Randomized controlled trial of the safety and efficacy of Daptomycin versus standard-of-care therapy for management of patients with osteomyelitis associated with prosthetic devices undergoing two-stage revision arthroplasty

Abstract

The prevalence of Staphylococcus aureus causing prosthetic joint infection (PJI) supports investigation of higher doses of daptomycin in the management of PJI. This was a prospective, randomized controlled trial studying safety and efficacy of daptomycin (6 and 8 mg/kg of body weight) compared with standard-of-care therapy for PJI. This open-label study randomized 75 patients undergoing 2-stage revision arthroplasty to daptomycin at 6 or 8 mg/kg or a comparator (vancomycin, teicoplanin, or semisynthetic penicillin). After prosthesis removal, patients received 6 weeks of antibiotic treatment and a 2- to 6-week antibiotic-free period before implantation of a new prosthesis. Test of cure (TOC) was within 1 to 2 weeks after reimplantation. The primary objective was evaluation of creatine phosphokinase (CPK) levels. Secondary objectives were clinical efficacy and microbiological assessments. Of 73 CPK safety population patients, CPK elevation of >500 U/liter occurred in 4 of 25 (16.0%) (daptomycin, 6 mg/kg) and 5 of 23 (21.7%) (daptomycin, 8 mg/kg) daptomycin-treated patients and 2 of 25 (8.0%) comparator patients. Adverse-event rates were similar among daptomycin and comparator groups. Among modified intent-to-treat patients at TOC, clinical success rates were 14 of 24 (58.3%) for 6 mg/kg daptomycin, 14 of 23 (60.9%) for 8 mg/kg daptomycin, and 8 of 21 (38.1%) for the comparator. Overall microbiological success at TOC was 12 of 24 (50.0%) for 6 mg/kg daptomycin, 12 of 23 (52.2%) for 8 mg/kg daptomycin, and 8 of 21 (38.1%) for comparator patients. In conclusion, daptomycin at 6 and 8 mg/kg given for up to 6 weeks was safe and appeared to be effective in managing staphylococcal PJI using a 2-stage revision arthroplasty technique in a total of 49 patients.

Trial registration: ClinicalTrials.gov NCT00428844.

Figures

Fig 1

Patient enrollment and reasons for early discontinuations. The safety population was comprised of any patient who received any amount of study medication. The ITT population was comprised of all patients who were randomized and received any amount of study medication. The CPK safety population was comprised of patients who received a minimum of 3 days of dosing with study drug, had a baseline CPK value, and had a minimum of 1 post baseline CPK assessment as assessed by the central laboratory between day 3 of study drug administration through 7 days after the last dose of study drug. The mITT population was comprised of patients in the ITT population who had at least 1 staphylococcal baseline infecting pathogen. The TOC was defined as the time of hospital discharge or within 1 to 2 weeks after reimplantation if the patient remained hospitalized. The follow-up visit was a visit on which patients who were considered a success at TOC were clinically assessed 3 to 4 months after reimplantation. One patient randomized to the comparator group withdrew prior to receiving study treatment.