Azole antifungal resistance in Aspergillus fumigatus: 2008 and 2009

Bueid, Ahmed S.; Howard, Susan J.; Moore, Caroline B.; Richardson, Malcolm; Harrison, Elizabeth; Bowyer, Paul; Denning, David W.

doi:10.1093/jac/dkq279

Cited by 294 publications

(272 citation statements)

References 11 publications

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“…It has not yet been clearly demonstrated that the beneficial effects of azoles in ABPA and SAFS are due to their antifungal activity as opposed to alterations in concomitantly administered glucocorticosteroid metabolism or independent anti-inflammatory azole effects [43,51]. Most troubling, however, is the emerging evidence that increased azole usage for various medical conditions and (at least in some geographical regions) agricultural applications is leading to a higher prevalence of azole resistance in clinical A. fumigatus isolates, most commonly due to point mutations in the cyp51A gene [100][101][102][103][104][105][106][107][108]. The Aspergillus cyp51A gene encodes cytochrome P450 sterol 14a-demethylase and is the target for azole drugs.…”

Section: Antifungal Therapy In Abpa and Safsmentioning

confidence: 99%

Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis

Moss

2013

European Respiratory Journal

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Severe asthma with fungal sensitisation and allergic bronchopulmonary aspergillosis encompass two closely related subgroups of patients with severe allergic asthma. Pulmonary disease is due to pronounced host inflammatory responses to noninvasive subclinical endobronchial infection with filamentous fungi, usually Aspergillus fumigatus. These patients usually do not achieve satisfactory disease control with conventional treatment of severe asthma, i.e. high-dose inhaled corticosteroids and long-acting bronchodilators. Although prolonged systemic corticosteroids are effective, they carry a substantial toxicity profile. Supplementary or alternative therapies have primarily focused on use of antifungal agents including oral triazoles and inhaled amphotericin B. Immunomodulation with omalizumab, a humanised anti-IgE monoclonal antibody, or "pulse" monthly high-dose intravenous corticosteroid, has also been employed. This article considers the experience with these approaches, with emphasis on recent clinical trials. @ERSpublications Treatment of fungal asthma includes glucocorticoids, azoles, amphotericin and anti-IgE. Trial validation is needed.

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Section: Antifungal Therapy In Abpa and Safsmentioning

confidence: 99%

Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis

Moss

2013

European Respiratory Journal

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“…Austria, Belgium, Denmark, France, Germany, the Netherlands, Norway, Spain and Turkey), the USA, South America and Asian countries (e.g. China, India, Iran, Japan and Kuwait), with an incidence rate of 3.3-38 % (Badali et al, 2013;Bader et al, 2013;Bueid et al, 2010;Burgel et al, 2012;Chowdhary et al, 2011;Chryssanthou, 1997;Howard et al, 2009;Lockhart et al, 2011;Mortensen et al, 2010;Pham et al, 2014;Seyedmousavi et al, 2013;Snelders et al, 2008;van der Linden et al, 2011;van Ingen et al, 2014). According to a recent international surveillance study on the clinical isolates of azole-resistant A. fumigatus, an incidence rate of 3.2 % was reported, which introduced a novel phase in the management of invasive aspergillosis (van der Linden et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Over 90 % of azole-resistant A. fumigatus isolates harbour a leucine-to-histidine substitution at codon 98, along with a 34 bp tandem repeat in the CYP51A promoter region. This issue, which is associated with high rates of treatment failure, has become a major medical concern (Howard et al, 2009;Snelders et al, 2009;van der Linden et al, 2011;Verweij et al, 2007). However, a novel CYP51A-promoter duplication mutation, known as TR 46 /Y121F/T289A, has recently been introduced, which is considered responsible for the elevated MIC of voriconazole (Chowdhary et al, 2013;van der Linden et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

High prevalence of clinical and environmental triazole-resistant Aspergillus fumigatus in Iran: is it a challenging issue?

Nabili

Shokohi

Moazeni

et al. 2016

Journal of Medical Microbiology

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Triazole antifungal agents are the mainstay of aspergillosis treatment. As highlighted in numerous studies, the global increase in the prevalence of triazole resistance could hamper the management of aspergillosis. In the present three-year study, 513 samples (213 clinical and 300 environmental samples) from 10 provinces of Iran were processed and screened in terms of azole resistance (4 and 1 mg l À1 of itraconazole and voriconazole, respectively), using selective plates. Overall, 150 A. fumigatus isolates (71 clinical and 79 environmental isolates) were detected. The isolates were confirmed by partial sequencing of the b-tubulin gene. Afterwards, in vitro antifungal susceptibility tests against triazole agents were performed, based on the Clinical and Laboratory Standards Institute (CLSI) M38-A2 document. The CYP51A gene was sequenced in order to detect mutations. The MIC of itraconazole against 10 (6.6 %) strains, including clinical (n=3, 4.2 %) and environmental (n=7, 8.8 %) strains, was higher than the breakpoint and epidemiological cut-off value. Based on the findings, the prevalence of azole-resistant A. fumigatus in Iran has increased remarkablyfrom 3.3 % to 6.6 % in comparison with earlier epidemiological research. Among resistant isolates, TR 34 /L98H mutations in the CYP51A gene were the most prevalent (n=8, 80 %), whereas other point mutations (F46Y, G54W, Y121F, G138C, M172V, F219C, M220I, D255E, T289F, G432C and G448S mutations) were not detected. Although the number of patients affected by azole-resistant A. fumigatus isolates was limited, strict supervision of clinical azole-resistant A. fumigatus isolates and persistent environmental screening of azole resistance are vital to the development of approaches for the management of azole resistance in human pathogenic fungi.

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“…[6][7][8] In addition, a growing number of azole-resistant A. fumigatus strains has been identified in Europe over the past decade, contributing significantly to treatment failure. [9][10][11][12][13] Preclinical in vivo studies are indispensable for gaining a better understanding of the pathogenesis of infections caused by both azole-susceptible and -resistant strains and for assessing their response to antifungal drugs. However, the gold standard techniques used for evaluation of infections in small animal models, such as fungal load quantification by colony-forming unit (CFU) counts, galactomannan (GM) antigen detection and microscopy of tissue sections, have limitations.…”

mentioning

confidence: 99%

Longitudinal, in vivo assessment of invasive pulmonary aspergillosis in mice by computed tomography and magnetic resonance imaging

Poelmans

Hillen

Vanherp

et al. 2016

Laboratory Investigation

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Invasive aspergillosis is an emerging threat to public health due to the increasing use of immune suppressive drugs and the emergence of resistance against antifungal drugs. To deal with this threat, research on experimental disease models provides insight into the pathogenesis of infections caused by susceptible and resistant Aspergillus strains and by assessing their response to antifungal drugs. However, standard techniques used to evaluate infection in a preclinical setting are severely limited by their invasive character, thereby precluding evaluation of disease extent and therapy effects in the same animal. To enable non-invasive, longitudinal monitoring of invasive pulmonary aspergillosis in mice, we optimized computed tomography (CT) and magnetic resonance imaging (MRI) techniques for daily follow-up of neutropenic BALB/c mice intranasally infected with A. fumigatus spores. Based on the images, lung parameters (signal intensity, lung tissue volume and total lung volume) were quantified to obtain objective information on disease onset, progression and extent for each animal individually. Fungal lung lesions present in infected animals were successfully visualized and quantified by both CT and MRI. By using an advanced MR pulse sequence with ultrashort echo times, pathological changes within the infected lung became visually and quantitatively detectable at earlier disease stages, thereby providing valuable information on disease onset and progression with high sensitivity. In conclusion, these noninvasive imaging techniques prove to be valuable tools for the longitudinal evaluation of dynamic disease-related changes and differences in disease severity in individual animals that might be readily applied for rapid and cost-efficient drug screening in preclinical models in vivo.

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Azole antifungal resistance in Aspergillus fumigatus: 2008 and 2009

Abstract: Azole resistance is evolving and growing in frequency. Established and novel mechanisms may be responsible.

Cited by 294 publications

References 11 publications

Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis

Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis

High prevalence of clinical and environmental triazole-resistant Aspergillus fumigatus in Iran: is it a challenging issue?

Longitudinal, in vivo assessment of invasive pulmonary aspergillosis in mice by computed tomography and magnetic resonance imaging

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