title: Trimethoprim-sulfamethoxazole versus vancomycin for severe infections caused by meticillin resistant Staphylococcus aureus: randomised controlled trial.
abstract: OBJECTIVE
  To show non-inferiority of trimethoprim-sulfamethoxazole compared with vancomycin for the treatment of severe infections due to meticillin resistant Staphylococcus aureus (MRSA).
  
  
  METHODS
  Parallel, open label, randomised controlled trial.
  
  
  METHODS
  Four acute care hospitals in Israel.
  
  
  METHODS
  Adults with severe infections caused by MRSA susceptible to trimethoprim-sulfamethoxazole and vancomycin. Patients with left sided endocarditis, meningitis, chronic haemodialysis, and prolonged neutropenia were excluded.
  
  
  METHODS
  Trimethoprim-sulfamethoxazole 320 mg/1600 mg twice daily versus vancomycin 1 g twice daily for a minimum of seven days and then by indication.
  
  
  METHODS
  The primary efficacy outcome was treatment failure assessed at day 7, consisting of death, persistence of haemodynamic instability or fever, stable or worsening Sequential Organ Failure Assessment score, and persistence of bacteraemia. The primary safety outcome was all cause mortality at day 30. Non-inferiority was defined by a difference of less than 15% for treatment failure.
  
  
  RESULTS
  252 patients were included in the trial, of whom 91 (36%) had bacteraemia. No significant difference in treatment failure was seen for trimethoprim-sulfamethoxazole (51/135, 38%) versus vancomycin (32/117, 27%)-risk ratio 1.38 (95% confidence interval 0.96 to 1.99). However, trimethoprim-sulfamethoxazole did not meet the non-inferiority criterion-absolute difference 10.4% (95% confidence interval -1.2% to 21.5%). For patients with bacteraemia, the risk ratio was 1.40 (0.91 to 2.16). In a multivariable logistic regression analysis, trimethoprim-sulfamethoxazole was significantly associated with treatment failure (adjusted odds ratio 2.00, 1.09 to 3.65). The 30 day mortality rate was 32/252 (13%), with no significant difference between arms. Among patients with bacteraemia, 14/41 (34%) treated with trimethoprim-sulfamethoxazole and 9/50 (18%) with vancomycin died (risk ratio 1.90, 0.92 to 3.93).
  
  
  CONCLUSIONS
  High dose trimethoprim-sulfamethoxazole did not achieve non-inferiority to vancomycin in the treatment of severe MRSA infections. The difference was particularly marked for patients with bacteraemia. Trial registration Clinical trials NCT00427076.
authors.affiliation: Unit of Infectious Diseases, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel paulm@post.tau.ac.il.
authors.forename: Mical
authors.initials: M
authors.lastname: Paul
authors.affiliation: Unit of Infectious Diseases, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel.
authors.forename: Jihad
authors.initials: J
authors.lastname: Bishara
authors.affiliation: Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel Unit of Infectious Diseases, Medicine E, Rabin Medical Center, Beilinson Hospital, Petah-Tikva.
authors.forename: Dafna
authors.initials: D
authors.lastname: Yahav
authors.affiliation: Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel Unit of Infectious Diseases, Medicine F, Rabin Medical Center, Beilinson Hospital, Petah-Tikva.
authors.forename: Elad
authors.initials: E
authors.lastname: Goldberg
authors.affiliation: Division of Infectious Diseases, Medicine B, Rambam Health Care Campus, Haifa, Israel Technion-Israel Institute of Technology and the Ruth & Bruce Rappaport Faculty of Medicine, Haifa.
authors.forename: Ami
authors.initials: A
authors.lastname: Neuberger
authors.affiliation: Division of Infectious Diseases, Rambam Health Care Campus, Haifa.
authors.forename: Nesrin
authors.initials: N
authors.lastname: Ghanem-Zoubi
authors.affiliation: Technion-Israel Institute of Technology and the Ruth & Bruce Rappaport Faculty of Medicine, Haifa Division of Infectious Diseases, Medicine A, Rambam Health Care Campus, Haifa.
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Dickstein
authors.affiliation: Internal Medicine Department, Holy Family Hospital, Nazareth, Faculty of Medicine in the Galilee, Bar-Ilan Univesity, Safed, Israel.
authors.forename: William
authors.initials: W
authors.lastname: Nseir
authors.affiliation: Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel Infectious Diseases Unit, E Wolfson Hospital, Holon, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Dan
authors.affiliation: Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel Unit of Infectious Diseases, Medicine E, Rabin Medical Center, Beilinson Hospital, Petah-Tikva.
authors.forename: Leonard
authors.initials: L
authors.lastname: Leibovici
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D016470:Bacteremia / Q000188:drug therapy / Q000382:microbiology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D007557:Israel; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000302:isolation & purification*; D016017:Odds Ratio; D013203:Staphylococcal Infections / Q000188:drug therapy*; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000008:administration & dosage*; D014640:Vancomycin / Q000008:administration & dosage*
chemical_list: D000900:Anti-Bacterial Agents; D014640:Vancomycin; D015662:Trimethoprim, Sulfamethoxazole Drug Combination