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

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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 results will lay the foundation for future studies to validate optimal treatment strategies for enterococcal IE, and to translate these treatments into the clinic.