Dose Escalation Trial of Intrasite Vancomycin Pharmacokinetics

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified January 2013 by Washington University School of Medicine
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT01764750
First received: December 14, 2012
Last updated: January 9, 2013
Last verified: January 2013
  Purpose

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.


Condition Intervention Phase
Surgical Site Infection
Drug: Intrasite Vancomycin
Drug: IV Vancomycin
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Prevention
Official Title: A Prospective Dose-Escalation Trial of the Pharmacokinetics and Preliminary Safety of Intrasite Lyophilized Vancomycin to Prevent Wound Infections in Instrumented Spinal Surgery

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • Blood Vancomycin Concentration [ Time Frame: Post-operatively at daily intervals until surgical drain is removed (average of 4 days after surgery) ] [ Designated as safety issue: Yes ]
    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).

  • Seroma Vancomycin Concentration [ Time Frame: Post-operatively at daily intervals until surgical drain is removed (average of 4 days after surgery) ] [ Designated as safety issue: Yes ]
    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).


Secondary Outcome Measures:
  • Blood creatinine concentration [ Time Frame: Post-operatively at daily intervals until surgical drain is removed (average of 4 days after surgery) ] [ Designated as safety issue: Yes ]
    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.


Estimated Enrollment: 40
Study Start Date: January 2013
Estimated Primary Completion Date: August 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Low Dose Intrasite Vancomycin
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
Intrasite Vancomycin is placement of lyophilized Vancomycin powder directly into the surgical site at the completion of surgery.
Experimental: Mid-dose Intrasite Vancomycin
10 patients will be enrolled to receive mid-dose intrasite Vancomycin at the time of surgery.
Drug: Intrasite Vancomycin
Intrasite Vancomycin is placement of lyophilized Vancomycin powder directly into the surgical site at the completion of surgery.
Experimental: High-dose Intrasite Vancomycin
10 patients will be enrolled to receive high-dose intrasite Vancomycin at the time of surgery.
Drug: Intrasite Vancomycin
Intrasite Vancomycin is placement of lyophilized Vancomycin powder directly into the surgical site at the completion of surgery.
Active Comparator: Optimally-dosed IV Vancomycin
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
IV Vancomycin is the standard route for systemic antibiotic surgical site wound infection prophylaxis.

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Posterior instrumented spinal surgery patients 18 years of age and older with instrumented fusion of at least three vertebral levels

    1. 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.
  2. 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

  1. Children under 18 years old
  2. 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.

  3. Patients not receiving wound drains

    • drains provide the conduit for seroma fluid collection
  4. Patients with known or suspected current infection
  5. Use of systemic or topical antibiotics within 72 hours prior to surgery

    • other than standard pre-op dose of ancef
  6. Use of drugs or medications known to significantly increase the risk of renal toxicity within the perioperative period.
  7. Patients with known significant allergy to Vancomycin

    - Redman Syndrome patients will not be excluded

  8. 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
  1. Children under 18 years old
  2. 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.
  3. Patients not receiving wound drains

    - drains provide the conduit for seroma fluid collection

  4. Patients with known or suspected current infection
  5. Use of systemic or topical antibiotics within 72 hours prior to surgery

    • other than study related IV Vancomycin
  6. Use of drugs or medications known to significantly increase the risk of renal toxicity within the perioperative period.
  7. Patients with known significant allergy to Vancomycin

    • Redman Syndrome patients will not be excluded
  8. Use of intrasite Vancomycin for infection prophylaxis will exclude patients from participation in the IV Vancomycin study group.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01764750

Contacts
Contact: Terrence F Holekamp, MD, PhD 314-362-3570 holekampt@wudosis.wustl.edu
Contact: Lawrence G Lenke, MD 314-747-2535 lenkel@wudosis.wustl.edu

Locations
United States, Missouri
Washington University Not yet recruiting
St. Louis, Missouri, United States, 63110
Contact: Terrence F Holekamp, MD, PhD    314-362-3570    holekampt@wudosis.wustl.edu   
Contact: Linda Koester, RN    314-747-2535      
Sub-Investigator: Keith Bridwell, MD         
Sub-Investigator: Jacob Buchowski, MD, MS         
Sub-Investigator: Michael Kelly, MD         
Sub-Investigator: Lukas Zebala, MD         
Sub-Investigator: Neill Wright, MD         
Sub-Investigator: Paul Santiago, MD         
Sub-Investigator: Todd J Stewart, MD         
Sub-Investigator: Wilson Z Ray, MD         
Sponsors and Collaborators
Washington University School of Medicine
Investigators
Principal Investigator: Terrence F Holekamp, MD, PhD Washington University Early Recognition Center
Study Chair: Lawrence G Lenke, MD Washington University Early Recognition Center
  More Information

Publications:

Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT01764750     History of Changes
Other Study ID Numbers: 2012IntrasiteVanc
Study First Received: December 14, 2012
Last Updated: January 9, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Washington University School of Medicine:
Intrasite
Antibiotic
Vancomycin
Infection
Pharmacokinetics

Additional relevant MeSH terms:
Anti-Bacterial Agents
Vancomycin
Antibiotics, Antitubercular
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antitubercular Agents

ClinicalTrials.gov processed this record on August 21, 2014