Transition of triazole-resistant Aspergillus fumigatus isolates in a Japanese tertiary hospital and subsequent genetic analysis

Takazono, Takahiro; Ito, Yuya; Tashiro, Masato; Nakano, Yuichiro; Hirayama, Tatsuro; Hosogaya, Naoki; Saijo, Tomomi; Yamamoto, Kazuko; Imamura, Yoshifumi; Miyazaki, Taiga; Yanagihara, Katsunori; Kohno, Shigeru; Mukae, Hiroshi; Izumikawa, Koichi

doi:10.1016/j.jiac.2020.11.027

Cited by 8 publications

(3 citation statements)

References 13 publications

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“…1 ). Based on the macroscopic colony morphology, micromorphological characteristics, the ability to grow at 48 °C, and the sequences of the β-tubulin gene, these were identified as A. fumigatus sensu strico isolates [ 19 , 20 ].…”

Section: Case Presentationmentioning

confidence: 99%

Clinical and experimental phenotype of azole-resistant Aspergillus fumigatus with a HapE splice site mutation: a case report

et al. 2021

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Background The recent increase in cases of azole-resistant Aspergillus fumigatus (ARAf) infections is a major clinical concern owing to its treatment limitations. Patient-derived ARAf occurs after prolonged azole treatment in patients with aspergillosis and involves various cyp51A point mutations or non-cyp51A mutations. The prognosis of patients with chronic pulmonary aspergillosis (CPA) with patient-derived ARAf infection remains unclear. In this study, we reported the case of a patient with ARAf due to HapE mutation, as well as the virulence of the isolate. Case presentation A 37-year-old male was presented with productive cough and low-grade fever. The patient was diagnosed with CPA based on the chronic course, presence of a fungus ball in the upper left lobe on chest computed tomography (CT), positivity for Aspergillus-precipitating antibody and denial of other diseases. The patient underwent left upper lobe and left S6 segment resection surgery because of repeated haemoptysis during voriconazole (VRC) treatment. The patient was postoperatively treated with VRC for 6 months. Since then, the patient was followed up without antifungal treatment but relapsed 4 years later, and VRC treatment was reinitiated. Although an azole-resistant isolate was isolated after VRC treatment, the patient did not show any disease progression in either respiratory symptoms or radiological findings. The ARAf isolated from this patient showed slow growth, decreased biomass and biofilm formation in vitro, and decreased virulence in the Galleria mellonella infection model compared with its parental strain. These phenotypes could be caused by the HapE splice site mutation. Conclusions This is the first to report a case demonstrating the clinical manifestation of a CPA patient infected with ARAf with a HapE splice site mutation, which was consistent with the in vitro and in vivo attenuated virulence of the ARAf isolate. These results imply that not all the ARAf infections in immunocompetent patients require antifungal treatment. Further studies on the virulence of non-cyp51A mutations in ARAf are warranted.

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Section: Case Presentationmentioning

confidence: 99%

Clinical and experimental phenotype of azole-resistant Aspergillus fumigatus with a HapE splice site mutation: a case report

et al. 2021

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“…The genotypes of A. fumigatus that contain TR-mediated resistance are more common in environmental isolates and isolates obtained from azole-naïve patients. However, there is increasing awareness that resistance mechanisms in ARAf are complex and involve multiple genes (Table A1) [16,[26][27][28][29][30][31][32]. In studies that identified ARAf in CAPA isolates, Kirchoff et al [23] discovered only one CAPA isolate that contained TR 34 /L98H and five polymorphisms of ARAf via a non-cyp51A mechanism.…”

Section: Introductionmentioning

confidence: 99%

Genomic Epidemiology Identifies Azole Resistance Due to TR34/L98H in European Aspergillus fumigatus Causing COVID-19-Associated Pulmonary Aspergillosis

Simmons,

Rhodes,

Rogers

et al. 2023

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Aspergillus fumigatus has been found to coinfect patients with severe SARS-CoV-2 virus infection, leading to COVID-19-associated pulmonary aspergillosis (CAPA). The CAPA all-cause mortality rate is approximately 50% and may be complicated by azole resistance. Genomic epidemiology can help shed light on the genetics of A. fumigatus causing CAPA, including the prevalence of resistance-associated alleles. We present a population genomic analysis of 21 CAPA isolates from four European countries with these isolates compared against 240 non-CAPA A. fumigatus isolates from a wider population. Bioinformatic analysis and antifungal susceptibility testing were performed to quantify resistance and identify possible genetically encoded azole-resistant mechanisms. The phylogenetic analysis of the 21 CAPA isolates showed that they were representative of the wider A. fumigatus population with no obvious clustering. The prevalence of phenotypic azole resistance in CAPA was 14.3% (n = 3/21); all three CAPA isolates contained a known resistance-associated cyp51A polymorphism. The relatively high prevalence of azole resistance alleles that we document poses a probable threat to treatment success rates, warranting the enhanced surveillance of A. fumigatus genotypes in these patients. Furthermore, potential changes to antifungal first-line treatment guidelines may be needed to improve patient outcomes when CAPA is suspected.

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“…Genotypes of A. fumigatus that contain TR-mediated resistance are more common in environmental isolates and isolates obtained from azole-naïve pa ents. However, there is increasing awareness that resistance mechanisms in ARAf are complex and involve mul ple genes (Supp Info Table 1) (16,(30)(31)(32)(33)(34)(35)(36). In studies that iden fied ARAf in CAPA isolates, Kirchoff et al (27) discovered only one CAPA isolate that contained TR 34 /L98H and five polymorphisms of ARAf via a non-cyp51A route.…”

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Genomic epidemiology of EuropeanAspergillus fumigatuscausing COVID-19-associated pulmonary aspergillosis in Europe

Simmons¹,

Rhodes²,

Rogers³

et al. 2023

Preprint

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The opportunistic fungus Aspergillus fumigatus has been found to cause coinfections in patients with severe SARS-CoV-2 virus infection, leading to COVID-19-associated pulmonary aspergillosis (CAPA). The CAPA all-cause mortality rate is approximately 50% and may be complicated by azole-resistance. Genomic epidemiology can help shed light on the genetics of A. fumigatus causing CAPA including the prevalence of alleles that are associated with azole-resistance. Here, a population genomic analysis of 21 CAPA isolates from four European countries is presented. The CAPA isolates were compared with A. fumigatus from a wider population of 167 non-CAPA clinical isolates and 73 environmental isolates. Bioinformatic analysis and antifungal susceptibility testing were performed to quantify resistance and identify possible genetically-encoded azole-resistant mechanisms. Phylogenetic analysis of the 21 CAPA isolates showed a lack of genetic distinction from the wider A. fumigatus population, with isolates distributed within two distinct clades (A and B), with the majority of the CAPA isolates in clade B (71.4%). The prevalence of phenotypic azole-resistance in CAPA was 14.3% (n=3/21); all three CAPA isolates contained a known resistance-associated cyp51A polymorphism. CAPA isolates are drawn from the wider A. fumigatus population rather than forming a unique genetic background showing that COVID-19 patients are susceptible to the entire A. fumigatus population. However, the relatively high prevalence of azole-resistance alleles that we document poses a threat to treatment success rates, warranting enhanced detection and surveillance of A. fumigatus genotypes in these patients. Furthermore, potential changes to antifungal first-line treatment guidelines may be needed to improve patient outcomes.

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Transition of triazole-resistant Aspergillus fumigatus isolates in a Japanese tertiary hospital and subsequent genetic analysis

Cited by 8 publications

References 13 publications

Clinical and experimental phenotype of azole-resistant Aspergillus fumigatus with a HapE splice site mutation: a case report

Clinical and experimental phenotype of azole-resistant Aspergillus fumigatus with a HapE splice site mutation: a case report

Genomic Epidemiology Identifies Azole Resistance Due to TR34/L98H in European Aspergillus fumigatus Causing COVID-19-Associated Pulmonary Aspergillosis

Genomic epidemiology of EuropeanAspergillus fumigatuscausing COVID-19-associated pulmonary aspergillosis in Europe

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