Osteomyelitis is a complicated infectious process with various presentations and both acute and chronic types (17
). As a measure of the difficulty of studying this disease, no antibiotic has been approved for bone and joint infection in the past 25 years. The current study in patients with PJI undergoing 2-stage revision arthroplasty allowed an opportunity to document microbiological eradication at EOT and follow-up in a homogeneous population. This is the first randomized, controlled trial studying 2 doses of daptomycin (6 and 8 mg/kg) compared with standard of care for PJI. The findings demonstrate that daptomycin administered for prolonged time periods was as well tolerated as standard treatment regimens. Enrollment was a challenge in this study. The rigorous entry criteria, which included microbiological confirmation at the baseline surgery, and the patients' willingness to consent to a 6-week treatment period resulted in a total of 74 patients being eligible for inclusion in the trial.
Prior antibiotics were permitted in this study. Since baseline cultures positive for S. aureus, taken at surgery number 1, were mandated for randomization into the study, the use of antibiotics prior to surgery number 1 did not confound the clinical outcome. It is also important to note that due to ethical concerns, routine standard-of-care antibiotics, except for daptomycin, were permitted by the protocol to be administered between surgery number 1 (removal of infected device) and confirmed positive surgical cultures, within 3 to 5 days. Given the treatment modality in osteomyelitis, with an average treatment duration of 6 weeks, it was determined that the use of prior antibiotics for 3 to 5 days after surgery number 1 and before starting study treatment would not confound clinical outcome. As the majority of the patients across all groups (>80% across all treatment groups) received antibiotics during this period, no sensitivity analysis to assess the impact of prior antibiotics was conducted.
In all treatment groups, antibiotic beads were used in 60/68 (88%) patients. The success rate for patients without antibiotic beads was 2/8 (25%) and in those with antibiotic beads it was 34/60 (57%) (not statistically significant). When comparing the success rates between treatment arms with and without antibiotic beads, the number of patients without beads was observed to be even smaller (3/24, 2/23, 3/21), and therefore, the effect of the antibiotic beads on the success rate could not be statistically evaluated. No sensitivity analysis was done to evaluate impact of different antibiotic beads.
Although the increases in CPK observed with both the 6- and 8-mg/kg doses of daptomycin in this study were numerically higher than those seen with the comparator group, they are consistent with other clinical trials of daptomycin at ≥6 mg/kg, where 2.5% to 8.3% of patients experienced CPK elevations (6
). Most CPK elevations in our study were of short duration and did not result in musculoskeletal symptoms. In the 2 patients who were diagnosed as having rhabdomyolysis, daptomycin treatment was discontinued as suggested in the current prescribing information, and CPK levels in these patients returned to normal within 4 to 7 days of stopping daptomycin treatment. The AE profile in patients receiving daptomycin was similar to that in the comparator group, indicative that daptomycin at doses of 6 and 8 mg/kg was well tolerated over a prolonged period of treatment duration.
Treatment success did not differ between the 2 daptomycin groups, with both having a numerically higher success rate than the comparator group. However, the study was not designed to have statistical power to compare the groups. Although clinical success rates in this study were lower than that expected in clinical practice and as seen in other trials conducted with PJI patients undergoing 2-stage procedures, an additional sensitivity analysis based on reasons for clinical failure showed that success rates ranged from 88% to 91% () when the reason for failure was limited to lack of clinical efficacy, excluding TEAEs and microbiological outcomes. Success rates in 2-stage exchange surgeries have been known to vary between 82% and 100% (12
). The difference is due to the definitions of outcomes used in this study, which were based on stringent criteria preferred by regulatory agencies rather than those used in clinical decision making (1
). For example, discontinuations due to AEs were considered failures in this study, whereas in clinical practice, a switch to alternative therapy that ended in a successful outcome would be considered a success (3
). Similarly, the presence of the baseline pathogen at reimplantation in the absence of signs and symptoms of an active infection would not require additional antibiotic therapy or surgical intervention in clinical practice but would be considered a failure using the methodology of this study.
Previous published reports of daptomycin in bone and joint infections, including those with prosthetic joint infections, show success rates of 50% to 82% (15
). An analysis of 67 patients with osteomyelitis from a registry of daptomycin use showed an overall success rate of 82% at follow-up, with a success rate of 88% in those who received >4 mg/kg. The subgroup of 17 patients with orthopedic devices also had an overall success rate of 82% (15
). Antony et al. also found lower success rates (3/8, 37%) with the use of daptomycin at 4 mg/kg for PJI, whereas 17 of 22 (77%) patients receiving 6 mg/kg had successful outcomes (2
), although this was not statistically significant.
In summary, daptomycin at 6 and 8 mg/kg in 49 patients was considered safe and appeared to be effective in managing staphylococcal PJI using a 2-stage revision arthroplasty technique, reflecting efficacy results from previous studies (2
). There was a trend for improved efficacy with daptomycin in the 49 treated patients compared with those observed with standard of care, indicating that daptomycin may represent an additional and convenient treatment alternative for management of the challenges associated with PJI. Further studies, however, are warranted to confirm these findings.