow device seems to be a promising alternative to galactomannan testing, which remains the diagnostic gold standard for aspergillosis. Clinical trial registered with www.clinicaltrials.gov (NCT 02058316).

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“…Invasive aspergillosis (IA) is the most common invasive mold infection, and voriconazole, considered to be first-line therapy for IA, has historically exhibited excellent in vitro activity against the most common Aspergillus species that cause invasive disease (3). However, triazole resistance among Aspergillus species is an emerging worldwide problem (4). Furthermore, non-Aspergillus molds, for which antifungal agents often have variable and unpredictable in vitro activities, account for increasing proportions of IFIs (1,2,5).…”

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Comparing Etest and Broth Microdilution for Antifungal Susceptibility Testing of the Most-Relevant Pathogenic Molds

Lamoth

Alexander

2015

J Clin Microbiol

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Invasive mold infections are life-threatening diseases for which appropriate antifungal therapy is crucial. Their epidemiology is evolving, with the emergence of triazole-resistant Aspergillus spp. and multidrug-resistant non-Aspergillus molds. Despite the lack of interpretive criteria, antifungal susceptibility testing of molds may be useful in guiding antifungal therapy. The standard broth microdilution method (BMD) is demanding and requires expertise. We assessed the performance of a commercialized gradient diffusion method (Etest method) as an alternative to BMD. The MICs or minimal effective concentrations (MECs) of amphotericin B, voriconazole, posaconazole, caspofungin, and micafungin were assessed for 290 clinical isolates of the most representative pathogenic molds (154 Aspergillus and 136 non-Aspergillus isolates) with the BMD and Etest methods. Essential agreements (EAs) within ؎2 dilutions of >90% between the two methods were considered acceptable. EAs for amphotericin B and voriconazole were >90% for most potentially susceptible species. For posaconazole, the correlation was acceptable for Mucoromycotina but Etest MIC values were consistently lower for Aspergillus spp. (EAs of <90%). Excellent EAs were found for echinocandins with highly susceptible (MECs of <0.015 g/ml) or intrinsically resistant (MECs of >16 g/ml) strains. However, MEC determinations lacked consistency between methods for strains exhibiting mid-range MECs for echinocandins. We concluded that the Etest method is an appropriate alternative to BMD for antifungal susceptibility testing of molds under specific circumstances, including testing with amphotericin B or triazoles for non-Aspergillus molds (Mucoromycotina and Fusarium spp.). Additional study of molecularly characterized triazole-resistant Aspergillus isolates is required to confirm the ability of the Etest method to detect voriconazole and posaconazole resistance among Aspergillus spp. Filamentous fungi account for about 50% to 75% of invasive fungal infections (IFIs) in severely immunocompromised patients, such as bone marrow and solid organ transplant recipients, and are associated with high morbidity and mortality rates (1, 2). Identification of the fungal species and targeted antifungal therapy are key for successful management of these infections. Invasive aspergillosis (IA) is the most common invasive mold infection, and voriconazole, considered to be first-line therapy for IA, has historically exhibited excellent in vitro activity against the most common Aspergillus species that cause invasive disease (3). However, triazole resistance among Aspergillus species is an emerging worldwide problem (4). Furthermore, non-Aspergillus molds, for which antifungal agents often have variable and unpredictable in vitro activities, account for increasing proportions of IFIs (1, 2, 5). Thus, clinicians are increasingly seeking guidance from clinical laboratories regarding antifungal drug activities against clinically significant mold isolates (6, 7).The Clinical and Laboratory Stand...

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Azole resistance in Aspergillus fumigatus

Abstract: Azole resistance in A. fumigatus is evolving to a global health problem.

Cited by 187 publications

References 43 publications

First Detection of TR34 L98H and TR46 Y121F T289A Cyp51 Mutations in Aspergillus fumigatus Isolates in the United States

First Detection of TR34 L98H and TR46 Y121F T289A Cyp51 Mutations in Aspergillus fumigatus Isolates in the United States

Novel Tests for Diagnosis of Invasive Aspergillosis in Patients with Underlying Respiratory Diseases

Comparing Etest and Broth Microdilution for Antifungal Susceptibility Testing of the Most-Relevant Pathogenic Molds

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