scholarly journals The Gastrointestinal Tract Is a Major Source of Echinocandin Drug Resistance in a Murine Model of Candida glabrata Colonization and Systemic Dissemination

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Kelley R. Healey ◽  
Yoji Nagasaki ◽  
Matthew Zimmerman ◽  
Milena Kordalewska ◽  
Steven Park ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Human Microbiome ◽  
Systemic Infection ◽  
Resistance Mutations ◽  
Content Type ◽  
Systemic Dissemination ◽  
Colonization Model ◽  
Echinocandin Resistance ◽  
Synthase Inhibitor ◽  
Resistance Rates

ABSTRACT Candida species are a part of the human microbiome and can cause systemic infection upon immune suppression. Candida glabrata infections are increasing and have greater rates of antifungal resistance than other species. Here, we present a C. glabrata gastrointestinal (GI) colonization model to explore whether colonized yeast exposed to caspofungin, an echinocandin antifungal, develop characteristic resistance mutations and, upon immunosuppression, breakthrough causing systemic infection. Daily therapeutic dosing (5 mg/kg of body weight) of caspofungin resulted in no reduction in fecal burdens, organ breakthrough rates similar to control groups, and resistance rates (0 to 10%) similar to those reported clinically. Treatment with 20 mg/kg caspofungin initially reduced burdens, but a rebound following 5 to 9 days of treatment was accompanied by high levels of resistance (FKS1/FKS2 mutants). Although breakthrough rates decreased in this group, the same FKS mutants were recovered from organs. In an attempt to negate drug tolerance that is critical for resistance development, we cotreated mice with daily caspofungin and the chitin synthase inhibitor nikkomycin Z. The largest reduction (3 log) in GI burdens was obtained within 3 to 5 days of 20 mg/kg caspofungin plus nikkomycin treatment. Yet, echinocandin resistance, characterized by a novel Fks1-L630R substitution, was identified following 5 to 7 days of treatment. Therapeutic caspofungin plus nikkomycin treatment left GI burdens unchanged but significantly reduced organ breakthrough rates (20%; P < 0.05). Single-dose pharmacokinetics demonstrated low levels of drug penetration into the GI lumen posttreatment with caspofungin. Overall, we show that C. glabrata echinocandin resistance can arise within the GI tract and that resistant mutants can readily disseminate upon immunosuppression.

scholarly journals De Novo Acquisition of Resistance to SCY-078 in Candida glabrata Involves FKS Mutations That both Overlap and Are Distinct from Those Conferring Echinocandin Resistance

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Cristina Jiménez-Ortigosa ◽  
Winder B. Perez ◽  
David Angulo ◽  
Katyna Borroto-Esoda ◽  
David S. Perlin
Keyword(s):  
Candida Glabrata ◽  
Drug Exposure ◽  
Inhibitory Concentration ◽  
De Novo ◽  
Resistance Mutations ◽  
Content Type ◽  
Kinetic Inhibition ◽  
Echinocandin Resistance ◽  
Orally Active

ABSTRACT SCY-078 is an orally active antifungal whose target is the β-(1,3)-d-glucan synthase (GS). We evaluated the spontaneous emergence of SCY-078-resistant Candida glabrata isolates following drug exposure in vitro. Resistant isolates were analyzed using broth microdilution methodology and FKS sequencing. The kinetic inhibition parameter IC50 (50% inhibitory concentration) was also determined from GS complexes. The spectrum of resistance mutations found suggested a partially overlapping but independent binding site for SCY-078 relative to echinocandins on GS.

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 Posttreatment Antifungal Resistance among Colonizing Candida Isolates in Candidemia Patients: Results from a Systematic Multicenter Study

2015 ◽  
Vol 60 (3) ◽  
pp. 1500-1508 ◽  
Author(s):  
R. H. Jensen ◽  
H. K. Johansen ◽  
L. M. Søes ◽  
L. E. Lemming ◽  
F. S. Rosenvinge ◽  
...  
Keyword(s):  
Genetic Relatedness ◽  
Acquired Resistance ◽  
Antifungal Drugs ◽  
Its Sequencing ◽  
Ionization Time ◽  
Content Type ◽  
Flight Mass Spectrometry ◽  
Echinocandin Resistance ◽  
Resistance Rates ◽  
Initial Blood

The prevalence of intrinsic and acquired resistance among colonizingCandidaisolates from patients after candidemia was investigated systematically in a 1-year nationwide study. Patients were treated at the discretion of the treating physician. Oral swabs were obtained after treatment. Species distributions and MIC data were investigated for blood and posttreatment oral isolates from patients exposed to either azoles or echinocandins for <7 or ≥7 days. Species identification was confirmed using matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) and internal transcribed spacer (ITS) sequencing, susceptibility was examined by EUCAST EDef 7.2 methodology, echinocandin resistance was examined byFKSsequencing, and genetic relatedness was examined by multilocus sequence typing (MLST). One hundred ninety-three episodes provided 205 blood and 220 oral isolates. MLST analysis demonstrated a genetic relationship for 90% of all paired blood and oral isolates. Patients exposed to azoles for ≥7 days (n= 93) had a significantly larger proportion of species intrinsically less susceptible to azoles (particularlyCandida glabrata) among oral isolates than among initial blood isolates (36.6% versus 12.9%;P< 0.001). A similar shift toward species less susceptible to echinocandins among 85 patients exposed to echinocandins for ≥7 days was not observed (4.8% of oral isolates versus 3.2% of blood isolates;P> 0.5). Acquired resistance inCandida albicanswas rare (<5%). However, acquired resistance to fluconazole (29.4%;P< 0.05) and anidulafungin (21.6%;P< 0.05) was common inC. glabrataisolates from patients exposed to either azoles or echinocandins. Our findings suggest that the colonizing mucosal microbiota may be an unrecognized reservoir of resistantCandidaspecies, especiallyC. glabrata, following treatment for candidemia. The resistance rates were high, raising concern in general for patients exposed to antifungal drugs.

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 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 Amphotericin B Induction with Voriconazole Consolidation as Salvage Therapy for FKS-Associated Echinocandin Resistance in Candida glabrata Septic Arthritis and Osteomyelitis

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
William F. Wright ◽  
Nika Bejou ◽  
Ryan K. Shields ◽  
Kieren Marr ◽  
Todd P. McCarty ◽  
...  
Keyword(s):  
Central Venous Catheter ◽  
Parenteral Nutrition ◽  
Septic Arthritis ◽  
Amphotericin B ◽  
Salvage Therapy ◽  
Candida Glabrata ◽  
Venous Catheter ◽  
Central Venous ◽  
Content Type ◽  
Echinocandin Resistance

ABSTRACT We report the case of a 61-year-old female with Crohn’s disease dependent on total parenteral nutrition who developed a central venous catheter bloodstream infection and septic arthritis, complicated further by osteomyelitis and persistent Candida glabrata fungemia. Fluconazole treatment led to persistent infection, and micafungin therapy failed with development of FKS-associated resistance. Infection responded after initiation of amphotericin B plus voriconazole. Echinocandin resistance is increasingly recognized, suggesting a role for alternative antifungal therapies.

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 Rapid Emergence of Echinocandin Resistance in Candida glabrata Resulting in Clinical and Microbiologic Failure

2013 ◽  
Vol 57 (9) ◽  
pp. 4559-4561 ◽  
Author(s):  
James S. Lewis ◽  
Nathan P. Wiederhold ◽  
Brian L. Wickes ◽  
Thomas F. Patterson ◽  
James H. Jorgensen
Keyword(s):  
Risk Factors ◽  
Hot Spots ◽  
Candida Glabrata ◽  
Content Type ◽  
Echinocandin Resistance ◽  
Initiation Of Therapy ◽  
Rapid Emergence

ABSTRACTWe report a case ofCandida glabratacandidemia that developed resistance to micafungin within 8 days of initiation of therapy in a patient without previous echinocandin exposure or other known risk factors for clinical or microbiological failure. Pre- and postresistant isolates were confirmed to be isogenic, and sequencing of hot spots known to confer echinocandin resistance revealed a phenylalanine deletion at codon 659 withinFKS2.

Antifungal susceptibility testing identifies the abdominal cavity as a source of Candida glabrata resistant isolates

2021 ◽  
Author(s):  
Judith Díaz-García ◽  
Aina Mesquida ◽  
Ana Gómez ◽  
Marina Machado ◽  
Pablo Martín-Rabadán ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Susceptibility Testing ◽  
Abdominal Cavity ◽  
Antifungal Susceptibility ◽  
Treatment Resistance ◽  
Resistance Rate ◽  
Blood Cultures ◽  
Wild Type ◽  
Echinocandin Resistance ◽  
Resistance Rates

To identify unrecognized niches of resistant Candida isolates and compartmentalization we retrospectively studied the antifungal susceptibility of 1,103 Candida spp. isolates from blood cultures, non-blood sterile samples, and non-sterile samples. Antifungal susceptibility was assessed by EUCAST E.Def 7.3.2; sequencing and genotyping of the FKS1-2 and ERG11 genes were carried out for non-wild type isolates. Resistance compartmentalization (presence of resistant and susceptible isogenic isolates in different anatomical sites of a given patient) was studied. Clinical charts of patients carrying non-wild type isolates were reviewed. Most isolates (63%) were Candida albicans , regardless the clinical source; Candida glabrata (27%) was the second most frequently found species in abdominal cavity samples. Fluconazole and echinocandin resistance rates were 1.5% and 1.3%, respectively, and highest in C. glabrata . We found 22 genotypes among non-wild type isolates, none of them widespread across the hospital. Fluconazole/echinocandin resistance rates of isolates from abdominal cavity (3.2%/3.2%) were significantly higher than those from blood cultures (0.7%/1.3%) ( P <0.05). Overall, fifteen patients with different forms of candidiasis were infected by resistant isolates, 80% of whom had received antifungals before or at the time of isolate collection; resistance compartmentalization was found in six patients, mainly due to C. glabrata . The highest antifungal resistance rate was detected in isolates from the abdominal cavity, mostly C. glabrata . Resistance was not caused by the spread of resistant clones, but because of antifungal treatment. Resistance compartmentalization illustrates how resistance might be overlooked if susceptibility testing is restricted to bloodstream isolates.

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.

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