Dataset Information

Determination of MIC Quality Control Parameters for Exebacase, a Novel Lysin with Antistaphylococcal Activity.

ABSTRACT: Exebacase (CF-301), a novel, antistaphylococcal lysin (cell wall hydrolase) is the first agent of this class to enter late-stage clinical development (phase 3, NCT04160468) for the treatment of Staphylococcus aureus bacteremia, including right-sided endocarditis. A multilaboratory Clinical and Laboratory Standards Institute (CLSI) M23-defined tier 2 quality control (QC) study was conducted to establish exebacase QC ranges for a new reference broth microdilution method. S. aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 were selected as reference QC strains. Broth microdilution MIC QC ranges for exebacase spanned 4 log₂ dilutions and contained 99.2% of the MIC results generated for the two reference strains. The QC ranges for exebacase were defined as 0.25 to 2 μg/ml and 8 to 64 μg/ml against S. aureus ATCC 29213 and E. faecalis ATCC 29212, respectively, and were approved by the CLSI Subcommittee on Antimicrobial Susceptibility Testing. These QC ranges established for use with the reference broth microdilution method developed for exebacase susceptibility testing will ensure the test performance and accuracy of results generated during clinical development.

SUBMITTER: Traczewski MM

PROVIDER: S-EPMC8218745 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Determination of MIC Quality Control Parameters for Exebacase, a Novel Lysin with Antistaphylococcal Activity.

Traczewski Maria M MM Ambler Jane E JE Schuch Raymond R

Journal of clinical microbiology 20210618 7

Exebacase (CF-301), a novel, antistaphylococcal lysin (cell wall hydrolase) is the first agent of this class to enter late-stage clinical development (phase 3, NCT04160468) for the treatment of Staphylococcus aureus bacteremia, including right-sided endocarditis. A multilaboratory Clinical and Laboratory Standards Institute (CLSI) M23-defined tier 2 quality control (QC) study was conducted to establish exebacase QC ranges for a new reference broth microdilution method. S. aureus ATCC 29213 and E ...[more]

PMID: 33910968

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Project description:Lysins (peptidoglycan hydrolases) are promising new protein-based antimicrobial candidates under development to address rising antibiotic resistance encountered among pathogenic bacteria. Exebacase is an antistaphylococcal lysin and the first member of the lysin class to have entered clinical trials in the United States. In this study, the bacteriolytic activity of exebacase was characterized with time-kill assays, turbidity reduction assays, and microscopy. Three methicillin-susceptible Staphylococcus aureus and three methicillin-resistant S. aureus isolates were tested in time-kill assays over a range of concentrations from 0.25 to 8 × MIC. Exebacase demonstrated a concentration-dependent killing and showed bactericidal activity (≥3 log10 kill achieved relative to the starting inoculum) within 3 h at 1 × MIC against all strains tested. Dose-dependent lysis by exebacase was, furthermore, observed in the turbidity reduction assay, wherein decreases in initial OD600 of 50% were observed within ~15 min at concentrations as low as 4 µg/mL. Membrane dissolution, loss of cytoplasmic material, and lysis were confirmed by video and electron microscopy. The demonstrated rapid bacteriolytic effect of exebacase is an important distinguishing feature of this novel modality. IMPORTANCE To guide the development of an investigational new antibacterial entity, microbiological data are required to evaluate the killing kinetics against target organism(s). Exebacase is a lysin (peptidoglycan hydrolase) that represents a novel antimicrobial modality based on degradation of the cell wall of Staphylococcus aureus. Killing by exebacase was determined in multiple assay formats including time-kill assays, wherein reductions of viability of ≥3 log10 colony-forming units/mL were observed within 3 h for multiple different isolates tested, consistent with very rapid bactericidal activity. Rapid reductions in optical density were likewise observed in exebacase-treated cultures, which were visually consistent with microscopic observations of rapid lysis. Overall, exebacase provides a novel antimicrobial modality against S. aureus, characterized by a rapid cidal and lytic activity.

Dataset Information

Determination of MIC Quality Control Parameters for Exebacase, a Novel Lysin with Antistaphylococcal Activity.

Publications

Determination of MIC Quality Control Parameters for Exebacase, a Novel Lysin with Antistaphylococcal Activity.

Similar Datasets

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