scholarly journals Genetic Basis of Azole and Echinocandin Resistance in Clinical Candida glabrata in Japan

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Hazim O. Khalifa ◽  
Teppei Arai ◽  
Hidetaka Majima ◽  
Akira Watanabe ◽  
Katsuhiko Kamei
Keyword(s):  
Candida Glabrata ◽  
Molecular Mechanisms ◽  
Hot Spot ◽  
Multidrug Resistant ◽  
Fungal Resistance ◽  
Patient Treatment ◽  
Azole Resistance ◽  
Nonsynonymous Mutation ◽  
Content Type ◽  
Echinocandin Resistance

ABSTRACT Infections caused by Candida glabrata have caused worldwide concern, especially when they are associated with increasing echinocandin and azole resistance. In this study, we analyzed the molecular mechanisms of azole and echinocandin resistance in C. glabrata isolates obtained from hospitalized patients in Japan from 1997 to 2019. All isolates were checked phenotypically for resistance and genotypically for mutations in PDR1, ERG11, hot spot 1 (HS1), HS2, and HS3 of FKS1, and HS1 and HS2 of FKS2, and all isolates were genotyped by multilocus sequence typing (MLST). Interestingly, 32.6% of the isolates were resistant to caspofungin, and 4.7% were resistant to micafungin. The isolates showed low rates of resistance to azoles, ranging from 2.3% to 9.3%, and only 4.7% of the isolates were non-wild type for flucytosine susceptibility. For the first time in Japan, 4.7% of the isolates were identified as multidrug-resistant strains. Nonsynonymous mutations in PDR1, including two novel mutations associated with azole resistance, were identified in 39.5% of the isolates, and a single nonsynonymous mutation was identified in ERG11. Nine isolates from the same patient harbored nonsynonymous mutations in HS1 of FKS2, and a single isolate harbored a single nonsynonymous mutation in HS1 of FKS1. MLST genotyping revealed 13 different sequence types (STs), with 3 new STs, and ST7 was the most prevalent among the patients (35%) and was associated with high resistance rates. Our results are of crucial clinical concern, since understanding the molecular mechanisms underlying fungal resistance is imperative for guiding specific therapy for efficient patient treatment and promoting strategies to prevent epidemic spread.

scholarly journals Role of FKS Mutations in Candida glabrata: MIC Values, Echinocandin Resistance, and Multidrug Resistance

2014 ◽  
Vol 58 (8) ◽  
pp. 4690-4696 ◽  
Author(s):  
Cau D. Pham ◽  
Naureen Iqbal ◽  
Carol B. Bolden ◽  
Randall J. Kuykendall ◽  
Lee H. Harrison ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Susceptibility Testing ◽  
Hot Spot ◽  
Case Reports ◽  
Multidrug Resistant ◽  
High Rate ◽  
Primary Therapy ◽  
Content Type ◽  
Major Mechanism ◽  
Echinocandin Resistance

ABSTRACTCandida glabratais the second leading cause of candidemia in U.S. hospitals. Current guidelines suggest that an echinocandin be used as the primary therapy for the treatment ofC. glabratadisease due to the high rate of resistance to fluconazole. Recent case reports indicate thatC. glabrataresistance to echinocandins may be increasing. We performed susceptibility testing on 1,380 isolates ofC. glabratacollected between 2008 and 2013 from four U.S. cities, Atlanta, Baltimore, Knoxville, and Portland. Our analysis showed that 3.1%, 3.3%, and 3.6% of the isolates were resistant to anidulafungin, caspofungin, and micafungin, respectively. We screened 1,032 of these isolates, including all 77 that had either a resistant or intermediate MIC value with respect to at least one echinocandin, for mutations in the hot spot regions ofFKS1andFKS2, the major mechanism of echinocandin resistance. Fifty-one isolates were identified with hot spot mutations, 16 inFKS1and 35 inFKS2. All of the isolates with anFKSmutation except one were resistant to at least one echinocandin by susceptibility testing. Of the isolates resistant to at least one echinocandin, 36% were also resistant to fluconazole. Echinocandin resistance among U.S.C. glabrataisolates is a concern, especially in light of the fact that one-third of those isolates may be multidrug resistant. Further monitoring of U.S.C. glabrataisolates for echinocandin resistance is warranted.

scholarly journals Fks1 and Fks2 Are Functionally Redundant but Differentially Regulated in Candida glabrata: Implications for Echinocandin Resistance

2012 ◽  
Vol 56 (12) ◽  
pp. 6304-6309 ◽  
Author(s):  
Santosh K. Katiyar ◽  
Ana Alastruey-Izquierdo ◽  
Kelley R. Healey ◽  
Michael E. Johnson ◽  
David S. Perlin ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Transcriptional Control ◽  
Mutational Analysis ◽  
Hot Spot ◽  
Normal Growth ◽  
Integral Membrane Protein ◽  
Content Type ◽  
Echinocandin Resistance ◽  
High Level ◽  
The Impact

ABSTRACTThe echinocandins caspofungin, micafungin, and anidulafungin, inhibitors of cell wall β-1,3-glucan synthesis, were recently elevated to first-line agents for treating infections due to the azole-refractory yeastCandida glabrata. InCandida albicans, echinocandin resistance is strictly associated with mutations in Fks1, a large integral membrane protein and putative β-1,3-glucan synthase, while mutations in both Fks1 and its paralog Fks2 (but not Fks3) have been associated with resistance inC. glabrata. To further explore their function, regulation, and role in resistance,C. glabratafksgenes were disrupted and subjected to mutational analysis, and their differential regulation was explored. Anfks1Δfks2Δ double disruptant was not able to be generated; otherwise, all three single and remaining two double disruptants displayed normal growth and echinocandin susceptibility, indicating Fks1-Fks2 redundancy. Selection on echinocandin-containing medium for resistant mutants was dependent on strain background: onlyfks1Δ andfks1Δfks3Δ strains consistently yielded mutants exhibiting high-level resistance, all with Fks2 hot spot 1 mutations. Thus, Fks1-Fks2 redundancy attenuates the rate of resistance; further analysis showed that it also attenuates the impact of resistance-conferring mutations. Growth of thefks1Δ and, especially,fks1Δfks3Δ strains was specifically susceptible to the calcineurin inhibitor FK506. Relatedly, FK506 addition or calcineurin geneCMP2disruption specifically reversed Fks2-mediated resistance of laboratory mutants and clinical isolates. RNA analysis suggests that transcriptional control is not the sole mechanism by which calcineurin modulates Fks2 activity.

scholarly journals Evaluation of Two Commercial Broth Microdilution Methods Using Different Interpretive Criteria for the Detection of Molecular Mechanisms of Acquired Azole and Echinocandin Resistance in Four Common Candida Species

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Ha Jin Lim ◽  
Jong Hee Shin ◽  
Mi-Na Kim ◽  
Dongeun Yong ◽  
Seung A. Byun ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Candida Glabrata ◽  
Molecular Mechanisms ◽  
Candida Parapsilosis ◽  
Broth Microdilution ◽  
Cutoff Value ◽  
Content Type ◽  
Clinical Breakpoints ◽  
Echinocandin Resistance ◽  
Vitek 2

ABSTRACT The abilities of the new Vitek 2 AST-YS08 (YS08) and Sensititre YeastOne (SYO) systems to detect the resistances of Candida isolates to azoles and echinocandins were evaluated. In total, 292 isolates, including 28 Candida albicans (6 Erg11 and 2 Fks mutants), 57 Candida parapsilosis (26 Erg11 mutants), 24 Candida tropicalis (10 Erg11 and 1 Fks mutants), and 183 Candida glabrata (39 Pdr1 and 13 Fks mutants) isolates, were tested. The categorical agreements (CAs) between the Clinical and Laboratory Standards Institute (CLSI) method and YS08 fluconazole MICs obtained using clinical breakpoints were 92.4% (C. albicans), 96.5% (C. parapsilosis), and 87.0% (C. tropicalis), and the CAs between the CLSI and SYO MICs were 92.3% (C. albicans), 77.2% (C. parapsilosis), 100% (C. tropicalis), and 98.9% (C. glabrata). For C. glabrata, the CAs with the CLSI micafungin MICs were 92.4% and 55.5% for the YS08 micafungin and caspofungin MICs, respectively; they were 100%, 95.6%, and 98.9% for the SYO micafungin, caspofungin, and anidulafungin MICs, respectively. YS08 does not provide fluconazole data for C. glabrata; the CA with the CLSI fluconazole MIC was 97.8% for the YS08 voriconazole MIC, using an epidemiological cutoff value (ECV) of 0.5 μg/ml. Increased CAs with the CLSI MIC were observed for the YS08 MIC using CLSI ECVs (for fluconazole and C. tropicalis, 100%; for micafungin and C. glabrata, 98.9%) and for the SYO MIC using method-specific ECVs (for fluconazole and C. parapsilosis, 91.2%; for caspofungin and C. glabrata, 98.9%). Therefore, the YS08 and SYO systems may have different abilities to detect mechanisms of azole and echinocandin resistance in four Candida species; the use of method-specific ECVs may improve the performance of both systems.

scholarly journals Abdominal Candidiasis Is a Hidden Reservoir of Echinocandin Resistance

2014 ◽  
Vol 58 (12) ◽  
pp. 7601-7605 ◽  
Author(s):  
Ryan K. Shields ◽  
M. Hong Nguyen ◽  
Ellen G. Press ◽  
Cornelius J. Clancy
Keyword(s):  
Candida Albicans ◽  
Candida Glabrata ◽  
Multidrug Resistant ◽  
Source Control ◽  
Resistant Bacteria ◽  
Multidrug Resistant Bacteria ◽  
Content Type ◽  
Echinocandin Resistance ◽  
Abdominal Candidiasis

ABSTRACTFKSmutantCandidaisolates were recovered from 24% (6/25) of abdominal candidiasis patients exposed to echinocandin.Candida glabrata(29%) andCandida albicans(14%) mutants were identified. Multidrug-resistant bacteria were recovered from 83% ofFKSmutant infections. Mutations were associated with prolonged echinocandin exposure (P= 0.01), breakthrough infections (P= 0.03), and therapeutic failures despite source control interventions (100%). Abdominal candidiasis is a hidden reservoir for the emergence of echinocandin-resistantCandida.

scholarly journals Breakthrough Candidemia Due to Multidrug-Resistant Candida glabrata during Prophylaxis with a Low Dose of Micafungin

2014 ◽  
Vol 58 (4) ◽  
pp. 2438-2440 ◽  
Author(s):  
Fernando César Bizerra ◽  
Cristina Jimenez-Ortigosa ◽  
Ana Carolina R. Souza ◽  
Giovanni Luis Breda ◽  
Flávio Queiroz-Telles ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Low Dose ◽  
Hot Spot ◽  
Multidrug Resistant ◽  
Blood Cultures ◽  
Glucan Synthase ◽  
Content Type ◽  
High Mics

ABSTRACTWe identified a case of breakthrough candidemia in a 25-year-old patient receiving micafungin prophylaxis (50 mg/day). FiveCandida glabrataisolates were obtained from blood cultures and were classified as multidrug-resistant isolates, since all of them exhibited high MICs for echinocandin and azole drugs. A mutation (S663F) in hot spot 1 of theFKS2 gene was found in all five isolates. This mutation yielded a 1,3-β-d-glucan synthase enzyme with highly reduced sensitivities to echinocandin drugs.

scholarly journals Comparative Genomics of Serial Candida glabrata Isolates and the Rapid Acquisition of Echinocandin Resistance during Therapy

2018 ◽  
Vol 63 (2) ◽  
pp. e01628-18 ◽  
Author(s):  
Amelia E. Barber ◽  
Michael Weber ◽  
Kerstin Kaerger ◽  
Jörg Linde ◽  
Hanna Gölz ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Comparative Genomics ◽  
Candida Glabrata ◽  
Opportunistic Pathogen ◽  
Sampling Interval ◽  
Azole Resistance ◽  
Content Type ◽  
Rapid Acquisition ◽  
Echinocandin Resistance ◽  
Insight Into

ABSTRACT The opportunistic pathogen Candida glabrata shows a concerning increase in drug resistance. Here, we present the analysis of two serial bloodstream isolates, obtained 12 days apart. Both isolates show pan-azole resistance and echinocandin resistance was acquired during the sampling interval. Genome sequencing identified nine nonsynonymous SNVs between the strains, including a S663P substitution in FKS2 and previously undescribed SNVs in MDE1 and FPR1, offering insight into how C. glabrata acquires drug resistance and adapts to a human host.

scholarly journals Molecular Analysis of Resistance and Detection of Non-Wild-Type Strains Using Etest Epidemiological Cutoff Values for Amphotericin B and Echinocandins for Bloodstream Candida Infections from a Tertiary Hospital in Qatar

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Saad J. Taj-Aldeen ◽  
Husam Salah ◽  
Winder B. Perez ◽  
Muna Almaslamani ◽  
Mary Motyl ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Hot Spot ◽  
Antifungal Susceptibility ◽  
Tertiary Hospital ◽  
Wild Type ◽  
Content Type ◽  
Cutoff Values ◽  
Echinocandin Resistance ◽  
Candida Infections ◽  
Type Strains

ABSTRACT A total of 301 Candida bloodstream isolates collected from 289 patients over 5 years at a tertiary hospital in Qatar were evaluated. Out of all Candida infections, 53% were diagnosed in patients admitted to the intensive care units. Steady increases in non-albicans Candida species were reported from 2009 to 2014 (30.2% for Candida albicans versus 69.8% for the other Candida species). Etest antifungal susceptibility testing was performed on all recovered clinical isolates to determine echinocandin (micafungin and anidulafungin) and amphotericin B susceptibilities and assess non-wild-type (non-WT) strains (strains for which MICs were above the epidemiological cutoff values). DNA sequence analysis was performed on all isolates to assess the presence of FKS mutations, which confer echinocandin resistance in Candida species. A total of 3.9% of isolates (12/301) among strains of C. albicans and C. orthopsilosis contained FKS hot spot mutations, including heterozygous mutations in FKS1. For C. tropicalis, the Etest appeared to overestimate strains non-WT for micafungin, anidulafungin, and amphotericin B, as 14%, 11%, and 35% of strains, respectively, had values above the epidemiological cutoff value. However, no FKS mutations were identified in this species. For all other species, micafungin best reported the echinocandin non-WT strains relative to the FKS genotype, as anidulafungin tended to overestimate non-wild-type strains. Besides C. tropicalis, few strains were classified as non-WT for amphotericin B.

scholarly journals In Vitro Exposure to Increasing Micafungin Concentrations Easily Promotes Echinocandin Resistance in Candida glabrata Isolates

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
María Ángeles Bordallo-Cardona ◽  
Pilar Escribano ◽  
Elia Gómez G. de la Pedrosa ◽  
Laura Judith Marcos-Zambrano ◽  
Rafael Cantón ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Content Type ◽  
Inhibition Of Growth ◽  
Direct Exposure ◽  
In Vitro Exposure ◽  
Echinocandin Resistance

ABSTRACT We assessed the in vitro susceptibility of five echinocandin-susceptible Candida glabrata isolates after exposure to micafungin. The direct exposure to plates at different micafungin concentrations resulted in the inhibition of growth at 0.062 μg/ml. The progressive exposure was performed on plates using 0.031 μg/ml of micafungin and sequential propagation on plates containing the next 2-fold concentration; the MICs of micafungin and anidulafungin increased sequentially, and all the isolates became echinocandin resistant, showing fks2 mutations.

scholarly journals Characterization of Multidrug-Resistant Escherichia coli Isolates from Animals Presenting at a University Veterinary Hospital

2011 ◽  
Vol 77 (20) ◽  
pp. 7104-7112 ◽  
Author(s):  
Maria Karczmarczyk ◽  
Yvonne Abbott ◽  
Ciara Walsh ◽  
Nola Leonard ◽  
Séamus Fanning
Keyword(s):  
Escherichia Coli ◽  
Molecular Mechanisms ◽  
Gene Array ◽  
Multidrug Resistant ◽  
Genetic Determinants ◽  
Gene Encoding ◽  
Content Type ◽  
E Coli ◽  
Class 1

ABSTRACTIn this study, we examined molecular mechanisms associated with multidrug resistance (MDR) in a collection ofEscherichia coliisolates recovered from hospitalized animals in Ireland. PCR and DNA sequencing were used to identify genes associated with resistance. Class 1 integrons were prevalent (94.6%) and contained gene cassettes recognized previously and implicated mainly in resistance to aminoglycosides, β-lactams, and trimethoprim (aadA1,dfrA1-aadA1,dfrA17-aadA5,dfrA12-orfF-aadA2,blaOXA-30-aadA1,aacC1-orf1-orf2-aadA1,dfr7). Class 2 integrons (13.5%) contained thedfrA1-sat1-aadA1gene array. The most frequently occurring phenotypes included resistance to ampicillin (97.3%), chloramphenicol (75.4%), florfenicol (40.5%), gentamicin (54%), neomycin (43.2%), streptomycin (97.3%), sulfonamide (98.6%), and tetracycline (100%). The associated resistance determinants detected includedblaTEM,cat,floR,aadB,aphA1,strA-strB,sul2, andtet(B), respectively. TheblaCTX-M-2gene, encoding an extended-spectrum β-lactamase (ESβL), andblaCMY-2, encoding an AmpC-like enzyme, were identified in 8 and 18 isolates, respectively. The mobility of the resistance genes was demonstrated using conjugation assays with a representative selection of isolates. High-molecular-weight plasmids were found to be responsible for resistance to multiple antimicrobial compounds. The study demonstrated that animal-associated commensalE. coliisolates possess a diverse repertoire of transferable genetic determinants. Emergence of ESβLs and AmpC-like enzymes is particularly significant. To our knowledge, theblaCTX-M-2gene has not previously been reported in Ireland.

scholarly journals Initial Assessment of the Molecular Epidemiology ofblaNDM-1in Colombia

2016 ◽  
Vol 60 (7) ◽  
pp. 4346-4350 ◽  
Author(s):  
Laura J. Rojas ◽  
Meredith S. Wright ◽  
Elsa De La Cadena ◽  
Gabriel Motoa ◽  
Kristine M. Hujer ◽  
...  
Keyword(s):  
Hot Spot ◽  
Multidrug Resistant ◽  
Sequence Type ◽  
Initial Assessment ◽  
Genome Sequences ◽  
Gram Negative ◽  
Content Type ◽  
E Coli ◽  
Resistance Determinants ◽  
Novel Complex

ABSTRACTWe report complete genome sequences of fourblaNDM-1-harboring Gram-negative multidrug-resistant (MDR) isolates from Colombia. TheblaNDM-1genes were located on 193-kb Inc FIA, 178-kb Inc A/C2, and 47-kb (unknown Inc type) plasmids. Multilocus sequence typing (MLST) revealed that these isolates belong to sequence type 10 (ST10) (Escherichia coli), ST392 (Klebsiella pneumoniae), and ST322 and ST464 (Acinetobacter baumanniiandAcinetobacter nosocomialis, respectively). Our analysis identified that the Inc A/C2 plasmid inE. colicontained a novel complex transposon (Tn125and Tn5393with three copies ofblaNDM-1) and a recombination “hot spot” for the acquisition of new resistance determinants.

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