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This work was supported in part by a Novartis Medical School Grant (Basel, Switzerland). The Spanish Network for Research in Infectious Diseases provided funding to J. M. M. under grant number REIPI RD06/0008. While the manuscript was being drafted, J. M. P. received an 'Emili Letang' Post-residency Scholarship (2013-14) from Hospital Clinic, Barcelona (Spain) and a 'Rio Hortega' Research Grant (CM14/00135; 2015-16) from Instituto de Salud Carlos III and the Ministerio de Economia and Competitividad, Madrid (Spain). J. M. M. received a personal intensification research grant no. INT15/00168 during 2016 from the Instituto de Salud Carlos III, Madrid, Spain. The European Regional Development Fund (ERDF) 'A way to build Europe' also provided funding.

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Early in vitro development of daptomycin non-susceptibility in high-level aminoglycoside-resistant Enterococcus faecalis predicts the efficacy of the combination of high-dose daptomycin plus ampicillin in an in vivo model of experimental endocarditis.

Publicated to:Journal Of Antimicrobial Chemotherapy. 72 (6): 1714-1722 - 2017-06-01 72(6), DOI: 10.1093/jac/dkx016

Authors: Pericàs, JM; García-de-la-Mària, C; Armero, Y; García-González, J; Moreno, A; Miró, JM; Brunet, M; Casals, G; Almela, M; Marco, F; Quintana, E; Ninot, S; Falces, C; Fuster, D; Llopis, J

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Abstract

Previous studies showed development of daptomycin non-susceptibility (DNS: MIC >4?mg/L) in Enterococcus faecalis infections. However, no studies have assessed the efficacy of the combination of daptomycin/ampicillin against E. faecalis strains developing DNS in the experimental endocarditis (EE) model.To assess the in vitro and in vivo efficacy of daptomycin at 10?mg/kg/day, daptomycin/ampicillin and ampicillin/ceftriaxone against two high-level aminoglycoside-resistant E. faecalis strains, one developing DNS after in vitro exposure to daptomycin and another that did not (DS).Subculture of 82 E. faecalis strains from patients with endocarditis with daptomycin MICs, time-kill and in vivo experiments using the EE model.33% of the strains (27 of 82) displayed DNS after subculture with daptomycin. Daptomycin MIC rose from 0.5-2 to 8-16?mg/L. In time-kill experiments, when using a high inoculum (10 8 cfu/mL), daptomycin/ampicillin was synergistic for one-third of DS strains and none of DNS strains, while ampicillin/ceftriaxone retained synergy in all cases. In the EE model, daptomycin did not significantly reduce cfu/g from vegetations compared with control against either strain, while daptomycin/ampicillin reduced significantly more cfu/g than daptomycin against the DS strain, but not against the DNS strain [2.9 (2.0-4.1) versus 6.1 (4.5-8.0); P? = ? 0.002]. Ampicillin/ceftriaxone was synergistic and bactericidal against both strains, displaying the same activity as daptomycin/ampicillin against the DS strain.Performance of an Etest for daptomycin MIC after subculture with daptomycin inhibitory doses on strains of high-level aminoglycoside-resistant E. faecalis endocarditis may be an easy test to predict the in vivo efficacy of daptomycin/ampicillin.© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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