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

2015 ◽  
Vol 59 (3) ◽  
pp. 1738-1744 ◽  
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.

scholarly journals Antimicrobial Susceptibility and Clonality of Clinical Ureaplasma Isolates in the United States

2016 ◽  
Vol 60 (8) ◽  
pp. 4793-4798 ◽  
Author(s):  
Javier Fernández ◽  
Melissa J. Karau ◽  
Scott A. Cunningham ◽  
Kerryl E. Greenwood-Quaintance ◽  
Robin Patel
Keyword(s):  
United States ◽  
Antimicrobial Susceptibility ◽  
Antimicrobial Agents ◽  
Ureaplasma Urealyticum ◽  
Resistance Mechanism ◽  
The United States ◽  
Resistance Mechanisms ◽  
Resistant Isolate ◽  
Limited Information ◽  
Content Type

ABSTRACTUreaplasma urealyticumandUreaplasma parvumare pathogens involved in urogenital tract and intrauterine infections and also in systemic diseases in newborns and immunosuppressed patients. There is limited information on the antimicrobial susceptibility and clonality of these species. In this study, we report the susceptibility of 250 contemporary isolates ofUreaplasma(202U. parvumand 48U. urealyticumisolates) recovered at Mayo Clinic, Rochester, MN. MICs of doxycycline, azithromycin, ciprofloxacin, tetracycline, erythromycin, and levofloxacin were determined by broth microdilution, with MICS of the last three interpreted according to CLSI guidelines. Levofloxacin resistance was found in 6.4% and 5.2% ofU. parvumandU. urealyticumisolates, respectively, while 27.2% and 68.8% of isolates, respectively, showed ciprofloxacin MICs of ≥4 μg/ml. The resistance mechanism of levofloxacin-resistant isolates was due to mutations inparC, with the Ser83Leu substitution being most frequent, followed by Glu87Lys. No macrolide resistance was found among the 250 isolates studied; a singleU. parvumisolate was tetracycline resistant.tet(M) was found in 10U. parvumisolates, including the single tetracycline-resistant isolate, as well as in 9 isolates which had low tetracycline and doxycycline MICs. Multilocus sequence typing (MLST) performed on a selection of 46 isolates showed high diversity within the clinicalUreaplasmaisolates studied, regardless of antimicrobial susceptibility. The present work extends previous knowledge regarding susceptibility to antimicrobial agents, resistance mechanisms, and clonality ofUreaplasmaspecies in the United States.

scholarly journals First Detection of TR34 L98H and TR46 Y121F T289A Cyp51 Mutations in Aspergillus fumigatus Isolates in the United States

2015 ◽  
Vol 54 (1) ◽  
pp. 168-171 ◽  
Author(s):  
Nathan P. Wiederhold ◽  
Veronica Garcia Gil ◽  
Felipe Gutierrez ◽  
Jonathan R. Lindner ◽  
Mohammad T. Albataineh ◽  
...  
Keyword(s):  
United States ◽  
Middle East ◽  
Aspergillus Fumigatus ◽  
East Africa ◽  
The United States ◽  
Azole Resistance ◽  
Content Type

Azole resistance inAspergillus fumigatusis an increasing problem. The TR34 L98H and TR46 Y121F T289A mutations that can occur in patients without previous azole exposure have been reported in Europe, Asia, the Middle East, Africa, and Australia. Here, we report the detection of both the TR34 L98H and TR46 Y121F T289A mutations in confirmedA. fumigatusisolates collected in institutions in the United States. These mutations, other mutations known to cause azole resistance, and azole MICs are reported here.

scholarly journals Molecular Characterization of a Voriconazole-Resistant, Posaconazole-Susceptible Aspergillus fumigatus Isolate in a Lung Transplant Recipient in the United States

2015 ◽  
Vol 60 (2) ◽  
pp. 1129-1133 ◽  
Author(s):  
Jose A. Vazquez ◽  
Elias K. Manavathu
Keyword(s):  
United States ◽  
Aspergillus Fumigatus ◽  
Molecular Characterization ◽  
Lung Transplant ◽  
Transplant Patient ◽  
The United States ◽  
Azole Resistance ◽  
Content Type ◽  
High Level

ABSTRACTMolecular characterization ofcyp51Afrom the azole-resistantAspergillus fumigatusisolate 50593 from a lung transplant patient showed Y121F/T289A changes coupled with a 46-bp tandem repeat (TR46) on the promoter, whereascyp51Afrom the pretherapy isolate,A. fumigatus47381, showed no changes. This is the first reported case ofA. fumigatusazole resistance due to Y121F/T289A/TR46 in the United States, suggesting that multiple mutational alterations ofcyp51Aresulting in high-level azole resistance could occur during prolonged antifungal therapy.

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 Interrogation of Related Clinical Pan-Azole-Resistant Aspergillus fumigatus Strains: G138C, Y431C, and G434C Single Nucleotide Polymorphisms incyp51A, Upregulation ofcyp51A, and Integration and Activation of TransposonAtf1in thecyp51APromoter

2011 ◽  
Vol 55 (11) ◽  
pp. 5113-5121 ◽  
Author(s):  
Ahmed M. Albarrag ◽  
Michael J. Anderson ◽  
Susan J. Howard ◽  
Geoff D. Robson ◽  
Peter A. Warn ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Resistance Mechanisms ◽  
Start Codon ◽  
Azole Resistance ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Content Type ◽  
Transcription Start Sites ◽  
Chronic Pulmonary Aspergillosis

ABSTRACTMultipleAspergillus fumigatusisolates from a patient with two aspergillomas complicating chronic pulmonary aspergillosis were pan-azole resistant. Microsatellite typing was identical for all isolates despite major phenotypic and some growth rate differences. Three differentcyp51Amutations were found (G138C, Y431C, and G434C), of which the first two were demonstrated by heterologous expression in a hypersusceptibleSaccharomyces cerevisiaestrain to be at least partly responsible for elevated MICs.cyp51Aandcyp51Bgene duplication was excluded, but increased expression ofcyp51Awas demonstrated in three isolates selected for additional study (7-to 13-fold increases). In the isolate with the greatestcyp51Aexpression, anAft1transposon was found inserted 370 bp upstream of the start codon of thecyp51Agene, an integration location never previously demonstrated inAspergillus. Two transcription start sites were identified at 49 and 136 bp upstream of the start codon. The role of theAft1transposon, if any, in modulatingcyp51Aexpression remains to be established. Increased mRNA expression of the transportersAfuMDR1andAfuMDR4also was demonstrated in some isolates, which could contribute to azole resistance or simply represent a stress response. The diversity of confirmed and possible azole resistance mechanisms demonstrated in a single series of isogenic isolates is remarkable, indicating the ability ofA. fumigatusto adapt in the clinical setting.

scholarly journals Rapid Induction of Multiple Resistance Mechanisms in Aspergillus fumigatus during Azole Therapy: a Case Study and Review of the Literature

2011 ◽  
Vol 56 (1) ◽  
pp. 10-16 ◽  
Author(s):  
Simone M. T. Camps ◽  
Jan W. M. van der Linden ◽  
Yi Li ◽  
Ed J. Kuijper ◽  
Jaap T. van Dissel ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Resistance Mechanisms ◽  
Resistant Isolate ◽  
Azole Resistance ◽  
Multiple Resistance ◽  
Review Of The Literature ◽  
Wild Type ◽  
Content Type ◽  
Type Isolate ◽  
Rapid Induction

ABSTRACTNine consecutive isogenicAspergillus fumigatusisolates cultured from a patient with aspergilloma were investigated for azole resistance. The first cultured isolate showed a wild-type phenotype, but four azole-resistant phenotypes were observed in the subsequent eight isolates. Four mutations were found in thecyp51Agene of these isolates, leading to the substitutions A9T, G54E, P216L, and F219I. Only G54 substitutions were previously proved to be associated with azole resistance. Using a Cyp51A homology model and recombination experiments in which the mutations were introduced into a susceptible isolate, we show that the substitutions at codons P216 and F219 were both associated with resistance to itraconazole and posaconazole. A9T was also present in the wild-type isolate and thus considered a Cyp51A polymorphism. Isolates harboring F219I evolved further into a pan-azole-resistant phenotype, indicating an additional acquisition of a non-Cyp51A-mediated resistance mechanism. Review of the literature showed that in patients who develop azole resistance during therapy, multiple resistance mechanisms commonly emerge. Furthermore, the median time between the last cultured wild-type isolate and the first azole-resistant isolate was 4 months (range, 3 weeks to 23 months), indicating a rapid induction of resistance.

scholarly journals Pharmacodynamics and Dose-Response Relationships of Liposomal Amphotericin B against Different Azole-Resistant Aspergillus fumigatus Isolates in a Murine Model of Disseminated Aspergillosis

2013 ◽  
Vol 57 (4) ◽  
pp. 1866-1871 ◽  
Author(s):  
Seyedmojtaba Seyedmousavi ◽  
Willem J. G. Melchers ◽  
Johan W. Mouton ◽  
Paul E. Verweij
Keyword(s):  
Aspergillus Fumigatus ◽  
Dose Response ◽  
Tandem Repeat ◽  
Murine Model ◽  
Promoter Region ◽  
Liposomal Amphotericin ◽  
Resistance Mechanism ◽  
Azole Resistance ◽  
Wild Type ◽  
Content Type

ABSTRACTThe management of invasive aspergillosis (IA) has become more complicated due to the emergence of acquired azole resistance inAspergillus fumigatus, which is associated with treatment failure and a mortality rate of 88%. Treatment with liposomal amphotericin B (L-AmB) may be a useful alternative to improve therapeutic outcome in azole-resistant IA. Four clinicalA. fumigatusisolates obtained from patients with proven IA were studied in a nonneutropenic murine model of infection: a wild-type isolate without mutations in thecyp51Agene and three azole-resistant isolates harboring a single mutation at codon 220 (M220I) and tandem repeat mutations (a 34-bp tandem repeat mutation in the promoter region of thecyp51Agene in combination with substitutions at codon L98 [TR34/L98H] and a 46-bp tandem repeat mutation in the promoter region of thecyp51Agene in combination with mutation at codons Y121 and T289 [TR46/Y121F/T289A]), respectively. Female CD-1 mice were infected intravenously 24 h prior to the start of therapy. Groups of 11 mice were treated at days 1, 2, and 5 postchallenge with increasing 4-fold doses of L-AmB ranging from 0.004 to 16 mg/kg/day and observed for 14 days. Survival for all 4 isolates at day 14 was significantly better than that of controls. A dose-response relationship was observed independent of the azole resistance mechanism. The Hill-type model with a variable slope fitted the relationship between the dose and 14-day survival well for all isolates, withR2values of 0.95 (wild-type), 0.97 (M220I), 0.85 (TR34/L98H), and 0.94 (TR46/Y121F/T289A), respectively. Multiple logistic regression analysis confirmed that there was no significant difference between groups. The results of these experiments indicate that L-AmB was able to prolong survivalin vivoin disseminated IA independent of the presence of an azole resistance mechanism in a dose-dependent manner, and therefore, they support a role for L-AmB in the treatment of azole-resistant IA.

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