Topical Gentamicin and Vancomycin for Vascular Surgical Site Infection Prophylaxis

Study Overview
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Brief Summary
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Many patients who undergo vascular surgery to improve the blood flow to their legs are at risk of developing an infection in the surgical site and are then at risk of serious complications such as hospital readmission, failure of the surgical procedure and lower limb amputation. Surgical site infections may be reduced in high-risk patients by applying two commonly used antibiotics (gentamicin and vancomycin) into the surgical incision at the end of the surgical procedure. This will be compared to the standard of care treatment at London Health Sciences Center.

Detailed Description
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Surgical site infections (SSI) are among the most common complications to develop following peripheral vascular surgery and increase the patient's risk for major amputation, graft failure and increase healthcare resource utilization. SSI are defined by the Center for Disease Control (CDC) as infections occurring within 30-90 days of a surgical procedure, or 1 year if a prosthetic implant was placed, and are divided into superficial, deep and organ space based on depth of microbial invasion. The incidence of SSI in patients undergoing limb saving vascular surgery has consistently been found to exceed the CDC average of 2.1% for other clean surgical procedures, despite the routine use of perioperative antibiotics and aggressive wound care. A recent review of SSI in vascular surgery showed rates as high as 30%, and the investigators' institution has reported a SSI rate of 20%. Coagulase-negative staphylococcus species are the most frequent isolates from SSI following peripheral vascular surgery, with the highly virulent organism, MRSA becoming increasingly prevalent. Gram-negative organisms account for another 20-30% of SSI, with Pseudomonas isolates commonly identified, particularly in the groin. Several procedure- and patient-related factors have emerged as important predictors of SSI following peripheral vascular surgery, among the most important of which are obesity, tissue loss, redo surgery, dialysis dependence and diabetes mellitus. Obesity has been found to double the risk of SSI. Obese patients are shown to have lower tissue concentrations of antibiotics, which would place them at higher risk of developing SSI. Patients with tissue loss secondary to critical limb ischemia also are at increased risk of SSI resulting from bacterial spread from contaminated ulcers and poor vascular supply to the wound. As well, patients undergoing redo surgery face an increased risk of wound and graft infection secondary to the impaired vascular supply and healing potential of scar tissue. Diabetes mellitus and dialysis dependence are also independent risk factors for SSI following infrainguinal bypass due to a multitude of disease factors, especially immunologic dysfunction and impaired blood supply to the healing tissue. Prophylactic intravenous antibiotics are the only intervention thus far consistently found to effectively prevent SSI in patients undergoing vascular surgery, however because of the aforementioned factors such measures are less effective in high-risk patients. Data to support other perioperative practices to prevent wound infections in vascular surgery are sparse. Among other surgical disciplines, topical antibiotics are re-emerging as a valid strategy to prevent SSI based on improved understanding of the mechanisms of drug delivery and identification of high-risk patients. In particular, vancomycin applied directly to surgical wounds has shown promise in preventing SSI. Topical vancomycin is believed to prevent gram-positive SSI, particularly those caused by MRSA, while minimizing adverse events related to systemic exposure to vancomycin such as nephrotoxicity or ototoxicity by virtue of limited absorption from the tissue bed. There is one retrospective study in the vascular surgery literature of 454 patients undergoing aortofemoral or infrainguinal procedures that showed reduction of 30-day SSI rates with use of topical vancomycin compared to controls (25.1 vs. 17.2%, p=0.049). More extensive data regarding the use of topical vancomycin prophylaxis comes from the orthopaedic literature. A recent review of orthopaedic studies, although mostly retrospective, highlighted benefits in spine surgery, total joint arthroplasty, foot and ankle surgery and elbow surgery. Further, 8 spine meta-analyses since 2014 have shown reduction in SSI rates with topical vancomycin administration. Local gentamicin applied to surgical wounds has also been found effective, particularly in the prevention of gram-negative SSI, providing broad gram-negative coverage including Pseudomonas species. One randomized controlled trial assessing the prophylactic use of collagen gentamicin sponge in 40 patients undergoing prosthetic femoropopliteal bypass found significant reduction in groin SSI with use of a collagen gentamicin sponge (Collatamp G). An additional prospective cohort study and case series data also show favorable results in small patient samples of patients An additional prospective cohort study and case series data also show favorable results in small patient samples of patients undergoing various vascular operations. Cardiac surgeons have reported effective use of this antibiotic locally in prevention of sternal wound infections. Notably, a large randomized, double blinded-controlled trial of 1950 patients undergoing cardiac surgery through median sternotomy demonstrated decreased SSI rates at 60 days with the use of gentamicin containing collagen implants compared to controls (4.3 vs. 9.0%, p<0.001). The ability of gentamicin eluting sponges to prevent SSI in sternal wounds was confirmed in a recent meta-analysis. These sponges achieve high local levels of gentamicin for 36 hours with minimal systemic absorption in addition to accelerating hemostasis. Recently, wound closure using topical vancomycin paste and gentamicin irrigation has been shown in a retrospective study to reduce SSI in cardiac surgery sternotomy wounds by almost two thirds. In this trial, an aggressive prophylactic approach using selective administration of topical vancomycin and gentamicin to the surgical wounds of patients undergoing open lower extremity revascularization at high-risk for SSI based on an elevated body mass index (BMI) >30, tissue loss, redo surgery, diabetes mellitus or renal failure will be compared to similar patients receiving standard perioperative antibiotic prophylaxis and wound care to evaluate the impact on 90-day SSI rates.

Official Title
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Topical Gentamicin and Vancomycin for Surgical Site Infection Prophylaxis in Patients Undergoing High-Risk Vascular Surgery

Conditions
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Vascular Diseases, Peripheral Vascular Disease, Surgical Site Infection, Bypass Complication

Intervention / Treatment
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* Drug: Topical vancomycin paste (1g vancomycin powder + 4mL sterile saline) and Collatamp G gentamicin-eluting sponge (Azralez Pharmaceuticals; 2.0mg gentamicin sulphate/cm2 to cover wound)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients identified as requiring lower extremity bypass for peripheral arterial disease by their consultant surgeon with high-risk features for vascular surgical site infection including, BMI >30 Dialysis dependence Redo surgery Diabetes mellitus (type 1 or 2) Tissue loss (ischemic ulceration or gangrene of the feet) Exclusion Criteria: Patient does not provide informed consent for surgery or study Patient received antibiotics for an active infection within 7 days prior to surgery Patient has an allergy to gentamicin or vancomycin Patient has a pre-existing infection of the surgical site

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Topical Gentamicin and Vancomycin<br>Immediately prior to closure of the incision, 1g of vancomycin will be mixed in 4mL of normal saline and applied as a paste directly to the muscle, fascia and subcutaneous tissue. Gentamicin-eluting collagen sponges will be cut to the appropriate size to cover the defect and applied after application of vancomycin. Following closure, the surgical site will be covered with a sterile dressing and left in place for 48hrs. | Drug: Topical vancomycin paste (1g vancomycin powder + 4mL sterile saline) and Collatamp G gentamicin-eluting sponge (Azralez Pharmaceuticals; 2.0mg gentamicin sulphate/cm2 to cover wound)<br>* Topical vancomycin paste and gentamicin-eluting collagen sponge will be applied directly to the deep layers of the wound following reconstruction, prior to closure.<br>|
| No Intervention: Control<br>The surgical wound is closed in the standard fashion with 3 layer closure with staples for skin. Following closure, the surgical site will be covered with a sterile dressing and left in place for 48hrs. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with surgical site infection (%) | Per CDC definition and according to Szilagyi classification | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of stay | In-hospital following initial surgery | Perioperative period | 
| Number of Emergency Department Visits | Between discharge and first post-operative follow-up appointment | 90 days | 
| Number of participants dying of any cause | Any cause | 90 days | 
| Number of participants requiring re-operation | For graft failure | 90 days | 
| Number of participants requiring major lower limb amputation | Above ankle | 90 days |