title: Evaluation of Effectiveness and Safety of High-Dose Daptomycin: Results from Patients Included in the European Cubicin(®) Outcomes Registry and Experience.
abstract: BACKGROUND
  Daptomycin, a rapid concentration-dependent bactericidal antibiotic, is approved at a dose of 4 mg/kg/day for the treatment of complicated skin and soft tissue infections (cSSTI) and at a dose of 6 mg/kg/day for the treatment of Staphylococcus aureus right-sided infective endocarditis (RIE) and bacteremia associated with cSSTI and RIE. Studies have reported the successful use of high-dose daptomycin (>6 mg/kg/day) in patients with difficult-to-treat infections. The present analysis evaluated the effectiveness and safety of high doses (>6 mg/kg/day) of daptomycin for the treatment of different Gram-positive infections.
  
  
  METHODS
  European Cubicin(®) Outcomes Registry and Experience (EU-CORE) is a non-interventional, multicenter, retrospective, patient registry designed to collect real-world data from patients treated with daptomycin between 2006 and 2012. Clinical outcomes were assessed at the end of daptomycin treatment for three dose groups: ≤6, >6 to <8, and ≥8 mg/kg/day. Safety was assessed for up to 30 days post-daptomycin treatment.
  
  
  RESULTS
  Of the 6075 patients enrolled in EU-CORE, 4892 patients received daptomycin doses ≤6 mg/kg/day, while 1097 patients received high doses (>6 mg/kg/day). The primary infections with the largest proportion of patients treated with a high dose (>6 mg/kg/day) were osteomyelitis (37.1%), foreign body/prosthetic infection (31.6%), and endocarditis (27.6%). S. aureus was identified in 42.9% of patients with positive cultures treated with either ≤6 or >6 mg/kg/day. The overall clinical success rate was 82.0% (899/1097) with high doses (>6 mg/kg/day) and 80.3% (3928/4890) with doses ≤6 mg/kg/day. Numerically higher clinical success rate was observed for endocarditis and foreign body/prosthetic infection, as well as for coagulase-negative staphylococcal and enterococcal infections, with high-dose daptomycin treatment. There were no new or unexpected safety findings at doses >6 mg/kg/day.
  
  
  CONCLUSIONS
  These results suggested that daptomycin at doses >6 mg/kg/day was effective and well tolerated. High-dose daptomycin is a potential therapeutic option in patients with difficult-to-treat Gram-positive infections.
  
  
  BACKGROUND
  This study was funded by Novartis Pharma AG.
authors.affiliation: Queen Elizabeth University Hospital, Glasgow, UK.
authors.forename: R Andrew
authors.initials: RA
authors.lastname: Seaton
authors.affiliation: Azienda Ospedaliera Universitaria Pisana-Ospedale Cisanello-U.O. Malattie Infettive, Pisa, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Menichetti
authors.affiliation: Departments of Medicine and Research Laboratory of Internal Medicine, School of Medicine, University of Thessaly, Larissa, Greece.
authors.forename: Georgios
authors.initials: G
authors.lastname: Dalekos
authors.affiliation: Klinik für Herzchirurgie, Universitätsklinik Großhadern, München, Germany.|Department of Cardiothoracic Surgery, University of Frankfurt, Frankfurt, Germany.
authors.forename: Andres
authors.initials: A
authors.lastname: Beiras-Fernandez
authors.affiliation: Instituto Cardiovascular de Buenos Aires, Ciudad de Buenos Aires, Argentina.
authors.forename: Francisco
authors.initials: F
authors.lastname: Nacinovich
authors.affiliation: Novartis Healthcare Pvt. Ltd., Hyderabad, India.
authors.forename: Rashidkhan
authors.initials: R
authors.lastname: Pathan
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. kamal.hamed@novartis.com.
authors.forename: Kamal
authors.identifier: http://orcid.org/0000-0003-1896-9736
authors.initials: K
authors.lastname: Hamed
mesh_terms: D000328:Adult; 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; D005060:Europe; D005260:Female; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012042:Registries; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D017576:Daptomycin
keywords: Clinical response; Daptomycin; EU-CORE; Gram-positive infections; High dose; Infectious diseases; Safety