Multicenter Study of Azole-Resistant <i>Aspergillus fumigatus</i> Clinical Isolates, Taiwan1

Wu, Chi Jung; Liu, Wei-Lun; Lai, Chih Cheng; Chao, Chien Ming; Ko, Wen Chien; Wang, Hsuan Chen; Dai, Ching Tzu; Hsieh, Ming I.; Choi, Pui Ching; Yang, Jiaying; Chen, Yee‐Chun

doi:10.3201/eid2604.190840

Cited by 24 publications

(35 citation statements)

References 10 publications

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“…More recently, the reports of A. fumigatus azole resistant isolates, without Cyp51A modifications, indicate that there are other novel mechanisms mediating resistance to azole drugs [ 11 , 12 ]. These studies have reported roles in azole resistance of other genes from the ergosterol biosynthesis pathway, including hmg1 [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ], erg6 [ 15 , 17 ], some transcriptional factors [ 20 , 21 , 22 ], hapE [ 23 ] or overexpression of drug efflux pumps [ 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

A Cyp51B Mutation Contributes to Azole Resistance in Aspergillus fumigatus

González-Jiménez

Lúcio

Amich

et al. 2020

JoF

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The emergence and spread of Aspergillus fumigatus azole resistance has been acknowledged worldwide. The main problem of azole resistance is the limited therapeutic options for patients suffering aspergillosis. Azole resistance mechanisms have been mostly linked to the enzyme Cyp51A, a target of azole drugs, with a wide variety of modifications responsible for the different resistance mechanisms described to date. However, there are increasing reports of A. fumigatus strains showing azole resistance without Cyp51A modifications, and thus, novel resistance mechanisms are being explored. Here, we characterized two isogenic A. fumigatus clinical strains isolated two years apart from the same patient. Both strains were resistant to clinical azoles but showed different azole resistance mechanisms. One strain (CM8940) harbored a previously described G54A mutation in Cyp51A while the other strain (CM9640) had a novel G457S mutation in Cyp51B, the other target of azoles. In addition, this second strain had a F390L mutation in Hmg1. CM9640 showed higher levels of gene expression of cyp51A, cyp51B and hmg1 than the CM8940 strain. The role of the novel mutation found in Cyp51B together with the contribution of a mutation in Hmg1 in azole resistance is discussed.

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Section: Introductionmentioning

confidence: 99%

A Cyp51B Mutation Contributes to Azole Resistance in Aspergillus fumigatus

González-Jiménez

Lúcio

Amich

et al. 2020

JoF

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“…Within our study, the E105K and the S541G mutation were also found in two (5%) and one (3%), respectively, of 39 isolates with a triazole WT phenotype. The S541G and H564Y hmg1 mutations located likewise outside the SSD, have also been reported in non-resistant isolates [ 8 , 11 ]. This a major issue, as it raises the probability that these mutations located outside the SSD most likely do not confer resistance and that other mechanisms are responsible for the observed resistant phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, mutations in the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase -encoding gene ( hmg1 ), were described and associated with triazole-resistance in a number of clinical A. fumigatus isolates [ 8 , 9 , 10 , 11 , 12 ]. Like the cyp51A gene, the hmg1 gene is involved in the ergosterol production pathway [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Hmg1 Gene Mutation Prevalence in Triazole-Resistant Aspergillus fumigatus Clinical Isolates

Reséndiz-Sharpe

Hokken

Mercier

et al. 2020

JoF

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Recently, mutations in the 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase-encoding gene (hmg1), a gene involved in ergosterol production, were associated with triazole-resistance in Aspergillus fumigatus. In this study, we determined the prevalence and characteristics of hmg1 mutations in a collection of clinical triazole-resistant A. fumigatus isolates collected during 2001–2019 from two international mycology reference centers: the Belgian National Reference Center for Mycosis and the Center of Expertise in Mycology Radboudumc/CWZ. Clinical isolates with and without cyp51A gene mutations and randomly selected wild-type (WT) controls were included. Isolates were characterized by in vitro susceptibility testing, cyp51A and hmg1 sequencing, and short tandem repeat typing. Available clinical records were analyzed for previous triazole exposure. In 23 isolates (24%) of the 95 triazole-resistant A. fumigatus isolates, hmg1 gene mutations were observed; including 5/23 (22%) isolates without cyp51A gene mutations and 18/72 (25%) with cyp51A mutations. Four previously described hmg1 gene mutations (E105K, G307R/D, G466V, and S541G) and two novel mutations (W273S and L304P) were found; 4/23 (17%) in the sterol-sensing-domain region. No triazole-antifungal exposure was reported in 75% (9/12) of patients harboring an isolate with hmg1 gene mutations. Three of 39 WT isolates (8%) contained a hmg1 gene mutation; E105K (2-isolates) and S541G. Hmg1 gene mutations were predominantly found in A. fumigatus with cyp51A mutations with voriconazole MICs ≥ 8 mg/L.

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“…When haematological (ESR, CRP, fungal G test, etc.) and imaging examinations indicate Aspergillus spondylitis, CT-guided puncture biopsy should be performed as soon as possible to confirm the diagnosis and guide antibacterial treatment [ 19 ]. Compared with intraoperative biopsy, CT-guided biopsy is less invasive and has a quicker recovery time, but the number of specimens is insufficient.…”

Section: Discussionmentioning

confidence: 99%

Aspergillus spondylitis: case series and literature review

Dai

Wang

Yin

et al. 2020

BMC Musculoskelet Disord

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Background: Spinal fungal infections, especially spinal Aspergillus infections, are rare in the clinic. Here, we introduce the clinical features, diagnosis, treatment, and prognoses of 6 cases of Aspergillus spondylitis. Methods: We retrospectively analysed the complete clinical data of patients with Aspergillus spondylitis treated in our hospital from January 2013 to January 2020. Results: Aspergillus fumigatus was isolated in 4 cases, and Aspergillus spp. and Aspergillus niger were isolated in 1 case each. All six patients reported varying degrees of focal spinal pain; one patient reported radiating pain, one patient experienced bowel dysfunction and numbness in both lower limbs, and three patients had fever symptoms. One case involved the thoracic spine, one case involved the thoracolumbar junction, and 4 cases involved the lumbar spine. Three patients were already in an immunosuppressed state, and three patients entered an immunosuppressed state after spinal surgery. All six patients were successfully cured, and five required surgery. Of the 5 patients who underwent surgical treatment, 2 had spinal cord compression symptoms, and 3 had spinal instability. At the end of follow-up, 1 patient reported left back pain and 1 patient reported left limb numbness. Conclusion: The clinical manifestations of Aspergillus spondylitis are non-specific, and the diagnosis depends on typical imaging findings and microbiological and histopathological examination results. When there is no spinal instability, spinal nerve compression symptoms, or progressive deterioration, antifungal therapy alone may be considered. If spinal instability, spinal nerve compression, or epidural abscess formation is present, surgery combined with antifungal therapy is recommended.

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Multicenter Study of Azole-Resistant Aspergillus fumigatus Clinical Isolates, Taiwan1

Cited by 24 publications

References 10 publications

A Cyp51B Mutation Contributes to Azole Resistance in Aspergillus fumigatus

A Cyp51B Mutation Contributes to Azole Resistance in Aspergillus fumigatus

Hmg1 Gene Mutation Prevalence in Triazole-Resistant Aspergillus fumigatus Clinical Isolates

Aspergillus spondylitis: case series and literature review

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