Vick‐Fragoso 2009.

Methods	Prospective, non‐inferiority randomised controlled, open‐label, parallel‐group trial Multicentric, 74 centres, worldwide Period of inclusion: April 2001 to April 2002
Participants	Inclusion criteria Patients ≥ 18 years Patients with a complicated skin and soft tissue infection (cSSSI) at one site only (cSSSI diagnoses were prospectively defined: diabetic foot infection, necrotizing fasciitis, post‐surgical wound infection, complicated cellulitis, complicated erysipelas, major abscess of the skin, infection of traumatic lesion, and infected Ischaemic ulcer) If it was anticipated that participants required systemic antimicrobial therapy If they had a sample culture taken within 24 hours prior to being included Patients had to had one of the following signs and symptoms: fever ≥ 38.0 C axillary or ≥ 38.5 C orally; leukocytosis (absolute white blood cell (WBC) count > 10,000 cells/mL) with neutrophilia (> 80% neutrophils), tachycardia (> 90 beats per minute), increased respiratory rate (> 20 breaths per minute), or elevated C‐reactive protein (CRP) – plus two or more of the following signs and symptoms within 24 hours preceding enrolment: local pain or tenderness, anaesthesia or hypoaesthesia of the affected area, swelling of the presumed affected area, purulent, serosanguinous, ‘dishwater’ or foul‐smelling discharge, gas formation detected under the skin, and changes in the appearance of the involved area, such as discolouration of skin, presence of black necrotic areas, red‐brown or haemorrhagic bullae, or skin colour changes from red‐blue to patches of blue‐grey. Exclusion criteria Patients with a diagnoses of uncomplicated mild‐to‐moderate SSSIs and of secondary infected burns, atopic dermatitis, or eczema Pregnant or nursing patients Patients with severe life‐threatening diseases with a life expectancy < 2 months End‐stage liver cirrhosis Severe renal impairment requiring dialysis, Hypersensitivity to fluoroquinolones, and beta‐lactams A congenital or sporadic syndromes of QTc prolongation or patients taking concomitant medication reported to increase the QTc Patients with hypersensitivity to fluoroquinolones, and beta‐lactams History of tendinopathy with quinolones Severe renal impairment requiring dialysis Septic shock Patients receiving chronic immunosuppressant treatment Patients with neutropenia (neutrophil absolute count < 1000 cells/mL) or at AIDS stage 1 or 2 (CD4+ absolute count < 200 cells/µL) HIV‐seropositive individuals receiving highly‐activated antiretroviral treatment SSSI secondary to prosthetic materials 18% of the skin and soft tissue affected Suspected underlying osteomyelitis not related to diabetic foot infection Requirement for systemic concomitant antibacterial agents fFilure to respond to previous antibacterial treatment only if previous treatment contained a fluoroquinolone, amoxicillin or a beta‐lactam/beta‐lactamase inhibitor combination Patients who had received systemic antibacterial treatment (orally or parenteral) for > 24 hours within the 24 hours immediately prior to enrolment in the study Baseline characteristics ITT population Subgroup of NSTI (n = 54): 57.4% of male; mean age 52.2 years (provided upon a request to the authors)
Interventions	Intervention 1(Per protocol (PP), n = 315); abscess n = 98; necrotizing fasciitis, n = 22; surgical wound infection n = 9; diabetic foot n = 49; complicated erysipelas n = 101; infected traumatic lesion n = 21; infected ischaemic ulcers n = 6; complicated cellulitis n = 9. moxifloxacin 400 mg per day intravenous (IV), for at least 3 days, followed by moxifloxacin 400 mg orally, once daily, for 7–21 days Intervention 2(PP, n = 317): abscess n = 93, necrotizing fasciitis, n = 13, surgical wound infection n = 13, diabetic foot n = 63, complicated erysipelas n = 95, infected traumatic lesion n = 19, infected ischaemic ulcers n = 4, complicated cellulitis n = 17 amoxicillin‐clavulanate, IV 1000 mg/200 mg three times daily for at least 3 days, followed by amoxicillin‐clavulanate 500 mg/125 mg orally, three times daily, for 7–21 days
Outcomes	Primary outcome Clinical response (CR) at test of cure (TOC) for the PP population CR at the TOC, days 14‐28, visit was defined as: cure (total resolution or marked improvement of all cSSSI signs and symptoms; no additional or alternative antimicrobial treatment necessary). Evaluations (both the visual description of the lesion and the assessment of clinical outcome) were performed by investigators. Secondary outcomes Clinical response at TOC days 14‐28 for the intention to treat (ITT) population Clinical response at TOC days14‐28 by indication in the PP and ITT population Bacteriological success (eradication/presumed eradication) at TOC days 14‐28 for the PP/microbiologically evaluable population Adverse events in ITT population*. Assessments for safety were based on physical examination and routine laboratory tests throughout the study
Notes	This study was sponsored by Bayer HealthCare AG. Authors declared conflict of interest for Atox Bio Ltd and Biomedical Statistical Consulting, Wynnewood, Pennsylvania. * outcomes reported that were of interest in the review
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: “randomised into two groups in a 1:1 ratio” Comment: the method used to generate the allocation sequence was not reported
Allocation concealment (selection bias)	Unclear risk	Quote: "Patients were randomised into two groups in a 1:1 ratio to receive either moxifloxacin or the control regimen." Comment: there was no mention of how allocation concealment was guaranteed
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: “open label” Comment: both participants and study personnel were aware of the assigned treatment
Blinding of outcome assessment (detection bias) All outcomes	High risk	Quote: “open‐label”, “Clinical outcomes were assessed bimodally as cure or failure, such that patients with only limited improvement in clinical status and partial resolution of symptoms would conservatively be considered as failures." Comment: assessment was performed by investigators who were not blinded
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: number of randomly assigned participants: 804 Number of analysed participants for the main outcome per protocol: 632 Patients withdrawn: 172 The main reasons for withdrawal after randomisation (moxifloxacin vs amoxicillin‐clavulanate) were adverse events (6.2% vs 3.8%), insufficient therapeutic effect (4.2% vs 5.3%), patient lost to follow‐up (3.9% vs 5.3%), and protocol violation (3.4% vs 2.8%) (P > 0.1 in all cases). There was a high rate of withdrawal mainly due to serious adverse events and insufficient therapeutic effect.
Selective reporting (reporting bias)	Unclear risk	Comment: no protocol was available, however, the outcomes predefined in the methods were well reported in the results section.
Other bias	High risk	Comment: there was baseline imbalance; number of patients in the NSTI subgroup was two‐fold higher in the moxifloxacin group (36/54) treatment than in the amoxicillin‐clavulanate group (18/54) treatment

AIDS: Acquired Immune Deficiency Syndrome; cSSSI: complicated skin and skin structure infections; cSSTI: complicated skin and soft tissue infection;CR: clinical response; ESM: electronic supplementary material; HBO: hyperbaric oxygen therapy;ICU: intensive care unit; IVIG: intravenous immunoglobulin; ITT: intention‐to‐treat;IV: intravenous; NSTI: necrotizing soft tissue infections; PCS: physical component summary; PP: per protocol; RBC: red blood cells; RRT: renal replacement therapy; SOFA: Sequential Organ Failure Assessment score; SF‐36: the Short Form (36) Health Survey; TOC: test of cure; WBC: white blood cells.