title: Efficacy of high doses of daptomycin versus alternative therapies against experimental foreign-body infection by methicillin-resistant Staphylococcus aureus.
abstract: Since the currently approved dose of daptomycin (6 mg/kg of body weight/day) has been associated with clinical failures and resistance development, higher doses for some difficult-to-treat infections are being proposed. We studied the efficacy of daptomycin at high doses (equivalent to 10 mg/kg/day in humans) and compared it to that of reference and alternative treatments in a model of foreign-body infection with methicillin (meticillin)-resistant Staphylococcus aureus. In vitro studies were conducted with bacteria in the log and stationary phases. For the in vivo model, therapy with daptomycin at 100 mg/kg/day, vancomycin at 50 mg/kg/12 h, rifampin (rifampicin) at 25 mg/kg/12 h, or linezolid at 35 mg/kg/12 h was administered for 7 days. Antibiotic efficacy was evaluated using either bacteria from tissue cage fluids or those attached to coverslips. We screened for the emergence of linezolid- and rifampin-resistant strains and analyzed the surviving population from the daptomycin-treated group. Only daptomycin was bactericidal in both the log- and stationary-phase studies. Daptomycin (decrease in the log number of CFU per milliliter of tissue cage fluid, 2.57) and rifampin (decrease, 2.6 log CFU/ml) were better (P < 0.05) than vancomycin (decrease, 1.1 log CFU/ml) and linezolid (decrease, 0.9 log CFU/ml) in the animal model. Rifampin-resistant strains appeared in 60% of cases, whereas no linezolid resistance emerged. No daptomycin-resistant subpopulations were detected at frequencies of 10(-7) or higher. In conclusion, daptomycin at high doses proved to be as effective as rifampin, and the two were the most active therapies for this experimental foreign-body infection. These high doses ensured a profile of safety from the development of resistance.
authors.affiliation: Laboratory of Experimental Infection, Infectious Diseases Service, IDIBELL, Hospital Universitari de Bellvitge, Feixa Llarga s/n, 08907 L'Hospitalet de Llobregat, Barcelona, Spain. 32186omr@comb.es
authors.forename: O
authors.initials: O
authors.lastname: Murillo
authors.forename: C
authors.initials: C
authors.lastname: Garrigós
authors.forename: M E
authors.initials: ME
authors.lastname: Pachón
authors.forename: G
authors.initials: G
authors.lastname: Euba
authors.forename: R
authors.initials: R
authors.lastname: Verdaguer
authors.forename: C
authors.initials: C
authors.lastname: Cabellos
authors.forename: J
authors.initials: J
authors.lastname: Cabo
authors.forename: F
authors.initials: F
authors.lastname: Gudiol
authors.forename: J
authors.initials: J
authors.lastname: Ariza
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017576:Daptomycin / Q000494:pharmacology / Q000627:therapeutic use*; D005549:Foreign-Body Reaction / Q000188:drug therapy* / Q000382:microbiology; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000472:pathogenicity*; D008826:Microbial Sensitivity Tests; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000900:Anti-Bacterial Agents; D017576:Daptomycin