Antifungal Susceptibilities of Aspergillus fumigatus Clinical Isolates Obtained in Nagasaki, Japan

Tashiro, Masato; Izumikawa, Koichi; Minematsu, Asuka; Hirano, Katsuji; Iwanaga, Naoki; Ide, Shotaro; Mihara, Tomo; Hosogaya, Naoki; Takazono, Takahiro; Morinaga, Yoshitomo; Nakamura, Shigeki; Kurihara, Shintaro; Imamura, Yoshifumi; Miyazaki, Taiga; Nishino, Tomoya; Tsukamoto, Misuzu; Kakeya, Hiroshi; Yamamoto, Yoshihiro; Yanagihara, Katsunori; Yasuoka, Akira; Tashiro, Takayoshi; Kohno, Shigeru

doi:10.1128/aac.05394-11

Cited by 74 publications

(59 citation statements)

References 38 publications

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“…We isolated azole-resistant A. fumigatus from clinical samples, such as sputum, but we did not isolate A. fumigatus from the environment or detect a TR/L98H mutant (28). It is interesting that the most common mechanism of resistance detected in this study was G54 substitution, because the selection pressure of itraconazole induces G54 mutation (13).…”

Section: Figmentioning

confidence: 85%

“…We previously reported results for antifungal susceptibility analysis and cyp51A sequencing (28). The breakpoints used for resistance were Ն4 g/ml for itraconazole and voriconazole and Ն1 g/ml for posaconazole (30).…”

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confidence: 99%

“…Recently, we reported the antifungal MIC distribution of 196 A. fumigatus clinical isolates with a cyp51A gene mutation in Nagasaki, Japan (28). Of those, we analyzed 154 isolates from 64 patients retrospectively in this study, and we evaluated the cumulative amount of azoles administered to patients at the time of isolation of each A. fumigatus clinical isolate.…”

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confidence: 99%

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Correlation between Triazole Treatment History and Susceptibility in Clinically Isolated Aspergillus fumigatus

Tashiro

Izumikawa

Hirano

et al. 2012

Antimicrob Agents Chemother

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b This is the first report of a detailed relationship between triazole treatment history and triazole MICs for 154 Aspergillus fumigatus clinical isolates. The duration of itraconazole dosage increased as the itraconazole MIC increased, and a positive correlation was observed (r ‫؍‬ 0.5700, P < 0.0001). The number of itraconazole-naïve isolates dramatically decreased as the itraconazole MIC increased, particularly for MICs exceeding 2 g/ml (0.5 g/ml versus 2 g/ml, P ‫؍‬ 0.03). We also examined the relationship between cumulative itraconazole usage and the MICs of other azoles. A positive correlation existed between itraconazole dosage period and posaconazole MIC (r ‫؍‬ 0.5237, P < 0.0001). The number of itraconazole-naïve isolates also decreased as the posaconazole MIC increased, particularly for MICs exceeding 0.5 g/ml (0.25 g/ml versus 0.5 g/ml, P ‫؍‬ 0.004). Conversely, the correlation coefficient obtained from the scattergram of itraconazole usage and voriconazole MICs was small (r ‫؍‬ ؊0.2627, P ‫؍‬ 0.001). Susceptibility to three triazole agents did not change as the duration of voriconazole exposure changed. In addition, we carried out detailed analysis, including microsatellite genotyping, for isolates obtained from patients infected with azole-resistant A. fumigatus. We confirmed the presence of acquired resistance to itraconazole and posaconazole due to a G54 substitution in the cyp51A gene for a patient with chronic pulmonary aspergillosis after oral itraconazole therapy. We should consider the possible appearance of azole-resistant A. fumigatus if itraconazole is used for extended periods.

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confidence: 85%

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confidence: 99%

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confidence: 99%

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Correlation between Triazole Treatment History and Susceptibility in Clinically Isolated Aspergillus fumigatus

Tashiro

Izumikawa

Hirano

et al. 2012

Antimicrob Agents Chemother

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“…Cyp51-independent triazole resistance mechanisms in A. fumigatus-Many triazole-resistant A. fumigatus isolates cultured from patients have a wild type cyp51A gene. In one study, 5 of 19 (26%) clinical A. fumigatus isolates with an MTR phenotype did not have any mutations in the cyp51A gene or the promoter region and in another study 7 of 22 (32%) triazole resistant isolates had a wild type copy of cyp51A [50,72]. This implies that A. fumigatus may possess other triazole resistance mechanism(s).…”

Section: A Triazole Resistant Aspergillimentioning

confidence: 99%

An Invisible Threat: Mutation-Mediated Resistance to Triazole Drugs in Aspergillus

Pham

Lockhart

2012

Curr Fungal Infect Rep

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Aspergillosis has emerged as an important contributor to infection-related morbidity and mortality in susceptible populations. This comes at a time when we are also seeing an increase in the vulnerable populations themselves. At the same time, some parts of the world are reporting an increased incidence of aspergillosis refractory to triazole therapy. Resistance to triazole drugs may have major implications for aspergillosis management since our antifungal armamentarium is limited. This review gives an overview of populations at risk of developing aspergillosis and highlights resistance mechanisms that may contribute to morbidity and mortality in these vulnerable populations.

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“…However, the management of invasive aspergillosis (IA) has become more complicated due to the emergence of acquired azole resistance in Aspergillus fumigatus (3), and azole resistance has been reported on different continents (4)(5)(6)(7)(8). There is increasing evidence that azole resistance is associated with treatment failure (5,9,10), and a mortality rate of 88% has been reported (5).…”

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Pharmacodynamics and Dose-Response Relationships of Liposomal Amphotericin B against Different Azole-Resistant Aspergillus fumigatus Isolates in a Murine Model of Disseminated Aspergillosis

Seyedmousavi

Melchers

Mouton

et al. 2013

Antimicrob Agents Chemother

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bThe management of invasive aspergillosis (IA) has become more complicated due to the emergence of acquired azole resistance in Aspergillus fumigatus, which is associated with treatment failure and a mortality rate of 88%. Treatment with liposomal amphotericin B (L-AmB) may be a useful alternative to improve therapeutic outcome in azole-resistant IA. Four clinical A. fumigatus isolates obtained from patients with proven IA were studied in a nonneutropenic murine model of infection: a wildtype isolate without mutations in the cyp51A gene and three azole-resistant isolates harboring a single mutation at codon 220 (M220I) and tandem repeat mutations (a 34-bp tandem repeat mutation in the promoter region of the cyp51A gene in combina Voriconazole is the recommended first-choice therapy for invasive infections caused by Aspergillus species (1, 2). However, the management of invasive aspergillosis (IA) has become more complicated due to the emergence of acquired azole resistance in Aspergillus fumigatus (3), and azole resistance has been reported on different continents (4-8). There is increasing evidence that azole resistance is associated with treatment failure (5, 9, 10), and a mortality rate of 88% has been reported (5). These clinical observations are also supported by animal models of IA, where the MIC was shown to have major implications for the efficacy of voriconazole and posaconazole (11,12). Therefore, it is important to explore alternative treatment regimens. Lipid formulations of the amphotericin B and echinocandin antifungals or combination therapy may be important alternative options, in patients with azole-resistant Aspergillus diseases.We previously investigated the pharmacodynamics of anidulafungin monotherapy and the combination of voriconazole and anidulafungin (13)(14)(15). Although anidulafungin treatment improved the survival of mice in a dose-dependent manner, a maximal response was not achieved when mice were infected with an azole-susceptible or azole-resistant isolate, even in those treated with the highest anidulafungin dose. The results of combination therapy suggested that voriconazole and anidulafungin have a synergistic interaction in mice infected with a voriconazole-susceptible isolate. However, the synergistic interaction was lost in the azole-resistant isolate (voriconazole MIC, 4 mg/liter), as only an additive interaction was observed (13). A relation between the voriconazole MIC and the fractional inhibitory concentration (FIC) index was observed in vitro, which indicated that further increase of the voriconazole MIC was associated with less favorable drug interaction (14). In infection due to isolates which are highly resistant to voriconazole, the efficacy of the combination might rely only on that of anidulafungin, which is suboptimal. In clinical practice, this is a major drawback, as isolates that are highly resistant to voriconazole are increasingly common (4), and in culture-negative patients we will be unable to determine voriconazole susceptibility.Treatment with a lipos...

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Antifungal Susceptibilities of Aspergillus fumigatus Clinical Isolates Obtained in Nagasaki, Japan

Cited by 74 publications

References 38 publications

Correlation between Triazole Treatment History and Susceptibility in Clinically Isolated Aspergillus fumigatus

Correlation between Triazole Treatment History and Susceptibility in Clinically Isolated Aspergillus fumigatus

An Invisible Threat: Mutation-Mediated Resistance to Triazole Drugs in Aspergillus

Pharmacodynamics and Dose-Response Relationships of Liposomal Amphotericin B against Different Azole-Resistant Aspergillus fumigatus Isolates in a Murine Model of Disseminated Aspergillosis

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