Background
Periprosthetic joint infections (PJI) of the hip and knee are disastrous complications that occur in approximately 1 to 2 % of patients after total joint arthroplasties [
1]. The management of PJI may require long-term antibiotic suppression, surgical debridement, one-stage or 2-stage revision, resection arthroplasty, arthrodesis, or amputation. The “gold standard” treatment for chronic PJI in North America is 2-stage revision [
2]. The procedure consists of removal of the infected prosthesis in the first stage, followed by replacing it with a high-dose antibiotic cement spacer to eradicate the infection and prevent joint space contracture between stages [
3]. Once the infection has been treated with systemic antibiotics, the second stage is performed to implant a new prosthesis.
Most PJI are caused by Gram-positive cocci, including
Staphylococcus species [
4]. Methicillin-resistant organisms account for up to 74 % of PJI in some reports [
5]. Vancomycin is most commonly incorporated into polymethylmethacrylate (PMMA) bone cement and subsequently used intravenously for the treatment of methicillin-resistant
Staphylococcus aureus (MRSA) [
6]. The successful clinical control of chronic PJI due to methicillin-resistant organisms varies from 48 to 89 % [
7,
8] in the hip and 60 to 74 % [
9,
10] in the knee when vancomycin is used in 2-stage exchange arthroplasty. These results have led orthopedic surgeons to seek new therapeutic strategies for PJI caused by methicillin-resistant
Staphylococcus spp.
Daptomycin is a novel cyclic lipopeptide antibiotic secreted by
Streptomyces roseosporus. Daptomycin has excellent activity against Gram-positive bacteria through disruption of multiple bacterial plasma membrane functions, without penetrating the cytoplasm [
11]. Clinical experience with daptomycin treatment of PJI is limited to systemic intravenous use in small case series [
12‐
14]. Several in vitro studies also showed that daptomycin could be locally delivered from PMMA bone cement without impairing cement strength [
15,
16]. Only one clinical report showed combined use of daptomycin in bone cement and intravenously to treat chronic PJI in a 2-stage surgery [
17].
The aim of this study was to review the results of daptomycin used in PMMA bone cement and systemically in 2-stage exchange surgeries for the treatment of PJI due to methicillin-resistant Staphylococcus species.
Results
Seventy-six patients had PJI of the knee and hip during the study period. Twenty-two (10 knees, 12 hips) had PJI caused by methicillin-resistant
Staphylococcus species and underwent 2-stage revision arthroplasty, with daptomycin used in PMMA bone cement and systemically (Table
1). There were 16 men and 6 women. Two patients had
Staphylococcus aureus bacteremia at first presentation. The average age at the time of the 2-stage revision was 64.4 years (range, 38–87 years). The mean Charlson comorbidity index was 3.95 (range, 2–6). The surgical procedures before enrolment included primary hip arthroplasty (10 patients), primary knee arthroplasty (8), revision total hip arthroplasty (2) and revision total knee arthroplasty (2). Fourteen subjects underwent debridement with prosthesis retention before the 2-stage revision. The mean interval between the previous surgery and the first stage of the two-stage revision was 32 (8–120) months. The mean interim period between the two-stage debridement and reimplantation was averaged 14 weeks (range, 10–18 weeks). There was no breakage of the cement spacer during the interim. The mean follow-up duration was 33.7 months (range, 24–57 months). No patient was lost to follow-up. The treatment success rate was 100 % without recurrence of infection. One patient developed asymptomatic transient elevation of the CPK level. No adverse effect related to daptomycin, such as myositis, rhabdomyolysis, peripheral neuropathy, derangement of liver function or eosinophilic pneumonia was observed in our study.
Table 1
Characteristics of patients with periprosthetic joint infections caused by methicillin-resistant Staphylococcus undergoing 2-stage revision arthroplasties
1 | M | 65 | DAIR for TKA | 4 | MRSA | DAP 4/DAP 6 | Y | 26 | Infection controlled |
2 | M | 51 | THA | 4 | MRSA | DAP 4 + CEF 4/DAP 6 | N | 32 | Infection controlled |
3 | M | 72 | DAIR for revision TKA | 5 | MRSE | DAP 4/DAP 6 | Y | 43 | Infection controlled |
4 | M | 53 | Revision THA | 2 | MRCoNS | DAP 4 + CEF 4/DAP 6 | N | 42 | Infection controlled |
5 | F | 60 | TKA | 3 | MRSA | DAP 4 + CEF 4/DAP 6 | Y | 38 | Infection controlled |
6 | F | 80 | DAIR for TKA | 5 | MRSE | DAP 4/DAP 6 | Y | 26 | Infection controlled |
7 | M | 66 | DAIR for THA | 3 | MRCoNS | DAP 4/DAP 6 | N | 51 | Infection controlled |
8 | M | 44 | DAIR for THA | 2 | MRSE | DAP 4/DAP 6 | N | 42 | Infection controlled |
9 | M | 74 | DAIR for TKA | 4 | MRSE | DAP 4/DAP 6 | Y | 25 | Infection controlled |
10 | M | 45 | DAIR for THA | 3 | MRSE | DAP 4/DAP 6 | N | 26 | Infection controlled |
11 | M | 51 | DAIR for THA | 4 | MRSA | DAP 4/DAP 6 | Y | 44 | Infection controlled |
12 | F | 67 | TKA | 5 | MRSA | DAP 4 + CEF 4/DAP 6 | Y | 32 | Infection controlled |
13 | F | 86 | TKA | 5 | MRSA | DAP 4 + CEF 4/DAP 6 | Y | 37 | Infection controlled |
14 | M | 51 | DAIR for THA | 5 | MRSA | DAP 4/DAP 6 | N | 40 | Infection controlled |
15 | F | 86 | TKA | 5 | MRSA | DAP 4 + CEF 4/DAP 6 | Y | 30 | Infection controlled |
16 | F | 81 | THA | 3 | MRSA | DAP 4 + CEF 4/DAP 6 | Y | 32 | Infection controlled |
17 | M | 81 | DAIR for revision TKA | 5 | MRSE | DAP 4/DAP 6 | Y | 30 | Infection controlled |
18 | M | 51 | DAIR for revision THA | 4 | MRCoNS | DAP 4/DAP 6 | N | 31 | Infection controlled |
19 | M | 50 | DAIR for THA | 2 | MRSE | DAP 4/DAP 6 | N | 27 | Infection controlled |
20 | M | 87 | TKA | 6 | MRSA | DAP 4 + CEF 4/DAP 6 | Y | 24 | Infection controlled |
21 | M | 38 | DAIR for THA | 2 | MRSE | DAP 4/DAP 6 | N | 30 | Infection controlled |
22 | M | 78 | DAIR for revision THA | 6 | MRCoNS | DAP 4/DAP 6 | Y | 33 | Infection controlled |
Discussion
Methicillin-resistant
Staphylococci remain a challenge because the current protocol often has inferior results compared with protocols used with other organisms for the treatment of PJI [
8,
24,
25]. The 2-stage protocol for resistant organisms has had success rates ranging between 48 and 89 % [
7‐
10,
24,
25], while the average success rate for less virulent organisms was 85 % ~ 95 % [
3,
8]. Most protocols used vancomycin and an aminoglycoside in PMMA bone cement combined with systemic vancomycin for 2 ~ 6 weeks after first-stage resection arthroplasty [
8‐
10,
26]. To our knowledge, this study was the first case-series report of daptomycin used in PMMA bone cement to treat PJI caused solely by methicillin-resistant
Staphylococcus species. Using 4 gm daptomycin in 40-g PMMA bone cement combined with subsequent systemic use for 14 days in the first stage, followed by 1 g daptomycin in 40-g PMMA bone cement in the second stage, we achieved a 100 % infection control rate with a mean follow-up of 2.8 years. We attributed the results to the readiness of daptomycin release from the PMMA bone cement and its excellent bactericidal effect against methicillin-resistant strains. Hall et al. showed that daptomycin could be released from PMMA cement at a rate similar to that of vancomycin in vitro study [
27]. These results suggested that local concentrations of daptomycin from daptomycin-loaded PMMA cement were above the MIC value for most Gram-positive cocci. The efficacy of daptomycin against
Staphylococci, compared to vancomycin, has been demonstrated in vivo and in vitro studies. Daptomycin had a higher bactericidal rate than vancomycin (92 % vs. 70 %) in an in vitro study [
28]. Daptomycin showed greater and more rapid bactericidal activity than vancomycin in mice infected by MRSA [
29]. Systemic daptomycin also had a higher success rate than vancomycin in 2-stage revision arthroplasty in a randomized controlled trial [
14].
The actual dosage of daptomycin added in the bone cement as a spacer to treat PJI is unclear. Cortes et al. reported the first case report of use of daptomycin 10 g and gentamicin 10 g in the bone cement (each agent at 5 % w/w) in two-stage revision hip surgery for prosthetic joint infection [
17]. In an international consensus meeting on periprosthetic joint infection, 2 g daptomycin (5 % w/w) was recommended in spacers [
30]. Rouse et al. found that 3 g daptomycin (7.5 % w/w) did not decrease the tensile or compressive strength of PMMA bone cement and retained biologic activity after PMMA cement polymerization in an in vivo rat model [
31]. According to an in vitro study, the mean percentage of daptomycin elution increased with an increase in daptomycin loading [2.5, 7.5, and 15.0 % w/w] in PMMA bone cement. Therefore, we thought higher dose daptomycin (10 % w/w) in PMMA bone cement to reach local therapeutic levels for the treatment of PJI due to methicillin-resistant
Staphylococcus species.
The safety of systemic use of daptomycin after resection arthroplasty is also a concern. Byren et al. [
14] used daptomycin at 6 or 8 mg/kg for 6 weeks after prosthesis removal in a randomized trial. They found 8 % (2 of 25) adverse events (AEs) in the 6-mg/kg group and 16.7 % (4 of 24) AEs in the 8-mg/kg group. The AEs included skin rash, rhabdomyolysis and increase CPK. In another study, severe side effects (one case of acute renal failure due to massive rhabdomyolysis, one of eosinophilic pneumonia and 2 cases of asymptomatic transient CPK level elevation) were also reported with daptomycin at a dose of 6.6 mg/kg/day for an average of 44.9 days in the treatment of PJI [
13]. Our group underwent 2-week systemic antibiotic therapy after first-stage surgery without obviously poorer results than in other reports [
32]. By decreasing the duration of systemic daptomycin use, 21 of 22 patients tolerated the treatment. No patients developed gastrointestinal or food intolerance. Only one patient developed asymptomatic transient elevation of the CPK level. No patient experienced any severe adverse effects related to daptomycin. Daptomycin also possesses clinical and practical advantage over vancomycin, like once daily versus twice daily dosing, less therapeutic drug monitoring and potential cost savings. We thought a shorter course of systemic use of daptomycin would be advisable because the adverse events would be fewer and the infection control rates would not be compromised.
In this study, we had used prophylactic intravenous vancomycin combined with local daptomycin for the treatment of MRSA PJI at reimplantaiton stage. Vancomycin has been known as the drug of choice to prevent MRSA PJI in primary or reimplantation arthroplasties following MRSA infection [
33,
34]. We did not choose intravenous daptomycin for 2 reasons. First, we would like to compare this result with our previous experience of using systemic and local vancomycin by changing the topical antibiotic regime only. This could reduce the confounding effect if systemic daptomycin were used. Second, our infection control policy precluded us to supersede the first-line vancomycin to the second-line daptomycin for systemic use without drug sensitivity test and minimal inhibition concentration test.
The study has limitations. First, it was a retrospective design, and we could not know what proportion of patients would fail the two-stage protocol if vancomycin were used. The evaluation of a prospective cohort comparing daptomycin to vancomycin may be warranted in the future. Second, the sample size was small, making it difficult to obtain statistically significant results. Third, the optimal ratio of daptomycin to PMMA cement in vivo study was unknown, and we did not check the daptomycin level in the joint fluid. The strength of our study is that it offered clinical data from a cohort of patients, and reported the safe use of daptomycin in PMMA cement and intravenously in 2-stage revision surgery. But further studies are required to evaluate the long-term outcomes.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
FCK established the clinical and the clinical database, conceived and designed the study and wrote the draft of manuscript. SHY conducted the study. KTP performed the analyses. FCK wrote the first draft of the manuscript. JWW and MSL performed critical revision the final version of the manuscript for important intellectual content, and final approval. All authors read and approved the final manuscript.