Noel 2008a.

Methods	Design: multicentre (129 sites), international, RCT,non‐inferiority trial Follow‐up period: 7‐14 days after the end of therapy
Participants	N: 828 participants randomised, 257 with DFI For all study participants: Sex (male): Intervention Group: 63%; Control Group 64% Age (mean): Intervention Group: 52.9 years; Control Group: 51.9 years Inclusion criteria: ≥18 years with complicated SSSI. SSSI was defined as an infection involving subcutaneous tissues or requiring surgery that required iv therapy, along with one or more of the following: infection 30 days after surgery or trauma (including partial thickness burns over < 10% body surface), with purulent drainage or ≥ 3 symptoms (temperature > 38 ºC, swelling, erythema ≥ 10mm, pain or tenderness); abscess (without open wound) in the 7 days before with purulent drainage or aspirate and loculated fluid requiring intervention in within 48 h and with erythema and/or induration of ≥ 20 mm or with tenderness; cellulitis for 7 days before, with oedema, erythema or induration and 1 symptom (fever for 3 days before, WBC ≥ 10 x 109 cells/L or ≥ 10% bands, lymphangitis and adenopathy); in diabetic participants, a foot infection consisting of infra‐malleolar full‐skin‐thickness ulcer, cellulitis, myositis or tendonitis with ≥3 symptoms (swelling, erythema, tenderness or increased skin temperature). Exclusion criteria: foreign body infection; osteomyelitis; critical limb ischaemia; septic arthritis
Interventions	Intervention (n = 168): ceftobiprole 500 mg for 120 minutes iv every 8 h Control (n = 89): vancomycin 1000 mg iv every 12 h and ceftazidime 1000 mg iv every 8 h Empirical metronidazole for 48 h at discretion depending on culture results: used in 22 and 17 participants in the Intervention and Control Groups respectively Treatment duration: 7‐14 days
Outcomes	Principal outcome Clinical cure rate at TOC visit (7‐14 days after the end of therapy) Secondary outcomes Microbiological eradication rate at the TOC visit Safety and tolerability
Notes	Funding source: Johnson & Johnson Pharmaceutical Research and Development. All study authors were employees of the funding company Other: sample size calculation not performed
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization was done via a central interactive voice response system
Allocation concealment (selection bias)	Low risk	Randomization was done via a central interactive voice response system
Incomplete outcome data (attrition bias) All outcomes	Low risk	8% and 10% of participants of each group did not complete the trial. The most common reason for not completing the trial was loss to follow‐up, which occurred for 3% of participants in both groups. The results of the evaluable participants' analysis were not different from the ITT analysis
Selective reporting (reporting bias)	Unclear risk	2 secondary outcomes described in the study protocol (NCT00210899) were not reported in the study: clinical cure rate and microbiological relapse rate at the late follow‐up visit
Other bias	Unclear risk	N/A
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blinded study. To ensure this, participants in the ceftobiprole group also received placebo in a manner that matched the vancomycin regimen. An unblinded pharmacist used coloured sleeves to blind the appearance of infusions
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Microbiological assessment was made centrally. An unblinded independent monitor checked the blinded staff at each site