Kevin J Westbrook, Gayatri Shankar Chilambi, Madison E Stellfox, Hayley R Nordstrom, Yanhong Li, Alina Iovleva, Niyati H Shah, Chelsea E Jones, Ellen G Kline, Kevin M Squires, William R Miller, Truc T Tran, Cesar A Arias, Yohei Doi, Ryan K Shields, Daria Van Tyne
The Journal of antimicrobial chemotherapy 2024 Apr 02To investigate the genomic diversity and β-lactam susceptibilities of Enterococcus faecalis collected from patients with infective endocarditis (IE). We collected 60 contemporary E. faecalis isolates from definite or probable IE cases identified between 2018 and 2021 at the University of Pittsburgh Medical Center. We used whole-genome sequencing to study bacterial genomic diversity and employed antibiotic checkerboard assays and a one-compartment pharmacokinetic-pharmacodynamic (PK/PD) model to investigate bacterial susceptibility to ampicillin and ceftriaxone both alone and in combination. Genetically diverse E. faecalis were collected, however, isolates belonging to two STs, ST6 and ST179, were collected from 21/60 (35%) IE patients. All ST6 isolates encoded a previously described mutation upstream of penicillin-binding protein 4 (pbp4) that is associated with pbp4 overexpression. ST6 isolates had higher ceftriaxone MICs and higher fractional inhibitory concentration index values for ampicillin and ceftriaxone (AC) compared to other isolates, suggesting diminished in vitro AC synergy against this lineage. Introduction of the pbp4 upstream mutation found among ST6 isolates caused increased ceftriaxone resistance in a laboratory E. faecalis isolate. PK/PD testing showed that a representative ST6 isolate exhibited attenuated efficacy of AC combination therapy at humanized antibiotic exposures. We find evidence for diminished in vitro AC activity among a subset of E. faecalis IE isolates with increased pbp4 expression. These findings suggest that alternate antibiotic combinations against diverse contemporary E. faecalis IE isolates should be evaluated. © The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Kevin J Westbrook, Gayatri Shankar Chilambi, Madison E Stellfox, Hayley R Nordstrom, Yanhong Li, Alina Iovleva, Niyati H Shah, Chelsea E Jones, Ellen G Kline, Kevin M Squires, William R Miller, Truc T Tran, Cesar A Arias, Yohei Doi, Ryan K Shields, Daria Van Tyne. Differential in vitro susceptibility to ampicillin/ceftriaxone combination therapy among Enterococcus faecalis infective endocarditis clinical isolates. The Journal of antimicrobial chemotherapy. 2024 Apr 02;79(4):801-809
PMID: 38334390
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