New therapeutic strategies for invasive aspergillosis in the era of azole resistance: how should the prevalence of azole resistance be defined? (original) (raw)
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Nationwide surveillance of azole resistance in Aspergillus disease
Antimicrobial Agents and Chemotherapy, 2015
209 words) 25 Aspergillus disease affects a broad patient population, from patients with asthma to 26 immunocompromised patients. Azole resistance is increasingly reported in both clinical and 27 environmental Aspergillus strains. The prevalence and clinical impact of azole resistance in 28 different patient populations is currently unclear.
Azole Resistance in Aspergillus fumigatus Isolates
Invasive Aspergillosis (IA) is an important cause of mortality and morbidity in the immunocompromised host such as, neutropenic individuals, chronic granulomatous disorder, leukemia, those undergoing solid organ transplantation, patients using broad spectrum antibiotics and steroids, patients with severe underlying diseases and patients with chronic pulmonary obstructive disease are among the main risk groups. Successful management in the treatment of IA depends on early diagnosis and treatment, the adequate choice of therapy, and antifungal resistance. The diagnosis of IA remains difficult and significant proportions of cases of IA remain undetected, thus in case of IA treatment should be considered as early as possible and carried out until the improvements. The treatment is usually based on surgery, antifungal therapy and reduction of immunosuppression. Azole-resistant Aspergillus fumigatus was first observed in Netherlands in 1999. Full mechanism of evolution of azole resistance...
Prospective evaluation of azole resistance in Aspergillus fumigatus clinical isolates in France
Objectives: Several studies, especially in Europe, have recently reported the emerging phenomenon of azole resistance in Aspergillus fumigatus, but very few data are available in France. Our study aimed to determine the resistance prevalence in A. fumigatus isolates recovered from clinical samples over a 1-year period in two university hospital centers. Methods: All A. fumigatus isolates were screened for azole resistance using RPMI agar plates supplemented with itraconazole and voriconazole. Resistance was then confirmed by the EUCAST method. A part of the beta-tubulin gene was amplified for resistant isolates to confirm the A. fumigatus species, and the Cyp51A gene and its promoter were afterward sequenced to detect mutations potentially responsible for this resistance. Results: One hundred sixty-five A. fumigatus isolates were recovered from 134 patients. Three isolates recovered from three patients were found resistant with MICs of >8 mg/l, 4 mg/l, and 1 mg/l for itraconazole, voriconazole, and posaconazole, respectively. The TR 34 /L98H mutation, previously and largely described in other countries, was detected in the three isolates. Conclusion: Our study demonstrated the occurrence of azole resistance among unselected A. fumigatus clinical isolates, with an overall prevalence of 1.8%.
Azole Resistance of Environmental and Clinical Aspergillus fumigatus Isolates from Switzerland
Antimicrobial agents and chemotherapy, 2018
is a ubiquitous opportunistic pathogen. This fungus can acquire resistance to azole antifungals due to mutations in the azole target (). Recently, mutations typical for environmental azole resistance acquisition (for example, TR/L98H) have been reported. These mutations can also be found in isolates recovered from patients. Environmental azole resistance acquisition has been reported on several continents. Here we describe, for the first time, the occurrence of azole-resistant isolates of environmental origin in Switzerland with mutations, and we show that these isolates can also be recovered from a few patients. While the TR/L98H mutation was dominant, a single azole-resistant isolate exhibited a mutation (G54R) that was reported only for clinical isolates. In conclusion, our study demonstrates that azole resistance with an environmental signature is present in environments and patients of Swiss origin and that mutations believed to be unique to clinical settings are now also obser...
Is Azole Resistance in Aspergillus fumigatus a Problem in Spain?
Antimicrobial Agents and Chemotherapy, 2013
Aspergillus fumigatus complex comprises A. fumigatus and other morphologically indistinguishable cryptic species. We retrospectively studied 362 A. fumigatus complex isolates (353 samples) from 150 patients with proven or probable invasive aspergillosis or aspergilloma (2, 121, and 6 samples, respectively) admitted to the hospital from 1999 to 2011. Isolates were identified using the -tubulin gene, and only 1 isolate per species found in each sample was selected. Antifungal susceptibility to azoles was determined using the CLSI M38-A2 procedure. Isolates were considered resistant if they showed an MIC above the breakpoints for itraconazole, voriconazole, or posaconazole (>2, >2, or >0.5 g/ml). Most of the samples yielded only 1 species (A. fumigatus [n ؍ 335], A. novofumigatus [n ؍ 4], A. lentulus [n ؍ 3], A. viridinutans [n ؍ 1], and Neosartorya udagawae [n ؍ 1]). The remaining samples yielded a combination of 2 species. Most of the patients were infected by a single species (A. fumigatus [n ؍ 143] or A. lentulus [n ؍ 2]). The remaining 5 patients were coinfected with multiple A. fumigatus complex species, although A. fumigatus was always involved; 4 of the 5 patients were diagnosed in 2009 or later. Cryptic species were less susceptible than A. fumigatus. The frequency of resistance among A. fumigatus complex and A. fumigatus to itraconazole, voriconazole, and posaconazole was 2.5 and 0.3%, 3.1 and 0.3%, and 4.2 and 1.8%, respectively, in the per-isolate analysis and 1.3 and 0.7%, 2.6 and 0.7%, and 6 and 4% in the per-patient analysis. Only 1 of the 6 A. fumigatus isolates in which the cyp51A gene was sequenced had a mutation at position G448. The proportion of patients infected by azole-resistant A. fumigatus isolates was low. FIG 1 Number of patients with invasive aspergillosis during the study period. Patients were grouped according to infection with A. fumigatus sensu stricto (AfumSS) or cryptic species.
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2016
Azole resistant Aspergillus fumigatus originating from the environment as well as induced during therapy are continuously emerging in Danish clinical settings. We performed a laboratory based retrospective study (2010-2014) of azole resistance and genetic relationship of A. fumigatus at the national mycology reference laboratory of Denmark. 1162 clinical and 133 environmental A. fumigatus isolates were identified by morphology, thermotolerance and/or β-tubulin sequencing. Screening for azole resistance was carried out using azole-agar and resistant isolates were susceptibility tested by the EUCAST E.Def 9.2 reference method and CYP51A sequenced. Genotyping was performed for outbreak investigation and when appropriate using the Short Tandem Repeat Aspergillus fumigatus microsatellite assay. All 133 environmental A. fumigatus isolates were azole susceptible. However, from 2010-2014 there was an increasing prevalence of azole resistance (from 1.4% to 6% isolates (P<0.001) and 1.8% t...
The Journal of antimicrobial chemotherapy, 2018
The prevalence of azole resistance in Aspergillus fumigatus is uncertain in Australia. Azole exposure may select for resistance. We investigated the frequency of azole resistance in a large number of clinical and environmental isolates. A. fumigatus isolates [148 human, 21 animal and 185 environmental strains from air (n = 6) and azole-exposed (n = 64) or azole-naive (n = 115) environments] were screened for azole resistance using the VIPcheck™ system. MICs were determined using the Sensititre™ YeastOne YO10 assay. Sequencing of the Aspergillus cyp51A gene and promoter region was performed for azole-resistant isolates, and cyp51A homology protein modelling undertaken. Non-WT MICs/MICs at the epidemiological cut-off value of one or more azoles were observed for 3/148 (2%) human isolates but not amongst animal, or environmental, isolates. All three isolates grew on at least one azole-supplemented well based on VIPcheck™ screening. For isolates 9 and 32, the itraconazole and posaconazo...
Journal of Global Antimicrobial Resistance, 2020
This study was conducted to assess the prevalence of azole resistance in Aspergillus isolates from patients with haematological malignancies or who were undergoing haematopoietic stem cell transplantation and to identify the molecular mechanism of resistance. Methods: In this 28-month prospective study involving 18 Italian centres, Aspergillus isolates from surveillance cultures were collected and screened for azole resistance, and mutations in the cyp51A gene were identified. Resistant isolates were genotyped by microsatellite analysis, and the allelic profiles were compared with those of resistant environmental and clinical isolates from the same geographical area that had been previously genotyped. Results: There were 292 Aspergillus isolates collected from 228 patients. The isolates belonged mainly to the section Fumigati (45.9%), Nigri (20.9%), Flavi (16.8%) and Terrei (4.8%). Three isolates showed itraconazole resistance: Aspergillus fumigatus sensu stricto, Aspergillus lentulus (section Fumigati) and Aspergillus awamori (section Nigri). The itraconazole resistance rates were 1% and 1.48% considering all Aspergillus spp. isolates and the Aspergillus section Fumigati, respectively. The prevalence of azole resistance among all the patients was 1.3%. Among patients harbouring A. fumigatus sensu stricto isolates, the resistance rate was 0.79%. The A. fumigatus isolate, with the TR 34 /L98H mutation, was genotypically distant from the environmental and clinical strains previously genotyped.
Emerging Infectious Diseases, 2009
Azoles are the mainstay of oral therapy for aspergillosis. Azole resistance in Aspergillus has been reported infrequently. The first resistant isolate in Manchester, UK, was detected in 1999. In a clinical collection of 519 A. fumigatus isolates, the frequency of itraconazole resistance was 5%, a significant increase since 2004 (p<0.001). Of the 34 itraconazole-resistant isolates we studied, 65% were cross-resistant to voriconazole and 74% (25) were crossresistant to posaconazole. Thirteen of 14 evaluable patients in our study had prior azole exposure; 8 infections failed therapy (progressed), and 5 failed to improve (remained stable). Eighteen amino acid alterations were found in the target enzyme, Cyp51A, 4 of which were novel. A population genetic analysis of microsatellites showed the existence of resistant mutants that evolved from originally susceptible strains, different cyp51A mutations in the same strain, and microalterations in microsatellite repeat number. Azole resistance in A. fumigatus is an emerging problem and may develop during azole therapy.