title: Daptomycin dose-effect relationship against resistant gram-positive organisms.
abstract: Daptomycin exhibits in vitro bactericidal activity against clinically significant gram-positive bacteria. We employed pharmacodynamic modeling to determine a once-daily dosing regimen of daptomycin that correlates to pharmacodynamic endpoints for different resistant gram-positive clinical strains. An in vitro pharmacodynamic model with an initial inoculum of 6 log(10) CFU/ml was used to simulate daptomycin regimens ranging in dose from 0 to 9 mg/kg of body weight/day, with corresponding exposures reflecting free-daptomycin concentrations in serum. Bacterial density was profiled over 48 h for two methicillin-resistant Staphylococcus aureus (MRSA-67 and -R515), two glycopeptide intermediate-resistant S. aureus (GISA-992 and -147398), and two vancomycin-resistant Enterococcus faecium (VREF-12366 and -SF12047) strains. A sigmoid dose-response model was used to estimate the effective dose required to achieve 50% (ED(50)) and 80% (ED(80)) bacterial density reduction at 48 h. Daptomycin MICs for study isolates ranged from 0.125 to 4 micro g/ml. Model fitting resulted in an r(2) of >0.80 for all tested isolates. Control growths at 48 h ranged from 7.3 to 8.5 log(10) CFU/ml. Sigmoid relationships were not superimposable between categorical resistant species: ED(50) and ED(80) values were 1.9 and 3.1, 4.2 and 5.6, and 5.4 and 6.8 mg/kg for MRSA, GISA, and VREF isolates, respectively. Doses required to achieve ED(50) and ED(80) values correlated with MIC differences between tested organisms. Corresponding area under the concentration-time curve from 0 to 24 h/MIC exposure ratios demonstrated a wide range of ED(80) values among the tested isolates. Doses ranging between 3 and 7 mg/kg produced significant bactericidal activity (ED(80)) against these multidrug-resistant S. aureus and E. faecium isolates.
authors.affiliation: Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, Michigan 48201, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Cha
authors.forename: Richard G
authors.initials: RG
authors.lastname: Grucz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rybak
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017576:Daptomycin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016984:Enterococcus faecium / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects; D020713:Vancomycin Resistance
chemical_list: D000900:Anti-Bacterial Agents; D017576:Daptomycin