# Deciphering the genetic basis of differential antibiotic efficacy in Enterococcus faecalis endocarditis

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $197,969

## Abstract

SUMMARY
Enterococcus faecalis causes infective endocarditis (IE), and mortality rates associated with E. faecalis IE are
as high as 30%. Treatment for E. faecalis IE has shifted over the last decade from ampicillin and gentamicin
(AG) to ampicillin and ceftriaxone (AC), due to prior studies showing equal efficacy and improved tolerance of
AC. Despite the rapid adoption of AC in clinical practice, our review of nearly 200 cases of E. faecalis IE at our
center over the last decade showed strikingly high mortality rates among patients treated with AC. We
investigated the genomic epidemiology of E. faecalis IE at our center since 2018, and found that 36% of all
collected isolates belonged to multi-locus sequence types ST6 and ST179. All ST6 isolates harbored a mutation
previously associated with overexpression of the low-affinity penicillin-binding protein 4 (PBP4) and increased
resistance to beta-lactams, cephalosporins, and carbapenems. We also found that all ST179 isolates possessed
a mutation in the coding sequence of PBP4 (P520S), that was previously correlated with lowered beta-lactam
affinity. We tested isolates for their susceptibility to AC synergy using checkerboard assays, and observed
decreased synergy for ST6 isolates, as well as for an isolate encoding a mutation in the PP2C-type protein
phosphatase IreP. Finally, we tested how effectively AC could kill E. faecalis using a one-compartment
pharmacokinetic-pharmacodynamic (PK-PD) model of AC tolerance, and found that ST6 and ST179 isolates
were able to regrow after 24-48 hours of AC exposure, while an unrelated isolate with a wild type PBP4 sequence
showed no regrowth. Here we propose to test the hypothesis that E. faecalis causing IE encode genetic features
that cause diminished AC synergy and that may lead to treatment failure in some patients. We propose to first
investigate the genomic epidemiology of E. faecalis IE in the United States, and to identify E. faecalis mutations
that are associated with diminished AC synergy in vitro. Then, we will evaluate the pharmacodynamics of AC
against genetically diverse E. faecalis IE isolates, and will test alternative antibiotic combinations against isolates
with reduced susceptibility to AC synergy. The practice change from AG to AC has been made without knowing
how genetically diverse E. faecalis respond to AC, and our preliminary data suggest that this change may not
be benefiting all patients. There is an urgent need to determine whether the E. faecalis IE treatment paradigm
requires revision, and if so, which alternative combinations are likely to be most effective. Our early findings
indicate that not all E. faecalis IE isolates respond equally well to AC, and a more individualized approach that
incorporates bacterial genotypes and tailored antibiotic combinations may be required. Enabled by compelling
preliminary data, the proposed study will integrate epidemiologic, genomic, and PK-PD approaches to address
these important questions. The ...

## Key facts

- **NIH application ID:** 10452049
- **Project number:** 1R21AI164018-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Daria N Van Tyne
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $197,969
- **Award type:** 1
- **Project period:** 2022-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452049

## Citation

> US National Institutes of Health, RePORTER application 10452049, Deciphering the genetic basis of differential antibiotic efficacy in Enterococcus faecalis endocarditis (1R21AI164018-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10452049. Licensed CC0.

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