In Vitro Susceptibility Of MK-3118 Against Candida And Aspergillus Species Including Echinocandin And Azole Resistant Variants

Ref ID: 18723

Author:

C. Jimenez-Ortigosa, PhD – Postdoctoral fellow1, P. Paderu, MS – Research Associate 1, M. R. Motyl, PhD – Scientific Lead, Infectious Diseases Discovery 2, D. S. Perlin, PhD – Professor 1;

Author address:

1Publ. Hlth. Res. Inst., Newark, NJ, 2Merck Sharp & Dohme Corp., Kenilworth, NJ.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background and Objectives: MK-3118 is as an orally-active glucan synthesis inhibitor in clinical development. The aim of this study was to assess the efficacy of MK-3118 against a large collection of Candida and Aspergillus spp., including echinocandin-resistant (ER) fks Candida and Aspergillus mutants, fluconazole (FLZ) resistant Candida mutants and azole-resistant cyp51A A. fumigatus mutants. Methods: MICs were determined for a panel of 124 CS (43 C. albicans, 22 C. glabrata, 2 C. dubliniensis, 17 C. krusei, 19 C. parapsilosis and 21 C. tropicalis) and 46 AS (18 A. fumigatus, 12 A. flavus, 10 A. niger and 6 A. terreus) with 30 isolates showing an ER phenotype [caspofungin (CSF) MIC>2 µg/ml] in accordance with the CLSI M27-A3 and M38-A2 methodologies. The in vitro susceptibility data was evaluated by species and resistance type. A subset of Candida spp. were evaluated for the effect of 50% serum on MIC values. Results and Conclusions: MK-3118 was effective against wild type and FLZ resistant Candida spp. strains with MIC values comparable to that of caspofungin (MIC range 0.03-0.06 µg/ml). Moreover, MK-3118 was highly active on fks-mediated ER strains especially those from C. albicans (MIC range MK3118 vs CSF: 0.03-1 µg/ml vs 0.03-2 µg/ml) and C. glabrata (MIC range MK3118 vs CSF: 0.25-8 µg/ml vs 2-16 µg/ml). MK-3118 was also highly active on Aspergillus spp strains showing MIC values very similar to that of CSF (MIC range: 0.03-0.25 µg/ml), although this compound was not particularly effective on A. flavus after 24h. MK-3118 showed fungicidal activity against all Aspergillus species at high concentrations (8 µg/ml after 24h). Finally, as observed previously with echinocandin drugs, serum shifted the relative efficacy of MK-3118 between 3-6 dilutions depending on the Candida species. Overall, the data is consistent with MK-3118 inhibiting glucan synthase in an effective but largely echinocandin-independent manner.

Abstract Number: M-1715

Conference Poster: y

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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