Azole resistant Aspergillus fumigatus: An emerging problem

Lelièvre, L; Groh, Matthieu; Angebault, Cécile; Mahérault, Anne-Claire; Didier, E.; Bougnoux, Marie‐Elisabeth

doi:10.1016/j.medmal.2013.02.010

Cited by 76 publications

(55 citation statements)

References 47 publications

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“…The treatment of aspergillosis has proven difficult because of limited antifungal therapy possibilities and the prevalence of antifungal-resistant strains worldwide. Consequently, the number of cases for which treatment has failed is increasing (3,4). Recent studies from several research groups show that prolonged azole therapy tends to promote the occurrence of azole-resistant strains (5,6).…”

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confidence: 99%

“…Itraconazole (ITCZ) can treat chronic aspergillosis infections, such as aspergilloma, whereas voriconazole (VRCZ) is used to treat invasive aspergillosis. Since first being reported in 1997, a number of azole-resistant strains have been isolated primarily from aspergilloma patients on prolonged azole therapy (4,(8)(9)(10). Fungal tolerance is frequently caused by mutations in the gene encoding the target protein of azoles (cyp51A).…”

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confidence: 99%

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Whole-Genome Comparison of Aspergillus fumigatus Strains Serially Isolated from Patients with Aspergillosis

et al. 2014

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The emergence of azole-resistant strains of Aspergillus fumigatus during treatment for aspergillosis occurs by a mutation selection process. Understanding how antifungal resistance mechanisms evolve in the host environment during infection is of great clinical importance and biological interest. Here, we used next-generation sequencing (NGS) to identify mutations that arose during infection by A. fumigatus strains sequentially isolated from two patients, one with invasive pulmonary aspergillosis (IPA) (five isolations) and the other with aspergilloma (three isolations). The serial isolates had identical microsatellite types, but their growth rates and conidia production levels were dissimilar. A whole-genome comparison showed that three of the five isolates from the IPA patient carried a mutation, while 22 mutations, including six nonsynonymous ones, were found among three isolates from the aspergilloma patient. One aspergilloma isolate carried the cyp51A mutation P216L, which is reported to confer azole resistance, and it displayed an MIC indicating resistance to itraconazole. This isolate harbored five other nonsynonymous mutations, some of which were found in the afyap1 and aldA genes. We further identified a large deletion in the aspergilloma isolate in a region containing 11 genes. This finding suggested the possibility that genomic deletions can occur during chronic infection with A. fumigatus. Overall, our results revealed dynamic alterations that occur in the A. fumigatus genome within its host during infection and treatment.

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Whole-Genome Comparison of Aspergillus fumigatus Strains Serially Isolated from Patients with Aspergillosis

et al. 2014

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“…Despite the introduction of better diagnostic tools and new antifungal drugs, clinical outcomes remain poor. Drug resistance is a particular problem, with multiple species demonstrating resistance to Amphotericin B [10][11][12][13] and rising frequencies of azole resistance in A fumigatus and Candida species [14][15][16][17].There is therefore a need for novel strategies to prevent and treat fungal infections.…”

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confidence: 99%

Stimulation with lysates of Aspergillus terreus, Candida krusei and Rhizopus oryzae maximizes cross-reactivity of anti-fungal T cells

et al. 2016

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“…Another class of antifungal agents is azoles, among them, voriconazole has been used for the primary therapy for IA, with posaconazole and itraconazole as the drugs for salvage therapy [13]. Similar to other antifungals, there have been increased incidences of resistance to azole antifungals in A. fumigatus [14], [15]. The echinocandins have been most promising but are available only as parenteral formulations [16].…”

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confidence: 99%

In Vivo Efficacy of a Synthetic Coumarin Derivative in a Murine Model of Aspergillosis

et al. 2014

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Despite advances in therapeutic modalities, aspergillosis remains a leading cause of mortality. This has necessitated the identification of effective and safe antifungal molecules. In the present study, in vivo safety and antifungal efficacy of a coumarin derivative, N, N, N-Triethyl-11-(4-methyl-2-oxo-2H-benzopyran-7-yloxy)-11-oxoundecan-1-aminium bromide (SCD-1), was investigated. The maximum tolerable dose of compound was determined according to OECD 423 guidelines. The compound could be assigned to category IV of the Globally Harmonized System and its LD50 cut-off was found to be 2000 mg/kg body weight. The survival increased in Aspergillus fumigatus-infected mice treated with a dose of 200 mg/kg, orally or 100 mg/kg body weight, intraperitoneally, of SCD-1 in comparison to infected-untreated animals. The SCD-1 treatment resulted in significant reduction in colony counts in vital organs of the animals. Its protective effect was also observed on day 14 as there was marked reduction in fungal colonies. The treatment with SCD-1 also reduced the levels of serum biochemical parameters with respect to infected-untreated animals. It could be concluded that SCD-1 is a quite safe antifungal compound, which conferred dose dependent protection against experimental aspergillosis. Therefore, SCD-1 holds potential for developing new formulations for aspergillosis.

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Azole resistant Aspergillus fumigatus: An emerging problem

Cited by 76 publications

References 47 publications

Whole-Genome Comparison of Aspergillus fumigatus Strains Serially Isolated from Patients with Aspergillosis

Whole-Genome Comparison of Aspergillus fumigatus Strains Serially Isolated from Patients with Aspergillosis

Stimulation with lysates of Aspergillus terreus, Candida krusei and Rhizopus oryzae maximizes cross-reactivity of anti-fungal T cells

In Vivo Efficacy of a Synthetic Coumarin Derivative in a Murine Model of Aspergillosis

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