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- Title
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.
- Authors
Pericàs, J. M.; García-de-la-Mària, C.; Brunet, M.; Armero, Y.; Garcfa-González, J.; Casals, G.; Almela, M.; Quintana, E.; Falces, C.; Ninot, S.; Fuster, D.; Llopis, J.; Marco, F.; Moreno, A.; Miró, J. M.; García-González, J; Hospital Clinic Endocarditis Study Group
- Abstract
<bold>Background: </bold>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.<bold>Objectives: </bold>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).<bold>Methods: </bold>Subculture of 82 E. faecalis strains from patients with endocarditis with daptomycin MICs, time-kill and in vivo experiments using the EE model.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
AMINOGLYCOSIDES; DRUG resistance; ENTEROCOCCUS faecalis; AMPICILLIN; CLINICAL trials; THERAPEUTICS; ANIMAL experimentation; ANTIBIOTICS; COMBINATION drug therapy; DRUG resistance in microorganisms; DRUG synergism; DOSE-effect relationship in pharmacology; ENTEROCOCCUS; INFECTIVE endocarditis; MICROBIAL sensitivity tests; PEPTIDE antibiotics; RABBITS; GRAM-positive bacterial infections; CEFTRIAXONE; PHARMACODYNAMICS
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2017, Vol 72, Issue 6, p1714
- ISSN
0305-7453
- Publication type
journal article
- DOI
10.1093/jac/dkx016