title: High-dose daptomycin for treatment of complicated gram-positive infections: a large, multicenter, retrospective study.
abstract: OBJECTIVE
  To evaluate the clinical response and safety of high-dose daptomycin for treatment of complicated gram-positive infections.
  
  
  METHODS
  Multicenter, retrospective, observational, case series analysis.
  
  
  METHODS
  Five academic medical centers in four major United States cities.
  
  
  METHODS
  Two hundred fifty adults, not undergoing dialysis, who received high-dose daptomycin (≥ 8 mg/kg/day) for at least 72 hours for complicated gram-positive infections between January 1, 2005, and March 1, 2010.
  
  
  RESULTS
  Clinical and microbiologic outcomes were assessed at the end of high-dose daptomycin therapy. Safety evaluations were recorded for all patients, and when available, baseline, end-of-therapy, and highest observed serum creatine phosphokinase (CPK) levels were recorded. Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE) were the primary organisms isolated. The median dose of daptomycin was 8.9 mg/kg/day (interquartile range [IQR] 8.0-10.0 mg/kg/day). The median duration of daptomycin during hospitalization for MRSA and VRE infection was 10 days (IQR 5-16 days) and 13 days (IQR 6-18 days), respectively. Among the 250 patients, high-dose daptomycin was primarily used as salvage therapy after vancomycin treatment (184 patients [73.6%]). Primary infections included complicated bacteremia (119 patients [47.6%]), endocarditis (59 [23.6%]), skin or wound (70 [28.0%]), and bone or joint (67 [26.8%]). Overall, clinical response and microbiologic success were assessed in 83.6% (209/250 patients) and 80.3% (175/218 patients), respectively. Isolates from 13 patients (5.2%) developed nonsusceptibility to daptomycin, with most of these patients having extended vancomycin exposure. Three patients (1.2%) developed an adverse event attributable to high-dose daptomycin therapy, with the event considered either mild or moderate in severity. The median end-of-therapy CPK level was 39 U/L (IQR 26-67 U/L). No significant correlation was found between daptomycin dose and highest observed CPK level.
  
  
  CONCLUSIONS
  Daptomycin dosages of 8 mg/kg/day or greater may be safe and effective in patients with complicated gram-positive infections. Further clinical studies are warranted.
authors.affiliation: Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, Michigan, USA.
authors.forename: Ravina
authors.initials: R
authors.lastname: Kullar
authors.forename: Susan L
authors.initials: SL
authors.lastname: Davis
authors.forename: Donald P
authors.initials: DP
authors.lastname: Levine
authors.forename: Jing J
authors.initials: JJ
authors.lastname: Zhao
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Crank
authors.forename: John
authors.initials: J
authors.lastname: Segreti
authors.forename: George
authors.initials: G
authors.lastname: Sakoulas
authors.forename: Sara E
authors.initials: SE
authors.lastname: Cosgrove
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rybak
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017576:Daptomycin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014481:United States
chemical_list: D000900:Anti-Bacterial Agents; D017576:Daptomycin