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.
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.
authors.affiliation: Infectious Diseases Service, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Pericàs
authors.affiliation: Infectious Diseases Service, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: García-de-la-Mària
authors.affiliation: Pharmacology and Toxicology Unit, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Brunet
authors.affiliation: Infectious Diseases Service, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Spain.
authors.forename: Y
authors.initials: Y
authors.lastname: Armero
authors.affiliation: Infectious Diseases Service, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: García-González
authors.affiliation: Pharmacology and Toxicology Unit, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Casals
authors.affiliation: Microbiology Service, Center Diagnostic Biomedical (CDB), Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Almela
authors.affiliation: Cardiac Surgery Service, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Quintana
authors.affiliation: Cardiology Department, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Falces
authors.affiliation: Cardiac Surgery Service, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Ninot
authors.affiliation: Nuclear Medicine Department, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Fuster
authors.affiliation: Department of Statistics, Faculty of Biology, University of Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Llopis
authors.affiliation: Microbiology Service, Center Diagnostic Biomedical (CDB), Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Spain.|ISGlobal, Barcelona Ctr. Int, Health Res. (CRESIB), Hospital Clinic of Barcelona, University of Barcelona, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Marco
authors.affiliation: Infectious Diseases Service, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Moreno
authors.affiliation: Infectious Diseases Service, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), University of Barcelona, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Miró
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology*; D000667:Ampicillin / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002443:Ceftriaxone / Q000494:pharmacology; D017576:Daptomycin / Q000008:administration & dosage* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004697:Endocarditis, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D013293:Enterococcus faecalis / Q000187:drug effects*; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D011817:Rabbits
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D002443:Ceftriaxone; D000667:Ampicillin; D017576:Daptomycin