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. Prosthetic joint infection (PJI) occurs in 0.5% to 1.0% and 0.5% to 2% of hip and knee replacements, respectively (5,20,24,25). PJI is predominantly caused by Staphylococcus aureus (28%) and coagulase-negative staphylococci (CoNS) (25%) (23). PJI is associated with mortality (up to 2.5%) and significant morbidity, and outcomes are poor (8). There are no prospective, randomized controlled trials to guide treatment in this area (16,21). Conducting trials is challenging due to the difficulty of identifying patients and confounding outcomes by prior use of antibiotics.The ideal antimicrobial agent should be bactericidal, with activity against biofilm-producing microorganisms (26). Daptomycin exhibits rapid, concentration-dependent bactericidal activity in vitro against Gram-positive organisms, including S. aureus (regardless of methicillin susceptibility), Staphylococcus haemolyticus, and Staphylococcus epidermidis (4). Clinical outcomes in osteomyelitis from a retrospective, noncomparative registry showed that daptomycin doses of Ͼ4 mg/kg of body weight were more effective than doses of Յ4 mg/kg (88% versus 65%; P ϭ 0.013) (15).This study assessed the safety and efficacy of 6 and 8 mg/kg daptomycin compared with standard-of-care therapy in patients with hip or knee PJI c...

The safety and efficacy of high-dose daptomycin combined with rifampicin for the treatment of Gram-positive osteoarticular infections

“…Emergence of daptomycin resistance remains a rare event in staphylococci and is limited to individual case reports [9,10]. While recent clinical data assessed the efficacy and safety of high-dose daptomycin in Gram-positive osteoarticular infections [2][3][4][5][6], no specific study evaluated the combined regimen of high-dose daptomycin (8 mg/kg/day) and rifampicin (600 mg/day) in this context. In view of the quite variable (from 300 to 1,200 mg/day) regimens of rifampicin that have been described in the literature, official recommendations for a standard rifampicin regimen in the context of osteoarticular infections would be most appropriate.…”

“…Recent studies indicate a growing interest in the design of novel therapeutic protocols for deep-seated multi-resistant Gram-positive infections, as alternatives to the standard glycopeptide therapy [2][3][4][5][6][7][8]. Daptomycin has attractive properties for treating osteoarticular infections, because of its rapid bactericidal activity against susceptible as well as multi-resistant, Gram-positive isolates.…”

“…Very few antimicrobial agents remain available for therapy of osteoarticular infections that are due to multi-resistant Gram-positive pathogens, in particular methicillin-resistant S. aureus (MRSA). Besides glycopeptides that remain the mainstay for therapy of MRSA deep-seated infections, some recently developed agents that are active against both susceptible and multi-resistant, gram-positive pathogens including MRSA, in particular daptomycin [2][3][4][5][6] and linezolid [7,8], have been recently evaluated for therapy of osteoarticular infections.…”

Success After Treatment of Periprosthetic Joint Infection: A Delphi-based International Multidisciplinary Consensus

“…Success was defined as resolution or improvement of baseline clinical and radiologic findings and negative cultures at the ''testof-cure visit'' (conducted at hospital discharge or within 2 weeks after reimplantation if still hospitalized). Byren et al [7] concluded that daptomycin ''was considered safe and appeared to be effective in managing staphylococcal PJI using a two-stage revision arthroplasty technique.'' From the perspective of the current study definition, the cited randomized controlled trial evaluated the results using an extremely short time.…”

“…For example, the definition of infection eradication might include amputation; our multidimensional approach limits problems of this nature. In a recent Level-1 study involving patients undergoing two-stage revision for PJI, the use of intravenous daptomycin was compared with standard-of-care therapy [7]. The primary end point was creatine phosphokinase (used to measure the safety of the intervention).…”