title: Daptomycin plus fosfomycin versus daptomycin monotherapy in treating MRSA: protocol of a multicentre, randomised, phase III trial.
abstract: BACKGROUND
  Despite the availability of new antibiotics such as daptomycin, methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia continues to be associated with high clinical failure rates. Combination therapy has been proposed as an alternative to improve outcomes but there is a lack of clinical studies. The study aims to demonstrate that combination of daptomycin plus fosfomycin achieves higher clinical success rates in the treatment of MRSA bacteraemia than daptomycin alone.
  
  
  METHODS
  A multicentre open-label, randomised phase III study. Adult patients hospitalised with MRSA bacteraemia will be randomly assigned (1:1) to group 1: daptomycin 10 mg/kg/24 h intravenous; or group 2: daptomycin 10 mg/kg/24 h intravenous plus fosfomycin 2 gr/6 g intravenous. The main outcome will be treatment response at week 6 after stopping therapy (test-of-cure (TOC) visit). This is a composite variable with two values: Treatment success: resolution of clinical signs and symptoms (clinical success) and negative blood cultures (microbiological success) at the TOC visit. Treatment failure: if any of the following conditions apply: (1) lack of clinical improvement at 72 h or more after starting therapy; (2) persistent bacteraemia (positive blood cultures on day 7); (3) therapy is discontinued early due to adverse effects or for some other reason based on clinical judgement; (4) relapse of MRSA bacteraemia before the TOC visit; (5) death for any reason before the TOC visit. Assuming a 60% cure rate with daptomycin and a 20% difference in cure rates between the two groups, 103 patients will be needed for each group (α:0.05, ß: 0.2). Statistical analysis will be based on intention to treat, as well as per protocol and safety analysis.
  
  
  BACKGROUND
  The protocol was approved by the Spanish Medicines and Healthcare Products Regulatory Agency (AEMPS). The sponsor commits itself to publishing the data in first quartile peer-review journals within 12 months of the completion of the study.
  
  
  BACKGROUND
  NCT01898338.
authors.affiliation: Hospital Universitari de Bellvitge-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Shaw
authors.affiliation: Hospital Universitari Clínic-IDIBAPS, Barcelona, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Miró
authors.affiliation: Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Puig-Asensio
authors.affiliation: Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Pigrau
authors.affiliation: Hospital Universitari Arnau de Vilanova, Lleida, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Barcenilla
authors.affiliation: Hospital Universitari Son Espases, Mallorca, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Murillas
authors.affiliation: Hospital Universitari Joan XXIII, Tarragona, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Garcia-Pardo
authors.affiliation: Hospital Universitari de Terrassa, Terrassa, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Espejo
authors.affiliation: Hospital Universitario Gregorio Marañon, Madrid, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Padilla
authors.affiliation: Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Garcia-Reyne
authors.affiliation: Hospital Universitario Virgen de las Nieves, Granada, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Pasquau
authors.affiliation: Hospital Universitario Virgen Macarena, Sevilla, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Rodriguez-Baño
authors.affiliation: Hospital Universitari Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: López-Contreras
authors.affiliation: Hospital Universitari Parc de Salut Mar, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Montero
authors.affiliation: Hospital Universitari Clínic-IDIBAPS, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: de la Calle
authors.affiliation: Hospital Universitario Ramón y Cajal, Madrid, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Pintado
authors.affiliation: Hospital Universitari Mutúa de Terrassa, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Calbo
authors.affiliation: Corporació Sanitaria Parc Taulí, Sabadell, Barcelona, Spain.
authors.forename: O
authors.initials: O
authors.lastname: Gasch
authors.affiliation: Hospital Universitario de Cruces, Barakaldo, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Montejo
authors.affiliation: Hospital Universitari i Politècnic la Fe, Valencia, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Salavert
authors.affiliation: Hospital Universitario Lucus Augusti, Lugo, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Garcia-Pais
authors.affiliation: Hospital Universitari de Bellvitge-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Carratalà
authors.affiliation: Hospital Universitari de Bellvitge-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Pujol
mesh_terms: D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D016470:Bacteremia / Q000188:drug therapy* / Q000382:microbiology; D017576:Daptomycin / Q000627:therapeutic use*; D004338:Drug Combinations; D005578:Fosfomycin / Q000627:therapeutic use*; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D012107:Research Design; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D005578:Fosfomycin; D017576:Daptomycin
keywords: bacteraemia; combination therapy; daptomycin; fosfomycin; methicillin-resistant Staphylococcus aureus (MRSA)