This study was a randomized, double blind, active-control, parallel-group phase II clinical trial conducted at 11 centers in the United States and 7 centers in South Africa. Centers received approval from their institutional review boards or ethics committees, and informed consent was obtained from all patients prior to participation in the study.
A central interactive voice response system was employed to randomize patients as they were enrolled. The randomization was stratified by choice of standard therapy (antistaphylococcal penicillin or vancomycin) and geographic region (the United States or South Africa).
Patients were eligible for the study if they were males or nonpregnant females ≥18 years of age with a diagnosis of cSSSI caused by a suspected or confirmed gram-positive organism. cSSSI was defined as the presence of the following conditions: a major abscess requiring surgical drainage; deep, extensive cellulitis; an infected wound or ulcer; or an infected burn. In addition, patients were also required to have purulent drainage or collection or at least three of the following: erythema, heat and/or localized warmth, fluctuance, swelling and/or induration, pain and/or tenderness upon palpation, fever (>38°C), a white blood cell count of >10,000/mm3, or >15% bands.
Patients were excluded if they had received prior antibiotic therapy for >24 h within 7 days prior to enrollment (unless the pathogen was resistant or the patient was clinically failing therapy) or had osteomyelitis, necrotizing fasciitis, chronic diabetic foot ulcers, gangrene, burns involving >20% of the body surface, or mediastinitis. Patients were also excluded if they had an un-cSSSI, moderate-to-severe liver disease (Child-Pugh class B or C), an alanine transaminase or aspartate aminotransferase level more than five times the upper normal limit, human immunodeficiency virus infection with a CD4 cell count of <100/mm3, an absolute neutrophil count of <500 cells/mm3, or a QTc interval of >500 ms.
Patients were randomized on a 1:1 basis to receive either intravenous telavancin (10 mg/kg once a day) or intravenous standard therapy (vancomycin at 1 g every 12 h or nafcillin or oxacillin at 2 g or cloxacillin at 0.5 to 1 g every 6 h). The choice of standard therapy was made by the investigator prior to randomization. Dose adjustment was permitted (including adjustment of vancomycin dosing using local serum level monitoring) as dictated by the standard practice of the individual participating site. The dose of telavancin was adjusted in patients with a creatinine clearance of <50 ml/min. Study medications were prepared and doses adjusted in a blinded fashion by an individual (usually a pharmacist) who did not participate in patient evaluation. Site personnel involved in the evaluation of clinical response remained blinded to treatment assignment (including serum vancomycin level reports).
Also, change in the choice of standard therapy was allowed based on baseline culture and susceptibility test results. For example, patients who were randomized to standard therapy and preassigned to vancomycin but with MSSA isolated from baseline cultures could be switched to an antistaphylococcal penicillin. Study medications were administered for a minimum of 4 days and a maximum of 14 days. In order to maintain blinding between the once daily and two or four times daily dosing regimens, dummy infusions were utilized. No switch to oral therapy was permitted. Aztreonam and/or metronidazole were allowed as concomitant antibacterial therapy for those patients with proven or suspected polymicrobial infections.
Clinical and microbiological evaluations.
Clinical assessments were performed at baseline and daily through the end of therapy (EOT). The EOT evaluation was conducted within 3 days following administration of the last dose of the study medication. The test-of-cure visit (TOC) was scheduled 7 to 14 days after administration of the last dose of the study medication. At each evaluation, investigators assessed the extent of the infection, surgical procedures, adverse events (AEs), and concomitant medications. Electrocardiograms (ECGs) and laboratory tests were also performed.
Gram stains and culture specimens were obtained from all patients at baseline. They were repeated at EOT and/or TOC if drainage or significant lesions were present. Needle aspiration was performed in patients with cellulitis. In patients with deeper infections, specimens were collected by needle aspiration or surgical procedures. Culture, organism identification, and susceptibility testing were performed at each site. Confirmatory identification of the pathogens and susceptibility testing against telavancin was conducted in a central laboratory (ICON Laboratories, Farmingdale, NY).
The FAST 2 study was designed to assess safety and to explore the efficacy of telavancin in patients with cSSSI. The sample size was based on clinical judgment as to the number of subjects required to provide clinically meaningful descriptive results. All P values and confidence intervals (CIs) were two sided, and statistical significance was declared at the 0.05 level. For baseline patient characteristics, a two-sample t test for continuous variables, an unadjusted Pearson chi-square test, or Fisher's exact test was used, as appropriate. For clinical and microbiological responses, Barnard's unconditional test of superiority was used, as well as a CI for the difference in proportions to evaluate noninferiority.
The following populations were defined for analysis. (i) The all-treated population consisted of patients with a confirmed cSSSI diagnosis who received at least one dose of the study medication. (ii) The clinically evaluable population consisted of patients in the all-treated population who complied with all exclusion and inclusion criteria and had a clinical response of either cure or failure, as assessed at the TOC visit. Patients were excluded from this population if they had only a gram-negative pathogen(s) or a gram-negative pathogen resistant to aztreonam isolated at baseline in patients with polymicrobial infection. (iii) The microbiologically evaluable population consisted of patients in the clinically evaluable population who also had a baseline pathogen recovered from pretreatment cultures.
Patients who received at least one dose of study medication were evaluated for safety. AEs, vital signs, digital ECGs using the same ECG recorders at all sites, and laboratory parameters were evaluated. The relationship between study medications and AEs was determined by the site investigators. A blinded core laboratory (eResearch Technology, Philadelphia, PA) processed and analyzed all ECGs. A central laboratory (ICON Laboratories, Farmingdale, NY) conducted analysis of safety laboratory samples.
Clinical response was classified as cure, failure, or indeterminate at the EOT and TOC visits. Cure was defined as resolution of clinically significant signs and symptoms associated with the skin and skin structure infection present at study admission or improvement to the extent that the infectious process had been controlled and no further antimicrobial therapy was necessary. Failure was defined as inadequate response to study therapy or a need for significant surgical management (e.g., more than routine debridement) of the infection site following antibiotic therapy and prior to the TOC visit. Indeterminate was defined as an inability to determine the outcome. A Clinical Events Committee, blinded as to treatment assignment, reviewed and adjudicated the derived TOC clinical response for all patients in the following categories: (i) indeterminate, (ii) failure, (iii) enrollment under protocol exception, (iv) death or surgical procedure on or before the TOC visit, and (v) a gram-negative pathogen resistant to aztreonam isolated at baseline.
In the microbiologically evaluable population, the baseline pathogen was considered eradicated at EOT or TOC if the pathogen was not detected by culture or if the subject's clinical response was a cure and there was nothing available for culture.