title: Addition of gentamicin or rifampin does not enhance the effectiveness of daptomycin in treatment of experimental endocarditis due to methicillin-resistant Staphylococcus aureus.
abstract: This study evaluated the activity of daptomycin combined with either gentamicin or rifampin against three methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates in vitro and one isolate in vivo against a representative strain (MRSA-572). Time-kill experiments showed that daptomycin was bactericidal against these strains at concentrations over the MIC. Daptomycin at sub-MIC concentrations plus gentamicin at 1x and 2x the MIC yielded synergy, while the addition of rifampin at 2 to 4 microg/ml resulted in indifference (two strains) or antagonism (one strain). The in vivo activity of daptomycin (6 mg/kg of body weight once a day) was evaluated +/- gentamicin (1 mg/kg intravenously [i.v.] every 8 h [q8h]) or rifampin (300 mg i.v. q8h) in a rabbit model of infective endocarditis by simulating human pharmacokinetics. Daptomycin plus gentamicin (median, 0 [interquartile range, 0 to 2] log10 CFU/g vegetation) was as effective as daptomycin alone (0 [0 to 2] log10 CFU/g vegetation) in reducing the density of bacteria in valve vegetations (P = 0.83), and both were more effective than daptomycin plus rifampin (3 [2 to 3.5] log10 CFU/g vegetation; P < 0.05) for the strain studied. In addition, daptomycin sterilized a ratio of vegetations that was similar to that of daptomycin plus gentamicin (10/15 [67%] versus 9/15 [60%]; P = 0.7), and both regimens did so more than daptomycin plus rifampin (3/15 [20%]; P = 0.01 and P = 0.02, respectively). No statistical difference was noted between daptomycin plus gentamicin and daptomycin alone for MRSA treatment. In the combination arm, all isolates from vegetations remained susceptible to daptomycin, gentamicin, and rifampin. Sixty-one percent of the isolates (8/13) acquired resistance to rifampin during monotherapy. In the daptomycin arm, resistance was detected in only one case, in which the daptomycin MIC rose to 2 microg/ml among the recovered bacteria. In conclusion, the addition of gentamicin or rifampin does not enhance the effectiveness of daptomycin in the treatment of experimental endocarditis due to MRSA.
authors.affiliation: Infectious Diseases Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona School of Medicine, Barcelona, Catalunya, Spain. jmmiro@ub.edu
authors.forename: J M
authors.initials: JM
authors.lastname: Miró
authors.forename: C
authors.initials: C
authors.lastname: García-de-la-Mària
authors.forename: Y
authors.initials: Y
authors.lastname: Armero
authors.forename: D
authors.initials: D
authors.lastname: Soy
authors.forename: A
authors.initials: A
authors.lastname: Moreno
authors.forename: A
authors.initials: A
authors.lastname: del Río
authors.forename: M
authors.initials: M
authors.lastname: Almela
authors.forename: M
authors.initials: M
authors.lastname: Sarasa
authors.forename: C A
authors.initials: CA
authors.lastname: Mestres
authors.forename: J M
authors.initials: JM
authors.lastname: Gatell
authors.forename: M T
authors.initials: MT
authors.lastname: Jiménez de Anta
authors.forename: F
authors.initials: F
authors.lastname: Marco
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D017576:Daptomycin / Q000627:therapeutic use*; D004697:Endocarditis, Bacterial / Q000188:drug therapy / Q000382:microbiology; D005839:Gentamicins / Q000627:therapeutic use*; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000472:pathogenicity*; D008826:Microbial Sensitivity Tests; D011817:Rabbits
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins; D017576:Daptomycin