Molecular typing and in-vitro activity of azoles against clinical isolates of Aspergillus fumigatus and A. niger in Japan

Asano, Moe; Kano, Rui; Makimura, Koichi; Hasegawa, Atsuhiko; Kamata, Hiroshi

doi:10.1007/s10156-010-0202-1

Cited by 16 publications

(6 citation statements)

References 18 publications

(23 reference statements)

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“…The three azoles tested here (VRC, PSC, and ITC) showed good activity, with POS being the most active one, a finding in accordance with previous studies (23)(24)(25). The low modal POS MIC and its narrow MIC range are also indicative of its elevated in vitro activity against these fungi.…”

Section: Discussionsupporting

confidence: 91%

New Insights into the Cyp51 Contribution to Azole Resistance in Aspergillus Section Nigri

Pérez-Cantero

López-Fernández

Guarro

et al. 2019

Antimicrob Agents Chemother

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Invasive aspergillosis (IA) is a severe condition mainly caused by Aspergillus fumigatus, although other species of the genus, such as section Nigri members, can also be involved. Voriconazole (VRC) is the recommended treatment for IA; however, the prevalence of azole-resistant Aspergillus isolates has alarmingly increased in recent years, and the underlying resistance mechanisms in non-fumigatus species remain unclear. We have determined the in vitro susceptibility of 36 strains from section Nigri to VRC, posaconazole (POS), and itraconazole (ITC), and we have explored the role of Cyp51A and Cyp51B, both targets of azoles, in azole resistance. The three drugs were highly active; POS displayed the best in vitro activity, while ITC and VRC showed MICs above the established epidemiological cutoff values in 9 and 16% of the strains, respectively. Furthermore, expression studies of cyp51A and cyp51B in control condition and after VRC exposure were performed in 14 strains with different VRC susceptibility. We found higher transcription of cyp51A, which was upregulated upon VRC exposure, but no correlation between MICs and cyp51 transcription levels was observed. In addition, cyp51A sequence analyses revealed nonsynonymous mutations present in both, wild-type and non-wild-type strains of A. niger and A. tubingensis. Nevertheless, a few mutations were exclusively present in non-wild-type A. tubingensis strains. Altogether, our results suggest that azole resistance in section Nigri is not clearly explained by Cyp51A protein alteration or by cyp51 gene upregulation, which indicates that other mechanisms might be involved.

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Section: Discussionsupporting

confidence: 91%

New Insights into the Cyp51 Contribution to Azole Resistance in Aspergillus Section Nigri

Pérez-Cantero

López-Fernández

Guarro

et al. 2019

Antimicrob Agents Chemother

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“…The same resistance mechanism was subsequently reported in clinical and environmental azole‐resistant A. fumigatus from all over the world including Africa, Americas, Asia, Australia and the Middle East . In contrast, more recently few studies from Japan, described azole resistance in clinical A. fumigatus isolates but interestingly none of them exhibited TR 34 /L98H resistance mechanism, instead several SNPs and novel mutations, F332K and P216L were reported . A single centre study from Japan reported 5.2% azole‐resistant isolates harbouring only G54E/R/W and I266N mutation …”

Section: Molecular Mechanisms Of Azole Resistance In Candida Spp Andmentioning

confidence: 62%

Epidemiology and molecular mechanisms of antifungal resistance in Candida and Aspergillus

Gonçalves

Souza

Chowdhary

et al. 2016

Mycoses

147

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The significant increase in the use of antifungal agents, both for the treatment of candidiasis and invasive aspergillosis and as azole fungicides in agricultural crop protection has resulted in the emergence of resistant clinical isolates, particularly to triazoles and echinocandins. Notably, among isolates that were primarily sensitive to fluconazole such as Candida parapsilosis and Candida tropicalis have witnessed an emerging resistance development. Also for echinocandins, the occurrence of Candida isolates with lower susceptibility to these drugs has been reported, which is possibly due to its broad clinical use. Triazole resistance among Aspergillus fumigatus and other Aspergillus species is commonly found in European and Asian countries. Specific mutations are associated with azole resistance in A. fumigatus and these mutations are now reported globally from six continents. Therefore, we highlight the need to conduct antifungal resistance surveillance studies using clinical isolates of Candida and Aspergillus in different geographical regions and monitoring of the infection rates in distinct population groups for early detection of resistance to these drugs and implementation of efficient policies for infection control and treatment.

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“…However, the first comprehensive report on the occurrence of TRAF isolates in Asia originated from China during 2008–2009 from the ARTEMIS global sentinel surveillance program demonstrating TR 34 /L98H resistance mechanism in 27.5% (8/29) A. fumigatus isolates ( Lockhart et al, 2011 ; Table 2 ). In contrast, more recently few studies from Japan, described TRAF in clinical isolates but interestingly none of them exhibited TR 34 /L98H resistance mechanism, instead several SNPs and novel mutations, F332K and P216L were reported ( Asano et al, 2011 ; Hagiwara et al, 2014 ). The single center study from Japan reported 5.2% (1/19) TRAF isolates harboring only G54E/R/W and I266N mutation ( Tashiro et al, 2012a , b ).…”

Section: Discussionmentioning

confidence: 89%

Prevalence and mechanism of triazole resistance in Aspergillus fumigatus in a referral chest hospital in Delhi, India and an update of the situation in Asia

et al. 2015

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Aspergillus fumigatus causes varied clinical syndromes ranging from colonization to deep infections. The mainstay of therapy of Aspergillus diseases is triazoles but several studies globally highlighted variable prevalence of triazole resistance, which hampers the management of aspergillosis. We studied the prevalence of resistance in clinical A. fumigatus isolates during 4 years in a referral Chest Hospital in Delhi, India and reviewed the scenario in Asia and the Middle East. Aspergillus species (n = 2117) were screened with selective plates for azole resistance. The isolates included 45.4% A. flavus, followed by 32.4% A. fumigatus, 15.6% Aspergillus species and 6.6% A. terreus. Azole resistance was found in only 12 (1.7%) A. fumigatus isolates. These triazole resistant A. fumigatus (TRAF) isolates were subjected to (a) calmodulin and β tubulin gene sequencing (b) in vitro antifungal susceptibility testing against triazoles using CLSI M38-A2 (c) sequencing of cyp51A gene and real-time PCR assay for detection of mutations and (d) microsatellite typing of the resistant isolates. TRAF harbored TR34/L98H mutation in 10 (83.3%) isolates with a pan-azole resistant phenotype. Among the remaining two TRAF isolates, one had G54E and the other had three non-synonymous point mutations. The majority of patients were diagnosed as invasive aspergillosis followed by allergic bronchopulmonary aspergillosis and chronic pulmonary aspergillosis. The Indian TR34/L98H isolates had a unique genotype and were distinct from the Chinese, Middle East, and European TR34/L98H strains. This resistance mechanism has been linked to the use of fungicide azoles in agricultural practices in Europe as it has been mainly reported from azole naïve patients. Reports published from Asia demonstrate the same environmental resistance mechanism in A. fumigatus isolates from two highly populated countries in Asia, i.e., China and India and also from the neighboring Middle East.

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Molecular typing and in-vitro activity of azoles against clinical isolates of Aspergillus fumigatus and A. niger in Japan

Cited by 16 publications

References 18 publications

New Insights into the Cyp51 Contribution to Azole Resistance in Aspergillus Section Nigri

New Insights into the Cyp51 Contribution to Azole Resistance in Aspergillus Section Nigri

Epidemiology and molecular mechanisms of antifungal resistance in Candida and Aspergillus

Prevalence and mechanism of triazole resistance in Aspergillus fumigatus in a referral chest hospital in Delhi, India and an update of the situation in Asia

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