In Vivo Selection of a Unique Tandem Repeat Mediated Azole Resistance Mechanism (TR<sub>120</sub>) in<i>Aspergillus fumigatus cyp51A</i>, Denmark

Hare, Rasmus Krøger; Gertsen, Jan Berg; Astvad, Karen Marie Thyssen; Degn, Kristine B.; Løkke, Anders; Stegger, Marc; Andersen, Paal Skytt; Kristensen, Lise; Arendrup, Maiken Cavling

doi:10.3201/eid2503.180297

Cited by 49 publications

(48 citation statements)

References 15 publications

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“…Furthermore, the TR 34 /L98H strain was discovered in a sample mixed with the TR 34 3 /L98H strain and had a white and slow-growing phenotype, which could help explain why it could potentially have been overlooked in earlier samples. Indeed, the in vivo acquisition of a tandem repeat in the promotor region has been reported from our group, where a 120-basepair tandem repeat evolved in a patient during azole therapy, supported by whole-genome sequencing (WGS) (Hare et al, 2019). It has also been suggested that the TR 34 helps compensate for loss of fitness associated with the L98H change (Verweij et al, 2016) and thus the additional TR 34 could potentially further improve fitness and outgrow the TR 34 /L98H, which in this patient appeared with a weaker phenotype (Verweij et al, 2016).…”

Section: Discussionmentioning

confidence: 95%

Azole-Resistant Aspergillus fumigatus Among Danish Cystic Fibrosis Patients: Increasing Prevalence and Dominance of TR34/L98H

et al. 2020

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Azole-resistant (azole-R) Aspergillus is an increasing challenge worldwide. Patients with cystic fibrosis (CF) are at risk of Aspergillus colonization and disease due to a favorable lung environment for microorganisms. We performed a nationwide study in 2018 of azole-non-susceptible Aspergillus in CF patients and compared with data from two prior studies. All airway samples with mold isolates from patients monitored at the two CF centers in Denmark (RH, Jan-Sept and AUH, Jan-Jun) were included. Classical species identification (morphology and thermo-tolerance) was performed and MALDI-TOF/β-tubulin sequencing was performed if needed. Susceptibility was determined using EUCAST E.Def 10.1, and E.Def 9.3.2. cyp51A sequencing and STRAf genotyping were performed for azole-non-susceptible isolates and relevant sequential isolates. In total, 340 mold isolates from 159 CF patients were obtained. The most frequent species were Aspergillus fumigatus (266/340, 78.2%) and Aspergillus terreus (26/340, 7.6%). Azole-R A. fumigatus was cultured from 7.3% (10/137) of patients, including 9.5% (9/95) of patients at RH and 2.4% at AUH (1/42), respectively. In a 10-year perspective, azole-non-susceptibility increased numerically among patients at RH (10.5% in 2018 vs 4.5% in 2007-2009). Cyp51A resistance mechanisms were found in nine azole-R A. fumigatus from eight CF patients. Five were of environmental origin (TR 34 /L98H), three were human medicine-driven (two M220K and one M220R), and one was novel (TR 34 3 /L98H) and found in a patient who also harbored a TR 34 /L98H isolate. STRAf genotyping identified 27 unique genotypes among 45 isolates and ≥2 genotypes in 8 of 12 patients. This included one patient carrying two unique TR 34 /L98H isolates, a rare phenomenon. Genotyping of sequential TR 34 3 /L98H and TR 34 /L98H isolates from the same patient showed only minor differences in 1/9 markers. Finally, azole-R A. terreus

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Section: Discussionmentioning

confidence: 95%

Azole-Resistant Aspergillus fumigatus Among Danish Cystic Fibrosis Patients: Increasing Prevalence and Dominance of TR34/L98H

et al. 2020

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“…Since environmental isolates harboring TR resistance mechanisms are identified in azole-naïve patients on five continents, and the same resistance mechanism was identified in environmental isolates treated with MDIs that share a higher genetic similarity with wild-type isolates, this strongly suggests that clinically acquired azole-resistant isolates are primarily acquired from the environment [4]. A recent study, however, through the use of whole-genome sequencing identified that azole-resistant A. fumigatus isolates harboring TR can also develop during the course of antifungal treatment, which shows the same genotype as the initial azole-susceptible A. fumigatus isolates [240]. It seems that the emergence of azole-resistant fungus in the clinic with the environmental source is not exclusive to molds.…”

Section: Role Of Agriculture In the Development Of Resistancementioning

confidence: 99%

The Quiet and Underappreciated Rise of Drug-Resistant Invasive Fungal Pathogens

Arastehfar

Lass‐Flörl

Garcia-Rubio

et al. 2020

JoF

104

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Human fungal pathogens are attributable to a significant economic burden and mortality worldwide. Antifungal treatments, although limited in number, play a pivotal role in decreasing mortality and morbidities posed by invasive fungal infections (IFIs). However, the recent emergence of multidrug-resistant Candida auris and Candida glabrata and acquiring invasive infections due to azole-resistant C. parapsilosis, C. tropicalis, and Aspergillus spp. in azole-naïve patients pose a serious health threat considering the limited number of systemic antifungals available to treat IFIs. Although advancing for major fungal pathogens, the understanding of fungal attributes contributing to antifungal resistance is just emerging for several clinically important MDR fungal pathogens. Further complicating the matter are the distinct differences in antifungal resistance mechanisms among various fungal species in which one or more mechanisms may contribute to the resistance phenotype. In this review, we attempt to summarize the burden of antifungal resistance for selected non-albicansCandida and clinically important Aspergillus species together with their phylogenetic placement on the tree of life. Moreover, we highlight the different molecular mechanisms between antifungal tolerance and resistance, and comprehensively discuss the molecular mechanisms of antifungal resistance in a species level.

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“…Exceptions to the categorization in resistance development routes were recently described as isolates with cyp51A point mutations that have been recovered from the environment and azole-naive patients [17]. In addition, an isolate harboring a tandem repeat in the promotor region (TR120) was shown to have developed in-host through azole therapy [17,18].…”

Section: Aspergillus Resistancementioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Posaconazole

Chen

Krekels

Verweij

et al. 2020

Drugs

109

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Posaconazole is typically used for preventing invasive yeast and mold infections such as invasive aspergillosis in high-risk immunocompromised patients. The oral suspension was the first released formulation and many pharmacokinetic and pharmacodynamic studies of this formulation have been published. Erratic absorption profiles associated with this formulation were widely reported. Posaconazole exposure was found to be significantly influenced by food and many gastrointestinal conditions, including pH and motility. As a result, low posaconazole plasma concentrations were obtained in large groups of patients. These issues of erratic absorption urged the development of the subsequently marketed delayed-release tablet, which proved to be associated with higher and more stable exposure profiles. Shortly thereafter, an intravenous formulation was released for patients who are not able to take oral formulations. Both new formulations require a loading dose on day 1 to achieve high posaconazole concentrations more quickly, which was not possible with the oral suspension. So far, there appears to be no evidence of increased toxicity correlated to the higher posaconazole exposure achieved with the regimen for these formulations. The higher systemic availability of posaconazole for the delayed-release tablet and intravenous formulation have resulted in these two formulations being preferable for both prophylaxis and treatment of invasive fungal disease. This review aimed to integrate the current knowledge on posaconazole pharmacokinetics, pharmacodynamics, major toxicity, existing resistance, clinical experience in special populations, and new therapeutic strategies in order to get a clear understanding of the clinical use of this drug.

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In Vivo Selection of a Unique Tandem Repeat Mediated Azole Resistance Mechanism (TR₁₂₀) inAspergillus fumigatus cyp51A, Denmark

Cited by 49 publications

References 15 publications

Azole-Resistant Aspergillus fumigatus Among Danish Cystic Fibrosis Patients: Increasing Prevalence and Dominance of TR34/L98H

Azole-Resistant Aspergillus fumigatus Among Danish Cystic Fibrosis Patients: Increasing Prevalence and Dominance of TR34/L98H

The Quiet and Underappreciated Rise of Drug-Resistant Invasive Fungal Pathogens

Pharmacokinetics and Pharmacodynamics of Posaconazole

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In Vivo Selection of a Unique Tandem Repeat Mediated Azole Resistance Mechanism (TR120) inAspergillus fumigatus cyp51A, Denmark

Cited by 49 publications

References 15 publications

Azole-Resistant Aspergillus fumigatus Among Danish Cystic Fibrosis Patients: Increasing Prevalence and Dominance of TR34/L98H

Azole-Resistant Aspergillus fumigatus Among Danish Cystic Fibrosis Patients: Increasing Prevalence and Dominance of TR34/L98H

The Quiet and Underappreciated Rise of Drug-Resistant Invasive Fungal Pathogens

Pharmacokinetics and Pharmacodynamics of Posaconazole

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Product

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In Vivo Selection of a Unique Tandem Repeat Mediated Azole Resistance Mechanism (TR₁₂₀) inAspergillus fumigatus cyp51A, Denmark