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Azole Resistance in Aspergillus spp.
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Azole Resistance in Aspergillus spp.

A special issue of Journal of Fungi (ISSN 2309-608X). This special issue belongs to the section "Fungal Genomics, Genetics and Molecular Biology".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 12897

Special Issue Editors

Dr. Teresa Peláez-García de la Rasilla

E-Mail Website
Guest Editor
1. Microbiology Department, Central University Hospital of Asturias (HUCA), 33011 Oviedo, Spain
2. Biosanitary Foundation for Research in the Principality of Asturias (FINBA), 33011 Oviedo, Spain
Interests: mycological diagnosis; antifungal resistance; antifungal tolerance; clinical implication of antifungal resistance; azole resistance in the environment
Special Issues, Collections and Topics in MDPI journals
Dr. Clara Valero

E-Mail Website
Guest Editor
Manchester Fungal Infection Group, Faculty of Biology, Medicine and Health, The University of Manchester, Core Technology Facility, Manchester, UK
Interests: Aspergillus molecular biology; antifungal resistance; antifungal tolerance; Aspergillus stress response

Special Issue Information

Dear Colleagues,

Aspergillus spp. fungi affect millions of patients and cause hundreds of thousands of life-threatening infections every year. Azoles have been used for many years as the main antifungal agent to treat and prevent Aspergillus spp. infections. However, these organisms can develop azole resistance in certain environments when exposed to azole compounds used as fungicides or during the long-term treatment of patients with chronic infections. Azole resistance can be devastating as almost 90% of invasive aspergillosis patients infected with a drug-resistant strain die, while chronic patients with resistant infections are administered treatments that are either poorly tolerated or less efficacious. Furthermore, some isolates show the remarkable ability to tolerate azole concentrations greater than the minimal inhibitory concentration, which may also impact clinical outcomes and act as a precursor of azole resistance. Thus, azole resistance poses a significant threat to human health with important economic implications.

This Special Issue is dedicated to Aspergillus spp. azole resistance. Among other topics, it will cover the important research and innovation needed to implement risk reduction strategies that can minimize the emergence of resistance and improve disease management.

Sincerely,

Dr. Teresa Peláez
Dr. Clara Valero
Guest Editors

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Keywords

  • azole resistance molecular mechanisms
  • clinical azole resistance
  • environmental azole resistance
  • evolution of azole resistance
  • detection of azole resistance
  • azole tolerance/persistence

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Published Papers (6 papers)

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36 pages, 6789 KiB  
Article
Genomic Epidemiology Identifies Azole Resistance Due to TR34/L98H in European Aspergillus fumigatus Causing COVID-19-Associated Pulmonary Aspergillosis
by Benjamin C. Simmons, Johanna Rhodes, Thomas R. Rogers, Paul E. Verweij, Alireza Abdolrasouli, Silke Schelenz, Samuel J. Hemmings, Alida Fe Talento, Auveen Griffin, Mary Mansfield, David Sheehan, Thijs Bosch and Matthew C. Fisher
J. Fungi 2023, 9(11), 1104; https://doi.org/10.3390/jof9111104 - 13 Nov 2023
Cited by 1 | Viewed by 1920
Abstract
Aspergillus fumigatus has been found to coinfect patients with severe SARS-CoV-2 virus infection, leading to COVID-19-associated pulmonary aspergillosis (CAPA). The CAPA all-cause mortality rate is approximately 50% and may be complicated by azole resistance. Genomic epidemiology can help shed light on the genetics [...] Read more.
Aspergillus fumigatus has been found to coinfect patients with severe SARS-CoV-2 virus infection, leading to COVID-19-associated pulmonary aspergillosis (CAPA). The CAPA all-cause mortality rate is approximately 50% and may be complicated by azole resistance. Genomic epidemiology can help shed light on the genetics of A. fumigatus causing CAPA, including the prevalence of resistance-associated alleles. We present a population genomic analysis of 21 CAPA isolates from four European countries with these isolates compared against 240 non-CAPA A. fumigatus isolates from a wider population. Bioinformatic analysis and antifungal susceptibility testing were performed to quantify resistance and identify possible genetically encoded azole-resistant mechanisms. The phylogenetic analysis of the 21 CAPA isolates showed that they were representative of the wider A. fumigatus population with no obvious clustering. The prevalence of phenotypic azole resistance in CAPA was 14.3% (n = 3/21); all three CAPA isolates contained a known resistance-associated cyp51A polymorphism. The relatively high prevalence of azole resistance alleles that we document poses a probable threat to treatment success rates, warranting the enhanced surveillance of A. fumigatus genotypes in these patients. Furthermore, potential changes to antifungal first-line treatment guidelines may be needed to improve patient outcomes when CAPA is suspected. Full article
(This article belongs to the Special Issue Azole Resistance in Aspergillus spp.)
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13 pages, 1829 KiB  
Article
Potential Implication of Azole Persistence in the Treatment Failure of Two Haematological Patients Infected with Aspergillus fumigatus
by Teresa Peláez-García de la Rasilla, Álvaro Mato-López, Clara E. Pablos-Puertas, Ana Julia González-Huerta, Alicia Gómez-López, Emilia Mellado and Jorge Amich
J. Fungi 2023, 9(8), 805; https://doi.org/10.3390/jof9080805 - 30 Jul 2023
Cited by 1 | Viewed by 2506
Abstract
Invasive aspergillosis (IA) is a major cause of morbidity and mortality in patients receiving allogeneic haematopoieticcell transplantation. The deep immunosuppression and a variety of potential additional complications developed in these patients result in IA reaching mortality rates of around 50–60%. This mortality is [...] Read more.
Invasive aspergillosis (IA) is a major cause of morbidity and mortality in patients receiving allogeneic haematopoieticcell transplantation. The deep immunosuppression and a variety of potential additional complications developed in these patients result in IA reaching mortality rates of around 50–60%. This mortality is even higher when the patients are infected with azole-resistant isolates, demonstrating that, despite the complexity of management, adequate azole treatment can have a beneficial effect. It is therefore paramount to understand the reasons why antifungal treatment of IA infections caused by azole-susceptible isolates is often unsuccessful. In this respect, there are already various factors known to be important for treatment efficacy, for instance the drug concentrations achieved in the blood, which are thus often monitored. We hypothesize that antifungal persistence may be another important factor to consider. In this study we present two case reports of haematological patients who developed proven IA and suffered treatment failure, despite having been infected with susceptible isolates, receiving correct antifungal treatment and reaching therapeutic levels of the azole. Microbiological analysis of the recovered infective isolates showed that the patients were infected with multiple strains, several of which were persisters to voriconazole and/or isavuconazole. Therefore, we propose that azole persistence may have contributed to therapeutic failure in these patients and that this phenomenon should be considered in future studies. Full article
(This article belongs to the Special Issue Azole Resistance in Aspergillus spp.)
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14 pages, 1170 KiB  
Article
Field-Crop Soils in Eastern France: Coldspots of Azole-Resistant Aspergillus fumigatus
by Chloé Godeau, Nadia Morin-Crini, Grégorio Crini, Jean-Philippe Guillemin, Anne-Sophie Voisin, Sylvie Dousset and Steffi Rocchi
J. Fungi 2023, 9(6), 618; https://doi.org/10.3390/jof9060618 - 27 May 2023
Cited by 2 | Viewed by 1762
Abstract
Triazole fungicides are widely used to treat fungal pathogens in field crops, but very few studies have investigated whether fields of these crops constitute hotspots of azole resistance in Aspergillus fumigatus. Soil samples were collected from 22 fields in two regions of [...] Read more.
Triazole fungicides are widely used to treat fungal pathogens in field crops, but very few studies have investigated whether fields of these crops constitute hotspots of azole resistance in Aspergillus fumigatus. Soil samples were collected from 22 fields in two regions of eastern France and screened for triazole residues and azole-resistant A. fumigatus (ARAf). Real-time quantitative PCR (qPCR) was used to quantify A. fumigatus in these soil samples. All the plots contained tebuconazole at concentrations from 5.5 to 19.1 ng/g of soil, and 5 of the 22 plots also contained epoxiconazole. Only a few fungal isolates were obtained, and no ARAf was detected. A. fumigatus qPCR showed that this fungal species was, on average, 5000 times more common in soil from flowerbeds containing ARAf than in soil from field crops. Thus, field-crop soils do not appear to promote A. fumigatus development, even if treated with azole fungicides, and cannot be considered hotspots of resistance. Indeed, our results suggest that they are instead a coldspot of resistance and highlight how little is known about the ecological niche of this species. Full article
(This article belongs to the Special Issue Azole Resistance in Aspergillus spp.)
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12 pages, 1151 KiB  
Article
Quantitative PCR Effectively Quantifies Triazole-Susceptible and Triazole-Resistant Aspergillus fumigatus in Mixed Infections
by Agustin Resendiz-Sharpe, Wannes Van Holm, Rita Merckx, Martine Pauwels, Wim Teughels, Katrien Lagrou and Greetje Vande Velde
J. Fungi 2022, 8(11), 1120; https://doi.org/10.3390/jof8111120 - 25 Oct 2022
Cited by 2 | Viewed by 2131
Abstract
Increasing resistance to triazole antifungals in Aspergillus fumigatus is worrisome because of the associated high mortality of triazole-resistant A. fumigatus (TRAF) infections. While most studies have focused on single triazole-susceptible (WT) or TRAF infections, reports of TRAF cases developing mixed WT and TRAF [...] Read more.
Increasing resistance to triazole antifungals in Aspergillus fumigatus is worrisome because of the associated high mortality of triazole-resistant A. fumigatus (TRAF) infections. While most studies have focused on single triazole-susceptible (WT) or TRAF infections, reports of TRAF cases developing mixed WT and TRAF infections have been described in several studies. However, the prevalence of mixed infections and their responses to current recommended therapies are unknown and could be inappropriate, leading to poor clinical outcomes. To address the urgent need for tools to diagnose, monitor disease development and therapy efficacies in mixed infection settings where quantification of WT versus TRAF is key, this study developed a novel qPCR assay to differentiate WT and TRAF harboring the cyp51A-TR34/L98H mutation. The proposed assay successfully quantified A. fumigatus and discriminated TRAF-TR34 in vitro and in vivo, which was achieved by increasing the yield of extracted DNA through improved homogenization and specific primers targeting the WT-sequence or TR34-insertion and a TaqMan-probe directed to A. fumigatus. The here-developed qPCR assay overcomes sensitivity issues of methodologies such as CFU counts, providing specific, reproducible, and reliable quantitative information to study and follow up the (interplay and individual) effects of mixed A. fumigatus infections on disease development and treatment responses. Full article
(This article belongs to the Special Issue Azole Resistance in Aspergillus spp.)
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11 pages, 600 KiB  
Article
Azole Resistance and cyp51A Mutation of Aspergillus fumigatus in a Tertiary Referral Hospital in Taiwan
by Tsun-Hao Hsu, Po-Yen Huang, Yun-Chen Fan and Pei-Lun Sun
J. Fungi 2022, 8(9), 908; https://doi.org/10.3390/jof8090908 - 26 Aug 2022
Cited by 8 | Viewed by 2533
Abstract
Azole resistance in Aspergillus fumigatus has increasingly been reported worldwide. Its major mechanism of resistance is mediated by mutations in cyp51A. The objective of this study was to test the antifungal susceptibilities of A. fumigatus isolates from Chang Gung Memorial Hospital (CGMH), [...] Read more.
Azole resistance in Aspergillus fumigatus has increasingly been reported worldwide. Its major mechanism of resistance is mediated by mutations in cyp51A. The objective of this study was to test the antifungal susceptibilities of A. fumigatus isolates from Chang Gung Memorial Hospital (CGMH), the largest tertiary referral hospital in Taiwan, and to investigate cyp51A mutations in azole-resistant strains. A. fumigatus isolates preserved in the Research Laboratory of Medical Mycology of CGMH from 2015 to 2021 were used. Antifungal susceptibility testing was performed using the YeastOneTM method. Isolates with high minimal inhibitory concentrations (MICs) against antifungals were further tested using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method. Mutations in the cyp51A in azole-resistant strains were detected by Sanger sequencing. The overall prevalence of azole-resistant isolates was 1.77% (two out of 113 isolates). The two azole-resistant strains had tandem repeats (TR) in the promoter region and mutations in the cyp51A gene (TR34/L98H and TR34/L98H/S297T/F495I). One strain showed intermediate susceptibility to voriconazole, and its Cyp51A protein had five amino acid substitutions (F46Y/M172V/N248T/D255E/E427K). TR34/L98H and TR34/L98H/S297T/F495I are the most prevalent cyp51A mutations in Taiwan, mediating azole resistance based on current publications and our results. YeastOneTM was validated as a rapid tool for the antifungal susceptibility test; however, further confirmation by CLSI should be considered when MIC values of voriconazole, posaconazole, and amphotericin B are close to the clinical breakpoints or ecological cutoff values. Full article
(This article belongs to the Special Issue Azole Resistance in Aspergillus spp.)
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8 pages, 279 KiB  
Case Report
First Report of Azole-Resistant Aspergillus fumigatus with TR46/Y121F/T289A Mutations in Kuwait and an Update on Their Occurrence in the Middle East
by Mohammad Asadzadeh, Khaled Alobaid, Suhail Ahmad and Sara Mazloum
J. Fungi 2023, 9(8), 784; https://doi.org/10.3390/jof9080784 - 25 Jul 2023
Viewed by 1301
Abstract
Pulmonary aspergillosis is a common fungal infection with several clinical manifestations including invasive, allergic and chronic chest diseases. Invasive pulmonary aspergillosis (IPA) is a leading cause of death in immunocompromised patients, particularly those receiving chemotherapy and among bone marrow transplant recipients. Aspergillus fumigatus [...] Read more.
Pulmonary aspergillosis is a common fungal infection with several clinical manifestations including invasive, allergic and chronic chest diseases. Invasive pulmonary aspergillosis (IPA) is a leading cause of death in immunocompromised patients, particularly those receiving chemotherapy and among bone marrow transplant recipients. Aspergillus fumigatus is the most prevalent causative agent and voriconazole is the first-line therapy for IPA. In this study, we report the first isolation of voriconazole-resistant A. fumigatus carrying TR46/Y121F/T289A mutations from an immunocompromised pregnant lady in Kuwait. The patient was successfully treated for a probable respiratory infection with caspofungin and voriconazole. The literature review from PubMed has identified itraconazole-resistant clinical and environmental A. fumigatus isolates with TR34/L98H mutations in the cyp51A from several Middle Eastern countries including Kuwait. However, clinical A. fumigatus isolates with cyp51A TR46/Y121F/T289A mutations have not been reported previously from any country in the region while environmental isolates have been reported only from Iran. The source of voriconazole-resistant A. fumigatus CYP51A TR46/Y121F/T289A mutant in our patient remained unknown. Surveillance for azole resistance among clinical and environmental isolates of A. fumigatus is warranted in Kuwait. Full article
(This article belongs to the Special Issue Azole Resistance in Aspergillus spp.)
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