scholarly journals Evaluation of Endpoints for Antifungal Susceptibility Determinations with LY303366

1998 ◽  
Vol 42 (6) ◽  
pp. 1387-1391 ◽  
Author(s):  
Michael E. Klepser ◽  
Erika J. Ernst ◽  
Michael E. Ernst ◽  
Shawn A. Messer ◽  
Michael A. Pfaller
Keyword(s):  
Candida Glabrata ◽  
Fungicidal Activity ◽  
Antifungal Susceptibility ◽  
Poor Correlation ◽  
Drug Induced ◽  
Rpmi Medium ◽  
Visible Growth ◽  
Time Kill ◽  
Scanning Electron

ABSTRACT We have previously reported poor correlation between the in vitro fungicidal activity of LY303366 and MIC results in RPMI medium based upon the manufacturer’s suggested susceptibility endpoint, lack of visual growth. Additionally, we have noted a significant trailing effect with LY303366 when MICs are determined in RPMI medium. These observations have led us to evaluate an alternative susceptibility endpoint for LY303366, an 80% reduction in growth compared with control (similar to that utilized for azoles). Two isolates each of Candida albicans,Candida glabrata, and Candida tropicalis were selected for testing. MICs were determined for LY303366 in RPMI 1640 medium buffered with morpholinepropanesulfonic acid. MICs were determined with suggested (MIC100) and experimental (MIC80) endpoints. The minimal fungicidal concentration (MFC) of LY303366 for each isolate was also determined. Time-kill curves were determined in RPMI medium with each isolate at concentrations of LY303366 ranging from 0.125 to 16× MIC80to assess the correlation between MIC80 and fungicidal activity. Lastly, fungi exposed to LY303366 were examined via scanning electron microscope (SEM) for evidence of drug-induced ultrastructure change. MIC80s for test isolates ranged from 0.015 to 0.12 μg/ml and were consistently three to five wells less than MIC100s. Good correlation was observed between fungicidal activity, as assessed by kill curves, and the MIC80. SEM data revealed significant ultrastructure changes induced by LY303366 even at sub-MIC80s. Based on our results demonstrating better correlation between MIC80 and fungicidal activity, i.e., time-kill curves and MFCs, we suggest that 80% reduction in visible growth be utilized as the endpoint for susceptibility determinations with LY303366 in RPMI medium.

scholarly journals Biofilm Formation by and Antifungal Susceptibility of Candida Isolates from Urine

2007 ◽  
Vol 73 (6) ◽  
pp. 1697-1703 ◽  
Author(s):  
N. Jain ◽  
R. Kohli ◽  
E. Cook ◽  
P. Gialanella ◽  
T. Chang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Growth Medium ◽  
Biofilm Formation ◽  
Chart Review ◽  
Antifungal Susceptibility ◽  
Retrospective Chart Review ◽  
Urine Samples ◽  
Rpmi Medium

ABSTRACT Biofilm formation (BF) in the setting of candiduria has not been well studied. We determined BF and MIC to antifungals in Candida spp. isolates grown from urine samples of patients and performed a retrospective chart review to examine the correlation with risk factors. A total of 67 Candida spp. isolates were grown from urine samples from 55 patients. The species distribution was C. albicans (54%), C. glabrata (36%), and C. tropicalis (10%). BF varied greatly among individual Candida isolates but was stable in sequential isolates during chronic infection. BF also depended on the growth medium and especially in C. albicans was significantly enhanced in artificial urine (AU) compared to RPMI medium. In nine of the C. albicans strains BF was 4- to 10-fold higher in AU, whereas in three of the C. albicans strains and two of the C. glabrata strains higher BF was measured in RPMI medium than in AU. Determination of the MICs showed that planktonic cells of all strains were susceptible to amphotericin B (AMB) and caspofungin (CASPO) and that three of the C. glabrata strains and two of the C. albicans strains were resistant to fluconazole (FLU). In contrast, all biofilm-associated adherent cells were resistant to CASPO and FLU. The biofilms of 14 strains (28%) were sensitive to AMB (MIC50 of <1 μg/ml). Correlation between degree of BF and MIC of AMB was not seen in RPMI grown biofilms but was present when grown in AU. A retrospective chart review demonstrated no correlation of known risk factors of candiduria with BF in AU or RPMI. We conclude that BF is a stable characteristic of Candida strains that varies greatly among clinical strains and is dependent on the growth medium. Resistance to AMB is associated with higher BF in AU, which may represent the more physiologic medium to test BF. Future studies should address whether in vitro BF can predict treatment failure in vivo.

scholarly journals Posaconazole against Candida glabrata Isolates with Various Susceptibilities to Fluconazole

2008 ◽  
Vol 52 (6) ◽  
pp. 1929-1933 ◽  
Author(s):  
Elisabetta Spreghini ◽  
Carmelo Massimo Maida ◽  
Serena Tomassetti ◽  
Fiorenza Orlando ◽  
Daniele Giannini ◽  
...  
Keyword(s):  
Experimental Model ◽  
Candida Glabrata ◽  
Therapeutic Option ◽  
Resistant Isolate ◽  
Dependent Manner ◽  
Fungal Burden ◽  
Systemic Infections ◽  
Time Kill ◽  
Dose Dependent

ABSTRACT We investigated the in vitro activities of posaconazole (POS), fluconazole (FLC), amphotericin B (AMB), and caspofungin (CAS) against four clinical isolates of Candida glabrata with various susceptibilities to FLC (FLC MICs ranging from 1.0 to >64 μg/ml). POS MICs ranged from ≤0.03 to 0.5 μg/ml; AMB MICs ranged from 0.25 to 2.0 μg/ml, while CAS MICs ranged from 0.03 to 0.25 μg/ml. When FLC MICs increased, so did POS MICs, although we did not observe any isolate with a POS MIC greater than 0.5 μg/ml. Time-kill experiments showed that POS, FLC, and CAS were fungistatic against all isolates, while AMB at eight times the MIC was fungicidal against three out of four isolates of C. glabrata tested. Then, we investigated the activity of POS in an experimental model of disseminated candidiasis using three different isolates of C. glabrata: one susceptible to FLC (S; FLC MICs ranging from 1.0 to 4.0 μg/ml; POS MIC of ≤0.03 μg/ml), one susceptible in a dose-dependent manner (SDD; FLC MICs ranging from 32 to 64 μg/ml; POS MICs ranging from 0.125 to 0.25 μg/ml), and another one resistant to FLC (R; FLC MIC of >64 μg/ml; POS MIC of 0.5 μg/ml). FLC significantly reduced the kidney burden of mice infected with the S strain (P = 0.0070) but not of those infected with the S-DD and R strains. POS was significantly effective against all three isolates at reducing the kidney fungal burden with respect to the controls (P ranging from 0.0003 to 0.029). In conclusion, our data suggest that POS may be a useful option in the management of systemic infections caused by C. glabrata. Additionally, the new triazole may be a therapeutic option in those cases where an FLC-resistant isolate is found to retain a relatively low POS MIC.

scholarly journals Mutations in the fks1 Gene in Candida albicans, C. tropicalis, and C. krusei Correlate with Elevated Caspofungin MICs Uncovered in AM3 Medium Using the Method of the European Committee on Antibiotic Susceptibility Testing

2008 ◽  
Vol 52 (9) ◽  
pp. 3092-3098 ◽  
Author(s):  
Marie Desnos-Ollivier ◽  
Stéphane Bretagne ◽  
Dorothée Raoux ◽  
Damien Hoinard ◽  
Françoise Dromer ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Antibiotic Susceptibility ◽  
Susceptibility Testing ◽  
Antifungal Susceptibility ◽  
Clinical Isolates ◽  
Antibiotic Susceptibility Testing ◽  
Wild Type ◽  
European Committee ◽  
Rpmi Medium

ABSTRACT Mutations in two specific regions of the Fks1 subunit of 1,3-β-d-glucan synthase are known to confer decreased caspofungin susceptibility on Candida spp. Clinical isolates of Candida spp. (404 Candida albicans, 62 C. tropicalis, and 21 C. krusei isolates) sent to the French National Reference Center were prospectively screened for susceptibility to caspofungin in vitro by the broth microdilution reference method of the Antifungal Susceptibility Testing Subcommittee of the European Committee on Antibiotic Susceptibility Testing (AFST-EUCAST). Twenty-eight isolates (25 C. albicans, 2 C. tropicalis, and 1 C. krusei isolate) for which the caspofungin MIC was above the MIC that inhibited 90% of the isolates of the corresponding species (MIC90) were subjected to molecular analysis in order to identify mutations in the fks1 gene. Substitutions in the deduced protein sequence of Fks1 were found for 8 isolates, and 20 isolates had the wild-type sequence. Among the six C. albicans isolates harboring mutations, six patterns were observed involving amino acid changes at positions 641, 645, 649, and 1358. For C. tropicalis, one isolate showed an L644W mutation, and for one C. krusei isolate, two mutations, L658W and L701M, were found. Two media, RPMI medium and AM3, were tested for their abilities to distinguish between isolates with wild-type Fks1 and those with mutant Fks1. In RPMI medium, caspofungin MICs ranged from 0.25 to 2 μg/ml for wild-type isolates and from 1 to 8 μg/ml for mutant isolates. A sharper difference was observed in AM3: all wild-type isolates were inhibited by 0.25 μg/ml of caspofungin, while caspofungin MICs for all mutant isolates were ≥0.5 μg/ml. These data demonstrate that clinical isolates of C. albicans, C. tropicalis, and C. krusei with decreased susceptibility to caspofungin in vitro have diverse mutations in the fks1 gene and that AM3 is potentially a better medium than RPMI for distinguishing between mutant and wild-type isolates using the AFST-EUCAST method.

scholarly journals SCY-078 Is Fungicidal against Candida Species in Time-Kill Studies

2017 ◽  
Vol 61 (3) ◽  
Author(s):  
Bernard Scorneaux ◽  
David Angulo ◽  
Katyna Borroto-Esoda ◽  
Mahmoud Ghannoum ◽  
Michael Peel ◽  
...  
Keyword(s):  
Fungicidal Activity ◽  
Candida Parapsilosis ◽  
Maximum Effect ◽  
Synthesis Inhibitor ◽  
Content Type ◽  
Orally Bioavailable ◽  
Glucan Synthesis ◽  
Time Kill ◽  
Time Point

ABSTRACT SCY-078 is an orally bioavailable ß-1,3-glucan synthesis inhibitor (GSI) and the first-in-class of structurally novel triterpene antifungals in clinical development for treating candidemia and invasive candidiasis. In vitro susceptibilities by broth microdilution, antifungal carryover, and time-kill dynamics were determined for three reference (ATCC) strains (Candida albicans 90028, Candida parapsilosis 90018, and Candida tropicalis 750), a quality-control (QC) strain (Candida krusei 6258), and four other strains (C. albicans MYA-2732, 64124, and 76485 and Candida glabrata 90030). Caspofungin (CASP), fluconazole (FLC), and voriconazole (VRC) were comparators. For time-kill experiments, SCY-078 and CASP were evaluated at 0.25, 1, 2, 4, 8, and 16 times the MIC80, and FLU and VRC were evaluated at 4× MIC80. The time to reach 50%, 90%, and 99.9% reduction in the number of CFUs from the starting inoculum was determined. Net change in the number of CFU per milliliter was used to determine 50% and 90% effective concentrations and maximum effect (EC50, EC90, and E max, respectively). The SCY-078 MIC range was between 0.0625 and 1 μg/ml and generally similar to that of CASP. Antifungal carryover was not observed for SCY-078. SCY-078 was fungicidal against seven isolates at ≥4× MIC (kill of ≥3 log10) and achieved a 1.7-log10 reduction in CFU count/milliliter against C. albicans 90028. CASP behaved similarly against each isolate and achieved a 1.5-log10 reduction in the number of CFU/milliliter against C. albicans 90028. Reductions of 50% in CFU count/milliliter were achieved rapidly (1 to 2.8 h); fungicidal endpoints were reached at 12.1 to 21.8 h at ≥4× MIC. EC90 was reached at ∼5× MIC at each time point to 24 h. The EC50 and EC90 values were generally similar (8 to 24 h). Time-kill behavior of CASP was similar to that of SCY-078. FLC and VRC were fungistatic. Overall, SCY-078 has primarily fungicidal activity against Candida spp. and behaved comparably to CASP.

scholarly journals In Vitro Activity of a New Polyene, SPA-S-843, against Yeasts

1998 ◽  
Vol 42 (11) ◽  
pp. 3012-3013 ◽  
Author(s):  
C. Rimaroli ◽  
T. Bruzzese
Keyword(s):  
Candida Albicans ◽  
Amphotericin B ◽  
Candida Tropicalis ◽  
Candida Glabrata ◽  
Fungicidal Activity ◽  
Candida Krusei ◽  
Water Soluble ◽  
Vitro Activity ◽  
In Vitro Activity

ABSTRACT The in vitro activity of a new water-soluble polyene, SPA-S-843, was evaluated against 116 strains of Candida,Cryptococcus, and Saccharomyces spp. and compared with that of amphotericin B. SPA-S-843 demonstrated better inhibitory activity against all of the yeasts examined and better fungicidal activity against Candida albicans, Candida glabrata, Candida krusei, and Candida tropicalis than did amphotericin B.

scholarly journals Time-Kill Kinetics and In Vitro Antifungal Susceptibility of Non-fumigatus Aspergillus Species Isolated from Patients with Ocular Mycoses

2015 ◽  
Vol 181 (3-4) ◽  
pp. 225-233 ◽  
Author(s):  
Yasemin Öz ◽  
Havva Gül Özdemir ◽  
Egemen Gökbolat ◽  
Nuri Kiraz ◽  
Macit Ilkit ◽  
...  
Keyword(s):  
Antifungal Susceptibility ◽  
Aspergillus Species ◽  
In Vitro Antifungal Susceptibility ◽  
Time Kill

scholarly journals Comparison of the Fungicidal Activities of Caspofungin and Amphotericin B against Candida glabrata

2005 ◽  
Vol 49 (12) ◽  
pp. 4989-4992 ◽  
Author(s):  
Francesco Barchiesi ◽  
Elisabetta Spreghini ◽  
Serena Tomassetti ◽  
Daniela Arzeni ◽  
Daniele Giannini ◽  
...  
Keyword(s):  
Body Weight ◽  
Mouse Model ◽  
Amphotericin B ◽  
Fungal Pathogen ◽  
Candida Glabrata ◽  
Fungicidal Activity ◽  
Disseminated Infection ◽  
Fungicidal Effect ◽  
Time Kill

ABSTRACT We investigated the fungicidal activity of caspofungin (CAS) and amphotericin B (AMB) against 16 clinical isolates of Candida glabrata. The minimum fungicidal concentrations (MFCs) of CAS were similar to those of AMB, ranging from 2.0 to >8.0 μg/ml. Time-kill assays performed on selected isolates showed that AMB was fungicidal at concentrations four times the MIC while CAS was not. A neutropenic-mouse model of disseminated infection was utilized to determine the residual fungal kidney burden. While doses as low as 0.3 and 1 mg/kg of body weight/day of CAS and AMB, respectively, were effective at reducing the counts with respect to controls, organ sterilization was reached when both drugs were administered at 5 mg/kg/day. Our study reveals that, similar to AMB, CAS has the potential for a fungicidal effect in vivo against this difficult-to-treat fungal pathogen.

scholarly journals The Emergence of Echinocandin-Resistant Candida glabrata Exhibiting High MICs and Related FKS Mutations in Turkey

2021 ◽  
Vol 7 (9) ◽  
pp. 691
Author(s):  
Ali Korhan Sig ◽  
Meliha Cagla Sonmezer ◽  
Dolunay Gülmez ◽  
Serhat Duyan ◽  
Ömrüm Uzun ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Fungal Infections ◽  
Antifungal Susceptibility ◽  
Venous Catheter ◽  
High Dose ◽  
High Morbidity ◽  
First Case ◽  
Hospitalization Period ◽  
Echinocandin Resistance

The frequency of invasive fungal infections shows a rising trend as well as a high morbidity and mortality. Among the causative agents, a shift toward the non-albicans Candida species including Candida glabrata species complex is being observed in several centers. Echinocandin resistance is increasingly published; however, isolates presenting with an in vitro resistance have not yet been reported from Turkey. We, herein, report the first FKS mutant and phenotypically echinocandin-resistant C. glabrata clinical strains from a single center in Turkey. In a 43-year-old female patient, several enterocutaneous fistulae developed after a long term hospitalization period and several complicated surgeries. She eventually required parenteral nutrition via a tunneled central venous catheter (CVC). Following a number of bacteremic and fungemic episodes as well as intensive antimicrobial interventions (including fluconazole, caspofungin and anidulafungin), a CVC-related candidemia caused by C. glabrata was detected. The isolated strain yielded high minimum inhibitory concentration (MIC) values for echinocandins and was categorized as resistant. A resistance-related mutation was detected in FKS2 HS1 (D666V). Blood cultures remained negative after the removal of the CVC and treatment with caspofungin and high-dose fluconazole. Following this first case, two additional C. glabrata strains with high echinocandin MICs were isolated from the urine cultures of two unrelated patients from different wards with different mutations in FKS2 HS1 (S663P and delF659). Our findings indicate that routine antifungal susceptibility testing is crucial and underlines the need for attention for the increasing trend of acquired echinocandin resistance in C. glabrata.

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 Antifungal Activity of Caspofungin in Combination with Amphotericin B against Candida glabrata: Comparison of Disk Diffusion, Etest, and Time-Kill Methods

2008 ◽  
Vol 53 (2) ◽  
pp. 788-790 ◽  
Author(s):  
Nuri Kiraz ◽  
Ilknur Dağ ◽  
Mustafa Yamac ◽  
Abdurrahman Kiremitci ◽  
Nilgun Kaşifoğlu ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Amphotericin B ◽  
Candida Glabrata ◽  
Disk Diffusion ◽  
In Vitro Experiments ◽  
Positive Interaction ◽  
Time Kill

ABSTRACT The in vitro activities of caspofungin plus amphotericin B against 50 Candida glabrata isolates were evaluated by the time-kill, disk diffusion, and Etest methods. In vitro experiments showed a positive interaction. Even though each of these methods uses different conditions and endpoints, the results of the different methods frequently agreed.

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