Faculty Opinions recommendation of Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism.

ABSTRACT A single mechanism of azole resistance was shown to predominate in clinical and environmental Aspergillus fumigatus isolates from the Netherlands, and a link to the use of azoles in the environment was suggested. To explore the prevalence of azole-resistant A. fumigatus and other aspergilli in the environment in other European countries, we collected samples from the surroundings of hospitals in Copenhagen, Innsbruck, and Madrid, flowerbeds in an amusement park in Copenhagen, and compost bags purchased in Austria, Denmark, and Spain and screened for azole resistance using multidish agars with itraconazole, voriconazole, and posaconazole. EUCAST method E.DEF 9.1 was used to confirm azole resistance. The promoter and entire coding sequence of the cyp51A gene were sequenced to identify azole-resistant A. fumigatus isolates. A. fumigatus was recovered in 144 out of 185 samples (77.8%). Four A. fumigatus isolates from four Danish soil samples displayed elevated azole MICs (8%), and all harbored the same TR/L98H mutation of cyp51A. One A. lentulus isolate with voriconazole MIC of 4 mg/liter was detected in Spain. No azole-resistant aspergilli were detected in compost. Finally, A. terreus was present in seven samples from Austria. Multi-azole-resistant A. fumigatus is present in the environment in Denmark. The resistance mechanism is identical to that of environmental isolates in the Netherlands. No link to commercial compost could be detected. In Spain and Austria, only Aspergillus species with intrinsic resistance to either azoles or amphotericin B were found.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00872-18 ◽

2018 ◽

Vol 62 (10) ◽

Cited By ~ 8

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.

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Recreation of in-host acquired single nucleotide polymorphisms by CRISPR-Cas9 reveals an uncharacterised gene playing a role in Aspergillus fumigatus azole resistance via a non-cyp51A mediated resistance mechanism

Fungal Genetics and Biology ◽

10.1016/j.fgb.2019.05.005 ◽

2019 ◽

Vol 130 ◽

pp. 98-106 ◽

Cited By ~ 10

Author(s):

Eloise Ballard ◽

Jakob Weber ◽

Willem J.G. Melchers ◽

Seshu Tammireddy ◽

Phillip D. Whitfield ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Aspergillus Fumigatus ◽

Resistance Mechanism ◽

Azole Resistance ◽

Nucleotide Polymorphisms ◽

Single Nucleotide

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Clonal Expansion of Environmental Triazole Resistant Aspergillus fumigatus in Iran

Journal of Fungi ◽

10.3390/jof6040199 ◽

2020 ◽

Vol 6 (4) ◽

pp. 199

Author(s):

Fatemeh Ahangarkani ◽

Hamid Badali ◽

Kiana Abbasi ◽

Mojtaba Nabili ◽

Sadegh Khodavaisy ◽

...

Keyword(s):

Aspergillus Fumigatus ◽

Microsatellite Loci ◽

Resistance Mechanism ◽

Clonal Expansion ◽

Antifungal Resistance ◽

Azole Resistance ◽

Surveillance Studies ◽

Sabouraud Dextrose Agar ◽

Clonal Spread

Azole-resistance in Aspergillus fumigatus is a worldwide medical concern complicating the management of aspergillosis (IA). Herein, we report the clonal spread of environmental triazole resistant A. fumigatus isolates in Iran. In this study, 63 A. fumigatus isolates were collected from 300 compost samples plated on Sabouraud dextrose agar supplemented with itraconazole (ITR) and voriconazole (VOR). Forty-four isolates had the TR34/L98H mutation and three isolates a TR46/Y121F/T289A resistance mechanism, while two isolates harbored a M172V substitution in cyp51A. Fourteen azole resistant isolates had no mutations in cyp51A. We found that 41 out of 44 A. fumigatus strains with the TR34/L98H mutation, isolated from compost in 13 different Iranian cities, shared the same allele across all nine examined microsatellite loci. Clonal expansion of triazole resistant A. fumigatus in this study emphasizes the importance of establishing antifungal resistance surveillance studies to monitor clinical Aspergillus isolates in Iran, as well as screening for azole resistance in environmental A. fumigatus isolates.

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The Strength of Synergistic Interaction between Posaconazole and Caspofungin Depends on the Underlying Azole Resistance Mechanism of Aspergillus fumigatus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04469-14 ◽

2015 ◽

Vol 59 (3) ◽

pp. 1738-1744 ◽

Cited By ~ 15

Author(s):

Eleftheria Mavridou ◽

Joseph Meletiadis ◽

Antony Rijs ◽

Johan W. Mouton ◽

Paul E. Verweij

Keyword(s):

Aspergillus Fumigatus ◽

Resistance Mechanism ◽

Fungal Growth ◽

Resistance Mechanisms ◽

Azole Resistance ◽

Wild Type ◽

Content Type ◽

Synergistic Interactions ◽

Drug Concentrations

ABSTRACTThe majority of azole resistance mechanisms inAspergillus fumigatuscorrespond to mutations in thecyp51Agene. As azoles are less effective against infections caused by multiply azole-resistantA. fumigatusisolates, new therapeutic options are warranted for treating these infections. We therefore investigated thein vitrocombination of posaconazole (POSA) and caspofungin (CAS) against 20 wild-type and resistantA. fumigatusisolates with 10 different resistance mechanisms. Fungal growth was assessed with the XTT [2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide inner salt] method. Pharmacodynamic interactions were assessed with the fractional inhibitory concentration (FIC) index (FICi) on the basis of 10% (FICi-0), 25% (FICi-1), or 53 0% (FICi-2) growth, and FICs were correlated with POSA and CAS concentrations. Synergy and antagonism were concluded when the FICi values were statistically significantly (ttest,P< 0.05) lower than 1 and higher than 1.25, respectively. Significant synergy was found for all isolates with mean FICi-0 values ranging from 0.28 to 0.75 (median, 0.46). Stronger synergistic interactions were found with FICi-1 (median, 0.18; range, 0.07 to 0.47) and FICi-2 (0.31; 0.07 to 0.6). The FICi-2 values of isolates with tandem-repeat-containing mutations or codon M220 were lower than those seen with the other isolates (P< 0.01). FIC-2 values were inversely correlated with POSA MICs (rs= −0.52,P= 0.0006) and linearly with the ratio of drug concentrations in combination over the MIC of POSA (rs= 0.76,P< 0.0001) and CAS (rs= 0.52,P= 0.0004). The synergistic effect of the combination of POSA and CAS (POSA/CAS) againstA. fumigatusisolates depended on the underlying azole resistance mechanism. Moreover, the drug combination synergy was found to be increased against isolates with elevated POSA MICs compared to wild-type isolates.

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Azole-resistant invasive aspergillosis in a patient with acute myeloid leukaemia in Germany

Eurosurveillance ◽

10.2807/ese.17.36.20262-en ◽

2012 ◽

Vol 17 (36) ◽

Author(s):

A Hamprecht ◽

D Buchheidt ◽

J J Vehreschild ◽

O A Cornely ◽

B Spiess ◽

...

Keyword(s):

Acute Myeloid Leukaemia ◽

Invasive Aspergillosis ◽

Aspergillus Fumigatus ◽

Myeloid Leukaemia ◽

Susceptibility Testing ◽

Resistance Mechanism ◽

Azole Resistance ◽

Breakthrough Infection ◽

Proven Case ◽

Acute Myeloid

We report the first culture-proven case of invasive aspergillosis (IA) caused by azole-resistant Aspergillus fumigatus in a patient with acute myeloid leukaemia in Germany. IA presented as breakthrough infection under posaconazole prophylaxis. Analysis of the resistance mechanism revealed the TR/L98H mutation in the cyp51A gene, which indicates an environmental origin of the strain. This case underscores the need for monitoring azole resistance in Aspergillus spp. and for routine susceptibility testing of moulds.

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