Dose Escalation Trial of Intrasite Vancomycin Pharmacokinetics

NCT01764750 | Terminated Phase 1 DMC

• 1 other identifier: 2012IntrasiteVanc
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Surgical Site Infection

Keywords

Intrasite; Antibiotic; Vancomycin; Infection; Pharmacokinetics

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (1)

• Blood creatinine concentration

  Post-operatively at daily intervals until surgical drain is removed (average of 4 days after surgery)

Study Arms (4)

Low Dose Intrasite Vancomycin

EXPERIMENTAL

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

Mid-dose Intrasite Vancomycin

EXPERIMENTAL

10 patients will be enrolled to receive mid-dose intrasite Vancomycin at the time of surgery.

Drug: Intrasite Vancomycin

High-dose Intrasite Vancomycin

EXPERIMENTAL

10 patients will be enrolled to receive high-dose intrasite Vancomycin at the time of surgery.

Drug: Intrasite Vancomycin

Optimally-dosed IV Vancomycin

ACTIVE COMPARATOR

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

Interventions

Intrasite Vancomycin DRUG

Intrasite Vancomycin is placement of lyophilized Vancomycin powder directly into the surgical site at the completion of surgery.

High-dose Intrasite Vancomycin; Low Dose Intrasite Vancomycin; Mid-dose Intrasite Vancomycin

IV Vancomycin DRUG

IV Vancomycin is the standard route for systemic antibiotic surgical site wound infection prophylaxis.

Optimally-dosed IV Vancomycin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
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• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University

St Louis, Missouri, 63110, United States

Location

Related Publications (22)

• Molinari RW, Khera OA, Molinari WJ 3rd. Prophylactic intraoperative powdered vancomycin and postoperative deep spinal wound infection: 1,512 consecutive surgical cases over a 6-year period. Eur Spine J. 2012 Jun;21 Suppl 4(Suppl 4):S476-82. doi: 10.1007/s00586-011-2104-z. Epub 2011 Dec 8.

  PMID: 22160172 BACKGROUND

• O'Neill KR, Smith JG, Abtahi AM, Archer KR, Spengler DM, McGirt MJ, Devin CJ. Reduced surgical site infections in patients undergoing posterior spinal stabilization of traumatic injuries using vancomycin powder. Spine J. 2011 Jul;11(7):641-6. doi: 10.1016/j.spinee.2011.04.025. Epub 2011 May 19.

  PMID: 21600853 BACKGROUND

• 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 Nov 15;36(24):2084-8. doi: 10.1097/BRS.0b013e3181ff2cb1.

  PMID: 21304438 BACKGROUND

• Friedman ND, Sexton DJ, Connelly SM, Kaye KS. Risk factors for surgical site infection complicating laminectomy. Infect Control Hosp Epidemiol. 2007 Sep;28(9):1060-5. doi: 10.1086/519864. Epub 2007 Jun 28.

  PMID: 17932827 BACKGROUND

• Olsen MA, Nepple JJ, Riew KD, Lenke LG, Bridwell KH, Mayfield J, Fraser VJ. Risk factors for surgical site infection following orthopaedic spinal operations. J Bone Joint Surg Am. 2008 Jan;90(1):62-9. doi: 10.2106/JBJS.F.01515.

  PMID: 18171958 BACKGROUND

• Linam WM, Margolis PA, Staat MA, Britto MT, Hornung R, Cassedy A, Connelly BL. Risk factors associated with surgical site infection after pediatric posterior spinal fusion procedure. Infect Control Hosp Epidemiol. 2009 Feb;30(2):109-16. doi: 10.1086/593952.

  PMID: 19125680 BACKGROUND

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  PMID: 20150831 BACKGROUND

• Schimmel JJ, Horsting PP, de Kleuver M, Wonders G, van Limbeek J. Risk factors for deep surgical site infections after spinal fusion. Eur Spine J. 2010 Oct;19(10):1711-9. doi: 10.1007/s00586-010-1421-y. Epub 2010 May 6.

  PMID: 20445999 BACKGROUND

• Gerometta A, Rodriguez Olaverri JC, Bitan F. Infections in spinal instrumentation. Int Orthop. 2012 Feb;36(2):457-64. doi: 10.1007/s00264-011-1426-0. Epub 2012 Jan 5.

  PMID: 22218913 BACKGROUND

• Li Y, Glotzbecker M, Hedequist D. Surgical site infection after pediatric spinal deformity surgery. Curr Rev Musculoskelet Med. 2012;5(2):111-9. doi: 10.1007/s12178-012-9111-5. Epub 2012 Feb 9.

  PMID: 22315161 BACKGROUND

• Pull ter Gunne AF, Hosman AJ, Cohen DB, Schuetz M, Habil D, van Laarhoven CJ, van Middendorp JJ. A methodological systematic review on surgical site infections following spinal surgery: part 1: risk factors. Spine (Phila Pa 1976). 2012 Nov 15;37(24):2017-33. doi: 10.1097/BRS.0b013e31825bfca8.

  PMID: 22565388 BACKGROUND

• van Middendorp JJ, Pull ter Gunne AF, Schuetz M, Habil D, Cohen DB, Hosman AJ, van Laarhoven CJ. A methodological systematic review on surgical site infections following spinal surgery: part 2: prophylactic treatments. Spine (Phila Pa 1976). 2012 Nov 15;37(24):2034-45. doi: 10.1097/BRS.0b013e31825f6652.

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  PMID: 21404004 BACKGROUND

• Calderone RR, Garland DE, Capen DA, Oster H. Cost of medical care for postoperative spinal infections. Orthop Clin North Am. 1996 Jan;27(1):171-82.

  PMID: 8539047 BACKGROUND

• Centers for Medicare and Medicaid Services (CMS), HHS. Medicaid program; payment adjustment for provider-preventable conditions including health care-acquired conditions. Final rule. Fed Regist. 2011 Jun 6;76(108):32816-38.

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• Klevens RM, Edwards JR, Richards CL Jr, Horan TC, Gaynes RP, Pollock DA, Cardo DM. Estimating health care-associated infections and deaths in U.S. hospitals, 2002. Public Health Rep. 2007 Mar-Apr;122(2):160-6. doi: 10.1177/003335490712200205.

  PMID: 17357358 BACKGROUND

• Klevens RM, Morrison MA, Nadle J, Petit S, Gershman K, Ray S, Harrison LH, Lynfield R, Dumyati G, Townes JM, Craig AS, Zell ER, Fosheim GE, McDougal LK, Carey RB, Fridkin SK; Active Bacterial Core surveillance (ABCs) MRSA Investigators. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA. 2007 Oct 17;298(15):1763-71. doi: 10.1001/jama.298.15.1763.

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  PMID: 20408503 BACKGROUND

• Lodise TP, Drusano GL, Butterfield JM, Scoville J, Gotfried M, Rodvold KA. Penetration of vancomycin into epithelial lining fluid in healthy volunteers. Antimicrob Agents Chemother. 2011 Dec;55(12):5507-11. doi: 10.1128/AAC.00712-11. Epub 2011 Sep 12.

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  PMID: 16323118 BACKGROUND

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  PMID: 19106348 BACKGROUND

MeSH Terms

Conditions

Surgical Wound Infection; Infections

Interventions

Vancomycin

Condition Hierarchy (Ancestors)

Wound Infection; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Glycopeptides; Glycoconjugates; Carbohydrates; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Terrence F Holekamp, MD, PhD

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

• Lawrence G Lenke, MD

  Washington University School of Medicine

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 14, 2012
• First Posted: January 10, 2013
• Study Start: January 1, 2013
• Primary Completion: December 1, 2013
• Study Completion: December 1, 2013
• Last Updated: May 11, 2018

Record last verified: 2018-05

Locations

US (1)