scholarly journals Characterization of Aspergillus fumigatus cross-resistance between clinical and DMI azole drugs

2020 ◽  
pp. AEM.02539-20 ◽  
Author(s):  
Rocio Garcia-Rubio ◽  
Irene Gonzalez-Jimenez ◽  
Jose Lucio ◽  
Emilia Mellado
Keyword(s):  
Aspergillus Fumigatus ◽  
Clinical Setting ◽  
Opportunistic Infections ◽  
Treatment Options ◽  
Critical Role ◽  
Crop Protection ◽  
Public Health Problem ◽  
Resistance Mechanisms ◽  
Cross Resistance ◽  
Azole Resistance

Drug resistance poses a serious threat to human health and agricultural production. Azole drugs are the largest group of 14-α sterol demethylation inhibitor fungicides that are used both in agriculture and in clinical practice. As plant pathogenic molds share their natural environment with fungi that cause opportunistic infections in humans, both are exposed to a strong and persistent pressure of demethylase inhibitor (DMI) fungicides, including imidazole and triazole drugs. As a result, a loss of efficacy has occurred for this drug class in several species. In the clinical setting, Aspergillus fumigatus azole resistance is a growing public health problem and finding the source of this resistance has gained much attention. It is urgent to determine if there is a direct link between the agricultural use of azole compounds and the different A. fumigatus resistance mechanisms described for clinical triazoles. In this work we have performed A. fumigatus susceptibility testing to clinical triazoles and crop protection DMIs using a collection of azole susceptible and resistant strains which harbor most of the described azole resistance mechanisms. Various DMI susceptibility profiles have been found in the different A. fumigatus populations groups based on their azole resistance mechanism and previous WGS analysis, which suggests that the different resistance mechanisms have different origins and are specifically associated to the local use of a particular DMI.Importance Due to the worldwide emergence of A. fumigatus azole resistance, this opportunistic pathogen poses a serious health threat and, therefore, it has been included in the Watch List of the CDC 2019 Antimicrobial Resistance Threats Report. Azoles play a critical role in the control and management of fungal diseases, not only in the clinical setting but also in agriculture. Thus, azole resistance leads to a limited therapeutic arsenal which reduces the treatment options for aspergillosis patients, increasing their mortality risk. Evidence is needed to understand whether A. fumigatus azole resistance is emerging from an agricultural source due to the extended use of demethylase inhibitors as fungicides, or whether it is coming from somewhere else such as the clinical setting. If the environmental route is demonstrated, the current use and management of azole antifungal compounds might be forced to change in the forthcoming years.

scholarly journals Clinical implications of globally emerging azole resistance in Aspergillus fumigatus

2016 ◽  
Vol 371 (1709) ◽  
pp. 20150460 ◽  
Author(s):  
Jacques F. Meis ◽  
Anuradha Chowdhary ◽  
Johanna L. Rhodes ◽  
Matthew C. Fisher ◽  
Paul E. Verweij
Keyword(s):  
De Novo ◽  
Animal Health ◽  
Treatment Options ◽  
Previous History ◽  
Resistance Mechanisms ◽  
Antifungal Drugs ◽  
Cross Resistance ◽  
Azole Resistance ◽  
Health Food ◽  
History Of

Aspergillus fungi are the cause of an array of diseases affecting humans, animals and plants. The triazole antifungal agents itraconazole, voriconazole, isavuconazole and posaconazole are treatment options against diseases caused by Aspergillus . However, resistance to azoles has recently emerged as a new therapeutic challenge in six continents. Although de novo azole resistance occurs occasionally in patients during azole therapy, the main burden is the aquisition of resistance through the environment. In this setting, the evolution of resistance is attributed to the widespread use of azole-based fungicides. Although ubiquitously distributed, A. fumigatus is not a phytopathogen. However, agricultural fungicides deployed against plant pathogenic moulds such as Fusarium , Mycospaerella and A. flavus also show activity against A. fumigatus in the environment and exposure of non-target fungi is inevitable. Further, similarity in molecule structure between azole fungicides and antifungal drugs results in cross-resistance of A. fumigatus to medical azoles. Clinical studies have shown that two-thirds of patients with azole-resistant infections had no previous history of azole therapy and high mortality rates between 50% and 100% are reported in azole-resistant invasive aspergillosis. The resistance phenotype is associated with key mutations in the cyp51A gene, including TR 34 /L98H, TR 53 and TR 46 /Y121F/T289A resistance mechanisms. Early detection of resistance is of paramount importance and if demonstrated, either with susceptibility testing or through molecular analysis, azole monotherapy should be avoided. Liposomal amphotericin B or a combination of voriconazole and an echinocandin are recomended for azole-resistant aspergillosis. This article is part of the themed issue ‘Tackling emerging fungal threats to animal health, food security and ecosystem resilience’.

scholarly journals Multi-resistance to non-azole fungicides in Aspergillus fumigatus TR 34 /L98H azole resistant isolates.

2021 ◽  
Author(s):  
I Gonzalez-Jimenez ◽  
R Garcia-Rubio ◽  
S Monzon ◽  
J Lucio ◽  
I Cuesta ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Plant Pathogens ◽  
Crop Protection ◽  
Resistance Mechanisms ◽  
Azole Resistance ◽  
Sequencing Analysis ◽  
Human Fungal Pathogen ◽  
Evolution Pattern ◽  
Environmental Setting ◽  
Resistant Strains

Drug resistance is a worldwide problem affecting all pathogens. The human fungal pathogen Aspergillus fumigatus coexists in the environment with other fungi targeted by crop protection compounds being unintentionally exposed to the selective pressure of multiple antifungal classes leading to the selection of resistant strains. A. fumigatus azole resistant isolates are emerging in both the clinical and environmental setting. Since their approval, azole drugs have dominated the clinical treatment for aspergillosis infections, and the agriculture fungicide market. However, other antifungal classes are used for crop protection including benzimidazoles (MBC), strobilurins (QoIs) and succinate dehydrogenase inhibitors (SDHIs). Mutations responsible for resistance to these fungicides have been widely researched in plant pathogens, but it has not been explored in A. fumigatus . In this work, the genetic basis underlying resistance to MBCs, QoIs and SDHIs were studied in azole susceptible and resistant A. fumigatus strains. E198A/Q and F200Y mutations in the β-tubulin conferred resistance to MBCs, G143A and F129L substitutions in the Cytochrome b to QoIs and H270R/Y mutations in SdhB to SDHIs. Characterization of the susceptibility to azoles showed a correlation between strains resistant to these fungicides and the ones with TR-based azole resistance mechanisms. Whole genome sequencing analysis showed a genetic relationship among fungicide multi resistant strains, which grouped together into subclusters that only included strains carrying the TR-based azole resistance mechanisms, indicating a common ancestor/evolution pattern and confirming the environmental origin of this type of azole resistant A. fumigatus .

scholarly journals Epidemiology and Molecular Characterizations of Azole Resistance in Clinical and Environmental Aspergillus fumigatus Isolates from China

2016 ◽  
Vol 60 (10) ◽  
pp. 5878-5884 ◽  
Author(s):  
Yong Chen ◽  
Zhongyi Lu ◽  
Jingjun Zhao ◽  
Ziying Zou ◽  
Yanwen Gong ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Antifungal Susceptibility ◽  
Public Health Problem ◽  
Wide Distribution ◽  
Resistance Mechanisms ◽  
Azole Resistance ◽  
Common Mutation ◽  
Content Type ◽  
Environmental Resistance ◽  
Resistant Strains

ABSTRACTAzole resistance inAspergillus fumigatushas emerged as a worldwide public health problem. We sought here to demonstrate the occurrence and characteristics of azole resistance inA. fumigatusfrom different parts of China. A total of 317 clinical and 144 environmentalA. fumigatusisolates from 12 provinces were collected and subjected to screening for azole resistance. Antifungal susceptibility,cyp51Agene sequencing, and genotyping were carried out for all suspected azole-resistant isolates and a subset of azole-susceptible isolates. As a result, 8 (2.5%) clinical and 2 (1.4%) environmentalA. fumigatusisolates were identified as azole resistant. Five azole-resistant strains exhibit the TR34/L98H mutation, whereas four carry the TR34/L98H/S297T/F495I mutation in thecyp51Agene. Genetic typing and phylogenetic analysis showed that there was a worldwide clonal expansion of the TR34/L98H isolates, while the TR34/L98H/S297T/F495I isolates from China harbored a distinct genetic background with resistant isolates from other countries. High polymorphisms existed in thecyp51Agene that produced amino acid changes among azole-susceptibleA. fumigatusisolates, with N248K being the most common mutation. These data suggest that the wide distribution of azole-resistantA. fumigatusmight be attributed to the environmental resistance mechanisms in China.

scholarly journals Nonrandom Distribution of Azole Resistance across the Global Population of Aspergillus fumigatus

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Thomas R. Sewell ◽  
Jianing Zhu ◽  
Johanna Rhodes ◽  
Ferry Hagen ◽  
Jacques F. Meis ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Drug Resistance ◽  
Aspergillus Fumigatus ◽  
Pathogenic Fungus ◽  
Crop Protection ◽  
Resistance Mechanisms ◽  
Health Concern ◽  
Azole Resistance ◽  
Content Type ◽  
Global Population

ABSTRACT The emergence of azole resistance in the pathogenic fungus Aspergillus fumigatus has continued to increase, with the dominant resistance mechanisms, consisting of a 34-nucleotide tandem repeat (TR34)/L98H and TR46/Y121F/T289A, now showing a structured global distribution. Using hierarchical clustering and multivariate analysis of 4,049 A. fumigatus isolates collected worldwide and genotyped at nine microsatellite loci using analysis of short tandem repeats of A. fumigatus (STRAf), we show that A. fumigatus can be subdivided into two broad clades and that cyp51A alleles TR34/L98H and TR46/Y121F/T289A are unevenly distributed across these two populations. Diversity indices show that azole-resistant isolates are genetically depauperate compared to their wild-type counterparts, compatible with selective sweeps accompanying the selection of beneficial mutations. Strikingly, we found that azole-resistant clones with identical microsatellite profiles were globally distributed and sourced from both clinical and environmental locations, confirming that azole resistance is an international public health concern. Our work provides a framework for the analysis of A. fumigatus isolates based on their microsatellite profile, which we have incorporated into a freely available, user-friendly R Shiny application (AfumID) that provides clinicians and researchers with a method for the fast, automated characterization of A. fumigatus genetic relatedness. Our study highlights the effect that azole drug resistance is having on the genetic diversity of A. fumigatus and emphasizes its global importance upon this medically important pathogenic fungus. IMPORTANCE Azole drug resistance in the human-pathogenic fungus Aspergillus fumigatus continues to emerge, potentially leading to untreatable aspergillosis in immunosuppressed hosts. Two dominant, environmentally associated resistance mechanisms, which are thought to have evolved through selection by the agricultural application of azole fungicides, are now distributed globally. Understanding the effect that azole resistance is having on the genetic diversity and global population of A. fumigatus will help mitigate drug-resistant aspergillosis and maintain the azole class of fungicides for future use in both medicine and crop protection.

scholarly journals Azole Resistance in Aspergillus fumigatus: A Five-Year Follow Up Experience in a Tertiary Hospital With a Special Focus on Cystic Fibrosis

2021 ◽  
Vol 10 ◽  
Author(s):  
Hélène Guegan ◽  
Emilie Prat ◽  
Florence Robert-Gangneux ◽  
Jean-Pierre Gangneux
Keyword(s):  
Cystic Fibrosis ◽  
Aspergillus Fumigatus ◽  
Clinical Setting ◽  
Tertiary Hospital ◽  
Cross Resistance ◽  
Azole Resistance ◽  
Special Focus ◽  
Drug Pressure ◽  
Resistance Level ◽  
Multiple Strains

Azole-resistant Aspergillus fumigatus (ARAf) has emerged worldwide during the last decades. Drug pressure after long term treatments of chronically infected patients and the propagation of environmental clones selected under the pressure of imidazoles fungicides used in agriculture and farming both account for this emergence. The objectives of this study were to determine the rate of azole resistance in Aspergillus fumigatus during a 5-year period, taking into account (i) differences between underlying diseases of the patients treated, (ii) cross-resistance between azoles, and (iii) focusing on the 5-year evolution of our center’s cystic fibrosis cohort. Overall, the rates of voriconazole (VRC)-resistant and itraconazole (ITC)-resistant A. fumigatus isolates were 4.1% (38/927) and 14.5% (95/656), respectively, corresponding to 21/426 (4.9%) and 44/308 (14.3%) patients, respectively. Regarding cross-resistance, among VRC-R isolates tested for ITC, nearly all were R (20/21;95%), compared to only 27% (20/74) of VRC-R among ITC-R isolates. The level of azole resistance remained somewhat stable over years but greatly varied according to the azole drug, patient origin, and clinical setting. Whereas azole resistance during invasive aspergillosis was very scarce, patients with cystic fibrosis were infected with multiple strains and presented the highest rate of resistance: 5% (27/539) isolates were VRC-R and 17.9% (78/436) were ITC-R. These results underline that the interpretation of the azole resistance level in Aspergilllus fumigatus in a routine setting may consider the huge variability depending on the azole drug, the clinical setting, the patient background and the type of infection.

scholarly journals Citizen-science surveillance of triazole-resistant Aspergillus fumigatus in UK residential garden soils

2022 ◽  
Author(s):  
Jennifer M. G. Shelton ◽  
Roseanna Collins ◽  
Christopher B. Uzzell ◽  
Asmaa Alghamdi ◽  
Paul S. Dyer ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Public Awareness ◽  
Health Hazard ◽  
Resistance Mechanisms ◽  
Soil Samples ◽  
Cross Resistance ◽  
Potential Health ◽  
Potential Health Hazard ◽  
Lung Infections ◽  
The Uk

Compost is an ecological niche for Aspergillus fumigatus due to its role as a decomposer of organic matter and its ability to survive the high temperatures associated with the composting process. Subsequently, composting facilities are associated with high levels of A. fumigatus spores that are aerosolised from compost and cause respiratory illness in workers. In the UK, gardening is an activity enjoyed by individuals of all ages and it is likely that they are being exposed to A. fumigatus spores when handling commercial compost or compost they have produced themselves. In this study, 246 citizen scientists collected 509 soil samples from locations in their garden in the UK, from which were cultured 5,174 A. fumigatus isolates. Of these isolates, 736 (14%) were resistant to tebuconazole: the third most-sprayed triazole fungicide in the UK, which confers cross-resistance to the medical triazoles used to treat A. fumigatus lung infections in humans. These isolates were found to contain the common resistance mechanisms in the A. fumigatus cyp51A gene TR 34 /L98H or TR 46 /Y121F/T289A, and less common resistance mechanisms TR 34 , TR 53 , TR 46 /Y121F/T289A/S363P/I364V/G448S and (TR 46 ) 2 /Y121F/M172I/T289A/G448S. Regression analyses found that soil samples containing compost were significantly more likely to grow susceptible and tebuconazole-resistant A. fumigatus than those that did not, and that compost samples grew significantly higher numbers of A. fumigatus than other samples. Importance These findings highlight compost as a potential health hazard to individuals with pre-disposing factors to A. fumigatus lung infections, and a potential health hazard to immunocompetent individuals who could be exposed to sufficiently high numbers of spores to develop infection. Furthermore, this study found that 14% of A. fumigatus isolates in garden soils were resistant to an agricultural triazole, which confers cross-resistance to medical triazoles used to treat A. fumigatus lung infections. This raises the question of whether compost bags should carry additional health warnings regarding inhalation of A. fumigatus spores, whether individuals should be advised to wear facemasks whilst handling compost or whether commercial producers should be responsible for sterilising compost before shipping. The findings support increasing public awareness of the hazard posed by compost and investigating measures that can be taken to reduce the exposure risk.

scholarly journals Azole-resistant Aspergillus fumigatus in the environment: Identifying key reservoirs and hotspots of antifungal resistance

2021 ◽  
Vol 17 (7) ◽  
pp. e1009711
Author(s):  
Caroline Burks ◽  
Alexandria Darby ◽  
Luisa Gómez Londoño ◽  
Michelle Momany ◽  
Marin T. Brewer
Keyword(s):  
Aspergillus Fumigatus ◽  
Crop Protection ◽  
Pathogenic Fungi ◽  
Sampling Bias ◽  
Azole Resistance ◽  
Antifungal Stewardship ◽  
Respiratory Illnesses ◽  
Plant Matter ◽  
Ergosterol Synthesis ◽  
Opportunistic Human Pathogen

Aspergillus fumigatus is an opportunistic human pathogen that causes aspergillosis, a spectrum of environmentally acquired respiratory illnesses. It has a cosmopolitan distribution and exists in the environment as a saprotroph on decaying plant matter. Azoles, which target Cyp51A in the ergosterol synthesis pathway, are the primary class of drugs used to treat aspergillosis. Azoles are also used to combat plant pathogenic fungi. Recently, an increasing number of azole-naive patients have presented with pan-azole–resistant strains of A. fumigatus. The TR34/L98H and TR46/Y121F/T289A alleles in the cyp51A gene are the most common ones conferring pan-azole resistance. There is evidence that these mutations arose in agricultural settings; therefore, numerous studies have been conducted to identify azole resistance in environmental A. fumigatus and to determine where resistance is developing in the environment. Here, we summarize the global occurrence of azole-resistant A. fumigatus in the environment based on available literature. Additionally, we have created an interactive world map showing where resistant isolates have been detected and include information on the specific alleles identified, environmental settings, and azole fungicide use. Azole-resistant A. fumigatus has been found on every continent, except for Antarctica, with the highest number of reports from Europe. Developed environments, specifically hospitals and gardens, were the most common settings where azole-resistant A. fumigatus was detected, followed by soils sampled from agricultural settings. The TR34/L98H resistance allele was the most common in all regions except South America where the TR46/Y121F/T289A allele was the most common. A major consideration in interpreting this survey of the literature is sampling bias; regions and environments that have been extensively sampled are more likely to show greater azole resistance even though resistance could be more prevalent in areas that are under-sampled or not sampled at all. Increased surveillance to pinpoint reservoirs, as well as antifungal stewardship, is needed to preserve this class of antifungals for crop protection and human health.

scholarly journals Progressive Dispersion of Azole Resistance in Aspergillus fumigatus: Fatal Invasive Aspergillosis in a Patient with Acute Myeloid Leukemia Infected with an A. fumigatus Strain with a cyp51A TR46 Y121F M172I T289A Allele

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Susann Rößler ◽  
Oliver Bader ◽  
Friedrich Stölzel ◽  
Ulrich Sommer ◽  
Birgit Spiess ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Invasive Aspergillosis ◽  
Aspergillus Fumigatus ◽  
Myeloid Leukemia ◽  
Treatment Options ◽  
Hematologic Malignancies ◽  
Azole Resistance ◽  
Hematopoietic Stem ◽  
Content Type ◽  
Acute Myeloid

ABSTRACT Patients with hematologic malignancies as well as allogeneic hematopoietic stem cell transplantation (HSCT) patients are at high risk for invasive aspergillosis. Here, we report a culture- and autopsy-proven fatal invasive aspergillosis in an allogeneic HSTC patient which he developed despite posaconazole prophylaxis. The agent was determined to be an azole-resistant Aspergillus fumigatus strain bearing the cyp51A mutation combination TR46 Y121F M172I T289A. At increasing frequency, the azole resistance of A. fumigatus is being reported globally, limiting treatment options and complicating regimens.

scholarly journals First Clinical Isolation of an Azole-Resistant Aspergillus fumigatus Isolate Harboring a TR46 Y121F T289A Mutation in South America

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Guillermina Isla ◽  
Florencia Leonardelli ◽  
Iris N. Tiraboschi ◽  
Nicolás Refojo ◽  
Alejandra Hevia ◽  
...  
Keyword(s):  
United States ◽  
South America ◽  
Aspergillus Fumigatus ◽  
Resistance Mechanism ◽  
Resistance Mechanisms ◽  
Azole Resistance ◽  
Content Type

ABSTRACT One of the most recently described Aspergillus fumigatus CYP51A-mediated azole resistance mechanisms is TR46 Y121F T289A. Clinical A. fumigatus strains harboring these substitutions have been reported worldwide, with the exception of South America. We describe the first clinical A. fumigatus strain with this resistance mechanism isolated from an Argentinian patient. The strain was isolated in 2009 (1 year after the first-described mutant in United States), demonstrating that these alleles were scattered worldwide earlier than previously thought.

scholarly journals Emerging aspergillosis by azole-resistant Aspergillus fumigatus at an intensive care unit in the Netherlands, 2010 to 2013

2016 ◽  
Vol 21 (30) ◽  
Author(s):  
Judith van Paassen ◽  
Anne Russcher ◽  
Astrid WM in 't Veld - van Wingerden ◽  
Paul E Verweij ◽  
Eduard J Kuijper
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
The Netherlands ◽  
Aspergillus Fumigatus ◽  
Resistance Mechanisms ◽  
Antifungal Treatment ◽  
University Hospital ◽  
Resistant Isolate ◽  
Azole Resistance ◽  
Icu Patients

The prevalence of invasive aspergillosis (IA) at the intensive care unit (ICU) is unknown and difficult to assess since IA also develops in patients lacking specific host factors. In the Netherlands, increasing azole-resistance in Aspergillus fumigatus complicates treatment of patients with IA. The aim of this study was to determine the prevalence of IA by azole-resistant A. fumigatus at the ICU among patients receiving antifungal treatment and to follow their clinical outcome and prognosis. A retrospective cohort study was conducted in a university hospital ICU from January 2010 to December 2013. From all patients who received antifungal treatment for suspected IA, relevant clinical and microbiological data were collected using a standardised questionnaire. Of 9,121 admitted ICU-patients, 136 had received antifungal treatment for suspected IA, of which 38 had a positive A. fumigatus culture. Ten of the 38 patients harboured at least one azole-resistant isolate. Resistance mechanisms consisted of alterations in the cyp51A gene, more specific TR34/L98H and TR46/T289A/Y121F. Microsatellite typing did not show clonal relatedness, though isolates from two patients were genetically related. The overall 90-day mortality of patients with IA by azole-resistant A. fumigatus and patients with suspicion of IA by azole-susceptible isolates in the ICU was 100% (10/10) vs 82% (23/28) respectively. We conclude that the changing pattern of IA in ICU patients requires appropriate criteria for recognition, diagnosis and rapid resistance tests. The increase in azole resistance rates also challenges a reconsideration of empirical antifungal therapy.

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