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 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 Anidulafungin Susceptibility Testing of Candida glabrata Isolates from Blood Cultures by the MALDI Biotyper Antibiotic (Antifungal) Susceptibility Test Rapid Assay

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Mansoureh Vatanshenassan ◽  
Amir Arastehfar ◽  
Teun Boekhout ◽  
Judith Berman ◽  
Cornelia Lass-Flörl ◽  
...  
Keyword(s):  
Rapid Detection ◽  
Candida Glabrata ◽  
Susceptibility Testing ◽  
Hot Spot ◽  
Antifungal Susceptibility ◽  
Blood Cultures ◽  
Susceptibility Test ◽  
Content Type ◽  
Maldi Biotyper ◽  
Antifungal Susceptibility Test

ABSTRACT Echinocandins are the recommended first-line antifungals for treatment of invasive candidiasis. The increasing number of Candida glabrata strains resistant against echinocandins is an emerging health care concern. The rapid detection of resistant C. glabrata isolates is an urgent requirement for clinical laboratories. In this study, we developed the MALDI Biotyper antibiotic (antifungal) susceptibility test rapid assay (MBT ASTRA) for the rapid detection of anidulafungin-resistant C. glabrata isolates directly from positive blood cultures. Of 100 C. glabrata strains, MBT ASTRA classified 69 as susceptible and 29 as resistant. Microdilution assays performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines, used as a standard reference, identified 65 susceptible, 9 intermediate, and 26 resistant isolates. Sequencing of hot spot 1 and hot spot 2 regions of the FKS1 and FKS2 genes classified 86 susceptible and 14 resistant isolates. The MBT ASTRA had sensitivity and specificity of 80% and 95%, respectively, compared to the microdilution method. Positive and negative agreement of MBT ASTRA was calculated at 100% and 80%, respectively, compared with the molecular sequencing approach. Together, these results revealed a high accuracy of MBT ASTRA compared to microdilution according to the CLSI and PCR analysis, resulting in a categorical agreement of 90% and 83%, respectively. The validity of MBT ASTRA was 98%. Importantly, MBT ASTRA provided antifungal susceptibility testing (AFST) within 6 h that was both accurate and reliable compared to the other two approaches, which require at least 24 h or are costly. Therefore, this method has the potential to facilitate clinical AFST rapidly at low sample costs for clinical labs already equipped with matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS).

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 In Vitro Activity of Ibrexafungerp, a Novel Glucan Synthase Inhibitor against Candida glabrata Isolates with FKS Mutations

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Natalie S. Nunnally ◽  
Kizee A. Etienne ◽  
David Angulo ◽  
Shawn R. Lockhart ◽  
Elizabeth L. Berkow
Keyword(s):  
Candida Glabrata ◽  
Vitro Activity ◽  
Good Activity ◽  
In Vitro Activity ◽  
Broth Microdilution ◽  
Glucan Synthase ◽  
Content Type ◽  
Synthase Inhibitor

ABSTRACT Ibrexafungerp is a first-in-class glucan synthase inhibitor. In vitro activity was determined for 89 Candida glabrata isolates with molecularly identified FKS1 or FKS2 mutations conferring resistance to the echinocandins. All isolates were resistant to at least one echinocandin (i.e., anidulafungin, caspofungin, or micafungin) by broth microdilution. Results for ibrexafungerp were compared with those for each echinocandin. Ibrexafungerp had good activity against all echinocandin-resistant C. glabrata isolates.

scholarly journals Discovery of a Novel Class of Orally Active Antifungal β-1,3-d-Glucan Synthase Inhibitors

2011 ◽  
Vol 55 (11) ◽  
pp. 5099-5106 ◽  
Author(s):  
Scott S. Walker ◽  
Yiming Xu ◽  
Ilias Triantafyllou ◽  
Michelle F. Waldman ◽  
Cara Mendrick ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Candida Glabrata ◽  
Pharmacokinetic Data ◽  
Morphological Response ◽  
Glucan Synthase ◽  
Content Type ◽  
Safety Issues ◽  
Spontaneous Mutants ◽  
Orally Active

ABSTRACTThe echinocandins are a class of semisynthetic natural products that target β-1,3-glucan synthase (GS). Their proven clinical efficacy combined with minimal safety issues has made the echinocandins an important asset in the management of fungal infection in a variety of patient populations. However, the echinocandins are delivered only parenterally. A screen for antifungal bioactivities combined with mechanism-of-action studies identified a class of piperazinyl-pyridazinones that target GS. The compounds exhibitedin vitroactivity comparable, and in some cases superior, to that of the echinocandins. The compounds inhibit GSin vitro, and there was a strong correlation between enzyme inhibition andin vitroantifungal activity. In addition, like the echinocandins, the compounds caused a leakage of cytoplasmic contents from yeast and produced a morphological response in molds characteristic of GS inhibitors. Spontaneous mutants ofSaccharomyces cerevisiaewith reduced susceptibility to the piperazinyl-pyridazinones had substitutions inFKS1. The sites of these substitutions were distinct from those conferring resistance to echinocandins; likewise, echinocandin-resistant isolates remained susceptible to the test compounds. Finally, we present efficacy and pharmacokinetic data on an example of the piperazinyl-pyridazinone compounds that demonstrated efficacy in a murine model ofCandida glabratainfection.

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.

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 Enhanced Efflux Pump Activity in OldCandida glabrataCells

2018 ◽  
Vol 62 (3) ◽  
Author(s):  
Somanon Bhattacharya ◽  
Bettina C. Fries
Keyword(s):  
Amphotericin B ◽  
Abc Transporters ◽  
Resistant Strain ◽  
Candida Glabrata ◽  
Efflux Pump ◽  
Antifungal Resistance ◽  
Replicative Aging ◽  
Glucan Synthase ◽  
Content Type ◽  
Pump Activity

ABSTRACTWe investigated the effect of replicative aging on antifungal resistance inCandida glabrata. Our studies demonstrate significantly increased transcription of ABC transporters and efflux pump activity in old versus youngC. glabratacells of a fluconazole-sensitive and -resistant strain. In addition, higher tolerance to killing by micafungin and amphotericin B was noted and is associated with higher transcription of glucan synthase geneFKS1and lower ergosterol content in older cells.

scholarly journals Sequencing of FKS Hot Spot 1 from Saprochaete capitata To Search for a Relationship to Reduced Echinocandin Susceptibility

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Inés Arrieta-Aguirre ◽  
Pilar Menéndez-Manjón ◽  
María Soledad Cuétara ◽  
Iñigo Fernández de Larrinoa ◽  
Juan Carlos García-Ruiz ◽  
...  
Keyword(s):  
Nucleotide Sequence ◽  
Fungal Pathogen ◽  
Hot Spot ◽  
Fungal Species ◽  
Catalytic Subunit ◽  
Glucan Synthase ◽  
Content Type ◽  
Oligonucleotide Primers ◽  
Geotrichum Capitatum ◽  
Flanking Regions

ABSTRACT Saprochaete capitata, formerly known as Geotrichum capitatum, is an emerging fungal pathogen with low susceptibility to echinocandins. Here, we report the nucleotide sequence of the S. capitata hot spot 1 region of the FKS gene (FKS HS1), which codifies for the catalytic subunit of β-1,3-d-glucan synthase, the target of echinocandins. For that purpose, we first designed degenerated oligonucleotide primers derived from conserved flanking regions of the FKS1 HS1 segment of 12 different fungal species. Interestingly, analysis of the translated FKS HS1 sequences of 12 isolates of S. capitata revealed that all of them exhibited the same F-to-L substitution in a position that is highly related to reduced echinocandin susceptibility.

scholarly journals Activity of a Novel 1,3-Beta-D-Glucan Synthase Inhibitor, Ibrexafungerp (Formerly SCY-078), against Candida glabrata

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
M. Ghannoum ◽  
L. Long ◽  
N. Isham ◽  
C. Hager ◽  
R. Wilson ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Wild Type ◽  
Glucan Synthase ◽  
Content Type ◽  
Clinical Strains ◽  
Resistant Strains ◽  
Oral Availability ◽  
Synthase Inhibitor ◽  
Time Kill ◽  
Type Strains

ABSTRACT Ibrexafungerp (formerly SCY-078), a novel glucan synthase inhibitor with oral availability, was evaluated for activity against Candida glabrata. The susceptibility of clinical strains to ibrexafungerp was determined by microdilution and time-kill assays. The MIC range against wild-type strains was 1 to 2 μg/ml. Ibrexafungerp was also active against the majority of echinocandin-resistant strains. Time-kill studies showed 4- to 6-log-unit reductions in growth at 24 and 48 h with concentrations of 0.25 to 4 μg/ml.

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