title: Characterization of high-level daptomycin resistance in Viridans group Streptococci developed upon in vitro exposure to daptomycin.
abstract: Viridans group streptococci (VGS) are part of the normal flora that may cause bacteremia, often leading to endocarditis. We evaluated daptomycin against four clinical strains of VGS (MICs = 1 or 2 μg/ml) using an in vitro-simulated endocardial vegetation model, a simulated bacteremia model, and kill curves. Daptomycin exposure was simulated at 6 mg/kg of body weight and 8 mg/kg every 24 h for endocardial and bacteremia models. Total drug concentrations were used for analyses containing protein (albumin and pooled human serum), and free (unbound) drug concentrations (93% protein bound) were used for analyses not containing protein. Daptomycin MICs in the presence of protein were significantly higher than those in the absence of protein. Despite MICs below or at the susceptible breakpoint, all daptomycin regimens demonstrated limited kill in both pharmacodynamic models. A reduction of approximately 1 to 2 log10 CFU was seen for all isolates and dosages except daptomycin at 6 mg/kg, which achieved a reduction of 2.7 log10 CFU/g against one strain (Streptococcus gordonii 1649) in the endocardial model. Activity was similar in both pharmacodynamic models in the presence or absence of protein. Similar activity was noted in the kill curves over all multiples of the MIC. Regrowth by 24 h was seen even at 8× MIC. Postexposure daptomycin MICs for both pharmacodynamic models increased to >256 μg/ml for all isolates by 24 and 72 h. Despite susceptibility to daptomycin by standard MIC methods, these VGS developed high-level daptomycin resistance (HLDR) after a short duration following drug exposure not attributed to modification or inactivation of daptomycin. Further evaluation is warranted to determine the mechanism of resistance and clinical implications.
authors.affiliation: Methodist Charlton Medical Center, Dallas, Texas, USA Louisiana State University Health Sciences Center-Shreveport, School of Medicine, Shreveport, Louisiana, USA rondaakins@mhd.com.
authors.forename: Ronda L
authors.initials: RL
authors.lastname: Akins
authors.affiliation: Cubist Pharmaceuticals, Lexington, Massachusetts, USA.
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Katz
authors.affiliation: Cubist Pharmaceuticals, Lexington, Massachusetts, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Monahan
authors.affiliation: Cubist Pharmaceuticals, Lexington, Massachusetts, USA.
authors.forename: Dylan
authors.initials: D
authors.lastname: Alexander
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016470:Bacteremia / Q000382:microbiology; D002118:Calcium / Q000378:metabolism; D015169:Colony Count, Microbial; D017576:Daptomycin / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D004697:Endocarditis, Bacterial / Q000382:microbiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D013290:Streptococcal Infections / Q000382:microbiology; D054773:Streptococcus gordonii / Q000187:drug effects; D034363:Viridans Streptococci / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D017576:Daptomycin; D002118:Calcium