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.

scholarly journals Differential Activity of the Oral Glucan Synthase Inhibitor SCY-078 against Wild-Type and Echinocandin-Resistant Strains of Candida Species

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Michael A. Pfaller ◽  
Shawn A. Messer ◽  
Paul R. Rhomberg ◽  
Katyna Borroto-Esoda ◽  
Mariana Castanheira
Keyword(s):  
Antifungal Agents ◽  
Wild Type ◽  
Active Inhibitor ◽  
Glucan Synthase ◽  
Content Type ◽  
Upper Limit ◽  
Resistant Strains ◽  
Synthase Inhibitor ◽  
Orally Active

ABSTRACT SCY-078 (formerly MK-3118) is a novel orally active inhibitor of fungal β-(1,3)-glucan synthase (GS). SCY-078 is a derivative of enfumafungin and is structurally distinct from the echinocandin class of antifungal agents. We evaluated the in vitro activity of this compound against wild-type (WT) and echinocandin-resistant isolates containing mutations in the FKS genes of Candida spp. Against 36 Candida spp. FKS mutants tested, 30 (83.3%) were non-WT to 1 or more echinocandins, and only 9 (25.0%) were non-WT (MIC, >WT-upper limit) to SCY-078. Among C. glabrata isolates carrying FKS alterations, 84.0% were non-WT to the echinocandins versus only 24.0% for SCY-078. In contrast to the echinocandin comparators, the activity of SCY-078 was minimally affected by the presence of FKS mutations, suggesting that this agent is useful in the treatment of Candida infections due to echinocandin-resistant strains.

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 Pharmacodynamics of Itraconazole against Aspergillus fumigatus in anIn VitroModel of the Human Alveolus: Perspectives on the Treatment of Triazole-Resistant Infection and Utility of Airway Administration

2012 ◽  
Vol 56 (8) ◽  
pp. 4146-4153 ◽  
Author(s):  
Zaid Al-Nakeeb ◽  
Ajay Sudan ◽  
Adam R. Jeans ◽  
Lea Gregson ◽  
Joanne Goodwin ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Therapeutic Strategies ◽  
Wild Type ◽  
Content Type ◽  
Exposure Response ◽  
Prevention And Treatment ◽  
Resistant Infection ◽  
Resistant Strains ◽  
Type Strains

ABSTRACTItraconazole is used for the prevention and treatment of infections caused byAspergillus fumigatus. An understanding of the pharmacodynamics of itraconazole against wild-type and triazole-resistant strains provides a basis for innovative therapeutic strategies for treatment of infections. Anin vitromodel of the human alveolus was used to define the pharmacodynamics of itraconazole. Galactomannan was used as a biomarker. The effect of systemic and airway administration of itraconazole was assessed, as was a combination of itraconazole administered to the airway and systemically administered 5FC. Systemically administered itraconazole against the wild type induced a concentration-dependent decline in galactomannan in the alveolar and endothelial compartments. No exposure-response relationships were apparent for the L98H, M220T, or G138C mutant. The administration of itraconazole to the airway resulted in comparable exposure-response relationships to those observed with systemic therapy. This was achieved without detectable concentrations of drug within the endothelial compartment. The airway administration of itraconazole resulted in a definite but submaximal effect in the endothelial compartment against the L98H mutant. The administration of 5FC resulted in a concentration-dependent decline in galactomannan in both the alveolar and endothelial compartments. The combination of airway administration of itraconazole and systemically administered 5FC was additive. Systemic administration of itraconazole is ineffective against Cyp51 mutants. The airway administration of itraconazole is effective for the treatment of wild-type strains and appears to have some activity against the L98H mutants. Combination with other agents, such as 5FC, may enable the attainment of near-maximal antifungal activity.

scholarly journals In VitroActivity of Ceftazidime-Avibactam Combination inIn VitroCheckerboard Assays

2014 ◽  
Vol 59 (2) ◽  
pp. 1138-1144 ◽  
Author(s):  
Johanna Berkhout ◽  
Maria J. Melchers ◽  
Anita C. van Mil ◽  
Wright W. Nichols ◽  
Johan W. Mouton
Keyword(s):  
Antibacterial Activity ◽  
Enterobacter Cloacae ◽  
Resistance Mechanisms ◽  
Maximum Effect ◽  
Wild Type ◽  
Dependent Effect ◽  
Content Type ◽  
Resistant Strains ◽  
Type Strains

ABSTRACTTo evaluate thein vitroeffects of the combination of ceftazidime and avibactam on the MICs of both compounds, checkerboard assays were performed for 81 clinical strains, including 55Enterobacteriaceaestrains (32Klebsiella pneumoniae, 19Escherichia coli, 1Citrobacter freundii, and 3Enterobacter cloacae) and 26 strains ofPseudomonas aeruginosa, all with known resistance mechanisms such as extended-spectrum β-lactamases (ESBLs) and carbapenemases, phenotypically or molecularly determined. Phenotypically ceftazidime-resistant strains (n= 69) were analyzed in more detail. For theEnterobacteriaceaestrains, a concentration-dependent effect of avibactam was found for most strains with a maximum effect of avibactam at a concentration of 4 mg/liter, which decreased all ceftazidime MICs to ≤4 mg/liter. Avibactam alone also showed antibacterial activity (the MIC50and MIC90being 8 and 16 mg/liter, respectively). For the ceftazidime-resistantP. aeruginosastrains, considerable inhibition of β-lactamases by avibactam was acquired at a concentration of 4 mg/liter, which decreased all ceftazidime MICs except one to ≤8 mg/liter (the CLSI and EUCAST susceptible breakpoint). Increasing the concentration of avibactam further decreased the MICs, resulting in a maximum effect for most strains at 8 to 16 mg/liter. In summary, for most strains, the tested addition of avibactam of 4 mg/liter restored the antibacterial activity of ceftazidime to a level comparable to that of wild-type strains, indicating full inhibition, and strains became susceptible according to the EUCAST and CLSI criteria. Based on thesein vitrodata, avibactam is a promising inhibitor of different β-lactamases, including ESBLs and carbapenemases.

scholarly journals Frequency offksMutations among Candida glabrata Isolates from a 10-Year Global Collection of Bloodstream Infection Isolates

2013 ◽  
Vol 58 (1) ◽  
pp. 577-580 ◽  
Author(s):  
Mariana Castanheira ◽  
Leah N. Woosley ◽  
Shawn A. Messer ◽  
Daniel J. Diekema ◽  
Ronald N. Jones ◽  
...  
Keyword(s):  
Bloodstream Infection ◽  
Hot Spots ◽  
Candida Glabrata ◽  
Wild Type ◽  
Glucan Synthase ◽  
Content Type

ABSTRACTAmong 119 echinocandin non-wild-type (non-WT)Candida glabratastrains from two global surveys, mutations infkshot spots (HSs) were detected in 28 (from 7 countries and 8 U.S. states): 24 strains (85.7%) had non-WT MICs for micafungin, 22 (78.6%) for anidulafungin, and 25 (89.3%) for caspofungin. The most common FKS substitutions among non-WT strains were at positions F659 (n= 7) and S663 (n= 7). Three isolates displaying WT MIC results had F625Y, L630I, and D632Y substitutions or non-HS mutations. Mutations that have been reported to decrease the echinocandin binding to the 1,3-β-d-glucan synthase were categorized as resistant by applying the new CLSI breakpoint criteria for all three echinocandins.

scholarly journals Comparative Effects of Micafungin, Caspofungin, and Anidulafungin against a Difficult-To-Treat Fungal Opportunistic Pathogen, Candida glabrata

2011 ◽  
Vol 56 (3) ◽  
pp. 1215-1222 ◽  
Author(s):  
Elisabetta Spreghini ◽  
Fiorenza Orlando ◽  
Maurizio Sanguinetti ◽  
Brunella Posteraro ◽  
Daniele Giannini ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Laboratory Strain ◽  
Opportunistic Pathogen ◽  
Content Type ◽  
Susceptible Isolate ◽  
Resistant Strains ◽  
Time Kill ◽  
Higher Doses

ABSTRACTThe aim of this study was to compare thein vitroandin vivoactivities of micafungin, caspofungin, and anidulafungin againstCandida glabrata. The MICs against 28 clinical isolates showed that the overall susceptibilities to caspofungin and to micafungin were not statistically different in the absence of human serum, whereas the isolates were less susceptible to micafungin than to caspofungin in its presence. Minimum fungicidal concentrations, as well as time-kill experiments, showed that caspofungin was more active than anidulafungin, while micafungin was superior to either caspofungin or anidulafungin without serum; its addition rendered caspofungin and micafungin equally effective. A murine model of systemic candidiasis against aC. glabrata-susceptible isolate was performed to study the effects of all three echinocandins, and kidney burden counts showed that caspofungin, micafungin, and anidulafungin were active starting from 0.25, 1, and 5 mg/kg of body weight/day, respectively. Two echinocandin-resistant strains ofC. glabratawere selected:C. glabrata30, a laboratory strain harboring the mutation Fks2p-P667T, andC. glabrata51, a clinical isolate harboring the mutation Fks2p-D666G. Micafungin activity was shown to be as effective as or more effective than that of caspofungin or anidulafungin in terms of MICs.In vivostudies against these resistant strains showed that micafungin was active starting from 1 mg/kg/day, while caspofungin was effective only when administrated at higher doses of 5 or 10 mg/kg/day. Although a trend toward colony reduction was observed with the highest doses of anidulafungin, a significant statistical difference was never reached.

scholarly journals Ibrexafungerp, a Novel Oral Triterpenoid Antifungal in Development: Overview of Antifungal Activity Against Candida glabrata

2021 ◽  
Vol 11 ◽  
Author(s):  
Ahmed Gamal ◽  
Sherman Chu ◽  
Thomas S. McCormick ◽  
Katyna Borroto-Esoda ◽  
David Angulo ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Systemic Disease ◽  
Wild Type ◽  
First Line ◽  
Life Threatening ◽  
Oral Availability ◽  
Synthase Inhibitor ◽  
Preclinical And Clinical Studies ◽  
Systemic Infections

Systemic infections caused by Candida species are an important cause of morbidity and mortality among immunocompromised and non-immunocompromised patients. In particular, Candida glabrata is an emerging species within the Candida family that causes infections ranging from superficial to life-threatening systemic disease. Echinocandins and azoles are typically the first-line therapies used to treat infections caused by C. glabrata, however, there is an increasing prevalence of resistance to these antifungal agents in patients. Thus, a need exists for novel therapies that demonstrate high efficacy against C. glabrata. Ibrexafungerp is a first-in-class glucan synthase inhibitor with oral availability developed to address this increasing antifungal resistance. Ibrexafungerp demonstrates broad in vitro activity against wild-type, azole-resistant, and echinocandin-resistant C. glabrata species. Furthermore, ibrexafungerp has shown efficacy in low pH environments, which suggests its potential effectiveness in treating vulvovaginal candidiasis. Additional preclinical and clinical studies are needed to further examine the mechanism(s) of ibrexafungerp, including acting as a promising new agent for treating C. glabrata infections.

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 Bactericidal Activity, Absence of Serum Effect, and Time-Kill Kinetics of Ceftazidime-Avibactam against β-Lactamase-Producing Enterobacteriaceae and Pseudomonas aeruginosa

2014 ◽  
Vol 58 (9) ◽  
pp. 5297-5305 ◽  
Author(s):  
Tiffany R. Keepers ◽  
Marcela Gomez ◽  
Chris Celeri ◽  
Wright W. Nichols ◽  
Kevin M. Krause
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Human Serum ◽  
Bactericidal Activity ◽  
Minimum Bactericidal Concentration ◽  
Wild Type ◽  
Content Type ◽  
Positive Isolate ◽  
New Treatment ◽  
Time Kill ◽  
Kinetics Of

ABSTRACTAvibactam, a non-β-lactam β-lactamase inhibitor with activity against extended-spectrum β-lactamases (ESBLs), KPC, AmpC, and some OXA enzymes, extends the antibacterial activity of ceftazidime against most ceftazidime-resistant organisms producing these enzymes. In this study, the bactericidal activity of ceftazidime-avibactam against 18Pseudomonas aeruginosaisolates and 15Enterobacteriaceaeisolates, including wild-type isolates and ESBL, KPC, and/or AmpC producers, was evaluated. Ceftazidime-avibactam MICs (0.016 to 32 μg/ml) were lower than those for ceftazidime alone (0.06 to ≥256 μg/ml) against all isolates except for 2P. aeruginosaisolates (1blaVIM-positive isolate and 1blaOXA-23-positive isolate). The minimum bactericidal concentration/MIC ratios of ceftazidime-avibactam were ≤4 for all isolates, indicating bactericidal activity. Human serum and human serum albumin had a minimal effect on ceftazidime-avibactam MICs. Ceftazidime-avibactam time-kill kinetics were evaluated at low MIC multiples and showed time-dependent reductions in the number of CFU/ml from 0 to 6 h for all strains tested. A ≥3-log10decrease in the number of CFU/ml was observed at 6 h for allEnterobacteriaceae, and a 2-log10reduction in the number of CFU/ml was observed at 6 h for 3 of the 6P. aeruginosaisolates. Regrowth was noted at 24 h for some of the isolates tested in time-kill assays. These data demonstrate the potent bactericidal activity of ceftazidime-avibactam and support the continued clinical development of ceftazidime-avibactam as a new treatment option for infections caused byEnterobacteriaceaeandP. aeruginosa, including isolates resistant to ceftazidime by mechanisms dependent on avibactam-sensitive β-lactamases.

scholarly journals Antifungal Activity of SCY-078 and Standard Antifungal Agents against 178 Clinical Isolates of Resistant and Susceptible Candida Species

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Wiley A. Schell ◽  
A. M. Jones ◽  
Katyna Borroto-Esoda ◽  
Barbara D. Alexander
Keyword(s):  
Candida Glabrata ◽  
Antifungal Agents ◽  
Candida Parapsilosis ◽  
Candida Krusei ◽  
Wild Type ◽  
Content Type ◽  
Clinical Resistance ◽  
Excellent Activity ◽  
Candida Lusitaniae

ABSTRACT SCY-078 in vitro activity was determined for 178 isolates of resistant or susceptible Candida albicans, Candida dubliniensis, Candida glabrata, Candida krusei, Candida lusitaniae, and Candida parapsilosis, including 44 Candida isolates with known genotypic (FKS1 or FKS2 mutations), phenotypic, or clinical resistance to echinocandins. Results were compared to those for anidulafungin, caspofungin, micafungin, fluconazole, and voriconazole. SCY-078 was shown to have excellent activity against both wild-type isolates and echinocandin- and azole-resistant isolates of Candida species.

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