Dose Escalation Trial of Intrasite Vancomycin Pharmacokinetics

Study Overview
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Brief Summary
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Surgical wound infections remain a serious problem despite aseptic techniques and the use of prophylactic systemic antibiotics. Such infections can occur at rates up to  20% in high-risk patients receiving long segment instrumented spinal fusions for deformity correction and present potentially catastrophic consequences. Given this, the high cost of treatment, and a payer system unable to support such expenses, investigators must make every effort to find new cost-effective ways to prevent these complications. Increasingly surgeons have sought to address this problem by placing lyophilized Vancomycin into spinal surgery wounds immediately prior to wound closure. This method, known as intrasite application, is adapted from techniques used to prevent infection in joint replacement surgeries. The motivation for this practice is to maximize antibiotic concentration within the wound while minimizing systemic concentration and toxicity, (the inverse of the situation when using IV antibiotics). While the popularity of intrasite delivery has grown rapidly, this has occurred without prospective scientific evidence. Recently, three retrospective papers including nearly 2,500 treated patients, indicated that intrasite Vancomycin reduces wound infections without increasing adverse events[1-3]. However, there are no published data on the dosing or pharmacokinetics of intrasite Vancomycin, let alone prospective trials of its efficacy and safety. The investigators propose to perform the first prospective trial of intrasite Vancomycin pharmacokinetics and safety. Study objectives will include standardizing application and dosing, defining peak/trough concentrations and clearance parameters, verifying bactericidal potency, and dose selection for use in future studies. This will be accomplished by enrolling groups of patients (n=10) to receive one of three doses of intrasite lyophilized Vancomycin (3, 6 or 12 mg/cm2), prior to wound closure. Vancomycin concentrations in venous blood and wound seroma fluid will be measured at regular intervals after surgery to establish pharmacokinetic parameters. Preliminary data regarding local and systemic adverse events including wound healing, fusion rate, and toxicity will be prospectively collected. The ultimate goal of this learning-phase study is to gather sufficient information regarding application, dosing, pharmacokinetics, measurement strategies, and adverse events to prepare for a Phase III efficacy trial.

Detailed Description
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Despite extremely close attention to aseptic technique and the use of prophylactic IV antibiotics, wound infection rates for posterior instrumented spinal surgery have been as high as  20% in published studies[4-13]. Such infections can be devastating for patients, frequently requiring multiple re-operations to remove and then replace spinal implants, lengthy hospital stays, prolonged courses of intravenous antibiotics, pain, immobility, and increased risk of other complications. While the cost of the initial surgical episode can be upwards of $250,000, the total cost of care can increase to more than quadruple this number when complications like wound infection occur[14, 15]. Given the impetus to decrease healthcare costs and a federal reimbursement policy denying payment for any care surrounding a wound infection, it is critical to search for cost-effective ways of preventing surgical wound infections[14, 16]. For several decades the standard of care in North America for surgical wound infection prophylaxis has been IV cephalosporin administration within one hour of incision, followed by interval IV dosing for 24 to 48hrs post-procedure[5, 13]. In some settings these antibiotics now effectively treat less than half of identified infection-causing organisms[17, 18]. In response, some groups of surgeons, including at the investigators' own institution, have begun placing lyophilized Vancomycin into the surgical wound bed at the conclusion of the procedure in an effort to further reduce wound infection rates[1-3]. The rationale behind this intrasite antibiotic application is to increase local concentrations of antibiotic to many times the minimally inhibitory concentration (MIC) for even moderately-resistant gram-positive organisms, thereby increasing the bacterial kill rate[3]. It is also thought that local antibiotic application should minimize blood concentrations of the drug, thereby minimizing systemic complications like renal toxicity. Additionally, it is hypothesized that intrasite antibiotic therapy could be less inclined to generate resistant organisms due to a steep concentration gradient from the wound to the systemic circulation. The site of potential infection (the wound) receives a dose of antibiotic vastly exceeding the saturation concentration for bactericidal effect while the systemic concentration remains extremely low. Bacteria should therefore be completely exterminated in the area of the wound or elsewhere exposed to such a minimal concentration of Vancomycin that selection for resistant organisms is avoided. While none of these hypotheses have been rigorously or prospectively tested, three retrospective studies have recently published a total of 2,479 spinal fusion patients treated with intrasite Vancomycin for wound infection prophylaxis[1-3]. The largest of these studies demonstrated a 0.99% infection rate in the treatment group, among the lowest rates ever published[1]. Two of the studies showed large and statistically significant decreases in the wound infection rate, compared to historical controls, when using intrasite Vancomycin in addition to standard of care IV cephalosporins. Preliminary evidence in one study also indicated high levels of Vancomycin within the wound and low or undetectable levels within the blood following surgery[3]. All of these studies specifically cited that no adverse events had been observed related to the treatment[1-3]. If intrasite Vancomycin proves to be safe and effective for preventing spinal fusion surgical site infections, the treatment will offer great clinical value both for reducing morbidity and also for decreasing large unsupported costs. A future large prospective efficacy trial would be required to provide high-level evidence for this new mode of antibiotic therapy in order to justify wide-spread adoption of the practice in spine surgery. Such data in any population might also be generalizable to surgical wounds at large and prompt a paradigm shift in infection prophylaxis for all types of surgical wounds. The proposed study addresses necessary prerequisites for such a large-scale efficacy trial, including basic pharmacokinetic and preliminary prospective safety data.

Official Title
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A Prospective Dose-Escalation Trial of the Pharmacokinetics and Preliminary Safety of Intrasite Lyophilized Vancomycin to Prevent Wound Infections in Instrumented Spinal Surgery

Conditions
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Surgical Site Infection

Intervention / Treatment
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* Drug: Intrasite Vancomycin
* Drug: IV Vancomycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Posterior instrumented spinal surgery patients 18 years of age and older with instrumented fusion of at least three vertebral levels Revision, elderly, obese, and diabetic patients will not be excluded since these patients are known to be at higher risk of wound infection and represent an important fraction of the elective surgical patient population. Patients requiring IV Vancomycin for infection prophylaxis (i.e. due to cephalosporin allergy) will be eligible for participation in the IV Vancomycin group. Exclusion Criteria: Intrasite Vancomycin Study Arm Exclusion Criteria Children under 18 years old Patients not receiving instrumentation or having less than three segment surgery - therefore having small wound bed surface areas, close operative quarters, and lower infection risk. Patients not receiving wound drains drains provide the conduit for seroma fluid collection Patients with known or suspected current infection Use of systemic or topical antibiotics within 72 hours prior to surgery other than standard pre-op dose of ancef Use of drugs or medications known to significantly increase the risk of renal toxicity within the perioperative period. Patients with known significant allergy to Vancomycin - Redman Syndrome patients will not be excluded Use of IV Vancomycin for perioperative infection prophylaxis (for example, in cases of penicillin/cephalosporin allergy) will exclude patients from participation in the intrasite Vancomycin groups of the study. IV Vancomycin Study Arm Exclusion Criteria Children under 18 years old Patients not receiving instrumentation or having less than three segment surgery - therefore having small wound bed surface areas, close operative quarters, and lower infection risk. Patients not receiving wound drains - drains provide the conduit for seroma fluid collection Patients with known or suspected current infection Use of systemic or topical antibiotics within 72 hours prior to surgery other than study related IV Vancomycin Use of drugs or medications known to significantly increase the risk of renal toxicity within the perioperative period. Patients with known significant allergy to Vancomycin Redman Syndrome patients will not be excluded Use of intrasite Vancomycin for infection prophylaxis will exclude patients from participation in the IV Vancomycin study group.

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Dose Intrasite Vancomycin<br>10 patients will be enrolled to receive low dose (see protocol) intrasite Vancomycin at the time of surgery. This will be the first group enrolled in the dose-escalation trial. | Drug: Intrasite Vancomycin<br>* Intrasite Vancomycin is placement of lyophilized Vancomycin powder directly into the surgical site at the completion of surgery.<br>|
| Experimental: Mid-dose Intrasite Vancomycin<br>10 patients will be enrolled to receive mid-dose intrasite Vancomycin at the time of surgery. | Drug: Intrasite Vancomycin<br>* Intrasite Vancomycin is placement of lyophilized Vancomycin powder directly into the surgical site at the completion of surgery.<br>|
| Experimental: High-dose Intrasite Vancomycin<br>10 patients will be enrolled to receive high-dose intrasite Vancomycin at the time of surgery. | Drug: Intrasite Vancomycin<br>* Intrasite Vancomycin is placement of lyophilized Vancomycin powder directly into the surgical site at the completion of surgery.<br>|
| Active Comparator: Optimally-dosed IV Vancomycin<br>10 patients will be enrolled to receive optimally-dosed IV Vancomycin at the time of surgery and two doses post-operatively (standard peri-operative IV antibiotics) | Drug: IV Vancomycin<br>* IV Vancomycin is the standard route for systemic antibiotic surgical site wound infection prophylaxis.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Vancomycin Concentration | Blood Vancomycin concentration will be measured within two hours post-operatively as well as each morning (between 07:00 and 09:00) until the surgical drain is removed (normally around 4 days after surgery). | Post-operatively at daily intervals until surgical drain is removed (average of 4 days after surgery) | 
| Seroma Vancomycin Concentration | Seroma Vancomycin concentration will be measured within two hours post-operatively as well as each morning (between 07:00 and 09:00) until the surgical drain is removed (normally around 4 days after surgery). | Post-operatively at daily intervals until surgical drain is removed (average of 4 days after surgery) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood creatinine concentration | Blood serum creatinine concentration will be measured at daily intervals each morning (between 07:00 to 09:00) post-operatively until surgical drain is removed approximately 4 days after surgery. | Post-operatively at daily intervals until surgical drain is removed (average of 4 days after surgery) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intrasite, Antibiotic, Vancomycin, Infection, Pharmacokinetics