scholarly journals In VitroSusceptibility of Aspergillus fumigatus to Isavuconazole: Correlation with Itraconazole, Voriconazole, and Posaconazole

2013 ◽  
Vol 57 (11) ◽  
pp. 5778-5780 ◽  
Author(s):  
Lea Gregson ◽  
Joanne Goodwin ◽  
Adam Johnson ◽  
Laura McEntee ◽  
Caroline B. Moore ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Clinical Isolates ◽  
Cross Resistance ◽  
Azole Resistance ◽  
First Line ◽  
Content Type

ABSTRACTTriazoles are first-line agents for treating aspergillosis. The prevalence of azole resistance inAspergillus fumigatusis increasing, and cross-resistance is a growing concern. In this study, the susceptibilities of 40A. fumigatusclinical isolates were tested by using the CLSI method with amphotericin B, itraconazole, voriconazole, posaconazole, and the new triazole isavuconazole. Isavuconazole MICs were higher in strains with reduced susceptibilities to other triazoles, mirroring changes in voriconazole susceptibility. Isavuconazole MICs differed depending on the Cyp51A substitution.

scholarly journals Multiplecyp51A-Based Mechanisms Identified in Azole-Resistant Isolates of Aspergillus fumigatus from China

2015 ◽  
Vol 59 (7) ◽  
pp. 4321-4325 ◽  
Author(s):  
Musang Liu ◽  
Rong Zeng ◽  
Lili Zhang ◽  
Dongmei Li ◽  
Guixia Lv ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Clinical Isolates ◽  
Resistant Isolate ◽  
Azole Resistance ◽  
Content Type ◽  
Resistant Strains

ABSTRACTSeventy-twoA. fumigatusclinical isolates from China were investigated for azole resistance based on mutations ofcyp51A. We identified four azole-resistant strains, among which we found three strains highly resistant to itraconazole, two of which exhibit the TR34/L98H/S297T/F495I mutation, while one carries only the TR34/L98H mutation. To our knowledge, the latter has not been found previously in China. The fourth multiazole-resistant isolate (with only moderate itraconazole resistance) carries a new G432A mutation.

scholarly journals Azole Resistance in Aspergillus fumigatus Clinical Isolates from an Italian Culture Collection

2015 ◽  
Vol 60 (1) ◽  
pp. 682-685 ◽  
Author(s):  
Cristina Lazzarini ◽  
Maria Carmela Esposto ◽  
Anna Prigitano ◽  
Massimo Cogliati ◽  
Gabriella De Lorenzis ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Culture Collection ◽  
Resistance Rate ◽  
Clinical Isolates ◽  
Resistant Isolate ◽  
Azole Resistance ◽  
Content Type ◽  
Italian Culture

ABSTRACTThe aims of the study were to investigate the prevalence of azole resistance amongAspergillus fumigatusclinical isolates. A total of 533 clinical isolates that had been collected between 1995 and 2006, from 441 patients, were screened. No resistance was detected in isolates collected between 1995 and 1997. Starting in 1998, the resistance rate was 6.9%; a total of 24 patients (6.25%) harbored a resistant isolate. The TR34/L98H substitution was found in 21 of 30 tested isolates.

scholarly journals Azole Resistance of Environmental and Clinical Aspergillus fumigatus Isolates from Switzerland

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Arnaud Riat ◽  
Jérôme Plojoux ◽  
Katia Gindro ◽  
Jacques Schrenzel ◽  
Dominique Sanglard
Keyword(s):  
Aspergillus Fumigatus ◽  
Opportunistic Pathogen ◽  
Clinical Isolates ◽  
Resistant Isolate ◽  
Azole Resistance ◽  
Clinical Settings ◽  
Content Type ◽  
Azole Antifungals ◽  
First Time

ABSTRACT Aspergillus fumigatus is a ubiquitous opportunistic pathogen. This fungus can acquire resistance to azole antifungals due to mutations in the azole target ( cyp51A ). Recently, cyp51A mutations typical for environmental azole resistance acquisition (for example, TR 34 /L98H) have been reported. These mutations can also be found in isolates recovered from patients. Environmental azole resistance acquisition has been reported on several continents. Here we describe, for the first time, the occurrence of azole-resistant A. fumigatus isolates of environmental origin in Switzerland with cyp51A mutations, and we show that these isolates can also be recovered from a few patients. While the TR 34 /L98H mutation was dominant, a single azole-resistant isolate exhibited a cyp51A mutation (G54R) that was reported only for clinical isolates. In conclusion, our study demonstrates that azole resistance with an environmental signature is present in environments and patients of Swiss origin and that mutations believed to be unique to clinical settings are now also observed in the environment.

scholarly journals Cryptic Species and Azole Resistance in the Aspergillus niger Complex

2011 ◽  
Vol 55 (10) ◽  
pp. 4802-4809 ◽  
Author(s):  
Susan J. Howard ◽  
Elizabeth Harrison ◽  
Paul Bowyer ◽  
Janos Varga ◽  
David W. Denning
Keyword(s):  
Aspergillus Niger ◽  
Cryptic Species ◽  
Phylogenetic Trees ◽  
Antifungal Susceptibility ◽  
Clinical Isolates ◽  
Cross Resistance ◽  
Azole Resistance ◽  
Beta Tubulin ◽  
Data Set ◽  
Content Type

ABSTRACTAspergillus nigeris a common clinical isolate. Multiple species comprise theAspergillussectionNigriand are separable using sequence data. The antifungal susceptibility of these cryptic species is not known. We determined the azole MICs of 50 black aspergilli, 45 from clinical specimens, using modified EUCAST (mEUCAST) and Etest methods. Phylogenetic trees were prepared using the internal transcribed spacer, beta-tubulin, and calmodulin sequences to identify strains to species level and the results were compared with those obtained withcyp51Asequences. We attempted to correlatecyp51Amutations with azole resistance. Etest MICs were significantly different from mEUCAST MICs (P< 0.001), with geometric means of 0.77 and 2.79 mg/liter, respectively. Twenty-six of 50 (52%) isolates were itraconazole resistant by mEUCAST (MICs > 8 mg/liter), with limited cross-resistance to other azoles. Using combined beta-tubulin/calmodulin sequences, the 45 clinical isolates grouped into 5 clades,A. awamori(55.6%),A. tubingensis(17.8%),A. niger(13.3%),A. acidus(6.7%), and an unknown group (6.7%), none of which were morphologically distinguishable. Itraconazole resistance was found in 36% of the isolates in theA. awamorigroup, 90% of theA. tubingensisgroup, 33% of theA. nigergroup, 100% of theA. acidusgroup, and 67% of the unknown group. These data suggest thatcyp51Amutations in sectionNigrimay not play as important a role in azole resistance as inA. fumigatus, although some mutations (G427S, K97T) warrant further study. Numerous cryptic species are found in clinical isolates of theAspergillussectionNigriand are best reported as “A. nigercomplex” by clinical laboratories. Itraconazole resistance was common in this data set, but azole cross-resistance was unusual. The mechanism of resistance remains obscure.

scholarly journals Species Identification andIn VitroAntifungal Susceptibility ofAspergillus terreusSpecies Complex Clinical Isolates from a French Multicenter Study

2018 ◽  
Vol 62 (5) ◽  
pp. e02315-17 ◽  
Author(s):  
S. Imbert ◽  
A. C. Normand ◽  
S. Ranque ◽  
J. M. Costa ◽  
J. Guitard ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Antifungal Susceptibility ◽  
Sensu Stricto ◽  
Antifungal Drugs ◽  
Clinical Isolates ◽  
Clinical Samples ◽  
Azole Resistance ◽  
University Hospitals ◽  
Content Type ◽  
Interesting Alternative

ABSTRACTAspergillussectionTerreiis a species complex currently comprised of 14 cryptic species whose prevalence in clinical samples as well as antifungal susceptibility are poorly known. The aims of this study were to investigateA. Terreiclinical isolates at the species level and to perform antifungal susceptibility analyses by reference and commercial methods. Eighty-two clinicalA. Terreiisolates were collected from 8 French university hospitals. Molecular identification was performed by sequencing parts of beta-tubulin and calmodulin genes. MICs or minimum effective concentrations (MECs) were determined for 8 antifungal drugs using both EUCAST broth microdilution (BMD) methods and concentration gradient strips (CGS). Among the 79A. Terreiisolates,A. terreus stricto sensu(n= 61),A. citrinoterreus(n= 13),A. hortai(n= 3), andA. alabamensis(n= 2) were identified. All strains had MICs of ≥1 mg/liter for amphotericin B, except for two isolates (bothA. hortai) that had MICs of 0.25 mg/liter. FourA. terreusisolates were resistant to at least one azole drug, including one with pan-azole resistance, yet no mutation in theCYP51Agene was found. All strains had low MECs for the three echinocandins. The essential agreements (EAs) between BMD and CGS were >90%, except for those of amphotericin B (79.7%) and itraconazole (73.4%). Isolates belonging to theA. sectionTerreiidentified in clinical samples show wider species diversity beyond the knownA. terreus sensu stricto. Azole resistance inside the sectionTerreiis uncommon and is not related to CYP51A mutations here. Finally, CGS is an interesting alternative for routine antifungal susceptibility testing.

scholarly journals Antifungal Susceptibilities of Aspergillus fumigatus Clinical Isolates Obtained in Nagasaki, Japan

2011 ◽  
Vol 56 (1) ◽  
pp. 584-587 ◽  
Author(s):  
Masato Tashiro ◽  
Koichi Izumikawa ◽  
Asuka Minematsu ◽  
Katsuji Hirano ◽  
Naoki Iwanaga ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Clinical Isolates ◽  
Wild Type ◽  
Content Type

ABSTRACTWe investigated the triazole, amphotericin B, and micafungin susceptibilities of 196A. fumigatusclinical isolates in Nagasaki, Japan. The percentages of non-wild-type (non-WT) isolates for which MICs of itraconazole, posaconazole, and voriconazole were above the ECV were 7.1%, 2.6%, and 4.1%, respectively. A G54 mutation incyp51Awas detected in 64.2% (9/14 isolates) and 100% (5/5 isolates) of non-WT isolates for itraconazole and posaconazole, respectively. Amphotericin B MICs of ≥2 μg/ml and micafungin minimum effective concentrations (MECs) of ≥16 μg/ml were recorded for two and one isolates, respectively.

scholarly journals Aspergillus fumigatus Clinical Isolates Carrying CYP51A with TR34/L98H/S297T/F495I Substitutions Detected after Four-Year Retrospective Azole Resistance Screening in Brazil

2019 ◽  
Vol 64 (3) ◽  
Author(s):  
Laís Pontes ◽  
Caio Augusto Gualtieri Beraquet ◽  
Teppei Arai ◽  
Guilherme Leite Pigolli ◽  
Luzia Lyra ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Tandem Repeat ◽  
Antifungal Susceptibility ◽  
Antifungal Resistance ◽  
Clinical Isolates ◽  
Azole Resistance ◽  
Resistance Screening ◽  
Environmental Isolates ◽  
Content Type ◽  
Susceptibility Tests

ABSTRACT Azole antifungal resistance in Aspergillus fumigatus is a worldwide concern. As in most public hospitals in Brazil, antifungal susceptibility tests are not routinely performed for filamentous fungi at our institution. A 4-year retrospective azole antifungal resistance screening revealed two azole-resistant A. fumigatus clinical isolates carrying the CYP51A TR34 (34-bp tandem repeat)/L98H (change of L to H at position 98)/S297T/F495I resistance mechanism mutations, obtained from two unrelated patients. Broth microdilution antifungal susceptibility testing showed high MICs for itraconazole, posaconazole, and miconazole. Short tandem repeat (STR) typing analysis presented high levels of similarity between these two isolates and clinical isolates with the same mutations reported from the Netherlands, Denmark, and China, as well as environmental isolates from Taiwan. Our findings might indicate that active searching for resistant A. fumigatus is necessary. They also represent a concern considering that our hospital provides tertiary care assistance to immunocompromised patients who may be exposed to resistant environmental isolates. We also serve patients who receive prophylactic antifungal therapy or treatment for invasive fungal infections for years. In these two situations, isolates resistant to the antifungal in use may be selected within the patients themselves. We do not know the potential of this azole-resistant A. fumigatus strain to spread throughout our country. In this scenario, the impact on the epidemiology and use of antifungal drugs will significantly alter patient care, as in other parts of the world. In summary, this finding is an important contribution to alert hospital laboratories conducting routine microbiological testing to perform azole resistance surveillance and antifungal susceptibility tests of A. fumigatus isolates causing infection or colonization in patients at high risk for systemic aspergillosis.

scholarly journals CRISPR/Cas9 Genome Editing To Demonstrate the Contribution of Cyp51A Gly138Ser to Azole Resistance inAspergillus fumigatus

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Takashi Umeyama ◽  
Yuta Hayashi ◽  
Hisaki Shimosaka ◽  
Tatsuya Inukai ◽  
Satoshi Yamagoe ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Genome Editing ◽  
Genetic Recombination ◽  
Clinical Isolates ◽  
Azole Resistance ◽  
Content Type ◽  
Guide Rna ◽  
Cas9 Protein ◽  
Increased Susceptibility

ABSTRACTA pan-azole-resistantAspergillus fumigatusstrain with thecyp51Amutations Gly138Ser and Asn248Lys was isolated from a patient receiving long-term voriconazole treatment. PCR fragments containingcyp51Awith the mutations were introduced along with the Cas9 protein and single guide RNA into the azole-resistant/susceptible strains. Recombinant strains showed increased susceptibility via the replacement of Ser138 by glycine. Genetic recombination, which has been hampered thus far in clinical isolates, can now be achieved using CRISPR/Cas9 genome editing.

scholarly journals Dectin-2-Targeted Antifungal Liposomes Exhibit Enhanced Efficacy

mSphere ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Suresh Ambati ◽  
Emma C. Ellis ◽  
Jianfeng Lin ◽  
Xiaorong Lin ◽  
Zachary A. Lewis ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Aspergillus Fumigatus ◽  
Effective Dose ◽  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Antifungal Drugs ◽  
Extracellular Matrices ◽  
Content Type ◽  
Order Of Magnitude ◽  
Life Threatening

ABSTRACT Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus cause life-threatening candidiasis, cryptococcosis, and aspergillosis, resulting in several hundred thousand deaths annually. The patients at the greatest risk of developing these life-threatening invasive fungal infections have weakened immune systems. The vulnerable population is increasing due to rising numbers of immunocompromised individuals as a result of HIV infection or immunosuppressed individuals receiving anticancer therapies and/or stem cell or organ transplants. While patients are treated with antifungals such as amphotericin B, all antifungals have serious limitations due to lack of sufficient fungicidal effect and/or host toxicity. Even with treatment, 1-year survival rates are low. We explored methods of increasing drug effectiveness by designing fungicide-loaded liposomes specifically targeted to fungal cells. Most pathogenic fungi are encased in cell walls and exopolysaccharide matrices rich in mannans. Dectin-2 is a mammalian innate immune membrane receptor that binds as a dimer to mannans and signals fungal infection. We coated amphotericin-loaded liposomes with monomers of Dectin-2’s mannan-binding domain, sDectin-2. sDectin monomers were free to float in the lipid membrane and form dimers that bind mannan substrates. sDectin-2-coated liposomes bound orders of magnitude more efficiently to the extracellular matrices of several developmental stages of C. albicans, C. neoformans, and A. fumigatus than untargeted control liposomes. Dectin-2-coated amphotericin B-loaded liposomes reduced the growth and viability of all three species more than an order of magnitude more efficiently than untargeted control liposomes and dramatically decreased the effective dose. Future efforts focus on examining pan-antifungal targeted liposomal drugs in animal models of fungal diseases. IMPORTANCE Invasive fungal diseases caused by Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus have mortality rates ranging from 10 to 95%. Individual patient costs may exceed $100,000 in the United States. All antifungals in current use have serious limitations due to host toxicity and/or insufficient fungal cell killing that results in recurrent infections. Few new antifungal drugs have been introduced in the last 2 decades. Hence, there is a critical need for improved antifungal therapeutics. By targeting antifungal-loaded liposomes to α-mannans in the extracellular matrices secreted by these fungi, we dramatically reduced the effective dose of drug. Dectin-2-coated liposomes loaded with amphotericin B bound 50- to 150-fold more strongly to C. albicans, C. neoformans, and A. fumigatus than untargeted liposomes and killed these fungi more than an order of magnitude more efficiently. Targeting drug-loaded liposomes specifically to fungal cells has the potential to greatly enhance the efficacy of most antifungal drugs.

scholarly journals Development and Validation of a High-Resolution Melting Assay To Detect Azole Resistance in Aspergillus fumigatus

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
L. Bernal-Martínez ◽  
H. Gil ◽  
O. Rivero-Menéndez ◽  
S. Gago ◽  
M. Cuenca-Estrella ◽  
...  
Keyword(s):  
High Resolution ◽  
Aspergillus Fumigatus ◽  
Tandem Repeats ◽  
High Resolution Melting ◽  
Screening Method ◽  
Melting Curve ◽  
Health Concern ◽  
Azole Resistance ◽  
Content Type ◽  
Selection Of

ABSTRACT The global emergence of azole-resistant Aspergillus fumigatus strains is a growing public health concern. Different patterns of azole resistance are linked to mutations in cyp51A. Therefore, accurate characterization of the mechanisms underlying azole resistance is critical to guide selection of the most appropriate antifungal agent for patients with aspergillosis. This study describes a new sequencing-free molecular screening tool for early detection of the most frequent mutations known to be associated with azole resistance in A. fumigatus. PCRs targeting cyp51A mutations at positions G54, Y121, G448, and M220 and targeting different tandem repeats (TRs) in the promoter region were designed. All PCRs were performed simultaneously, using the same cycling conditions. Amplicons were then distinguished using a high-resolution melting assay. For standardization, 30 well-characterized azole-resistant A. fumigatus strains were used, yielding melting curve clusters for different resistance mechanisms for each target and allowing detection of the most frequent azole resistance mutations, i.e., G54E, G54V, G54R, G54W, Y121F, M220V, M220I, M220T, M220K, and G448S, and the tandem repeats TR34, TR46, and TR53. Validation of the method was performed using a blind panel of 80 A. fumigatus azole-susceptible or azole-resistant strains. All strains included in the blind panel were properly classified as susceptible or resistant with the developed method. The implementation of this screening method can reduce the time needed for the detection of azole-resistant A. fumigatus isolates and therefore facilitate selection of the best antifungal therapy in patients with aspergillosis.

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