Evidence Corner: Daptomycin for Osteomyelitis in Prosthesis Arthroplasty

Dear Readers:   When infection expands beyond superficial soft tissue, it can negatively affect healing outcomes, mortality, and morbidity. Vigorous measures are needed to manage the infection, and potential osteomyelitis, which can increase the burden of orthopedic surgery, arthroplasty, and diabetic foot ulcer treatment.^1-3 Increasing evidence supports decisions about use of systemic and/or local antibiotics,^1,3 and shortening hospital stays,¹ for individuals with bone and/or joint infections while preserving the quality of clinical and patient-centered outcomes. However, much remains to be learned about appropriate usage, methods, and timing of local antibiotic application to optimize clinical outcomes when infection invades deeper tissue.   Here we review 2 recent randomized controlled trials (RCT) designed to test efficacy of options for managing these potentially dangerous infections. Laura Bolton, PhD, FAPWCA Adjunct Associate Professor, Department of Surgery, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School WOUNDS Editorial Advisory Board Member and Department Editor

Daptomycin for Osteomyelitis in Prosthesis Arthroplasty

  References: Byren I, Rege S, Campanaro E, et al. 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. Antimicrob Agents Chemother. 2012;56(11):5626-5632.   Rationale: There are currently no prospective, RCT that inform treatment of prosthetic joint infection (PJI) which occurs in 0.5% -1.0% of hip replacements, and 0.5% to 2% of knee replacements, with poor outcomes, significant morbidity, and up to 2.5% mortality. A retrospective registry of osteomyelitis cases showed that daptomycin doses of more than 4 mg/kg of body weight were 88% effective, as compared to 65% for doses of P Objective: Conduct a RCT to compare safety and efficacy of 6 mg/kg or 8 mg/kg daptomycin to standard-of-care (SOC) therapy in patients with hip or knee PJI caused by methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible S. aureus (MSSA), or coagulase-negative staphylococci (CoNS) and managed using a 2-stage revision arthroplasty technique.   Methods: A prospective, 22-center, open-label RCT was conducted in the United States, United Kingdom, and Russia from June 2007 to June 2010. Subjects with a PJI and with baseline cultures at the first surgery positive for S. aureus, were stratified by anatomical location of the infected joint (hip or knee) and degree of renal function (30 ml/min to 50 ml/min or > 50 ml/min), then randomized to receive either SOC (n = 26) or a 30-minute intravenous infusion of either 6 mg/kg (n = 25) or 8 mg/kg (n = 24) daptomycin every 24 hours. Standard-of-care, administered according to institutional protocols, consisted of intravenous vancomycin 1 g every 12 hours over 60-100 minutes; teicoplanin 6 mg/kg every 24 hours over 30 minutes; or a semi-synthetic penicillin (SSP). Subjects receiving perioperative antibiotics up to 72 hours postoperatively, and/or beads or cement impregnated with vancomycin, gentamicin, or tobramycin, were included, as were subjects receiving concomitant antimicrobial agents with no known activity against the PJI organisms to manage unrelated same-subject infections.   Patients were evaluated at end-of-therapy, which was followed by 2-6 weeks antibiotic-free, then reimplantation of a new prosthesis with perioperative antibiotics. Clinical resolution or improvement of baseline clinical and radiological findings and negative microbiologic cultures defined efficacy of the test or SOC infusions. This was determined at a test-of-cure (TOC) visit at hospital discharge; within 2 weeks after reimplantation if the subject was still hospitalized; and again 3-4 months after reimplantation. Subjects were tested for adverse events and for creatine phosphokinase elevation > 500 U/liter (primary safety outcome) from day 3 of study drug administration to 7 days after the last dose. This pilot study was not powered for statistical significance of safety or efficacy effects. Proportions were compared between the two groups for the safety outcomes.   Results: Subjects were comparable at baseline. Creatine phosphokinase was > 500 U/liter in 16% of subjects in the daptomycin 6-mg/kg group, 22% of those receiving 8 mg/kg, and 8% of those receiving SOC. Neither this difference nor any difference in adverse events was statistically significant. In the subset of subjects remaining enrolled through TOC evaluation, clinical success was reported in 58.3% of 24 subjects receiving 6 mg/kg daptomycin, 60.9% of 23 subjects receiving 8 mg/kg daptomycin, and 38.1% of 21 SOC subjects, paralleling microbiological success rates. No statistical comparison was reported.   Author’s Conclusions: Daptomycin at 6 mg/kg and 8 mg/kg in 49 patients appeared to be safe and effective in managing staphylococcal PJI using a 2-stage revision arthroplasty technique. Further studies are needed to confirm these findings.

Adding Local Gentamicin-Collagen Sponge to Diabetic Foot Standard-of-Care

  Reference: Lipsky BA, Kuss M, Edmonds M, Reyzelman A, Sigal F. Topical application of a gentamicin-collagen sponge combined with systemic antibiotic therapy for the treatment of diabetic foot infections of moderate severity: a randomized, controlled, multicenter clinical trial. J Am Podiatr Med Assoc. 2012;102(3):223-232.   Rationale: A gentamicin-collagen sponge (GCS), used in Europe as a biodegradable surgical implant for adjuvant treatment of localized bone or soft tissue infections, may serve as an effective topical delivery system combined with systemic antibiotic therapy to help ensure high local antibiotic concentrations at the site of a diabetic foot ulcer infection.   Objective: Explore whether daily applied GCS, combined with standardized daily oral or intravenous systemic antibiotic therapy, improves resolution of infection in patients with diabetic foot ulcer infections of moderate severity compared to the same systemic antibiotic therapy alone.   Methods: An open-label multicenter RCT assigned subjects with a moderately infected diabetic foot ulcer with at least 2 signs of inflammation, and involvement of muscle, tendon, joint, or bone, to receive daily SOC for diabetic foot ulcer with (n = 38) or without (n = 18) once-daily topical GCS with size selected to completely cover the ulcer (5 cm x 5 cm or 10 cm x 10 cm). Standard-of-care included daily oral or intravenous systemic antibiotic therapy (750 mg of levofloxacin) plus sharp surgical debridement at each visit, if appropriate, and pressure off-loading as needed. Nonadherent, moisture-permeable primary dressings were changed daily and covered with a saline-moistened gauze secondary dressing secured with rolled gauze. Wound severity scores reflecting infection and ulcer area were recorded at each observation. Subjects with longest ulcer length >10 cm were excluded. Treatment continued for 7-28 days. Main outcomes reported were safety, clinical, and microbiological assessments^3,7 (primary outcome), 10, 14, 21, 28, and 42 days after the first treatment. Test-of-cure 2 weeks after the last GCS treatment was rated nonblinded to treatment as 1) cure (resolution of all baseline signs and symptoms of infection), 2) clinical improvement of at least 1, but not all, baseline signs and symptoms of infection, and 3) failure (no improvement of any baseline sign or symptom of infection). Blinding was not possible due to unknown effects of implanting a nonmedicated collagen sponge in these high-risk ulcers. At each time-point a third party blinded to treatment rated microbiology results by isolated pathogen as ‘‘documented eradication,’’ “presumed eradication,’’ ‘‘documented persistence,’’ ‘‘presumed persistence,’’ or ‘‘unknown,’’ and classified each patient as a ‘‘microbiological success’’ or ‘‘microbiological failure’’ based on culture results obtained at the subject’s final study visit. Statistically, clinical cure rate was compared for the 2 groups using the chi-squared test. Time to clinical cure or eradication of the baseline pathogen was determined using Kaplan-Meier time-to-event analysis with log rank tests comparing groups. Wound severity scores were compared using t tests.   Results: By chance, baseline wound severity was initially greater in the GCS + SOC group (P = 0.011). This difference was maintained through day 7, when 3 control subjects and no GCS subjects achieved a clinical cure (primary outcome: P = 0.017). This result was reversed at TOC 2 weeks after the last treatment, with all 22 (100%) GCS evaluable subjects clinically cured compared to 7/10 (70%) evaluable control subjects (P = 0.024). Microbial success preceded clinical success. By day 3 of treatment the baseline pathogen was eradicated in a higher proportion of GCS subjects than controls (P P Author’s Conclusions: Despite the small sample size and lack of blinding of the clinical outcome, GCS was safe when combined with appropriate systemic antibiotics and appears to add benefit in treating diabetic foot ulcer infections of moderate severity. A larger RCT of this effect is warranted.   Clinical Perspective: Both the daptomycin³ and GCS⁴ studies ventured into difficult territory performing pilot studies of repeatedly applied antibiotics to subjects with infected joints or bones. The true promise and safety of each of these agents remains to be tested in larger, well-stratified RCTs. Each of these RCTs was an important step towards conducting pivotal trials that will help avert or cure infections involving muscle, tendon, bones, and joints. There was a clinically and statistically higher clinical cure rate4 in moderately infected diabetic foot ulcers treated with SOC + GCS 2 weeks after the last antibiotic treatment, supported by blind-evaluated higher rates of eradication of the infecting microorganism throughout the study. These findings occurred despite chance assignment of more severe wounds to the GCS group and without significant impact on adverse events.   As noted in the October 2010 Evidence Corner, “Colorectal Surgical Wounds,” (WOUNDS. 2010;22(10):A-16-A17) there is an apparent lack of success when a single GCS is placed into closed pilonidal sinus excision sites⁶ or colorectal surgery sites.⁷ In contrast, 1 RCT⁸ reported shorter median healing time when GCS implants were added to standard postoperative care for diabetic foot minor amputation sites (n = 25/group). Another small RCT⁹ reported fewer reoperations required after osteomyelitis surgery sites were treated with 1-5 GCS implants as compared to gentamicin polymethylmethacrylate beads (n = 10/group). Treating a cohort of patients who have lower extremity osteomyelitis, and locally implanted sustained-release calcium sulfate tablets that are impregnated with antibiotics to which the infecting organism is sensitive, also reported promising results¹⁰ requiring confirmation in a RCT.   Nature may be trying to tell us something in this apparently conflicting literature. It remains for future studies to determine which variables define successful treatment strategies for managing bone or joint infection. How do wound closure techniques or repeated applications affect outcomes? There is still much to learn. A recent review of diabetic foot treatment,¹¹ possibly conducted without knowledge of the effects of adding GCS to SOC in infected diabetic foot ulcer management,⁴ found “no trial data to justify the adoption of any particular therapeutic approach in diabetic patients with infection of either soft tissue or bone of the foot.” New RCT evidence may tip the scales toward a change in this statement, including the patient and procedural variables that improve outcomes.

References

1. Mutluoglu M, Sivrioglu AK, Eroglu M, et al. The implications of the presence of osteomyelitis on outcomes of infected diabetic foot wounds. Scand J Infect Dis. 2013 Feb 5. [Epub ahead of print]. 2. Knaepler H. Local application of gentamicin-containing collagen implant in the prophylaxis and treatment of surgical site infection in orthopaedic surgery. Int J Surg. 2012;10 (suppl 1):S15-S20. 3. Byren I, Rege S, Campanaro E, et al. 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. Antimicrob Agents Chemother. 2012;56(11):5626-5632. 4. Lipsky BA, Kuss M, Edmonds M, Reyzelman A, Sigal F. Topical application of a gentamicin-collagen sponge combined with systemic antibiotic therapy for the treatment of diabetic foot infections of moderate severity: a randomized, controlled, multicenter clinical trial. J Am Podiatr Med Assoc. 2012;102(3):223-232. 5. Pääkkönen M, Kallio MJ, Kallio PE, Peltola H. Shortened hospital stay for childhood bone and joint infections: analysis of 265 prospectively collected culture-positive cases in 1983-2005. Scand J Infect Dis. 2012;44(9):683-688. 6. Andersson RE, Lukas G, Skullman S, Hugander A. Local administration of antibiotics by gentamicin-collagen sponge does not improve wound healing or reduce recurrence rate after pilonidal excision with primary suture: a prospective randomized controlled trial. World J Surg. 2010; 34(12):3042-3048. 7. Bennett-Guerrero E, Pappas TN, Koltun WA, et al. Gentamicin-collagen sponge for infection prophylaxis in colorectal surgery. N Engl J Med. 2010;363(11):1038-1049. 8. Varga M, Sixta B, Jirkovska A. Application of gentamicin-collagen sponge shortened wound healing after minor amputations in diabetic patients. Poster presented at: European Wound Management Association Conference; May 26-28, 2010; Geneva, Switzerland. 9. Letsch T, Rosenthal E, Joka T. Local antibiotic application in the treatment of osteomyelitis--a comparative study with two different carriers. Aktuelle Traumatol. 1993;23(7):324-329. 10. Gauland C. Managing lower-extremity osteomyelitis locally with surgical debridement and synthetic calcium sulfate antibiotic tablets. Adv Skin Wound Care. 2011;24(11):515-523. 11. Peters EJ, Lipsky BA, Berendt AR, et al. A systematic review of the effectiveness of interventions in the management of infection in the diabetic foot. Diabetes Metab Res Rev. 2012;28(suppl 1):142-162.