The Experts below are selected from a list of 2901 Experts worldwide ranked by ideXlab platform
Mariana Castanheira - One of the best experts on this subject based on the ideXlab platform.
-
activity of a long acting Echinocandin rezafungin and comparator antifungal agents tested against contemporary invasive fungal isolates sentry program 2016 to 2018
Antimicrobial Agents and Chemotherapy, 2020Co-Authors: Michael A. Pfaller, S A Messer, Paul R Rhomberg, Cecilia G Carvalhaes, Mariana CastanheiraAbstract:We evaluated the activity of rezafungin and comparators, using Clinical and Laboratory Standards Institute (CLSI) broth microdilution methods, against a worldwide collection of 2,205 invasive fungal isolates recovered from 2016 to 2018. Candida (n = 1,904 isolates; 6 species), Cryptococcus neoformans (n = 73), Aspergillus fumigatus (n = 183), and Aspergillus flavus (n = 45) isolates were tested for their susceptibility (S) to rezafungin as well as the comparators caspofungin, anidulafungin, micafungin, and azoles. Interpretive criteria were applied following CLSI published clinical breakpoints (CBPs) and epidemiological cutoff values (ECVs). Isolates displaying non-wild-type (non-WT) Echinocandin MIC values were sequenced for hot spot (HS) mutations. Rezafungin inhibited 99.8% of Candida albicans isolates (MIC50/90, 0.03/0.06 μg/ml), 95.7% of Candida glabrata isolates (MIC50/90, 0.06/0.12 μg/ml), 97.4% of Candida tropicalis isolates (MIC50/90, 0.03/0.06 μg/ml), 100.0% of Candida krusei isolates (MIC50/90, 0.03/0.06 μg/ml), and 100.0% of Candida dubliniensis isolates (MIC50/90, 0.06/0.12 μg/ml) at ≤0.12 μg/ml. All (329/329 [100.0%]) Candida parapsilosis isolates (MIC50/90,1/2 μg/ml) were inhibited by rezafungin at ≤4 μg/ml. Fluconazole resistance was detected among 8.6% of C. glabrata isolates, 12.5% of C. parapsilosis isolates, 3.2% of C. dubliniensis isolates, and 2.6% of C. tropicalis isolates. The activity of rezafungin against these 6 Candida spp. was similar to the activity of the other Echinocandins. Detection of the HS mutation was performed by sequencing Echinocandin-resistant or non-WT Candida isolates. Good activity against C. neoformans was observed for fluconazole and the other azoles, whereas the Echinocandins, including rezafungin, displayed limited activity. Rezafungin displayed activity similar to that of the other Echinocandins against A. fumigatus and A. flavus These in vitro data contribute to accumulating research demonstrating the potential of rezafungin for preventing and treating invasive fungal infections.
-
cd101 a long acting Echinocandin and comparator antifungal agents tested against a global collection of invasive fungal isolates in the sentry 2015 antifungal surveillance program
International Journal of Antimicrobial Agents, 2017Co-Authors: Michael A. Pfaller, S A Messer, Paul R Rhomberg, Mariana CastanheiraAbstract:CD101 is a novel Echinocandin with exceptional chemical stability and long-acting pharmacokinetics. The activity of CD101 and comparators was evaluated using CLSI broth microdilution methods against 713 invasive fungal isolates, including 589 Candida spp. (6 species), 14 C. neoformans, 97 A. fumigatus and 13 A. flavus species complex collected worldwide during 2015. All C. tropicalis, C. krusei and C. dubliniensis, 99.7% of C. albicans and 98.3% of C. glabrata were inhibited by ≤0.12 µg/mL of CD101, and these isolates were susceptible/wild type to other Echinocandins using CLSI clinical breakpoint and epidemiological cutoff value (ECV) interpretive criteria. C. parapsilosis displayed higher MIC values (range 0.25-2 µg/mL), but similar results were observed for other Echinocandins. One C. glabrata and one C. albicans with CD101 MIC value at 1 and 0.25 µg/mL possessed F625S and S645P alterations on FKS1, respectively. These isolates also displayed elevated MIC values for at least one clinically available Echinocandin. Fluconazole resistance was noted for 6.6% of C. glabrata and 3.6% C. parapsilosis. Echinocandins had limited activity against C. neoformans. CD101 activity against A. fumigatus and A. flavus (MEC ≤0.03 µg/mL) was comparable to other Echinocandins (MEC ≤0.03 µg/mL). These moulds had MIC values below ECVs for the mould-active azoles. CD101 was as active as other Echinocandins against common fungal organisms recovered from invasive fungal infections. The extended half-life profile is very desirable as less frequent dosing of this agent should facilitate shorter and more cost-effective hospital stays, improve compliance for outpatients, and provide more convenient outpatient prophylaxis.
-
differential activity of the oral glucan synthase inhibitor scy 078 against wild type and Echinocandin resistant strains of candida species
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Michael A. Pfaller, S A Messer, Paul R Rhomberg, Katyna Borrotoesoda, Mariana CastanheiraAbstract: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.
-
activity of a long acting Echinocandin cd101 and comparator antifungal agents tested against contemporary worldwide invasive fungal isolates
Open Forum Infectious Diseases, 2016Co-Authors: Michael A. Pfaller, S A Messer, Paul R Rhomberg, Sarah E Costello, Mariana CastanheiraAbstract:Background: Echinocandins are important agents for treatment of invasive fungal infections. We evaluated the activity of CD101, a once-weekly Echinocandin with extended half-life, and comparators against 606 invasive fungal isolates collected worldwide during 2014 using CLSI broth microdilution methods. Methods: 531 Candida spp. (7 species), 19 C. neoformans (CNEO) and 56 A. fumigatus (ASF) were susceptibility (S) tested for CD101, anidulafungin (ANF), caspofungin (CSF), micafungin (MCF) and azoles. CLSI clinical breakpoint (CBP) and epidemiological cutoff value (ECV) interpretive criteria were applied. Isolates displaying Echinocandin MIC>ECV were sequenced for fks hot spot (HS) mutations. Results: The activity of CD101 was similar to that of other Echinocandins (Table). All C. albicans (CA), C. tropicalis (CTRO), C. krusei and C. dubliniensis (n=11) were inhibited by ≤0.12 μg/ml of CD101 and were S/wild-type to other Echinocandins using CBP/ECV. Five C. glabrata (CGLA) displayed CD101 MIC >0.12 μg/ml (MIC, 1-4 μg/ml), elevated CSF (2->8 μg/ml), ANF (2-4 μg/ml) and MCF (2-4 μg/ml) results and carried mutations on fks1 HS1 S629P (3 isolates/2 also had HS2 S663P), HS2 F659S (1) or S663P (3 isolates). C. parapsilosis (CPRP; n=92) and C. orthopsilosis (n=10) displayed higher MIC values (ranges 0.5-4 and 0.12-2 μg/ml, respectively), but similar results were observed for other Echinocandins. Fluconazole resistance was noted among 11.0% of CGLA, 4.3% CPRP and 2.0% CA and CTRO. Echinocandins had limited activity against CNEO. CD101 activity against ASF was similar to that of MCF, two-fold greater than CSF, but less than ANF. These moulds displayed MIC values below ECVs for the mould-active azoles (itraconazole, voriconazole and posaconazole). Conclusions: CD101 was as active as other Echinocandins against common fungal organisms recovered from invasive fungal infections. The extended half-life profile is very desirable for prevention and treatment of serious fungal infections, especially in patients that can then be discharged. INTRODUCTION Despite the broad utilization of Echinocandins to treat invasive candidiasis (IC) in critically ill hospitalized patients, clinical resistance to these agents remains uncommon, although both breakthrough infections and acquired resistance mutations in some species of Candida have been noted. Whereas the currently available Echinocandins are highly efficacious and relatively easy to use in the treatment of IC and other invasive fungal infections (IFI), they must be administered daily by intravenous infusion, potentially prolonging the hospitalization of patients undergoing therapy and limiting their use to the inpatient setting. The availability of an Echinocandin with activity that is comparable to those presently in use but with a pharmacokinetic (PK) profile that allows for less frequent administration, would alter the standard-of-care therapy (e.g., Echinocandin therapy) to be more easily administered in both inpatient and outpatient settings. CD101 IV is a novel Echinocandin antifungal agent that displays chemical stability in plasma, aqueous solution, and at elevated temperature as well as possessing a long-acting PK. CD101 IV is being developed for once-weekly IV administration for the treatment and prevention of serious fungal infections. Less frequent administration while maintaining high exposure would alter hospital stays, improve compliance for outpatients and provide more convenient outpatient prophylaxis or maintenance treatment regimens. In the presented study, we determined the activity and potency of CD101 and comparator antifungal agents tested against 606 clinical fungal isolates collected worldwide from IFI (2014). MATERIALS AND METHODS Fungal organisms. A total of 606 non-duplicate prospectively collected fungal isolates from 38 medical centers located in North America (161 isolates; 10 sites), Europe (294; 17), the Asia-Pacific Region (82; 6) and Latin America (69; 5) were evaluated. Isolates selected were from the following sources: bloodstream, (379 strains), normally sterile body fluids, tissues or abscesses (22 strains), respiratory tract specimens (96 strains) and 109 were collected from other or non-specified body sites. Species identification. Yeast isolates were subcultured and screened using CHROMagar Candida (Becton Dickinson, Sparks, Maryland USA) to ensure purity and to differentiate Candida albicans/Candida dubliniensis, Candida tropicalis and Candida krusei. Isolates suspected to be either C. albicans or C. dubliniensis (green colonies on CHROMagar) were incubated at 45°C. All other yeast isolates were submitted to Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) using the MALDI Biotyper according to the manufacturer’s instructions (Bruker Daltonics, Billerica, Massachusetts USA). Isolates that were not identified by either phenotypic or proteomic methods were identified using sequencing-based methods as previously described. Antifungal susceptibility testing. All isolates were tested by broth microdilution according to Clinical and Laboratory Standards Institute (CLSI) methods outlined in documents M27-A3 and M38-A2. Frozen-form panels used RPMI 1640 broth supplemented with MOPS (morpholinepropane sulfonic acid) buffer and 0.2% glucose and inoculated with 0.5 to 2.5 X 103 cells/ml suspensions. MIC/MEC values were determined visually, after 24, 48 or 72 hours of incubation at 35oC, as the lowest concentration of drug that resulted in ≥50% inhibition of growth relative to the growth control or complete (100%) inhibition. CLSI clinical breakpoints were used for the five most common species of Candida (C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei) for Echinocandins, fluconazole and voriconazole. Epidemiological cutoff values (ECV) were applied when available. Quality control was performed as recommended in CLSI documents M27-A3 and M38-A2 using strains C. krusei ATCC 6258, C. parapsilosis ATCC 22019, A. flavus ATCC 204304 and A. fumigatus MYA-3626. RESULTS • CD101 (MIC50/90, 0.03/0.06 μg/ml) inhibited all 251 C. albicans isolates at ≤0.12 μg/ml (Table 1). This compound displayed activity most similar to that of caspofungin (MIC50/90, 0.03/0.06 μg/ml). • CD101 (MIC50 and MIC90, 0.03 and 0.06 μg/ml) inhibited 95 (95.0%) of the C. glabrata isolates at ≤0.12 μg/ml (Table 1). The activity of this investigational Echinocandin was two-fold greater when compared to anidulafungin or caspofungin (MIC50 and MIC90, 0.06 and 0.12 μg/ml for both compounds) and two-fold less than the activity of micafungin (MIC50 and MIC90, 0.015 and 0.03 μg/ml; Table 1). • All C. parapsilosis isolates were inhibited by CD101 (MIC50 and MIC90, 1 and 2 μg/ml) at ≤4 μg/ml (Table 1). CD101 displayed similar activity to that of micafungin (MIC50/90, 1/2 μg/ml), slightly greater activity when compared to anidulafungin (MIC50/90, 2/4 μg/ml) and was two-fold less active than caspofungin (MIC50/90, 0.5/1 μg/ml; Table 1). • C. tropicalis isolates (n=51) were considered susceptible to the clinically available Echinocandins and CD101 (MIC50/90, 0.015/0.06 μg/ml) inhibited all isolates at ≤0.06 μg/ml (Table 1). • CD101 (MIC50 and MIC90, 0.03 and 0.06 μg/ml) was very active against 16 C. krusei and all isolates were inhibited at ≤0.06 μg/ml (Table 1). • The activity of CD101 (MIC50 and MIC90, 0.03 and 0.06 μg/ml; Table 1) against C. dubliniensis isolates was comparable to that of caspofungin (MIC50 and MIC90, 0.03 and 0.06 μg/ml). • CD101 (MIC50 and MIC90, 0.5 and 1 μg/ml) activity against C. orthopsilosis was similar to the activity of anidulafungin and micafungin (MIC50/90, 0.5/1 μg/ml for both). Caspofungin was two-fold more active against C. orthopsilosis isolates (MIC50 and MIC90, 0.25 and 0.5 μg/ml; Table 1) when compared to other Echinocandins. • The Echinocandins, including CD101, had limited activity against C. neoformans var. grubii isolates (n=19; Table 1); all isolates had MIC values at ≥8 μg/ml for these compounds. • Echinocandins displayed good activity against A. fumigatus; CD101 (MEC50 and MEC90, 0.015 and 0.015 μg/ml) activity was two-fold greater than that of caspofungin (MEC50/90, 0.03/0.03 μg/ml) and similar to that of micafungin. Anidulafungin (MEC50/90, ≤0.008/0.015 μg/ml; Table 1) was slightly more active than the other compounds from the same class. • Among the five C. glabrata isolates displaying resistant MIC results for clinically available Echinocandins, one harbored a mutation on fks1 HS1 encoding alteration S629P and another two carried alterations on fks2 HS1 F659S or S663P. The two remaining isolates were collected from the same patient in Edmonton, Canada and both strains carried alterations on fks1 HS1 S629P and fks2 HS1 S663P conferring elevated caspofungin MIC results (>8 μg/ml) and MIC results of 2-4 μg/ml for CD101, anidulafungin and micafungin (Table 2). • The activity of comparator agents tested against organisms/organism groups is displayed in Figure 1. Fluconazole resistance was noted among 2.0% of C. albicans and C. tropicalis, 11.0% of C. glabrata and 4.3% of C. parapsilosis. All C. neoformans var. grubii and A. fumigatus isolates were considered wild-type for the azoles. CONCLUSIONS • The activity of CD101 tested by reference methods against common fungal species isolated from invasive infections worldwide during 2014 was comparable to currently available Echinocandins. • Further evaluation of CD101 against less common species is recommended, and expanded clinical development of this long-acting Echinocandin is warranted.
-
in vitro antifungal susceptibilities of isolates of candida spp and aspergillus spp from china to nine systemically active antifungal agents data from the sentry antifungal surveillance program 2010 through 2012
Mycoses, 2015Co-Authors: Michael A. Pfaller, Mariana Castanheira, S A Messer, Ronald N JonesAbstract:Summary We report the in vitro activity of nine systemically active antifungal agents against 237 contemporary clinical isolates of yeast and moulds obtained from 13 laboratories in China during 2010 through 2012. Susceptibility testing was performed using CLSI methods. Sequencing of fks hot spots was performed for Echinocandin non-wild-type (WT) strains. Isolates included 220 from eight species of Candida, 15 from four species of Aspergillus and one isolate each of Rhodotorula mucilaginosa and Trichosporon asahii. Resistance to amphotericin B (0.0%), flucytosine (0.0–1.7%) and the Echinocandins (0.0–3.4%) was distinctly uncommon among C. albicans, C. parapsilosis, C. tropicalis, C. glabrata and C. pelliculosa. Three C. albicans isolates showed resistance to Echinocandins and one harboured a mutation in HS1 of fks1. Resistance to the azoles was much more common with resistance to fluconazole, voriconazole and posaconazole detected among isolates of C. glabrata and C. tropicalis. Both C. parapsilosis and C. pelliculosa exhibited decreased susceptibility to fluconazole. Amphotericin B, the mould-active azoles and the Echinocandins were all quite active against isolates of A. fumigatus and A. flavus. Consistent with previous studies from China, resistance to fluconazole is prominent among Candida spp. isolates in this country.
Michael A. Pfaller - One of the best experts on this subject based on the ideXlab platform.
-
activity of a long acting Echinocandin rezafungin and comparator antifungal agents tested against contemporary invasive fungal isolates sentry program 2016 to 2018
Antimicrobial Agents and Chemotherapy, 2020Co-Authors: Michael A. Pfaller, S A Messer, Paul R Rhomberg, Cecilia G Carvalhaes, Mariana CastanheiraAbstract:We evaluated the activity of rezafungin and comparators, using Clinical and Laboratory Standards Institute (CLSI) broth microdilution methods, against a worldwide collection of 2,205 invasive fungal isolates recovered from 2016 to 2018. Candida (n = 1,904 isolates; 6 species), Cryptococcus neoformans (n = 73), Aspergillus fumigatus (n = 183), and Aspergillus flavus (n = 45) isolates were tested for their susceptibility (S) to rezafungin as well as the comparators caspofungin, anidulafungin, micafungin, and azoles. Interpretive criteria were applied following CLSI published clinical breakpoints (CBPs) and epidemiological cutoff values (ECVs). Isolates displaying non-wild-type (non-WT) Echinocandin MIC values were sequenced for hot spot (HS) mutations. Rezafungin inhibited 99.8% of Candida albicans isolates (MIC50/90, 0.03/0.06 μg/ml), 95.7% of Candida glabrata isolates (MIC50/90, 0.06/0.12 μg/ml), 97.4% of Candida tropicalis isolates (MIC50/90, 0.03/0.06 μg/ml), 100.0% of Candida krusei isolates (MIC50/90, 0.03/0.06 μg/ml), and 100.0% of Candida dubliniensis isolates (MIC50/90, 0.06/0.12 μg/ml) at ≤0.12 μg/ml. All (329/329 [100.0%]) Candida parapsilosis isolates (MIC50/90,1/2 μg/ml) were inhibited by rezafungin at ≤4 μg/ml. Fluconazole resistance was detected among 8.6% of C. glabrata isolates, 12.5% of C. parapsilosis isolates, 3.2% of C. dubliniensis isolates, and 2.6% of C. tropicalis isolates. The activity of rezafungin against these 6 Candida spp. was similar to the activity of the other Echinocandins. Detection of the HS mutation was performed by sequencing Echinocandin-resistant or non-WT Candida isolates. Good activity against C. neoformans was observed for fluconazole and the other azoles, whereas the Echinocandins, including rezafungin, displayed limited activity. Rezafungin displayed activity similar to that of the other Echinocandins against A. fumigatus and A. flavus These in vitro data contribute to accumulating research demonstrating the potential of rezafungin for preventing and treating invasive fungal infections.
-
cd101 a long acting Echinocandin and comparator antifungal agents tested against a global collection of invasive fungal isolates in the sentry 2015 antifungal surveillance program
International Journal of Antimicrobial Agents, 2017Co-Authors: Michael A. Pfaller, S A Messer, Paul R Rhomberg, Mariana CastanheiraAbstract:CD101 is a novel Echinocandin with exceptional chemical stability and long-acting pharmacokinetics. The activity of CD101 and comparators was evaluated using CLSI broth microdilution methods against 713 invasive fungal isolates, including 589 Candida spp. (6 species), 14 C. neoformans, 97 A. fumigatus and 13 A. flavus species complex collected worldwide during 2015. All C. tropicalis, C. krusei and C. dubliniensis, 99.7% of C. albicans and 98.3% of C. glabrata were inhibited by ≤0.12 µg/mL of CD101, and these isolates were susceptible/wild type to other Echinocandins using CLSI clinical breakpoint and epidemiological cutoff value (ECV) interpretive criteria. C. parapsilosis displayed higher MIC values (range 0.25-2 µg/mL), but similar results were observed for other Echinocandins. One C. glabrata and one C. albicans with CD101 MIC value at 1 and 0.25 µg/mL possessed F625S and S645P alterations on FKS1, respectively. These isolates also displayed elevated MIC values for at least one clinically available Echinocandin. Fluconazole resistance was noted for 6.6% of C. glabrata and 3.6% C. parapsilosis. Echinocandins had limited activity against C. neoformans. CD101 activity against A. fumigatus and A. flavus (MEC ≤0.03 µg/mL) was comparable to other Echinocandins (MEC ≤0.03 µg/mL). These moulds had MIC values below ECVs for the mould-active azoles. CD101 was as active as other Echinocandins against common fungal organisms recovered from invasive fungal infections. The extended half-life profile is very desirable as less frequent dosing of this agent should facilitate shorter and more cost-effective hospital stays, improve compliance for outpatients, and provide more convenient outpatient prophylaxis.
-
differential activity of the oral glucan synthase inhibitor scy 078 against wild type and Echinocandin resistant strains of candida species
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Michael A. Pfaller, S A Messer, Paul R Rhomberg, Katyna Borrotoesoda, Mariana CastanheiraAbstract: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.
-
activity of a long acting Echinocandin cd101 and comparator antifungal agents tested against contemporary worldwide invasive fungal isolates
Open Forum Infectious Diseases, 2016Co-Authors: Michael A. Pfaller, S A Messer, Paul R Rhomberg, Sarah E Costello, Mariana CastanheiraAbstract:Background: Echinocandins are important agents for treatment of invasive fungal infections. We evaluated the activity of CD101, a once-weekly Echinocandin with extended half-life, and comparators against 606 invasive fungal isolates collected worldwide during 2014 using CLSI broth microdilution methods. Methods: 531 Candida spp. (7 species), 19 C. neoformans (CNEO) and 56 A. fumigatus (ASF) were susceptibility (S) tested for CD101, anidulafungin (ANF), caspofungin (CSF), micafungin (MCF) and azoles. CLSI clinical breakpoint (CBP) and epidemiological cutoff value (ECV) interpretive criteria were applied. Isolates displaying Echinocandin MIC>ECV were sequenced for fks hot spot (HS) mutations. Results: The activity of CD101 was similar to that of other Echinocandins (Table). All C. albicans (CA), C. tropicalis (CTRO), C. krusei and C. dubliniensis (n=11) were inhibited by ≤0.12 μg/ml of CD101 and were S/wild-type to other Echinocandins using CBP/ECV. Five C. glabrata (CGLA) displayed CD101 MIC >0.12 μg/ml (MIC, 1-4 μg/ml), elevated CSF (2->8 μg/ml), ANF (2-4 μg/ml) and MCF (2-4 μg/ml) results and carried mutations on fks1 HS1 S629P (3 isolates/2 also had HS2 S663P), HS2 F659S (1) or S663P (3 isolates). C. parapsilosis (CPRP; n=92) and C. orthopsilosis (n=10) displayed higher MIC values (ranges 0.5-4 and 0.12-2 μg/ml, respectively), but similar results were observed for other Echinocandins. Fluconazole resistance was noted among 11.0% of CGLA, 4.3% CPRP and 2.0% CA and CTRO. Echinocandins had limited activity against CNEO. CD101 activity against ASF was similar to that of MCF, two-fold greater than CSF, but less than ANF. These moulds displayed MIC values below ECVs for the mould-active azoles (itraconazole, voriconazole and posaconazole). Conclusions: CD101 was as active as other Echinocandins against common fungal organisms recovered from invasive fungal infections. The extended half-life profile is very desirable for prevention and treatment of serious fungal infections, especially in patients that can then be discharged. INTRODUCTION Despite the broad utilization of Echinocandins to treat invasive candidiasis (IC) in critically ill hospitalized patients, clinical resistance to these agents remains uncommon, although both breakthrough infections and acquired resistance mutations in some species of Candida have been noted. Whereas the currently available Echinocandins are highly efficacious and relatively easy to use in the treatment of IC and other invasive fungal infections (IFI), they must be administered daily by intravenous infusion, potentially prolonging the hospitalization of patients undergoing therapy and limiting their use to the inpatient setting. The availability of an Echinocandin with activity that is comparable to those presently in use but with a pharmacokinetic (PK) profile that allows for less frequent administration, would alter the standard-of-care therapy (e.g., Echinocandin therapy) to be more easily administered in both inpatient and outpatient settings. CD101 IV is a novel Echinocandin antifungal agent that displays chemical stability in plasma, aqueous solution, and at elevated temperature as well as possessing a long-acting PK. CD101 IV is being developed for once-weekly IV administration for the treatment and prevention of serious fungal infections. Less frequent administration while maintaining high exposure would alter hospital stays, improve compliance for outpatients and provide more convenient outpatient prophylaxis or maintenance treatment regimens. In the presented study, we determined the activity and potency of CD101 and comparator antifungal agents tested against 606 clinical fungal isolates collected worldwide from IFI (2014). MATERIALS AND METHODS Fungal organisms. A total of 606 non-duplicate prospectively collected fungal isolates from 38 medical centers located in North America (161 isolates; 10 sites), Europe (294; 17), the Asia-Pacific Region (82; 6) and Latin America (69; 5) were evaluated. Isolates selected were from the following sources: bloodstream, (379 strains), normally sterile body fluids, tissues or abscesses (22 strains), respiratory tract specimens (96 strains) and 109 were collected from other or non-specified body sites. Species identification. Yeast isolates were subcultured and screened using CHROMagar Candida (Becton Dickinson, Sparks, Maryland USA) to ensure purity and to differentiate Candida albicans/Candida dubliniensis, Candida tropicalis and Candida krusei. Isolates suspected to be either C. albicans or C. dubliniensis (green colonies on CHROMagar) were incubated at 45°C. All other yeast isolates were submitted to Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) using the MALDI Biotyper according to the manufacturer’s instructions (Bruker Daltonics, Billerica, Massachusetts USA). Isolates that were not identified by either phenotypic or proteomic methods were identified using sequencing-based methods as previously described. Antifungal susceptibility testing. All isolates were tested by broth microdilution according to Clinical and Laboratory Standards Institute (CLSI) methods outlined in documents M27-A3 and M38-A2. Frozen-form panels used RPMI 1640 broth supplemented with MOPS (morpholinepropane sulfonic acid) buffer and 0.2% glucose and inoculated with 0.5 to 2.5 X 103 cells/ml suspensions. MIC/MEC values were determined visually, after 24, 48 or 72 hours of incubation at 35oC, as the lowest concentration of drug that resulted in ≥50% inhibition of growth relative to the growth control or complete (100%) inhibition. CLSI clinical breakpoints were used for the five most common species of Candida (C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei) for Echinocandins, fluconazole and voriconazole. Epidemiological cutoff values (ECV) were applied when available. Quality control was performed as recommended in CLSI documents M27-A3 and M38-A2 using strains C. krusei ATCC 6258, C. parapsilosis ATCC 22019, A. flavus ATCC 204304 and A. fumigatus MYA-3626. RESULTS • CD101 (MIC50/90, 0.03/0.06 μg/ml) inhibited all 251 C. albicans isolates at ≤0.12 μg/ml (Table 1). This compound displayed activity most similar to that of caspofungin (MIC50/90, 0.03/0.06 μg/ml). • CD101 (MIC50 and MIC90, 0.03 and 0.06 μg/ml) inhibited 95 (95.0%) of the C. glabrata isolates at ≤0.12 μg/ml (Table 1). The activity of this investigational Echinocandin was two-fold greater when compared to anidulafungin or caspofungin (MIC50 and MIC90, 0.06 and 0.12 μg/ml for both compounds) and two-fold less than the activity of micafungin (MIC50 and MIC90, 0.015 and 0.03 μg/ml; Table 1). • All C. parapsilosis isolates were inhibited by CD101 (MIC50 and MIC90, 1 and 2 μg/ml) at ≤4 μg/ml (Table 1). CD101 displayed similar activity to that of micafungin (MIC50/90, 1/2 μg/ml), slightly greater activity when compared to anidulafungin (MIC50/90, 2/4 μg/ml) and was two-fold less active than caspofungin (MIC50/90, 0.5/1 μg/ml; Table 1). • C. tropicalis isolates (n=51) were considered susceptible to the clinically available Echinocandins and CD101 (MIC50/90, 0.015/0.06 μg/ml) inhibited all isolates at ≤0.06 μg/ml (Table 1). • CD101 (MIC50 and MIC90, 0.03 and 0.06 μg/ml) was very active against 16 C. krusei and all isolates were inhibited at ≤0.06 μg/ml (Table 1). • The activity of CD101 (MIC50 and MIC90, 0.03 and 0.06 μg/ml; Table 1) against C. dubliniensis isolates was comparable to that of caspofungin (MIC50 and MIC90, 0.03 and 0.06 μg/ml). • CD101 (MIC50 and MIC90, 0.5 and 1 μg/ml) activity against C. orthopsilosis was similar to the activity of anidulafungin and micafungin (MIC50/90, 0.5/1 μg/ml for both). Caspofungin was two-fold more active against C. orthopsilosis isolates (MIC50 and MIC90, 0.25 and 0.5 μg/ml; Table 1) when compared to other Echinocandins. • The Echinocandins, including CD101, had limited activity against C. neoformans var. grubii isolates (n=19; Table 1); all isolates had MIC values at ≥8 μg/ml for these compounds. • Echinocandins displayed good activity against A. fumigatus; CD101 (MEC50 and MEC90, 0.015 and 0.015 μg/ml) activity was two-fold greater than that of caspofungin (MEC50/90, 0.03/0.03 μg/ml) and similar to that of micafungin. Anidulafungin (MEC50/90, ≤0.008/0.015 μg/ml; Table 1) was slightly more active than the other compounds from the same class. • Among the five C. glabrata isolates displaying resistant MIC results for clinically available Echinocandins, one harbored a mutation on fks1 HS1 encoding alteration S629P and another two carried alterations on fks2 HS1 F659S or S663P. The two remaining isolates were collected from the same patient in Edmonton, Canada and both strains carried alterations on fks1 HS1 S629P and fks2 HS1 S663P conferring elevated caspofungin MIC results (>8 μg/ml) and MIC results of 2-4 μg/ml for CD101, anidulafungin and micafungin (Table 2). • The activity of comparator agents tested against organisms/organism groups is displayed in Figure 1. Fluconazole resistance was noted among 2.0% of C. albicans and C. tropicalis, 11.0% of C. glabrata and 4.3% of C. parapsilosis. All C. neoformans var. grubii and A. fumigatus isolates were considered wild-type for the azoles. CONCLUSIONS • The activity of CD101 tested by reference methods against common fungal species isolated from invasive infections worldwide during 2014 was comparable to currently available Echinocandins. • Further evaluation of CD101 against less common species is recommended, and expanded clinical development of this long-acting Echinocandin is warranted.
-
in vitro antifungal susceptibilities of isolates of candida spp and aspergillus spp from china to nine systemically active antifungal agents data from the sentry antifungal surveillance program 2010 through 2012
Mycoses, 2015Co-Authors: Michael A. Pfaller, Mariana Castanheira, S A Messer, Ronald N JonesAbstract:Summary We report the in vitro activity of nine systemically active antifungal agents against 237 contemporary clinical isolates of yeast and moulds obtained from 13 laboratories in China during 2010 through 2012. Susceptibility testing was performed using CLSI methods. Sequencing of fks hot spots was performed for Echinocandin non-wild-type (WT) strains. Isolates included 220 from eight species of Candida, 15 from four species of Aspergillus and one isolate each of Rhodotorula mucilaginosa and Trichosporon asahii. Resistance to amphotericin B (0.0%), flucytosine (0.0–1.7%) and the Echinocandins (0.0–3.4%) was distinctly uncommon among C. albicans, C. parapsilosis, C. tropicalis, C. glabrata and C. pelliculosa. Three C. albicans isolates showed resistance to Echinocandins and one harboured a mutation in HS1 of fks1. Resistance to the azoles was much more common with resistance to fluconazole, voriconazole and posaconazole detected among isolates of C. glabrata and C. tropicalis. Both C. parapsilosis and C. pelliculosa exhibited decreased susceptibility to fluconazole. Amphotericin B, the mould-active azoles and the Echinocandins were all quite active against isolates of A. fumigatus and A. flavus. Consistent with previous studies from China, resistance to fluconazole is prominent among Candida spp. isolates in this country.
S A Messer - One of the best experts on this subject based on the ideXlab platform.
-
activity of a long acting Echinocandin rezafungin and comparator antifungal agents tested against contemporary invasive fungal isolates sentry program 2016 to 2018
Antimicrobial Agents and Chemotherapy, 2020Co-Authors: Michael A. Pfaller, S A Messer, Paul R Rhomberg, Cecilia G Carvalhaes, Mariana CastanheiraAbstract:We evaluated the activity of rezafungin and comparators, using Clinical and Laboratory Standards Institute (CLSI) broth microdilution methods, against a worldwide collection of 2,205 invasive fungal isolates recovered from 2016 to 2018. Candida (n = 1,904 isolates; 6 species), Cryptococcus neoformans (n = 73), Aspergillus fumigatus (n = 183), and Aspergillus flavus (n = 45) isolates were tested for their susceptibility (S) to rezafungin as well as the comparators caspofungin, anidulafungin, micafungin, and azoles. Interpretive criteria were applied following CLSI published clinical breakpoints (CBPs) and epidemiological cutoff values (ECVs). Isolates displaying non-wild-type (non-WT) Echinocandin MIC values were sequenced for hot spot (HS) mutations. Rezafungin inhibited 99.8% of Candida albicans isolates (MIC50/90, 0.03/0.06 μg/ml), 95.7% of Candida glabrata isolates (MIC50/90, 0.06/0.12 μg/ml), 97.4% of Candida tropicalis isolates (MIC50/90, 0.03/0.06 μg/ml), 100.0% of Candida krusei isolates (MIC50/90, 0.03/0.06 μg/ml), and 100.0% of Candida dubliniensis isolates (MIC50/90, 0.06/0.12 μg/ml) at ≤0.12 μg/ml. All (329/329 [100.0%]) Candida parapsilosis isolates (MIC50/90,1/2 μg/ml) were inhibited by rezafungin at ≤4 μg/ml. Fluconazole resistance was detected among 8.6% of C. glabrata isolates, 12.5% of C. parapsilosis isolates, 3.2% of C. dubliniensis isolates, and 2.6% of C. tropicalis isolates. The activity of rezafungin against these 6 Candida spp. was similar to the activity of the other Echinocandins. Detection of the HS mutation was performed by sequencing Echinocandin-resistant or non-WT Candida isolates. Good activity against C. neoformans was observed for fluconazole and the other azoles, whereas the Echinocandins, including rezafungin, displayed limited activity. Rezafungin displayed activity similar to that of the other Echinocandins against A. fumigatus and A. flavus These in vitro data contribute to accumulating research demonstrating the potential of rezafungin for preventing and treating invasive fungal infections.
-
cd101 a long acting Echinocandin and comparator antifungal agents tested against a global collection of invasive fungal isolates in the sentry 2015 antifungal surveillance program
International Journal of Antimicrobial Agents, 2017Co-Authors: Michael A. Pfaller, S A Messer, Paul R Rhomberg, Mariana CastanheiraAbstract:CD101 is a novel Echinocandin with exceptional chemical stability and long-acting pharmacokinetics. The activity of CD101 and comparators was evaluated using CLSI broth microdilution methods against 713 invasive fungal isolates, including 589 Candida spp. (6 species), 14 C. neoformans, 97 A. fumigatus and 13 A. flavus species complex collected worldwide during 2015. All C. tropicalis, C. krusei and C. dubliniensis, 99.7% of C. albicans and 98.3% of C. glabrata were inhibited by ≤0.12 µg/mL of CD101, and these isolates were susceptible/wild type to other Echinocandins using CLSI clinical breakpoint and epidemiological cutoff value (ECV) interpretive criteria. C. parapsilosis displayed higher MIC values (range 0.25-2 µg/mL), but similar results were observed for other Echinocandins. One C. glabrata and one C. albicans with CD101 MIC value at 1 and 0.25 µg/mL possessed F625S and S645P alterations on FKS1, respectively. These isolates also displayed elevated MIC values for at least one clinically available Echinocandin. Fluconazole resistance was noted for 6.6% of C. glabrata and 3.6% C. parapsilosis. Echinocandins had limited activity against C. neoformans. CD101 activity against A. fumigatus and A. flavus (MEC ≤0.03 µg/mL) was comparable to other Echinocandins (MEC ≤0.03 µg/mL). These moulds had MIC values below ECVs for the mould-active azoles. CD101 was as active as other Echinocandins against common fungal organisms recovered from invasive fungal infections. The extended half-life profile is very desirable as less frequent dosing of this agent should facilitate shorter and more cost-effective hospital stays, improve compliance for outpatients, and provide more convenient outpatient prophylaxis.
-
differential activity of the oral glucan synthase inhibitor scy 078 against wild type and Echinocandin resistant strains of candida species
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Michael A. Pfaller, S A Messer, Paul R Rhomberg, Katyna Borrotoesoda, Mariana CastanheiraAbstract: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.
-
activity of a long acting Echinocandin cd101 and comparator antifungal agents tested against contemporary worldwide invasive fungal isolates
Open Forum Infectious Diseases, 2016Co-Authors: Michael A. Pfaller, S A Messer, Paul R Rhomberg, Sarah E Costello, Mariana CastanheiraAbstract:Background: Echinocandins are important agents for treatment of invasive fungal infections. We evaluated the activity of CD101, a once-weekly Echinocandin with extended half-life, and comparators against 606 invasive fungal isolates collected worldwide during 2014 using CLSI broth microdilution methods. Methods: 531 Candida spp. (7 species), 19 C. neoformans (CNEO) and 56 A. fumigatus (ASF) were susceptibility (S) tested for CD101, anidulafungin (ANF), caspofungin (CSF), micafungin (MCF) and azoles. CLSI clinical breakpoint (CBP) and epidemiological cutoff value (ECV) interpretive criteria were applied. Isolates displaying Echinocandin MIC>ECV were sequenced for fks hot spot (HS) mutations. Results: The activity of CD101 was similar to that of other Echinocandins (Table). All C. albicans (CA), C. tropicalis (CTRO), C. krusei and C. dubliniensis (n=11) were inhibited by ≤0.12 μg/ml of CD101 and were S/wild-type to other Echinocandins using CBP/ECV. Five C. glabrata (CGLA) displayed CD101 MIC >0.12 μg/ml (MIC, 1-4 μg/ml), elevated CSF (2->8 μg/ml), ANF (2-4 μg/ml) and MCF (2-4 μg/ml) results and carried mutations on fks1 HS1 S629P (3 isolates/2 also had HS2 S663P), HS2 F659S (1) or S663P (3 isolates). C. parapsilosis (CPRP; n=92) and C. orthopsilosis (n=10) displayed higher MIC values (ranges 0.5-4 and 0.12-2 μg/ml, respectively), but similar results were observed for other Echinocandins. Fluconazole resistance was noted among 11.0% of CGLA, 4.3% CPRP and 2.0% CA and CTRO. Echinocandins had limited activity against CNEO. CD101 activity against ASF was similar to that of MCF, two-fold greater than CSF, but less than ANF. These moulds displayed MIC values below ECVs for the mould-active azoles (itraconazole, voriconazole and posaconazole). Conclusions: CD101 was as active as other Echinocandins against common fungal organisms recovered from invasive fungal infections. The extended half-life profile is very desirable for prevention and treatment of serious fungal infections, especially in patients that can then be discharged. INTRODUCTION Despite the broad utilization of Echinocandins to treat invasive candidiasis (IC) in critically ill hospitalized patients, clinical resistance to these agents remains uncommon, although both breakthrough infections and acquired resistance mutations in some species of Candida have been noted. Whereas the currently available Echinocandins are highly efficacious and relatively easy to use in the treatment of IC and other invasive fungal infections (IFI), they must be administered daily by intravenous infusion, potentially prolonging the hospitalization of patients undergoing therapy and limiting their use to the inpatient setting. The availability of an Echinocandin with activity that is comparable to those presently in use but with a pharmacokinetic (PK) profile that allows for less frequent administration, would alter the standard-of-care therapy (e.g., Echinocandin therapy) to be more easily administered in both inpatient and outpatient settings. CD101 IV is a novel Echinocandin antifungal agent that displays chemical stability in plasma, aqueous solution, and at elevated temperature as well as possessing a long-acting PK. CD101 IV is being developed for once-weekly IV administration for the treatment and prevention of serious fungal infections. Less frequent administration while maintaining high exposure would alter hospital stays, improve compliance for outpatients and provide more convenient outpatient prophylaxis or maintenance treatment regimens. In the presented study, we determined the activity and potency of CD101 and comparator antifungal agents tested against 606 clinical fungal isolates collected worldwide from IFI (2014). MATERIALS AND METHODS Fungal organisms. A total of 606 non-duplicate prospectively collected fungal isolates from 38 medical centers located in North America (161 isolates; 10 sites), Europe (294; 17), the Asia-Pacific Region (82; 6) and Latin America (69; 5) were evaluated. Isolates selected were from the following sources: bloodstream, (379 strains), normally sterile body fluids, tissues or abscesses (22 strains), respiratory tract specimens (96 strains) and 109 were collected from other or non-specified body sites. Species identification. Yeast isolates were subcultured and screened using CHROMagar Candida (Becton Dickinson, Sparks, Maryland USA) to ensure purity and to differentiate Candida albicans/Candida dubliniensis, Candida tropicalis and Candida krusei. Isolates suspected to be either C. albicans or C. dubliniensis (green colonies on CHROMagar) were incubated at 45°C. All other yeast isolates were submitted to Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) using the MALDI Biotyper according to the manufacturer’s instructions (Bruker Daltonics, Billerica, Massachusetts USA). Isolates that were not identified by either phenotypic or proteomic methods were identified using sequencing-based methods as previously described. Antifungal susceptibility testing. All isolates were tested by broth microdilution according to Clinical and Laboratory Standards Institute (CLSI) methods outlined in documents M27-A3 and M38-A2. Frozen-form panels used RPMI 1640 broth supplemented with MOPS (morpholinepropane sulfonic acid) buffer and 0.2% glucose and inoculated with 0.5 to 2.5 X 103 cells/ml suspensions. MIC/MEC values were determined visually, after 24, 48 or 72 hours of incubation at 35oC, as the lowest concentration of drug that resulted in ≥50% inhibition of growth relative to the growth control or complete (100%) inhibition. CLSI clinical breakpoints were used for the five most common species of Candida (C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei) for Echinocandins, fluconazole and voriconazole. Epidemiological cutoff values (ECV) were applied when available. Quality control was performed as recommended in CLSI documents M27-A3 and M38-A2 using strains C. krusei ATCC 6258, C. parapsilosis ATCC 22019, A. flavus ATCC 204304 and A. fumigatus MYA-3626. RESULTS • CD101 (MIC50/90, 0.03/0.06 μg/ml) inhibited all 251 C. albicans isolates at ≤0.12 μg/ml (Table 1). This compound displayed activity most similar to that of caspofungin (MIC50/90, 0.03/0.06 μg/ml). • CD101 (MIC50 and MIC90, 0.03 and 0.06 μg/ml) inhibited 95 (95.0%) of the C. glabrata isolates at ≤0.12 μg/ml (Table 1). The activity of this investigational Echinocandin was two-fold greater when compared to anidulafungin or caspofungin (MIC50 and MIC90, 0.06 and 0.12 μg/ml for both compounds) and two-fold less than the activity of micafungin (MIC50 and MIC90, 0.015 and 0.03 μg/ml; Table 1). • All C. parapsilosis isolates were inhibited by CD101 (MIC50 and MIC90, 1 and 2 μg/ml) at ≤4 μg/ml (Table 1). CD101 displayed similar activity to that of micafungin (MIC50/90, 1/2 μg/ml), slightly greater activity when compared to anidulafungin (MIC50/90, 2/4 μg/ml) and was two-fold less active than caspofungin (MIC50/90, 0.5/1 μg/ml; Table 1). • C. tropicalis isolates (n=51) were considered susceptible to the clinically available Echinocandins and CD101 (MIC50/90, 0.015/0.06 μg/ml) inhibited all isolates at ≤0.06 μg/ml (Table 1). • CD101 (MIC50 and MIC90, 0.03 and 0.06 μg/ml) was very active against 16 C. krusei and all isolates were inhibited at ≤0.06 μg/ml (Table 1). • The activity of CD101 (MIC50 and MIC90, 0.03 and 0.06 μg/ml; Table 1) against C. dubliniensis isolates was comparable to that of caspofungin (MIC50 and MIC90, 0.03 and 0.06 μg/ml). • CD101 (MIC50 and MIC90, 0.5 and 1 μg/ml) activity against C. orthopsilosis was similar to the activity of anidulafungin and micafungin (MIC50/90, 0.5/1 μg/ml for both). Caspofungin was two-fold more active against C. orthopsilosis isolates (MIC50 and MIC90, 0.25 and 0.5 μg/ml; Table 1) when compared to other Echinocandins. • The Echinocandins, including CD101, had limited activity against C. neoformans var. grubii isolates (n=19; Table 1); all isolates had MIC values at ≥8 μg/ml for these compounds. • Echinocandins displayed good activity against A. fumigatus; CD101 (MEC50 and MEC90, 0.015 and 0.015 μg/ml) activity was two-fold greater than that of caspofungin (MEC50/90, 0.03/0.03 μg/ml) and similar to that of micafungin. Anidulafungin (MEC50/90, ≤0.008/0.015 μg/ml; Table 1) was slightly more active than the other compounds from the same class. • Among the five C. glabrata isolates displaying resistant MIC results for clinically available Echinocandins, one harbored a mutation on fks1 HS1 encoding alteration S629P and another two carried alterations on fks2 HS1 F659S or S663P. The two remaining isolates were collected from the same patient in Edmonton, Canada and both strains carried alterations on fks1 HS1 S629P and fks2 HS1 S663P conferring elevated caspofungin MIC results (>8 μg/ml) and MIC results of 2-4 μg/ml for CD101, anidulafungin and micafungin (Table 2). • The activity of comparator agents tested against organisms/organism groups is displayed in Figure 1. Fluconazole resistance was noted among 2.0% of C. albicans and C. tropicalis, 11.0% of C. glabrata and 4.3% of C. parapsilosis. All C. neoformans var. grubii and A. fumigatus isolates were considered wild-type for the azoles. CONCLUSIONS • The activity of CD101 tested by reference methods against common fungal species isolated from invasive infections worldwide during 2014 was comparable to currently available Echinocandins. • Further evaluation of CD101 against less common species is recommended, and expanded clinical development of this long-acting Echinocandin is warranted.
-
in vitro antifungal susceptibilities of isolates of candida spp and aspergillus spp from china to nine systemically active antifungal agents data from the sentry antifungal surveillance program 2010 through 2012
Mycoses, 2015Co-Authors: Michael A. Pfaller, Mariana Castanheira, S A Messer, Ronald N JonesAbstract:Summary We report the in vitro activity of nine systemically active antifungal agents against 237 contemporary clinical isolates of yeast and moulds obtained from 13 laboratories in China during 2010 through 2012. Susceptibility testing was performed using CLSI methods. Sequencing of fks hot spots was performed for Echinocandin non-wild-type (WT) strains. Isolates included 220 from eight species of Candida, 15 from four species of Aspergillus and one isolate each of Rhodotorula mucilaginosa and Trichosporon asahii. Resistance to amphotericin B (0.0%), flucytosine (0.0–1.7%) and the Echinocandins (0.0–3.4%) was distinctly uncommon among C. albicans, C. parapsilosis, C. tropicalis, C. glabrata and C. pelliculosa. Three C. albicans isolates showed resistance to Echinocandins and one harboured a mutation in HS1 of fks1. Resistance to the azoles was much more common with resistance to fluconazole, voriconazole and posaconazole detected among isolates of C. glabrata and C. tropicalis. Both C. parapsilosis and C. pelliculosa exhibited decreased susceptibility to fluconazole. Amphotericin B, the mould-active azoles and the Echinocandins were all quite active against isolates of A. fumigatus and A. flavus. Consistent with previous studies from China, resistance to fluconazole is prominent among Candida spp. isolates in this country.
Jose A. Vazquez - One of the best experts on this subject based on the ideXlab platform.
-
differential in vitro activity of anidulafungin caspofungin and micafungin against candida parapsilosis isolates recovered from a burn unit
Clinical Microbiology and Infection, 2009Co-Authors: Mahmoud A Ghannoum, Jose A. Vazquez, A Chen, M Buhari, Jyotsna Chandra, Pranab K Mukherjee, D Baxa, A GolembieskiAbstract:Recent studies suggest that differences in antifungal activity among Echinocandins may exist. In this study, the activities of three Echinocandins (anidulafungin, caspofungin, and micafungin) against Candida parapsilosis isolates from burn unit patients, healthcare workers and the hospital environment were determined. Additionally, the effect of these Echinocandins on the cell morphology of caspofungin-susceptible and caspofungin-non-susceptible isolates was assessed using scanning electron microscopy (SEM). The C. parapsilosis isolates obtained from patients were susceptible to anidulafungin, but were less so to caspofungin and micafungin. Isolates obtained from healthcare workers or environmental sources were susceptible to all antifungals. SEM data demonstrated that although anidulafungin and caspofungin were equally active against a caspofungin-susceptible C. parapsilosis strain, they differed in their ability to damage a caspofungin-non-susceptible strain, for which lower concentrations of anidulafungin (1 mg/L) than of caspofungin (16 mg/L) were needed to induce cellular damage and distortion of the cellular morphology. To determine whether the difference in the antifungal susceptibility of C. parapsilosis isolates to anidulafungin as compared to the other two Echinocandins could be due to different mutations in the FKS1 gene, the sequences of the 493-bp region of this gene associated with Echinocandin resistance were compared. No differences in the corresponding amino acid sequences were observed, indicating that differences in activity between anidulafungin and the other Echinocandins are not related to mutations in this region. The results of this study provide evidence that differences exist between the activities of anidulafungin and the other Echinocandins.
-
differential in vitro activity of anidulafungin caspofungin and micafungin against candida parapsilosis isolates recovered from a burn unit
Clinical Microbiology and Infection, 2009Co-Authors: Mahmoud A Ghannoum, Jose A. Vazquez, A Chen, M Buhari, Jyotsna Chandra, Pranab K Mukherjee, D Baxa, A GolembieskiAbstract:Recent studies suggest that differences in antifungal activity among Echinocandins may exist. In this study, the activities of three Echinocandins (anidulafungin, caspofungin, and micafungin) against Candida parapsilosis isolates from burn unit patients, healthcare workers and the hospital environment were determined. Additionally, the effect of these Echinocandins on the cell morphology of caspofungin-susceptible and caspofungin-non-susceptible isolates was assessed using scanning electron microscopy (SEM). The C. parapsilosis isolates obtained from patients were susceptible to anidulafungin, but were less so to caspofungin and micafungin. Isolates obtained from healthcare workers or environmental sources were susceptible to all antifungals. SEM data demonstrated that although anidulafungin and caspofungin were equally active against a caspofungin-susceptible C. parapsilosis strain, they differed in their ability to damage a caspofungin-non-susceptible strain, for which lower concentrations of anidulafungin (1 mg/L) than of caspofungin (16 mg/L) were needed to induce cellular damage and distortion of the cellular morphology. To determine whether the difference in the antifungal susceptibility of C. parapsilosis isolates to anidulafungin as compared to the other two Echinocandins could be due to different mutations in the FKS1 gene, the sequences of the 493-bp region of this gene associated with Echinocandin resistance were compared. No differences in the corresponding amino acid sequences were observed, indicating that differences in activity between anidulafungin and the other Echinocandins are not related to mutations in this region. The results of this study provide evidence that differences exist between the activities of anidulafungin and the other Echinocandins.
-
multiEchinocandin and multiazole resistant candida parapsilosis isolates serially obtained during therapy for prosthetic valve endocarditis
Antimicrobial Agents and Chemotherapy, 2005Co-Authors: Varsha Moudgal, Tania Little, Dina Boikov, Jose A. VazquezAbstract:Echinocandins are approved for the treatment of candidal infections. In vitro they have been shown to be less potent against strains of Candida parapsilosis than against other Candida spp. This is the first case report describing the development of a secondary multidrug (Echinocandin-azole)-resistant Candida strain during therapy.
Thomas F Patterson - One of the best experts on this subject based on the ideXlab platform.
-
oral glucan synthase inhibitor scy 078 is effective in an experimental murine model of invasive candidiasis caused by wt and Echinocandin resistant candida glabrata
Journal of Antimicrobial Chemotherapy, 2018Co-Authors: Nathan P Wiederhold, Laura K Najvar, Rosie Jaramillo, Marcos Olivo, Jason Pizzini, Gabriel Catano, Thomas F PattersonAbstract:Background Echinocandins are recommended as first-line therapy against Candida glabrata infections, although increased resistance to this class has been reported worldwide and they are currently only available for parenteral administration. SCY-078 is an investigational glucan synthase inhibitor that is orally available. Objectives To evaluate the in vivo efficacy of SCY-078 in an experimental model of invasive candidiasis due to WT and Echinocandin-resistant C. glabrata isolates. Methods Neutropenic ICR mice were inoculated intravenously with a WT isolate (SCY-078 and caspofungin MICs 0.25 and 0.125 mg/L, respectively) or an Echinocandin-resistant isolate (SCY-078 and caspofungin MICs 1 and 0.5 mg/L, respectively). Treatment with placebo, SCY-078 (8, 30 or 40 mg/kg orally every 12 h) or caspofungin (1 mg/kg by intraperitoneal injection once daily) began 24 h later. Kidney fungal burden was measured on day 8 post-inoculation. Results Significant reductions in kidney fungal burden were observed with 30 mg/kg SCY-078 against both isolates and with the 40 mg/kg dose against the Echinocandin-resistant isolate. These results were supported by SCY-078 plasma concentration data at the higher doses, where levels above the MICs for both isolates were observed 12 h after the last oral dose. Reductions in fungal burden were also observed with caspofungin against the WT isolate, but not against the resistant isolate. Conclusions SCY-078 demonstrated in vivo efficacy against infections caused by both WT and Echinocandin-resistant C. glabrata isolates in this experimental model. This orally available glucan synthase inhibitor has potential as a therapy against Echinocandin-resistant C. glabrata infections.
-
utilization and dosage pattern of Echinocandins for treatment of fungal infections in us hospital practice
Current Medical Research and Opinion, 2009Co-Authors: Sheenu Chandwani, Chuck Wentworth, Thomas A Burke, Thomas F PattersonAbstract:ABSTRACTObjective: With the availability of multiple Echinocandins in the US, recommended dosages and dosing schedules vary by agent but actual utilization practices are unknown. The purpose of this study was to describe the utilization and dosage pattern of intravenous Echinocandins for treatment of fungal infections in US hospitals.Methods: The Premier Perspective Database was used to describe Echinocandin use in 332 US hospitals. Adult patients hospitalized from January, 2006 through June, 2007 with at least one billing record for anidulafungin (Eraxis), caspofungin (Cancidas), or micafungin (Mycamine) were included. Hospitalizations with > 1 Echinocandin or ≥ 1 dosage with an FDA approved indication for fungal prophylaxis were excluded. Mixed multivariable models were developed to identify factors associated with mean daily dose. ** Eraxis, a registered trade name owned by Pfizer, Inc., New York, NY, USA † Cancidas, a registered trade name owned by Merck & Co., Inc., Whitehouse Station, NJ, USA ‡ Myca...
