Azole-Resistant Aspergillus fumigatus Isolate with the TR34/L98H Mutation in Both a Fungicide-Sprayed Field and the Lung of a Hematopoietic Stem Cell Transplant Recipient with Invasive Aspergillosis

Rocchi, Steffi; Daguindau, Étienne; Grenouillet, Frédéric; Deconinck, Eric; Bellanger, Anne‐Pauline; García-Hermoso, Dea; Bretagne, Stéphane; Reboux, Gabriel; Millon, Laurence

doi:10.1128/jcm.03182-13

Cited by 35 publications

(30 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As the two patients with TR 34 /L98H isolates in their homes were not colonized by A. fumigatus, the acquisition of ARAF isolates via domestic environmental exposure could not be confirmed in our study. However, our data confirm that, although most IA with TR 34 /L98H isolates were reported in hematology, transplant, or patients with cancer, patients with COPD are also exposed and at risk to be colonized by azole‐resistant isolates and to further develop IA.…”

Section: Discussionsupporting

confidence: 77%

“…As most patients acquire A. fumigatus from the environment, the emergence and spread of azole‐resistant strains in the environment will put more humans at risk. However, only a few studies have combined environmental assessment and clinical data, two of them reporting ARAF isolates (TR 34 /L98H or TR 46 /Y121F/T289A) in the soil around the home of hematology patients with IA due to isolates carrying the same mutation . Interestingly, in one of these two studies, ARAF isolates were further found in the patient's home .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Emergence ofAspergillus fumigatusazole resistance in azole-naïve patients with chronic obstructive pulmonary disease and their homes

et al. 2017

View full text Add to dashboard Cite

Azole-resistant Aspergillus fumigatus (ARAF) has been reported in patients with chronic obstructive pulmonary disease (COPD) but has not been specifically assessed so far. Here, we evaluated ARAF prevalence in azole-naïve COPD patients and their homes, and assessed whether CYP51A mutations were similar in clinical and environmental reservoirs. Sixty respiratory samples from 41 COPD patients with acute exacerbation and environmental samples from 36 of these patient's homes were prospectively collected. A. fumigatus was detected in respiratory samples from 11 of 41 patients (27%) and in 15 of 36 domiciles (42%). Cyp51A sequencing and selection on itraconazole medium of clinical (n = 68) and environmental (n = 48) isolates yielded ARAF detection in 1 of 11 A. fumigatus colonized patients with COPD (9%) and 2 of 15 A. fumigatus-positive patient's homes (13%). The clinical isolate had no CYP51A mutation. Two environmental isolates from two patients harbored TR /L98H mutation, and one had an H285Y mutation. Coexistence of different cyp51A genotypes and/or azole resistance profiles was detected in 3 of 8 respiratory and 2 of 10 environmental samples with more than one isolate, confirming the need for a systematic screening of all clinically relevant isolates. The high prevalence of ARAF in patients with COPD and their homes supports the need for further studies to assess the prevalence of azole resistance in patients with Aspergillus diseases in Northern France.

show abstract

Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Emergence ofAspergillus fumigatusazole resistance in azole-naïve patients with chronic obstructive pulmonary disease and their homes

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Furthermore, in a strain of A. fumigatus isolated in France (16) and displaying the environmentally acquired TR34/L98H mutation, PC945 was more active than voriconazole, although it did not achieve 90% inhibition of growth.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Antifungal Profile of a Novel and Long-Acting Inhaled Azole, PC945, on Aspergillus fumigatus Infection

Colley¹,

Alanio

Kelly

et al. 2017

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

The profile of PC945, a novel triazole antifungal designed for administration via inhalation, was assessed in a range of in vitro and in vivo studies. PC945 was characterized as a potent, tightly binding inhibitor of Aspergillus fumigatus sterol 14α-demethylase (CYP51A and CYP51B) activity (50% inhibitory concentrations [IC50s], 0.23 μM and 0.22 μM, respectively) with characteristic type II azole binding spectra. Against 96 clinically isolated A. fumigatus strains, the MIC values of PC945 ranged from 0.032 to >8 μg/ml, while those of voriconazole ranged from 0.064 to 4 μg/ml. Spectrophotometric analysis of the effects of PC945 against itraconazole-susceptible and -resistant A. fumigatus growth yielded IC50 (determined based on optical density [OD]) values of 0.0012 to 0.034 μg/ml, whereas voriconazole (0.019 to >1 μg/ml) was less effective than PC945. PC945 was effective against a broad spectrum of pathogenic fungi (with MICs ranging from 0.0078 to 2 μg/ml), including Aspergillus terreus, Trichophyton rubrum, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcus neoformans, and Rhizopus oryzae (1 or 2 isolates each). In addition, when A. fumigatus hyphae or human bronchial cells were treated with PC945 and then washed, PC945 was found to be absorbed quickly into both target and nontarget cells and to produce persistent antifungal effects. Among temporarily neutropenic immunocompromised mice infected with A. fumigatus intranasally, 50% of the animals survived until day 7 when treated intranasally with PC945 at 0.56 μg/mouse, while posaconazole showed similar effects (44%) at 14 μg/mouse. This profile affirms that topical treatment with PC945 should provide potent antifungal activity in the lung.

show abstract

“…In 2002, the landmark study by Herbrecht et al (4) showed that the treatment of IA with voriconazole resulted in improved survival. However, a series of recent publications described the appearance of azole resistance in A. fumigatus (5)(6)(7)(8)(9)(10). This resistance is caused by a mutation in the CYP51A gene of A. fumigatus at position 98 (L98H), together with a 34-bp tandem repeat (TR) in the promoter region (TR34).…”

mentioning

confidence: 99%

Validation of a New Aspergillus Real-Time PCR Assay for Direct Detection of Aspergillus and Azole Resistance of Aspergillus fumigatus on Bronchoalveolar Lavage Fluid

Chong

Sande

Dingemans³

et al. 2015

J Clin Microbiol

129

112

View full text Add to dashboard Cite

A spergillus fumigatus is the most frequent cause of invasive mold infections in immunocompromised patients. The mortality rate from these infections varies substantially and depends on patient characteristics and the extent of disease. Mortality in intensive care unit (ICU) patients with invasive aspergillosis (IA) can be as high as 90% (1). In hematology patients, a relatively low mortality is observed when the diagnosis is made early and treatment with voriconazole, the current standard of care (2), is initiated promptly (3). In 2002, the landmark study by Herbrecht et al. (4) showed that the treatment of IA with voriconazole resulted in improved survival. However, a series of recent publications described the appearance of azole resistance in A. fumigatus (5-10). This resistance is caused by a mutation in the CYP51A gene of A. fumigatus at position 98 (L98H), together with a 34-bp tandem repeat (TR) in the promoter region (TR34). CYP51A encodes cytochrome p450 sterol 14␣-demethylase, the target of azoles. The majority of these mutated strains were cultured from patients who were never exposed to azoles. It is assumed that resistance development is caused by environmental azole exposure (11). More recently, van der Linden et al. (12) described a second mutation, a 46-bp TR combined with the point mutations Y121F and T289A (12). In this study, 47 of 921 patients (5.1%) were diagnosed with TR34-L98H and 13 (1.4%) with the TR46-Y121F-T289A mutations. Other mutations have also been described (13-16). Infections with azole-resistant strains are associated with a very high mortality rate (17).Currently, the absence of a non-culture-based, fast, and readily available azole susceptibility testing method compromises the identification of azole resistance. This is a major limitation, as the mortality of IA increases substantially when the initiation of adequate therapy is delayed (18). Furthermore, most Aspergillus infections are diagnosed indirectly using galactomannan (or ␤-1,3-D-glucan) testing, because cultures remain negative in most patients. Therefore, even if culture-based azole resistance testing became broadly available, this would be helpful in only a subset of patients.This study describes the laboratory and first clinical validation of the AsperGenius, a new Aspergillus real-time PCR assay that detects Aspergillus species directly from bronchoalveolar lavage

show abstract

Azole-Resistant Aspergillus fumigatus Isolate with the TR34/L98H Mutation in Both a Fungicide-Sprayed Field and the Lung of a Hematopoietic Stem Cell Transplant Recipient with Invasive Aspergillosis

Cited by 35 publications

References 13 publications

Emergence ofAspergillus fumigatusazole resistance in azole-naïve patients with chronic obstructive pulmonary disease and their homes

Emergence ofAspergillus fumigatusazole resistance in azole-naïve patients with chronic obstructive pulmonary disease and their homes

In Vitro and In Vivo Antifungal Profile of a Novel and Long-Acting Inhaled Azole, PC945, on Aspergillus fumigatus Infection

Validation of a New Aspergillus Real-Time PCR Assay for Direct Detection of Aspergillus and Azole Resistance of Aspergillus fumigatus on Bronchoalveolar Lavage Fluid

Contact Info

Product

Resources

About