Long-term Antifungal Treatment Improves Health Status in Patients With Chronic Pulmonary Aspergillosis: A Longitudinal Analysis

Al-shair, Khaled; Atherton, Graham T.; Harris, Christine; Ratcliffe, Libuše; Newton, Peggy; Denning, David W.

doi:10.1093/cid/cit411

Cited by 74 publications

(76 citation statements)

References 32 publications

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“…The significant predilection to CPA is in agreement with the findings of recent studies in Iran which demonstrated that CPA is the most common clinical presentation of aspergillosis in individuals with healed tuberculosis (35). Importantly, patients with CPA require long-term maintenance antifungal therapy to improve symptoms and prevent the recurrence of infection (36,37). The acquisition of azole resistance in A. fumigatus is an emerging public health problem which definitely needs continued surveillance at the national and international levels (9).…”

Section: Discussionsupporting

confidence: 86%

Quantitative Analysis of Single-Nucleotide Polymorphism for Rapid Detection of TR ₃₄ /L98H- and TR ₄₆ /Y121F/T289A-Positive Aspergillus fumigatus Isolates Obtained from Patients in Iran from 2010 to 2014

Mohammadi

Hashemi

Zoll

et al. 2016

Antimicrob Agents Chemother

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gWe employed an endpoint genotyping method to update the prevalence rate of positivity for the TR 34 /L98H mutation (a 34-bp tandem repeat mutation in the promoter region of the cyp51A gene in combination with a substitution at codon L98) and the TR 46 A zole resistance in Aspergillus fumigatus is a global and evolving public health threat which translates into treatment failure (1). Surveillance studies indicate that the incidence of azole resistance is increasing (2-6), with the TR 34 /L98H mutation (a 34-bp tandem repeat mutation in the promoter region of the cyp51A gene in combination with a substitution at codon L98) emerging in multiple European countries and in the Middle East, Asia, and Africa and with a new resistance mechanism, the TR 46 /Y121F/ T289A mutation (a 46-bp tandem repeat mutation in the promoter region of the cyp51A gene in combination with substitutions at codons Y121 and T289), emerging more recently in Europe and India (2-6). We also previously reported the occurrence of the TR 34 /L98H mutation in 3.2% of clinical Aspergillus fumigatus isolates obtained from patients in Iran to the end of 2009 (5).The trend of increases in the rates of azole resistance among A. fumigatus isolates in different regions and patient groups exemplifies the fact that knowledge of the (local) epidemiology of azoleresistant Aspergillus diseases is important for clinical mycology/ microbiology reference laboratories (7-9). Moreover, rapid and specific molecular methods for the identification of the recently identified azole-resistant A. fumigatus strains can significantly influence a timely decision on patient management (10).In our search for a novel, rapid, sensitive, accurate, and highthroughput method for detection and screening of azole resistance in A. fumigatus, we found that endpoint genotyping targeting a single-nucleotide polymorphism (SNP) in the cyp51A gene could provide an option. The quantitative analysis of SNPs has been a reliable method in diagnostic microbiology for identification of a single nucleotide in the genomes of humans (11-15), viruses (16-20), and bacteria (18). In this assay, an extension probe can be simply designed to anneal to the template in a posi-

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Section: Discussionsupporting

confidence: 86%

Quantitative Analysis of Single-Nucleotide Polymorphism for Rapid Detection of TR ₃₄ /L98H- and TR ₄₆ /Y121F/T289A-Positive Aspergillus fumigatus Isolates Obtained from Patients in Iran from 2010 to 2014

Mohammadi

Hashemi

Zoll

et al. 2016

Antimicrob Agents Chemother

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“…Azole drugs are frequently used prophylactically, sometimes for long periods of time, to prevent Aspergillus infections, as well as to treat these infections (1,13). In addition, agricultural azoles are routinely used to control plant fungal pathogens (5).…”

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confidence: 99%

Azole Drug Import into the Pathogenic Fungus Aspergillus fumigatus

Esquivel

Smith

Zavřel

et al. 2015

Antimicrob Agents Chemother

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The fungal pathogen Aspergillus fumigatus causes serious illness and often death when it invades tissues, especially in immunocompromised individuals. The azole class of drugs is the most commonly prescribed treatment for many fungal infections and acts on the ergosterol biosynthesis pathway. One common mechanism of acquired azole drug resistance in fungi is the prevention of drug accumulation to toxic levels in the cell. While drug efflux is a well-known resistance strategy, reduced azole import would be another strategy to maintain low intracellular azole levels. Recently, azole uptake in Candida albicans and other yeasts was analyzed using [ 3 H]fluconazole. Defective drug import was suggested to be a potential mechanism of drug resistance in several pathogenic fungi, including Cryptococcus neoformans, Candida krusei, and Saccharomyces cerevisiae. We have adapted and developed an assay to measure azole accumulation in A. fumigatus using radioactively labeled azole drugs, based on previous work done with C. albicans. We used this assay to study the differences in azole uptake in A. fumigatus isolates under a variety of drug treatment conditions, with different morphologies and with a select mutant strain with deficiencies in the sterol uptake and biosynthesis pathway. We conclude that azole drugs are specifically selected and imported into the fungal cell by a pH-and ATPindependent facilitated diffusion mechanism, not by passive diffusion. This method of drug transport is likely to be conserved across most fungal species.T he fungal pathogen Aspergillus fumigatus is one of the most common and ubiquitous environmental molds. Aspergillus infections represent a significant human health burden. Aspergillus causes serious illnesses, ranging from sinus infections to invasive or chronic aspergillosis in immunocompromised individuals (1-3). Infection can be fatal when Aspergillus colonizes or invades tissues, such as the lungs and blood vessels (2). The patients most at risk for these infections are those with prior lung conditions such as asthma, tuberculosis, chronic obstructive pulmonary disease (COPD), or cystic fibrosis, as well as bone marrow transplant patients and people living with HIV, AIDS, or other immune deficiencies (1-4). Aspergillus infections greatly affect the quality of life, cause dramatically lengthened hospital stays, and cost the United States more than 1 billion dollars each year (3, 5). In recent years, there has been a significant rise in the number of fungal infections due to the growing subpopulation of individuals with weakened immune health (3).If not swiftly and appropriately treated, these fungal infections can progress to serious illness and rapidly become fatal (2, 6). The azole class of drugs is still the most commonly prescribed treatment for many fungal infections because the drugs are relatively cheap to produce, are generally nontoxic to humans, and are usually more effective for controlling an infection than other classes of antifungals (5, 7). Although A. fumigatus has an intri...

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“…For CPA, long-term antifungal treatment is usually required, but case-by-case surgery should be discussed [41]. Patients with poor pulmonary function are generally inoperable and can, alternatively, undergo endovascular treatment such as bronchial artery embolisation (BAE) in the case of life-threatening haemoptysis and also receive systemic antifungal therapy [42].…”

Section: Cpa: Current Treatment Optionsmentioning

confidence: 99%

“…In a very recent randomised controlled trial, Agarwal et al [31] reported the superiority of itraconazole therapy over standard supportive treatment. Two other trials have also shown an improvement in quality of life after initiating triazoles in the setting of CPA [41,55]. While several different classes of antifungal agents have been introduced, the emergence of triazole antifungal drugs has been found to be an effective therapeutic agent against almost all forms of CPA [48].…”

Section: Cpa: Current Treatment Optionsmentioning

confidence: 99%

Chronic Pulmonary Aspergillosis: An Update on Diagnosis and Treatment

Godet¹,

Philippe

Laurent

et al. 2014

Respiration

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Chronic pulmonary aspergillosis (CPA) affects individuals with non-systemic or mildly systemic immunodepression or altered pulmonary integrity due to underlying disease. It has been reported with a variety of clinical and radiological patterns. The condition should be distinguished from simple aspergilloma and allergic bronchopulmonary aspergillosis as well as invasive aspergillosis in severely immunocompromised patients. CPA generally requires long-term antifungal treatment and surgery may be considered. Life-threatening haemoptysis may be prevented by bronchial arteriography with embolisation. However, currently there are no documented treatment recommendations for CPA. This review provides an up-to-date practical overview of this condition, including a comprehensive update on diagnosis and management.

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Long-term Antifungal Treatment Improves Health Status in Patients With Chronic Pulmonary Aspergillosis: A Longitudinal Analysis

Abstract: Antifungal therapy improved health status and prevented CPA progression in most patients.

Cited by 74 publications

References 32 publications

Quantitative Analysis of Single-Nucleotide Polymorphism for Rapid Detection of TR ₃₄ /L98H- and TR ₄₆ /Y121F/T289A-Positive Aspergillus fumigatus Isolates Obtained from Patients in Iran from 2010 to 2014

Quantitative Analysis of Single-Nucleotide Polymorphism for Rapid Detection of TR ₃₄ /L98H- and TR ₄₆ /Y121F/T289A-Positive Aspergillus fumigatus Isolates Obtained from Patients in Iran from 2010 to 2014

Azole Drug Import into the Pathogenic Fungus Aspergillus fumigatus

Chronic Pulmonary Aspergillosis: An Update on Diagnosis and Treatment

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Long-term Antifungal Treatment Improves Health Status in Patients With Chronic Pulmonary Aspergillosis: A Longitudinal Analysis

Abstract: Antifungal therapy improved health status and prevented CPA progression in most patients.

Cited by 74 publications

References 32 publications

Quantitative Analysis of Single-Nucleotide Polymorphism for Rapid Detection of TR 34 /L98H- and TR 46 /Y121F/T289A-Positive Aspergillus fumigatus Isolates Obtained from Patients in Iran from 2010 to 2014

Quantitative Analysis of Single-Nucleotide Polymorphism for Rapid Detection of TR 34 /L98H- and TR 46 /Y121F/T289A-Positive Aspergillus fumigatus Isolates Obtained from Patients in Iran from 2010 to 2014

Azole Drug Import into the Pathogenic Fungus Aspergillus fumigatus

Chronic Pulmonary Aspergillosis: An Update on Diagnosis and Treatment

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Product

Resources

About

Quantitative Analysis of Single-Nucleotide Polymorphism for Rapid Detection of TR ₃₄ /L98H- and TR ₄₆ /Y121F/T289A-Positive Aspergillus fumigatus Isolates Obtained from Patients in Iran from 2010 to 2014

Quantitative Analysis of Single-Nucleotide Polymorphism for Rapid Detection of TR ₃₄ /L98H- and TR ₄₆ /Y121F/T289A-Positive Aspergillus fumigatus Isolates Obtained from Patients in Iran from 2010 to 2014