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Figure.  CONSORT Flowchart
CONSORT Flowchart

ITT indicates intention to treat.

Table 1.  Patient Characteristicsa
Patient Characteristicsa
Table 2.  Use of Vancomycin Powder in the Wound at Final Stage of Definitive Fixation
Use of Vancomycin Powder in the Wound at Final Stage of Definitive Fixation
Table 3.  Primary Outcome and Subgroup Analysis (Including Interaction Test Results)a
Primary Outcome and Subgroup Analysis (Including Interaction Test Results)a
Table 4.  Secondary Outcome and Tertiary Outcome
Secondary Outcome and Tertiary Outcome
1.
Harris  AM, Althausen  PL, Kellam  J, Bosse  MJ, Castillo  R; Lower Extremity Assessment Project (LEAP) Study Group.  Complications following limb-threatening lower extremity trauma.   J Orthop Trauma. 2009;23(1):1-6. doi:10.1097/BOT.0b013e31818e43dd PubMedGoogle ScholarCrossref
2.
Chen  AT, Vallier  HA.  Noncontiguous and open fractures of the lower extremity: epidemiology, complications, and unplanned procedures.   Injury. 2016;47(3):742-747. doi:10.1016/j.injury.2015.12.013 PubMedGoogle ScholarCrossref
3.
Metsemakers  WJ, Kuehl  R, Moriarty  TF,  et al.  Infection after fracture fixation: Current surgical and microbiological concepts.   Injury. 2018;49(3):511-522. doi:10.1016/j.injury.2016.09.019 PubMedGoogle ScholarCrossref
4.
Hospenthal  DR, Murray  CK, Andersen  RC,  et al.  Guidelines for the prevention of infection after combat-related injuries.   J Trauma. 2008;64(3)(suppl):S211-S220. doi:10.1097/TA.0b013e318163c421 PubMedGoogle Scholar
5.
Hospenthal  DR, Murray  CK, Andersen  RC,  et al; Infectious Diseases Society of America; Surgical Infection Society.  Guidelines for the prevention of infections associated with combat-related injuries: 2011 update: endorsed by the Infectious Diseases Society of America and the Surgical Infection Society.   J Trauma. 2011;71(2)(suppl 2):S210-S234. doi:10.1097/TA.0b013e318227ac4b PubMedGoogle Scholar
6.
Major Extremity Trauma Research Consortium (METRC).  Building a clinical research network in trauma orthopaedics: the major extremity trauma research consortium (METRC).   J Orthop Trauma. 2016;30(7):353-361. doi:10.1097/BOT.0000000000000549 PubMedGoogle ScholarCrossref
7.
OʼToole  RV, Joshi  M, Carlini  AR,  et al; METRC.  Local antibiotic therapy to reduce infection after operative treatment of fractures at high risk of infection: a multicenter, randomized, controlled trial (VANCO study).   J Orthop Trauma. 2017;31(suppl 1):S18-S24. doi:10.1097/BOT.0000000000000801 PubMedGoogle ScholarCrossref
8.
Gustilo  RB, Mendoza  RM, Williams  DN.  Problems in the management of type III (severe) open fractures: a new classification of type III open fractures.   J Trauma. 1984;24(8):742-746. doi:10.1097/00005373-198408000-00009 PubMedGoogle ScholarCrossref
9.
Gustilo  RB, Anderson  JT.  Prevention of infection in the treatment of one thousand and twenty-five open fractures of long bones: retrospective and prospective analyses.   J Bone Joint Surg Am. 1976;58(4):453-458. doi:10.2106/00004623-197658040-00004 PubMedGoogle ScholarCrossref
10.
Dubina  AG, Paryavi  E, Manson  TT, Allmon  C, O’Toole  RV.  Surgical site infection in tibial plateau fractures with ipsilateral compartment syndrome.   Injury. 2017;48(2):495-500. doi:10.1016/j.injury.2016.10.017 PubMedGoogle ScholarCrossref
11.
O’Neill  KR, Smith  JG, Abtahi  AM,  et al.  Reduced surgical site infections in patients undergoing posterior spinal stabilization of traumatic injuries using vancomycin powder.   Spine J. 2011;11(7):641-646. doi:10.1016/j.spinee.2011.04.025 PubMedGoogle ScholarCrossref
12.
Sweet  FA, Roh  M, Sliva  C.  Intrawound application of vancomycin for prophylaxis in instrumented thoracolumbar fusions: efficacy, drug levels, and patient outcomes.   Spine (Phila Pa 1976). 2011;36(24):2084-2088. doi:10.1097/BRS.0b013e3181ff2cb1 PubMedGoogle ScholarCrossref
13.
Molinari  RW, Khera  OA, Molinari  WJ  III.  Prophylactic intraoperative powdered vancomycin and postoperative deep spinal wound infection: 1,512 consecutive surgical cases over a 6-year period.   Eur Spine J. 2012;21(suppl 4):S476-S482. doi:10.1007/s00586-011-2104-z PubMedGoogle ScholarCrossref
14.
Pahys  JM, Pahys  JR, Cho  SK,  et al.  Methods to decrease postoperative infections following posterior cervical spine surgery.   J Bone Joint Surg Am. 2013;95(6):549-554. doi:10.2106/JBJS.K.00756 PubMedGoogle ScholarCrossref
15.
Montalvo  RN, Natoli  RM, OʼHara  NN,  et al.  Variations in the organisms causing deep surgical site infections in fracture patients at a level I trauma center (2006-2015).   J Orthop Trauma. 2018;32(12):e475-e481. doi:10.1097/BOT.0000000000001305 PubMedGoogle ScholarCrossref
16.
Centers for Disease Control and Prevention. Surgical Site Infection (SSI) Event. Centers for Disease Control and Prevention; January 2017. Accessed December 9, 2017. https://www.cdc.gov/nhsn/pdfs/pscmanual/9pscssicurrent.pdf
17.
R Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing; 2013. Accessed February 14, 2020. http://www.R-project.org/
18.
Bakhsheshian  J, Dahdaleh  NS, Lam  SK, Savage  JW, Smith  ZA.  The use of vancomycin powder in modern spine surgery: systematic review and meta-analysis of the clinical evidence.   World Neurosurg. 2015;83(5):816-823. doi:10.1016/j.wneu.2014.12.033 PubMedGoogle ScholarCrossref
19.
Chiang  HY, Herwaldt  LA, Blevins  AE, Cho  E, Schweizer  ML.  Effectiveness of local vancomycin powder to decrease surgical site infections: a meta-analysis.   Spine J. 2014;14(3):397-407. doi:10.1016/j.spinee.2013.10.012 PubMedGoogle ScholarCrossref
20.
Kanj  WW, Flynn  JM, Spiegel  DA, Dormans  JP, Baldwin  KD.  Vancomycin prophylaxis of surgical site infection in clean orthopedic surgery.   Orthopedics. 2013;36(2):138-146. doi:10.3928/01477447-20130122-10 PubMedGoogle ScholarCrossref
21.
Morgenstern  M, Vallejo  A, McNally  MA,  et al.  The effect of local antibiotic prophylaxis when treating open limb fractures: a systematic review and meta-analysis.   Bone Joint Res. 2018;7(7):447-456. doi:10.1302/2046-3758.77.BJR-2018-0043.R1 PubMedGoogle ScholarCrossref
22.
Tennent  DJ, Shiels  SM, Sanchez  CJ  Jr,  et al.  Time-dependent effectiveness of locally applied vancomycin powder in a contaminated traumatic orthopaedic wound model.   J Orthop Trauma. 2016;30(10):531-537. doi:10.1097/BOT.0000000000000617 PubMedGoogle ScholarCrossref
23.
Hovis  JP, Montalvo  R, Marinos  D,  et al.  Intraoperative vancomycin powder reduces Staphylococcus aureus surgical site infections and biofilm formation on fixation implants in a rabbit model.   J Orthop Trauma. 2018;32(5):263-268. doi:10.1097/BOT.0000000000001136 PubMedGoogle ScholarCrossref
24.
Caroom  C, Moore  D, Mudaliar  N,  et al.  Intrawound vancomycin powder reduces bacterial load in contaminated open fracture model.   J Orthop Trauma. 2018;32(10):538-541. doi:10.1097/BOT.0000000000001259 PubMedGoogle ScholarCrossref
25.
Owen  MT, Keener  EM, Hyde  ZB,  et al.  Intraoperative topical antibiotics for infection prophylaxis in pelvic and acetabular surgery.   J Orthop Trauma. 2017;31(11):589-594. doi:10.1097/BOT.0000000000000941 PubMedGoogle ScholarCrossref
26.
Armaghani  SJ, Menge  TJ, Lovejoy  SA, Mencio  GA, Martus  JE.  Safety of topical vancomycin for pediatric spinal deformity: nontoxic serum levels with supratherapeutic drain levels.   Spine (Phila Pa 1976). 2014;39(20):1683-1687. doi:10.1097/BRS.0000000000000465 PubMedGoogle ScholarCrossref
27.
Gans  I, Dormans  JP, Spiegel  DA,  et al.  Adjunctive vancomycin powder in pediatric spine surgery is safe.   Spine (Phila Pa 1976). 2013;38(19):1703-1707. doi:10.1097/BRS.0b013e31829e05d3 PubMedGoogle ScholarCrossref
28.
O’Toole  RV, Degani  Y, Carlini  AR, Castillo  RC, O’Hara  NN, Joshi  M; METRC.  Systemic absorption and nephrotoxicity associated with topical vancomycin powder for fracture surgery.   J Orthop Trauma. 2021;35(1):29-34. doi:10.1097/BOT.0000000000001866 PubMedGoogle ScholarCrossref
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    1 Comment for this article
    Bone healing
    Felix Blaesius, M.D. | University Hospital RWTH Aachen, Germany
    Dear Authors,

    you have included fractures with a high risk of infection. In particular, the open fractures are subject to a high risk of delayed bone healing or fracture nonunion. To what extent locally applied vancomycin affects bone healing is unknown, but an important observation. A lower infection rate should not be "bought" with a higher rate of delayed bone healing or fracture nonunion. Do you have data on healing rates from your study that you could present? That would be very helpful in the evaluation of the study.

    Yours sincerely,
    F. Bläsius
    CONFLICT OF INTEREST: None Reported
    Original Investigation
    March 24, 2021

    Effect of Intrawound Vancomycin Powder in Operatively Treated High-risk Tibia Fractures: A Randomized Clinical Trial

    The Major Extremity Trauma Research Consortium (METRC)
    JAMA Surg. 2021;156(5):e207259. doi:10.1001/jamasurg.2020.7259
    Key Points

    Question  Does intrawound vancomycin powder reduce deep surgical site infections in patients with high-risk tibial plateau and pilon fracture?

    Findings  In this randomized clinical trial of 980 patients, intrawound vancomycin reduced deep surgical site infection rates by 3.4%. A post hoc analysis found that this effect was a result of a reduction in gram-positive infections.

    Meaning  These findings suggest that intrawound vancomycin powder is a promising low-cost, low-risk intervention for reducing deep surgical site infections, particularly those with gram-positive organisms.

    Abstract

    Importance  Despite the widespread use of systemic antibiotics to prevent infections in surgically treated patients with fracture, high rates of surgical site infection persist.

    Objective  To examine the effect of intrawound vancomycin powder in reducing deep surgical site infections.

    Design, Setting, and Participants  This open-label randomized clinical trial enrolled adult patients with an operatively treated tibial plateau or pilon fracture who met the criteria for a high risk of infection from January 1, 2015, through June 30, 2017, with 12 months of follow-up (final follow-up assessments completed in April 2018) at 36 US trauma centers.

    Interventions  A standard infection prevention protocol with (n = 481) or without (n = 499) 1000 mg of intrawound vancomycin powder.

    Main Outcomes and Measures  The primary outcome was a deep surgical site infection within 182 days of definitive fracture fixation. A post hoc comparison assessed the treatment effect on gram-positive and gram-negative-only infections. Other secondary outcomes included superficial surgical site infection, nonunion, and wound dehiscence.

    Results  The analysis included 980 patients (mean [SD] age, 45.7 [13.7] years; 617 [63.0%] male) with 91% of the expected person-time of follow-up for the primary outcome. Within 182 days, deep surgical site infection was observed in 29 of 481 patients in the treatment group and 46 of 499 patients in the control group. The time-to-event estimated probability of deep infection by 182 days was 6.4% in the treatment group and 9.8% in the control group (risk difference, –3.4%; 95% CI, –6.9% to 0.1%; P = .06). A post hoc analysis of the effect of treatment on gram-positive (risk difference, –3.7%; 95% CI, –6.7% to –0.8%; P = .02) and gram-negative-only (risk difference, 0.3%; 95% CI, –1.6% to 2.1%; P = .78) infections found that the effect of vancomycin powder was a result of its reduction in gram-positive infections.

    Conclusions and Relevance  Among patients with operatively treated tibial articular fractures at a high risk of infection, intrawound vancomycin powder at the time of definitive fracture fixation reduced the risk of a gram-positive deep surgical site infection, consistent with the activity of vancomycin.

    Trial Registration  ClinicalTrials.gov Identifier: NCT02227446

    Introduction

    Despite the widespread use of systemic antibiotics to prevent surgical site infections, high rates of infection after plate and screw fixation of fractures of the tibial plateau and pilon persist.1,2 Furthermore, intravenous antibiotics can only be delivered to tissues with sufficient blood supply. This pathway may be compromised in acutely injured tissues at the time of fracture. By contrast, local antibiotic therapy can deliver much higher concentrations directly to the surgical sites, potentially leading to greater efficiency in the prevention of biofilm formation and fracture-related infection.3-5 Therefore, we conducted a randomized clinical trial to evaluate the effect of intrawound vancomycin powder in reducing deep surgical site infections within 182 days of plate and screw fixation for tibial plateau or pilon fractures deemed to be at high risk of infection.

    Methods
    Trial Design and Oversight

    The Local Antibiotic Therapy to Reduce Infection After Operative Treatment of Fractures at High Risk of Infection (VANCO) trial was an open-label randomized clinical trial under the coordination of the Major Extremity Trauma Research Consortium (METRC) at the Johns Hopkins Bloomberg School of Public Health.6 Vancomycin is a US Food and Drug Administration (FDA)–approved drug; however, the application of a topical vancomycin powder during fracture wound closure was considered off-label use. Therefore, an Investigational New Drug approval was obtained from the FDA before commencing the study. The study protocol (Supplement 1) was approved by the ethics committee at the Johns Hopkins Bloomberg School of Public Health as the coordinating center, the US Department of Defense Human Research Protection Office, and at each participating center. Each site was required to obtain US Department of Defense Human Research Protection Office approval of local ethics documents and certification by the coordinating center to ensure proper training on study procedures and data collection before initiation of the study. All study patients provided written informed consent, and all data were deidentified. Further details of the study design are available in the protocol (Supplement 1).7 This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

    Eligibility Criteria

    We enrolled patients at 36 US trauma centers from January 1, 2015, through June 30, 2017, with 12 months of planned follow-up. Eligible patients were 18 to 80 years of age with a tibial plateau or pilon fracture deemed to be at high risk of infection and definitively treated with plate and screw fixation. High-risk fractures were defined as injuries that met at least 1 of the following conditions: (1) were initially treated with a temporary external fixation because of swelling that prevented early fixation and had definitive fixation more than 3 days after injury, (2) had a Gustilo-Anderson type I, II, or IIIA open fracture,8,9 or (3) were associated with ipsilateral leg compartment syndrome treated with fasciotomy.10 We excluded patients who were already infected at the time of enrollment, had a Gustilo-Anderson type IIIB or IIIC open fracture, or had a known allergy to vancomycin.8,9

    Randomization and Blinding

    Patients were randomized in a 1:1 ratio, stratified by the study center and the fracture location. Randomization was performed by a central computerized system with variable block sizes. The study group allocation was concealed to the patients and end point adjudicators, but the treating surgeon had to be aware of the allocation at the time of surgery.

    Intervention

    The treatment group was to receive 1000 mg of sterile vancomycin powder placed directly over metal implants in the surgical wound at the time of definitive fracture fixation.11-14 Vancomycin was chosen for its activity against gram-positive pathogens, the most common bacteria encountered in deep surgical site infections after fracture surgery.15 A placebo powder was not used for the control group because of concern that a powder with no potential to reduce infection might be harmful. Patients in both study groups received all other infection prevention measures based on the standard of care at each participating hospital, including prophylactic perioperative antibiotics administered intravenously.

    Study Outcomes

    The primary outcome was the presence of a deep surgical site infection within 182 days of the definitive fracture fixation. Deep infections were initially identified by the treating surgeon and independently evaluated by a central adjudication committee, blinded to treatment arm, using a modified version of the 1999 Centers for Disease Control and Prevention’s National Healthcare Safety Network criteria for surgical site infections, which was further revised in 2017.16 The criteria modification required the deep infection to be treated surgically and extended the occurrence window to within 182 days of the definitive fracture fixation. We selected 182 days for the primary outcome as a pragmatic balance between capturing infections beyond the typical 90-day assessment and minimizing the patient and research burden of monitoring patients outside standard clinic needs. Secondary outcomes included a superficial surgical site infection, defined as an infection treated with antibiotics but without surgery; a nonunion of the fracture; and a revision surgery for wound dehiscence. The deep infections were cultured to identify pathogens per the protocol at each institution. Given that vancomycin only has activity against gram-positive organisms, a post hoc comparison assessed the treatment effect specific to gram-positive and gram-negative infections. Gram-positive infections were defined as any infection with a gram-positive organism but could have other pathogens for the subset with polymicrobial pathogens. Gram-negative-only infections were defined as infections with only gram-negative cultures with no other type of pathogens. No other post hoc analyses were performed. Patients were scheduled for assessments at 2 weeks, 3 months, and 6 months after the date of definitive fracture fixation.

    Statistical Analysis

    The planned sample size was based on an 11% baseline risk of a deep surgical site infection in the control arm.7 Under this assumption, 928 patients were required for 80% power to detect a 5.1% absolute risk reduction with a 2-sided α = .05 level. To account for 1 interim analysis using the O’Brien-Fleming stopping boundary, we inflated the sample size by 1% to preserve the overall type I error. The sample size was further inflated by 5% to account for attrition. On the basis of these considerations, the targeted sample size for the study was set at 500 patients per study arm.

    An interim analysis was conducted in November 2016, after one-third of enrolled patients reached 6 months of follow-up. On the basis of the analysis, the Data and Safety Monitoring Board recommended the continuance of the study.

    All analyses were performed according to a modified intention-to-treat paradigm in which all patients, except those who were deemed ineligible after randomization or refused participation after randomization, were analyzed according to the treatment group to which they were randomly assigned. The primary outcome was analyzed using both time-to-event and complete case approaches. For the time-to-event analyses, Kaplan-Meier was used to estimate the probability of being event free at 182 days after the definitive fixation. In the complete case approach, the numerator was the number of patients with an event observed within 224 days of definitive fixation (ie, 182 days plus 6 weeks), and the denominator was the total number of patients with events or at least 140 days of follow-up (ie, 182 days minus 6 weeks). This 6-week window was chosen to reflect the reality of clinical follow-up for this patient population. Extensive sensitivity analyses were conducted to evaluate robustness to timing decisions. We also conducted 2 post hoc analyses to assess the effect of intrawound vancomycin powder on deep gram-positive infections and deep gram-negative-only infections. We prespecified 2 subgroup analyses to investigate the modification of the effect of intrawound vancomycin powder on the primary end point by location of the fracture (tibial plateau vs pilon fractures) and by the severity of the fracture (open fractures vs closed fractures). We reported risk differences and relative risks with 95% CIs for each analysis as well as 2-sided P values, with P < .05 indicating statistical significance. No adjustments were made for multiple testing. All analyses were performed using R statistical software, version 3.5.3 (R Foundation for Statistical Computing).17

    Results
    Patients

    A total of 1036 patients (mean [SD] age, 45.8 [13.7] years; 639 [61.7%] male) were randomized to receive intrawound vancomycin powder (515 patients) or be in the control group (521 patients). The final follow-up assessments were completed in April 2018. Of the 1036 patients who underwent randomization, 980 (95%) were determined to be eligible for inclusion in the modified intention-to-treat sample (481 treatment and 499 control patients). Details on the patient flow are provided in the Figure. The distribution of follow-up duration by treatment group is displayed in eFigure 1 in Supplement 2.

    The split was nearly equal between the tibial plateau (497 [50.7%]) and pilon fracture (483 [49.3%]) groups. Overall, 191 fractures (19.4%) were open. The baseline characteristics were similar between the 2 treatment groups (Table 1). The mean (SD) time from injury to definitive fixation was 14.8 (9.8) days. eTable 1 in Supplement 2 details the number of patients deemed ineligible and the reasons why. Additional patient, injury, and surgical and antibiotic treatment characteristics are included in eTables 2 to 5 in Supplement 2.

    Adherence to Assigned Intervention

    Of 481 patients allocated to the treatment group, 445 (92.5%) received a 1000-mg dose of intrawound vancomycin powder (Table 2); an additional 12 patients (2.5%) received the incorrect dose of vancomycin powder. Of 499 patients allocated to the control group, 19 (3.8%) erroneously received intrawound vancomycin powder.

    Primary Outcome

    In the treatment group, a deep surgical site infection was observed in 29 participants within 182 days of wound closure and in 30 patients within 224 days of wound closure. In the control group, a deep surgical site infection was observed in 46 participants within 182 days of wound closure and 48 participants within 224 days of wound closure. Forty-seven uninfected patients (9.8%) were followed up for less than 140 days and excluded from the complete case analysis in the treatment group. An additional 59 uninfected patients (11.8%) in the control group did not meet the 140-day follow-up minimum and were excluded in the complete case analysis. The time-to-event estimates of the deep infection rate were 6.4% for the treatment group and 9.8% for the control groups (risk difference, –3.4%; 95% CI, –6.9% to 0.1%; P = .06) (Table 3; eFigure 2A in Supplement 2). The complete case estimates were 6.9% for the treatment group and 10.9% for the control group (risk difference, –4.0%; 95% CI, –7.9% to –0.2%; P = .04) (Table 3). Extensive sensitivity analyses for the time-to-event and complete case approaches are reported in eTables 6 and 7 in Supplement 2. These analyses are consistent with our overall findings.

    Post Hoc Analysis

    In the post hoc analysis of pathogen-specific deep infections, 16 patients (3.3%) in the treatment group and 34 patients (6.8%) in the control group developed deep gram-positive infections within 182 days of wound closure (risk difference, –3.7%; 95% CI, –6.7% to –0.8%; P = .02 for time-to-event analysis; risk difference, –4.4%; 95% CI, –7.8% to –1.2%; P = .01 for complete case analysis) (Table 3; eFigure 2B in Supplement 2). The effect of intrawound vancomycin powder on deep gram-negative infections was negligible, with 11 patients (2.3%) in the treatment group and 10 patients (2.0%) in the control group sustaining deep gram-negative infections within 182 days of wound closure (risk difference, 0.3%; 95% CI, –1.6% to 2.1%; P = .78 for time-to-event analysis; risk difference, 0.2%; 95% CI, –2.1% to 2.5%; P > .99 for complete case analysis) (Table 3; eFigure 2C in Supplement 2).

    Secondary Outcomes

    No evidence of appreciable differences appeared between the treatment and control groups with respect to superficial surgical site infection (risk difference, 0.7%; 95% CI, –1.8% to 3.3%; P = .59), nonunion (risk difference, 1.2%; 95% CI, –1.7% to 4.2%; P = .43), or wound dehiscence (risk difference, –1.3%; –4.2% to 1.5%; P = .42) (Table 4). Results for the additional secondary and tertiary outcomes, as well as serious adverse events, are given in eTables 8 and 9 in Supplement 2.

    Subgroup Analyses

    The estimates of effects, stratified by fracture location (plateau or pilon) and fracture severity (open or closed), are given in Table 3 and eFigure 2D and E in Supplement 2. Our analysis does not provide evidence of effect modification by fracture location. In the tibial plateau fracture subgroup, the deep infection rate was 6.0% in the treatment group and 8.8% in the control group (risk difference, –2.8%; 95% CI, –7.4% to 1.9%; P = .25). In the tibial pilon subgroup, the deep infection rate was 6.7% in the treatment group and 10.9% in the control group (risk difference, –4.2%; 95% CI, –9.5% to 1.2%; P = .13). Similarly, we did not observe evidence of effect modification by fracture severity. The deep infection rate in patients with open fracture was 12.7% in the treatment group and 19.3% in the control group (risk difference, –6.6%; –17.2% to 4.1%; P = .23). In the closed fracture subgroup, the deep infection rate was 4.6% in the treatment group and 7.6% in the control group (risk difference, 3.0%; –6.4% to 0.5%; P = .10).

    Discussion

    In this randomized clinical trial, among patients with a tibial plateau or pilon fracture, the use of intrawound vancomycin powder reduced the absolute risk of a deep surgical site infection by 3.4% to 4.0%. On a relative risk scale, the reduction is 35%. The protective effect appears to be attributable to a reduced risk of a deep gram-positive infection, where a 3.7% absolute and 51% relative risk scale reduction was observed. This observation is consistent with vancomycin’s mechanism of action on gram-positive bacteria only. As expected, the study intervention did not reduce the risk of a deep gram-negative infection. In addition, no appreciable effects of intrawound vancomycin powder on superficial site infection, bone nonunion, or wound dehiscence were observed.

    Strengths and Limitations

    The study has several strengths. This prospective randomized trial was conducted at 36 hospitals in the US, with more than 90% expected person-time of follow-up. Study enrollment was completed within 2 years, mitigating the effect of cointervention practice variation. Vancomycin was readily available at participating sites and easily administered, as evidenced by the limited patient crossover and very high protocol adherence. A central independent adjudication committee blinded to the study group was used to mitigate the risk of misclassification of deep and superficial infections.

    The trial also has limitations. The study was open label, given the concern regarding the ethics of using a placebo powder that might theoretically cause harm to a patient without a chance for benefit. However, as the diagnosis of deep surgical site infection after fracture is typically relatively unambiguous, the risk of an unblinded surgeon influencing the primary outcome was minimal. Medical records were not obtained for study patients who were treated at nonparticipating hospitals because of the assumption that most study patients would return to their index hospital for treatment of a deep infection. However, some patients with superficial infections may have been treated at a nonstudy hospital, potentially leading to an underreporting of this secondary study outcome. This occurrence is likely not differential between the study groups, and the high follow-up rates lessen this concern. The time from antibiotic delivery to surgical incision was not measured; however, it is unlikely that there was imbalance between the treatment groups on this covariate. A central laboratory was not used to culture suspected infections. Although allowing each participating center to culture suspected infections adds variance in the ability to detect specific bacteria, this process mirrors current clinical practice. A post hoc analysis of pathogen-specific deep surgical site infections was included. Although an analysis of the differences in pathogens between treatment groups was mentioned in the protocol (Supplement 1),7 it was not explicitly stated in the statistical analysis plan and hence deemed post hoc. The inclusion of these results is critical for practitioners in confirming the anticipated biologic rationale of the treatment because vancomycin only has activity against gram-positive organisms. However, in hindsight, gram-positive infections may have been a better suited primary outcome than infections from all pathogens. Finally, the study included only high-risk tibial pilon and plateau fractures treated with plate and screw fixation, so the generalizability to other fracture types or treatments is unknown.

    Although this is the first randomized clinical trial, to our knowledge, of intrawound vancomycin powder in fracture surgery, the results of this study are consistent with several meta-analyses and retrospective studies11-14,18-20 in the spine surgery literature. In nonrandomized designs, these studies11-14,20 similarly report effect estimates that favor the use of intrawound vancomycin powder to reduce surgical site infections. A recent meta-analysis21 of nonrandomized studies examining antibiotic-loaded polymethyl methacrylate beads and other local antibiotics without a carrier in patients with open fracture also reported an infection risk reduction. The current trial demonstrated the benefits of applying intrawound vancomycin powder in patients with high-risk fracture specifically to reduce the risk of a gram-positive infection.22-24 Additional research may consider combining local vancomycin therapy with a topical aminoglycoside25 to reduce the risk of infections across a broader spectrum of organisms as well as its effect in other fracture types.

    Conclusions

    Although not all prespecified analyses of the primary outcome were statistically significant at the conventional 5% level, the findings suggest that intrawound vancomycin powder substantially reduces gram-positive infections in patients with high-risk tibial plateau and pilon fracture, without any observed negative effects. Intrawound vancomycin powder is a low-cost intervention that can be easily incorporated into existing prophylactic protocols. In addition to the observed treatment benefits specific to reducing gram-positive infections, prior research12,23,26-28 suggests that topical antibiotics have little systemic exposure and minimal systemic toxicity compared with antibiotics administered intravenously.

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    Article Information

    Accepted for Publication: December 8, 2020.

    Published Online: March 24, 2021. doi:10.1001/jamasurg.2020.7259

    Corresponding Author: Robert V. O’Toole, MD, R Adams Cowley Shock Trauma Center, Department of Orthopaedics, University of Maryland School of Medicine, 22 S Greene St, Baltimore, MD 21201 (rotoole@som.umaryland.edu).

    The Major Extremity Trauma Research Consortium (METRC) Authors: Robert V. O’Toole, MD; Manjari Joshi, MBBS; Anthony R. Carlini, MS; Clinton K. Murray, MD; Lauren E. Allen, MA; Yanjie Huang, ScM; Daniel O. Scharfstein, ScD; Nathan N. O’Hara, MHA; Joshua L. Gary, MD; Michael J. Bosse, MD; Renan C. Castillo, PhD; Julius A. Bishop, MD; Michael J. Weaver, MD; Reza Firoozabadi, MD; Joseph R. Hsu, MD; Madhav A. Karunakar, MD; Rachel B. Seymour, PhD; Stephen H. Sims, MD; Christine Churchill, MA; Michael L. Brennan, MD; Gabriela Gonzales, CCRP; Rachel M. Reilly, MD; Robert D. Zura, MD; Cameron R. Howes, BA; Hassan R. Mir, MD; Emily A. Wagstrom, MD; Jerald Westberg, BA; Greg E. Gaski, MD; Laurence B. Kempton, MD; Roman M. Natoli, MD; Anthony T. Sorkin, MD; Walter W. Virkus, MD; Lauren C. Hill, BS; Robert A. Hymes, MD; Michael Holzman, MD; A. Stephen Malekzadeh, MD; Jeff E. Schulman, MD; Lolita Ramsey, PhD; Jaslynn A. N. Cuff, MA; Sharon Haaser, RN; Greg M. Osgood, MD; Babar Shafiq, MD, MSPT; Vaishali Laljani, BSc; Olivia C. Lee, MD; Peter C. Krause, MD; Cara J. Rowe, MSW; Colette L. Hilliard, MS; Massimo Max Morandi, MD; Angela Mullins, RN; Timothy S. Achor, MD; Andrew M. Choo, MD; John W. Munz, MD; Sterling J. Boutte, BS; Heather A. Vallier, MD; Mary A. Breslin, BA; H. Michael Frisch, MD; Adam M. Kaufman, MD; Thomas M. Large, MD; C. Michael LeCroy, MD; Christina Riggsbee, BSN; Christopher S. Smith, MD; Colin V. Crickard, MD; Laura S. Phieffer, MD; Elizabeth Sheridan, MPH; Clifford B. Jones, MD; Debra L. Sietsema, PhD; J. Spence Reid, MD; Kathy Ringenbach, RN; Roman Hayda, MD; Andrew R. Evans, MD; M.J. Crisco, RN; Jessica C. Rivera, MD; Patrick M. Osborn, MD; Joseph Kimmel, MS; Stanislaw P. Stawicki, MD; Chinenye O. Nwachuku, MD; Thomas R. Wojda, MD; Saqib Rehman, MD; Joanne M. Donnelly; Cyrus Caroom, MD; Mark D. Jenkins, MD; Christina L. Boulton, MD; Timothy G. Costales, MD; Christopher T. LeBrun, MD; Theodore T. Manson, MD, MS; Daniel C. Mascarenhas, MD; Jason W. Nascone, MD; Andrew N. Pollak, MD; Marcus F. Sciadini, MD; Gerard P. Slobogean, MD; Peter Z. Berger, BS; Daniel W. Connelly, BS; Yasmin Degani, MPH; Andrea L. Howe, BS; Dimitrius P. Marinos, BS; Ryan N. Montalvo, BS; G. Bradley Reahl, MS; Carrie D. Schoonover, BA; Lisa K. Schroder, MBA; Sandy Vang, BA; Patrick F. Bergin, MD; Matt L. Graves, MD; George V. Russell, MD; Clay A. Spitler, MD; Josie M. Hydrick, BS; David Teague, MD; William Ertl, MD; Lindsay E. Hickerson, MD; Gele B. Moloney, MD; John C. Weinlein, MD; Boris A. Zelle, MD; Animesh Agarwal, MD; Ravi A. Karia, MD; Ashoke K. Sathy, MD; Brigham Au, MD; Medardo Maroto, MD; Drew Sanders, MD; Thomas F. Higgins, MD; Justin M. Haller, MD; David L. Rothberg, MD; David B. Weiss, MD; Seth R. Yarboro, MD; Eric D. McVey, MEd; Veronica Lester-Ballard, RN; David Goodspeed, MD; Gerald J. Lang, MD; Paul S. Whiting, MD; Alexander B. Siy, BS; William T. Obremskey, MD, MPH, MMHC; A. Alex Jahangir, MD, MMHC; Basem Attum, MD, MS; Eduardo J. Burgos, MD; Cesar S. Molina, MD; Andres Rodriguez-Buitrago, MD; Vamshi Gajari, MBBS; Karen M. Trochez, MA; Jason J. Halvorson, MD; Anna N. Miller, MD; James Brett Goodman, MBA; Martha B. Holden, AAS; Christopher M. McAndrew, MD, MSc; Michael J. Gardner, MD; William M. Ricci, MD; Amanda Spraggs-Hughes, PhD; Susan C. Collins, MSc; Tara J. Taylor, MPH; Mary Zadnik, ScD.

    Affiliations of The Major Extremity Trauma Research Consortium (METRC) Authors: Department of Orthopaedics, R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore (O’Toole, O’Hara, Boulton, Costales, LeBrun, Manson, Mascarenhas, Nascone, Pollak, Sciadini, Slobogean, Berger, Connelly, Degani, Howe, Marinos, Montalvo, Reahl, Schoonover); Department of Infectious Diseases, R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore (Joshi); Major Extremity Trauma Research Consortium Coordinating Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (Carlini, Allen, Huang, Scharfstein, Castillo, Collins, Taylor, Zadnik); Department of Medicine, San Antonio Military Medical Center, San Antonio, Texas (Murray); Department of Orthopedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston (Gary, Achor, Choo, Munz, Boutte); Atrium Health Musculoskeletal Institute, Carolinas Medical Center, Charlotte, North Carolina (Bosse, Hsu, Karunakar, Seymour, Sims, Churchill); Department of Orthopaedic Surgery, Stanford University, Palo Alto, California (Bishop); Department of Orthopaedic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts (Weaver); Department of Orthopaedics and Sports Medicine, Harborview Medical Center/University of Washington, Seattle (Firoozabadi); Department of Orthopaedic Surgery, Baylor Scott and White Memorial Center, Temple, Texas (Brennan, Gonzales); Department of Orthopaedic Surgery, Duke University, Durham, North Carolina (Reilly, Zura, Howes); Florida Orthopaedic Institute/Tampa General Hospital, Tampa (Mir); Department of Orthopaedic Surgery, Hennepin County Medical Center, Minneapolis, Minnesota (Wagstrom, Westberg); Department of Orthopaedic Surgery, Indiana University Methodist Hospital, Indianapolis (Gaski, Kempton, Natoli, Sorkin, Virkus, Hill); Department of Orthopedic Surgery, Inova Fairfax Medical Campus, Fairfax, Virginia (Hymes, Holzman, Malekzadeh, Schulman, Ramsey, Cuff, Haaser); Department of Orthopaedic Surgery, Johns Hopkins Hospital, Baltimore, Maryland (Osgood, Shafiq, Laljani); Department of Orthopaedic Surgery, Louisiana State University Health Sciences Center, New Orleans (Lee, Krause, Rowe, Hilliard); Department of Orthopaedic Surgery, Louisiana State University Health Sciences Center, Shreveport (Morandi, Mullins); Department of Orthopaedics, MetroHealth, Cleveland, Ohio (Vallier, Breslin); Orthopaedic Trauma Service, Mission Health, Asheville, North Carolina (Frisch, Kaufman, Large, LeCroy); Research Institute, Mission Health, Asheville, North Carolina (Riggsbee); Department of Orthopaedic Surgery, Naval Medical Center Portsmouth, Portsmouth, Virginia (Smith, Crickard); Department of Orthopaedics, Ohio State University, Wexner Medical Center, Columbus (Phieffer, Sheridan); Spectrum Health, Grand Rapids, Michigan (Jones, Sietsema); Department of Orthopaedics and Rehabilitation, Penn State Health, Hershey, Pennsylvania (Reid, Ringenbach); Department of Orthopedic Surgery, Brown University/Rhode Island Hospital, Providence (Hayda, Evans, Crisco); Department of Orthopaedic Surgery, San Antonio Military Medical Center, San Antonio, Texas (Rivera, Osborn, Kimmel); Department of Research and Innovation, St. Luke’s University Health Network, Bethlehem, Pennsylvania (Stawicki); Department of Orthopedic Surgery, St. Luke’s University Health Network, Bethlehem, Pennsylvania (Nwachuku); Department of Family Medicine, St. Luke’s University Health Network, Bethlehem, Pennsylvania (Wojda); Department of Orthopaedic Surgery and Sports Medicine, Temple University, Philadelphia, Pennsylvania (Rehman, Donnelly); Department of Orthopaedics, Texas Tech University Health Sciences Center, Lubbock (Caroom, Jenkins); Department of Orthopaedic Surgery, University of Minnesota–Regions Hospital, St Paul (Schroder, Vang); Department of Orthopaedic Surgery, University of Mississippi Medical Center, Jackson (Bergin, Graves, Russell, Spitler, Hydrick); Department of Orthopedic Surgery and Rehabilitation, University of Oklahoma, Oklahoma City (Teague, Ertl, Hickerson); Department of Orthopaedic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (Moloney); Department of Orthopaedic Surgery, University of Tennessee–Campbell Clinic, Memphis (Weinlein); Department of Orthopaedics, University of Texas Health at San Antonio, San Antonio (Zelle, Agarwal, Karia); Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas (Sathy, Au, Maroto, Sanders); Department of Orthopaedics, University of Utah, Salt Lake City (Higgins, Haller, Rothberg); Department of Orthopaedic Surgery, University of Virginia School of Medicine, Charlottesville (Weiss, Yarboro, McVey, Lester-Ballard); Department of Orthopedics and Rehabilitation, University of Wisconsin School of Medicine and Public Health, Madison (Goodspeed, Lang, Whiting, Siy); Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (Obremskey, Jahangir, Attum, Burgos, Molina, Rodriguez-Buitrago, Gajari, Trochez); Department of Orthopaedic Surgery and Rehabilitation, Wake Forest Baptist University Medical Center, Winston-Salem, North Carolina (Halvorson, Miller, Goodman, Holden); Department of Orthopedic Surgery, Washington University in St Louis/Barnes Jewish Hospital, St Louis, Missouri (McAndrew, Gardner, Ricci, Spraggs-Hughes).

    Author Contributions: Dr O’Toole had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: O’Toole, Joshi, Carlini, Murray, Allen, Scharfstein, Bosse, Castillo, Hsu, Sims, Zura, Hill, Vallier, Smith, Crickard, Jones, Sietsema, Donnelly, Caroom, Manson, Nascone, Pollak, Teague, Maroto, Sanders, Obremskey, Attum, Ricci, Taylor, Zadnik.

    Acquisition, analysis, or interpretation of data: O’Toole, Joshi, Carlini, Allen, Huang, Scharfstein, O’Hara, Gary, Bosse, Castillo, Bishop, Weaver, Firoozabadi, Hsu, Karunakar, Seymour, Sims, Churchill, Brennan, Gonzales, Reilly, Zura, Howes, Mir, Wagstrom, Westberg, Gaski, Kempton, Natoli, Sorkin, Virkus, Hymes, Holzman, Malekzadeh, Schulman, Ramsey, Cuff, Haaser, Osgood, Shafiq, Laljani, Lee, Krause, Rowe, Hilliard, Morandi, Choo, Boutte, Vallier, Breslin, Frisch, Kaufman, Large, LeCroy, Riggsbee, Crickard, Phieffer, Sheridan, Jones, Sietsema, Ringenbach, Hayda, Crisco, Rivera, Osborn, Kimmel, Stawicki, Nwachuku, Wojda, Rehman, Caroom, Jenkins, Boulton, Costales, LeBrun, Manson, Mascarenhas, Nascone, Pollak, Sciadini, Slobogean, Berger, Connelly, Degani, Howe, Marinos, Montalvo, Reahl, Vang, Bergin, Russell, Spitler, Teague, Ertl, Hickerson, Moloney, Weinlein, Zelle, Agarwal, Karia, Mullins, Sathy, Au, Maroto, Sanders, Higgins, Haller, Rothberg, Yarboro, McVey, Whiting, Siy, Obremskey, Attum, Burgos, Jahangir, Molina, Rodriguez-Buitrago, Gajari, Trochez, Miller, Holden, McAndrew, Gardner, Ricci, Spraggs-Hughes, Collins, Taylor, Zadnik.

    Drafting of the manuscript: O’Toole, Joshi, Carlini, Huang, Scharfstein, O’Hara, Gary, Bosse, Castillo, Hymes, Haaser, Ringenbach, Hayda, Costales, Sciadini, Berger, Degani, Ertl, Mullins, Attum, Burgos, Rodriguez-Buitrago, Gajari, McAndrew, Collins, Taylor.

    Critical revision of the manuscript for important intellectual content: O’Toole, Joshi, Carlini, Murray, Allen, Scharfstein, O’Hara, Gary, Bosse, Castillo, Bishop, Weaver, Firoozabadi, Hsu, Karunakar, Seymour, Sims, Churchill, Brennan, Gonzales, Reilly, Zura, Howes, Mir, Wagstrom, Westberg, Gaski, Kempton, Natoli, Sorkin, Virkus, Hill, Hymes, Holzman, Malekzadeh, Schulman, Ramsey, Cuff, Osgood, Shafiq, Laljani, Lee, Krause, Rowe, Hilliard, Morandi, Choo, Boutte, Vallier, Breslin, Frisch, Kaufman, Large, LeCroy, Riggsbee, Smith, Crickard, Phieffer, Sheridan, Jones, Sietsema, Hayda, Crisco, Rivera, Osborn, Kimmel, Stawicki, Nwachuku, Wojda, Rehman, Donnelly, Caroom, Jenkins, Boulton, LeBrun, Manson, Mascarenhas, Nascone, Pollak, Slobogean, Connelly, Howe, Marinos, Montalvo, Reahl, Vang, Bergin, Russell, Spitler, Teague, Ertl, Hickerson, Moloney, Weinlein, Zelle, Agarwal, Karia, Sathy, Au, Maroto, Sanders, Higgins, Haller, Rothberg, Yarboro, McVey, Whiting, Siy, Obremskey, Attum, Jahangir, Molina, Gajari, Trochez, Miller, Holden, Gardner, Ricci, Spraggs-Hughes, Taylor, Zadnik.

    Statistical analysis: Huang, Scharfstein, Castillo, Weaver, Hayda, Mullins.

    Obtained funding: O’Toole, Scharfstein, Bosse, Castillo, Pollak, Teague, Maroto, Obremskey.

    Administrative, technical, or material support: O’Toole, Carlini, Murray, Allen, O’Hara, Gary, Castillo, Bishop, Weaver, Firoozabadi, Hsu, Seymour, Sims, Churchill, Gonzales, Wagstrom, Westberg, Kempton, Virkus, Hill, Hymes, Schulman, Ramsey, Cuff, Laljani, Lee, Krause, Rowe, Hilliard, Boutte, Vallier, Breslin, Frisch, Large, Crickard, Phieffer, Jones, Sietsema, Crisco, Rivera, Kimmel, Stawicki, Wojda, Donnelly, Caroom, Jenkins, Costales, LeBrun, Manson, Mascarenhas, Nascone, Pollak, Slobogean, Berger, Degani, Howe, Marinos, Montalvo, Vang, Spitler, Teague, Ertl, Zelle, Karia, Sathy, Maroto, Sanders, Higgins, Haller, Yarboro, McVey, Whiting, Siy, Attum, Burgos, Molina, Rodriguez-Buitrago, Trochez, Miller, Holden, McAndrew, Ricci, Spraggs-Hughes, Collins, Taylor, Zadnik.

    Supervision: O’Toole, Carlini, Murray, Allen, Scharfstein, Gary, Bosse, Castillo, Karunakar, Seymour, Sims, Churchill, Zura, Gaski, Kempton, Natoli, Hymes, Schulman, Morandi, Boutte, Vallier, Frisch, Kaufman, Smith, Jones, Hayda, Rivera, Osborn, Stawicki, Caroom, Jenkins, Boulton, Manson, Nascone, Pollak, Sciadini, Bergin, Teague, Weinlein, Maroto, Higgins, Obremskey, Burgos, Gardner, Spraggs-Hughes, Taylor.

    Conflict of Interest Disclosures: Dr O’Toole reported receiving grants from the U.S. Department of Defense (DOD) Congressionally Directed Medical Research Program during the conduct of the study and personal fees from Smith & Nephew, stock options from Imagen, personal fees and royalties from Lincotek, and personal fees from Zimmer outside the submitted work. Dr Joshi reported receiving grants from the DOD during the conduct of the study and grants from the DOD and the Patient-Centered Outcomes Research Institute (PRORP) outside the submitted work. Dr Carlini reported receiving grants from the DOD during the conduct of the study. Dr Scharfstein reported receiving grants from the DOD during the conduct of the study. Dr O’Hara reported receiving grants from the DOD during the conduct of the study. Dr Gary reported receiving grants from the DOD during the conduct of the study and being a paid presenter for Smith & Nephew and receiving honoria for teaching and personal fees from Stryker outside the submitted work. Dr Bosse reported receiving grants from the DOD during the conduct of the study. Dr Castillo reported receiving grants from the PRORP and DOD during the conduct of the study. Dr Bishop reported receiving personal fees from Stryker, KCI, Innomed, and Globus outside the submitted work. Dr Weaver reported receiving personal fees from OsteoCentric and royalties for fracture implants outside the submitted work. Dr Firoozabadi reported being a paid consultant for Smith & Nephew Consulting outside the submitted work. Dr Hsu reported receiving personal fees from Smith & Nephew, consulting and personal fees from Globus Medical consulting, personal fees from DePuy Synthes, and honoraria and personal fees from Stryker outside the submitted work. Dr Karunakar reported receiving grants from the DOD during the conduct of the study. Dr Seymour reported receiving grants from the DOD during the conduct of the study. Dr Sims reported receiving grants from the DOD during the conduct of the study. Dr Churchill reported receiving grants from Atrium Health Carolinas Medical Center during the conduct of the study. Dr Zura reported receiving personal fees from Bioventus and being a paid consultant for OsteoCentric Consulting outside the submitted work. Dr Wagstrom reported receiving grants from the DOD during the conduct of the study and personal fees from Stryker outside the submitted work. Dr Westberg reported receiving grants from Johns Hopkins via the DOD during the conduct of the study. Dr Kempton reported receiving grants from METRC consortium funding during the conduct of the study. Dr Sorkin reported receiving personal fees from Stryker outside the submitted work. Dr Virkus reported receiving grants from the Indiana University School of Medicine during the conduct of the study and grants from the DOD outside the submitted work. Dr Holzman reported receiving personal fees from Johnson & Johnson outside the submitted work. Dr Schulman reported receiving personal fees from Stryker outside the submitted work. Dr Ramsey reported receiving other from METRC funds during the conduct of the study. Dr Shafiq reported receiving nonfinancial support from DePuy Synthes and other from Bone Foam Board outside the submitted work. Dr Achor reported receiving personal fees from DePuy Synthes, personal fees from Stryker, and personal fees from Globus outside the submitted work. Dr Choo reported receiving personal fees from Synthes outside the submitted work. Dr Vallier reported receiving grants from the DOD during the conduct of the study; and grants from the PRORP, DOD, and the Orthopaedic Trauma Association (OTA) outside the submitted work. Dr Phieffer reported receiving personal fees from DePuy Synthes Consulting outside the submitted work. Dr Sietsema reported receiving grants from Johns Hopkins the DOD Subaward during the conduct of the study. Dr Reid reported receiving other from the DOD and financial support through the METRC consortium, which provided per–enrolled patient institutional support for this study during the conduct of the study; and personal and consulting fees for product development from DePuy Synthes and consulting fees from Smith & Nephew outside the submitted work. Dr Rehman reported receiving consulting fees from Globus Medical. Dr Costales reported receiving grants from the DOD during the conduct of the study. Dr Manson reported receiving grants from METRC during the conduct of the study. Dr Nascone reported receiving personal and consulting fees from Smith & Nephew, Zimmer, and Aona Travel; honoraria and personal fees from Coorstek Royalties; personal fees and royalties from DePuy Synthes; and Imagen stock options for consulting. Dr Pollak reported receiving grants from the DOD during the conduct of the study and personal fees from Globus and Zimmer outside the submitted work. Dr Slobogean reported receiving grants from the DOD during the conduct of the study and personal fees from Bayer AG outside the submitted work. Dr Schroder reported receiving grants from METRC funding during the conduct of the study; personal fees from Johnson & Johnson and DePuy Synthes, and consulting and personal fees from Exactech, and consulting fees outside the submitted work. Dr Vang reported receiving grants from the DOD during the conduct of the study. Dr Bergin reported receiving personal fees from Synthes outside the submitted work. Dr Spitler reported receiving personal fees from DePuy Synthes, personal fees from the Journal of Bone and Joint Surgery, and grants from Stryker outside the submitted work. Dr Teague reported receiving grants from METRC during the conduct of the study and being a board member of the OTA. Dr Moloney reported receiving grants from METRC during the conduct of the study. Dr Zelle reported receiving personal fees and grants from 3M, grants and personal fees from DePuy Synthes, and personal fees from AO North America outside the submitted work. Dr Sanders reported receiving educational fees from Smith & Nephew. Dr Higgins reported receiving personal fees from DePuy Synthes and personal fees from Globus and Imagen outside the submitted work and holding stock from Orthogrid, NT nPhase, and OsteoCentric. Dr Haller reported receiving personal fees from Stryker and NewClip Technics and grants from the OTA and the Arthritis Foundation outside the submitted work. Dr Weiss reported receiving grants from Johns Hopkins University/METRC during the conduct of the study and personal fees from DePuy Synthes, GlobusMedical, and Elsevier Publishing outside the submitted work. Dr Yarboro reported receiving intellectual property royalties from Advanced Orthopaedic Solutions and having a royalty agreement for product development outside the submitted work. Dr Goodspeed reported receiving honoria for teaching for AO North America. Dr Lang reported receiving grants from METRC during the conduct of the study. Dr Halvorson reported receiving grants from the DOD during the conduct of the study, being a paid speaker for AO North America, and being a paid consultant for Smith & Nephew. Dr McAndrew reported receiving grants from the DOD METRC during the conduct of the study; and grants from Zimmer Biomet outside the submitted work. Dr Ricci reported being a part owner of CableFix LLC; an investor with McGinley Orthopaedic Innovations; the owner of Primo MC LLC; and an investor with HS2; receiving royalties from MicroPort, Smith & Nephew, and Wolters-Kluwer; and being a designer with OsteoCentric outside the submitted work. Dr Collins reported receiving institutional grants from the DOD during the conduct of the study. No other disclosures were reported.

    Funding/Support: The study was funded by grant W81XWH-10-2-0134 from the DOD’s Congressionally Directed Medical Research Program (Drs O’Toole, Castillo, and Carlini).

    Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Data Sharing Statement: See Supplement 3.

    Additional Contributions: The late William G. DeLong, MD, of St Luke’s Health System contributed to the Local Antibiotic Therapy to Reduce Infection After Operative Treatment of Fractures at High Risk of Infection (VANCO) trial.

    References
    1.
    Harris  AM, Althausen  PL, Kellam  J, Bosse  MJ, Castillo  R; Lower Extremity Assessment Project (LEAP) Study Group.  Complications following limb-threatening lower extremity trauma.   J Orthop Trauma. 2009;23(1):1-6. doi:10.1097/BOT.0b013e31818e43dd PubMedGoogle ScholarCrossref
    2.
    Chen  AT, Vallier  HA.  Noncontiguous and open fractures of the lower extremity: epidemiology, complications, and unplanned procedures.   Injury. 2016;47(3):742-747. doi:10.1016/j.injury.2015.12.013 PubMedGoogle ScholarCrossref
    3.
    Metsemakers  WJ, Kuehl  R, Moriarty  TF,  et al.  Infection after fracture fixation: Current surgical and microbiological concepts.   Injury. 2018;49(3):511-522. doi:10.1016/j.injury.2016.09.019 PubMedGoogle ScholarCrossref
    4.
    Hospenthal  DR, Murray  CK, Andersen  RC,  et al.  Guidelines for the prevention of infection after combat-related injuries.   J Trauma. 2008;64(3)(suppl):S211-S220. doi:10.1097/TA.0b013e318163c421 PubMedGoogle Scholar
    5.
    Hospenthal  DR, Murray  CK, Andersen  RC,  et al; Infectious Diseases Society of America; Surgical Infection Society.  Guidelines for the prevention of infections associated with combat-related injuries: 2011 update: endorsed by the Infectious Diseases Society of America and the Surgical Infection Society.   J Trauma. 2011;71(2)(suppl 2):S210-S234. doi:10.1097/TA.0b013e318227ac4b PubMedGoogle Scholar
    6.
    Major Extremity Trauma Research Consortium (METRC).  Building a clinical research network in trauma orthopaedics: the major extremity trauma research consortium (METRC).   J Orthop Trauma. 2016;30(7):353-361. doi:10.1097/BOT.0000000000000549 PubMedGoogle ScholarCrossref
    7.
    OʼToole  RV, Joshi  M, Carlini  AR,  et al; METRC.  Local antibiotic therapy to reduce infection after operative treatment of fractures at high risk of infection: a multicenter, randomized, controlled trial (VANCO study).   J Orthop Trauma. 2017;31(suppl 1):S18-S24. doi:10.1097/BOT.0000000000000801 PubMedGoogle ScholarCrossref
    8.
    Gustilo  RB, Mendoza  RM, Williams  DN.  Problems in the management of type III (severe) open fractures: a new classification of type III open fractures.   J Trauma. 1984;24(8):742-746. doi:10.1097/00005373-198408000-00009 PubMedGoogle ScholarCrossref
    9.
    Gustilo  RB, Anderson  JT.  Prevention of infection in the treatment of one thousand and twenty-five open fractures of long bones: retrospective and prospective analyses.   J Bone Joint Surg Am. 1976;58(4):453-458. doi:10.2106/00004623-197658040-00004 PubMedGoogle ScholarCrossref
    10.
    Dubina  AG, Paryavi  E, Manson  TT, Allmon  C, O’Toole  RV.  Surgical site infection in tibial plateau fractures with ipsilateral compartment syndrome.   Injury. 2017;48(2):495-500. doi:10.1016/j.injury.2016.10.017 PubMedGoogle ScholarCrossref
    11.
    O’Neill  KR, Smith  JG, Abtahi  AM,  et al.  Reduced surgical site infections in patients undergoing posterior spinal stabilization of traumatic injuries using vancomycin powder.   Spine J. 2011;11(7):641-646. doi:10.1016/j.spinee.2011.04.025 PubMedGoogle ScholarCrossref
    12.
    Sweet  FA, Roh  M, Sliva  C.  Intrawound application of vancomycin for prophylaxis in instrumented thoracolumbar fusions: efficacy, drug levels, and patient outcomes.   Spine (Phila Pa 1976). 2011;36(24):2084-2088. doi:10.1097/BRS.0b013e3181ff2cb1 PubMedGoogle ScholarCrossref
    13.
    Molinari  RW, Khera  OA, Molinari  WJ  III.  Prophylactic intraoperative powdered vancomycin and postoperative deep spinal wound infection: 1,512 consecutive surgical cases over a 6-year period.   Eur Spine J. 2012;21(suppl 4):S476-S482. doi:10.1007/s00586-011-2104-z PubMedGoogle ScholarCrossref
    14.
    Pahys  JM, Pahys  JR, Cho  SK,  et al.  Methods to decrease postoperative infections following posterior cervical spine surgery.   J Bone Joint Surg Am. 2013;95(6):549-554. doi:10.2106/JBJS.K.00756 PubMedGoogle ScholarCrossref
    15.
    Montalvo  RN, Natoli  RM, OʼHara  NN,  et al.  Variations in the organisms causing deep surgical site infections in fracture patients at a level I trauma center (2006-2015).   J Orthop Trauma. 2018;32(12):e475-e481. doi:10.1097/BOT.0000000000001305 PubMedGoogle ScholarCrossref
    16.
    Centers for Disease Control and Prevention. Surgical Site Infection (SSI) Event. Centers for Disease Control and Prevention; January 2017. Accessed December 9, 2017. https://www.cdc.gov/nhsn/pdfs/pscmanual/9pscssicurrent.pdf
    17.
    R Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing; 2013. Accessed February 14, 2020. http://www.R-project.org/
    18.
    Bakhsheshian  J, Dahdaleh  NS, Lam  SK, Savage  JW, Smith  ZA.  The use of vancomycin powder in modern spine surgery: systematic review and meta-analysis of the clinical evidence.   World Neurosurg. 2015;83(5):816-823. doi:10.1016/j.wneu.2014.12.033 PubMedGoogle ScholarCrossref
    19.
    Chiang  HY, Herwaldt  LA, Blevins  AE, Cho  E, Schweizer  ML.  Effectiveness of local vancomycin powder to decrease surgical site infections: a meta-analysis.   Spine J. 2014;14(3):397-407. doi:10.1016/j.spinee.2013.10.012 PubMedGoogle ScholarCrossref
    20.
    Kanj  WW, Flynn  JM, Spiegel  DA, Dormans  JP, Baldwin  KD.  Vancomycin prophylaxis of surgical site infection in clean orthopedic surgery.   Orthopedics. 2013;36(2):138-146. doi:10.3928/01477447-20130122-10 PubMedGoogle ScholarCrossref
    21.
    Morgenstern  M, Vallejo  A, McNally  MA,  et al.  The effect of local antibiotic prophylaxis when treating open limb fractures: a systematic review and meta-analysis.   Bone Joint Res. 2018;7(7):447-456. doi:10.1302/2046-3758.77.BJR-2018-0043.R1 PubMedGoogle ScholarCrossref
    22.
    Tennent  DJ, Shiels  SM, Sanchez  CJ  Jr,  et al.  Time-dependent effectiveness of locally applied vancomycin powder in a contaminated traumatic orthopaedic wound model.   J Orthop Trauma. 2016;30(10):531-537. doi:10.1097/BOT.0000000000000617 PubMedGoogle ScholarCrossref
    23.
    Hovis  JP, Montalvo  R, Marinos  D,  et al.  Intraoperative vancomycin powder reduces Staphylococcus aureus surgical site infections and biofilm formation on fixation implants in a rabbit model.   J Orthop Trauma. 2018;32(5):263-268. doi:10.1097/BOT.0000000000001136 PubMedGoogle ScholarCrossref
    24.
    Caroom  C, Moore  D, Mudaliar  N,  et al.  Intrawound vancomycin powder reduces bacterial load in contaminated open fracture model.   J Orthop Trauma. 2018;32(10):538-541. doi:10.1097/BOT.0000000000001259 PubMedGoogle ScholarCrossref
    25.
    Owen  MT, Keener  EM, Hyde  ZB,  et al.  Intraoperative topical antibiotics for infection prophylaxis in pelvic and acetabular surgery.   J Orthop Trauma. 2017;31(11):589-594. doi:10.1097/BOT.0000000000000941 PubMedGoogle ScholarCrossref
    26.
    Armaghani  SJ, Menge  TJ, Lovejoy  SA, Mencio  GA, Martus  JE.  Safety of topical vancomycin for pediatric spinal deformity: nontoxic serum levels with supratherapeutic drain levels.   Spine (Phila Pa 1976). 2014;39(20):1683-1687. doi:10.1097/BRS.0000000000000465 PubMedGoogle ScholarCrossref
    27.
    Gans  I, Dormans  JP, Spiegel  DA,  et al.  Adjunctive vancomycin powder in pediatric spine surgery is safe.   Spine (Phila Pa 1976). 2013;38(19):1703-1707. doi:10.1097/BRS.0b013e31829e05d3 PubMedGoogle ScholarCrossref
    28.
    O’Toole  RV, Degani  Y, Carlini  AR, Castillo  RC, O’Hara  NN, Joshi  M; METRC.  Systemic absorption and nephrotoxicity associated with topical vancomycin powder for fracture surgery.   J Orthop Trauma. 2021;35(1):29-34. doi:10.1097/BOT.0000000000001866 PubMedGoogle ScholarCrossref
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