A clinical and in vitro assessment of outpatient parenteral benzylpenicillin and ceftriaxone combination therapy for enterococcal endovascular infections Paul R. Ingram 1,2,3 *, Jacinta Ng 1 , Claire Mathieson 3 , Shakeel Mowlaboccus 3,4 , Geoffrey Coombs 3,4 , Edward Raby 1,3 and John Dyer 1 1 Department Infectious Diseases, Fiona Stanley Hospital, Perth, Australia; 2 School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia; 3 Department of Microbiology, PathWest Laboratory Medicine, Murdoch, Western Australia, Australia; 4 College of Science, Health, Engineering and Education, Murdoch University, Perth, Australia *Corresponding author. E-mail: paul.ingram@health.wa.gov.au Received 8 February 2021; revised 20 June 2021; accepted 19 July 2021 Background: Amoxicillin plus ceftriaxone combination therapy is now standard of care for enterococcal endo- carditis. Due to amoxicillin instability in infusion devices, benzylpenicillin plus ceftriaxone may be substituted to facilitate outpatient parenteral antimicrobial therapy (OPAT) delivery, despite lack of guideline endorsement. Objectives: To assess the clinical efficacy of benzylpenicillin plus ceftriaxone for the management of enterococ- cal endovascular infections, in addition to assessing this combination’s in vitro synergy. Patients and methods: Retrospective cohort study assessing unplanned readmissions, relapses and mortality for 20 patients with endovascular Enterococcus faecalis infections treated with benzylpenicillin plus ceftriaxone delivered via OPAT. For a subset of isolates, synergism for both amoxicillin and benzylpenicillin in combination with ceftriaxone was calculated using a chequerboard method. Results: Patients had endovascular infections of native cardiac valves (n " 11), mechanical or bioprosthetic car- diac valves (n " 7), pacemaker leads (n " 1) or left ventricular assistant devices (n " 1). The median duration of OPAT was 22 days, and the most frequent antimicrobial regimen was benzylpenicillin 14 g/day via continuous in- fusion and ceftriaxone 4g once daily via short infusion. Rates of unplanned readmissions were high (30%), al- though rates of relapsed bacteraemia (5%) and 1 year mortality (15%) were comparable to the published litera- ture. Benzylpenicillin less frequently displayed a synergistic interaction with ceftriaxone when compared with amoxicillin (3 versus 4 out of 6 isolates). Conclusions: Lower rates of synergistic antimicrobial interaction and a significant proportion of unplanned read- missions suggest clinicians should exercise caution when treating enterococcal endovascular infection utilizing a combination of benzylpenicillin and ceftriaxone via OPAT. Introduction Enterococci are the third most frequent cause of infective endocar- ditis (IE). 1 As guidelines recommend prolonged treatment, 2 out- patient parenteral antimicrobial therapy (OPAT) is often utilized. 1 Although in vitro growth is typically inhibited by penicillins with low MICs, 3 enterococci are tolerant to the bactericidal effects of penicil- lins, often with minimum bactericidal concentrations (MBC) to MIC ratios more than 32. 3 To overcome this, endocarditis is managed with high dose b-lactams, plus combination therapy selected on the basis of in vitro synergism. 2 Either amoxicillin or benzylpenicillin in combination with an aminoglycoside is the traditional regimen for Enterococcus faecalis IE, 2 however, frequent high-level amino- glycoside resistance or renal dysfunction have led guidelines to equally endorse amoxicillin in combination with ceftriaxone 2 —a regimen supported by in vitro data, 4 animal model 5 and human observational studies. 1 Unlike benzylpenicillin, amoxicillin is too un- stable for outpatient use. 6 Thus, despite lack of guideline endorse- ment, 2 benzylpenicillin and ceftriaxone are not uncommonly utilized for enterococcal IE management via OPAT. 6,7 We aimed to assess the clinical efficacy of benzylpenicillin plus ceftriaxone therapy delivered via OPAT for the management of enterococcal endovascular infection, and assessed for in vitro syn- ergy between this combination. V C The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 1 of 5 JAC Antimicrob Resist doi:10.1093/jacamr/dlab128 JAC- Antimicrobial Resistance Downloaded from https://academic.oup.com/jacamr/article/3/3/dlab128/6344819 by guest on 25 August 2022