Clinical trial NCT04238923: Topical Gentamicin and Vancomycin for Vascular Surgical Site Infection Prophylaxis
Official title: Topical Gentamicin and Vancomycin for Surgical Site Infection Prophylaxis in Patients Undergoing High-Risk Vascular Surgery
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Vascular Diseases
Peripheral Vascular Disease
Surgical Site Infection
Bypass Complication
Lead sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
Sponsor class: OTHER
First posted: 2020-01-23
Enrollment: 356
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of participants with surgical site infection (%)
timeFrame: 90 days
Secondary outcomes:
measure: Length of stay
timeFrame: Perioperative period
measure: Number of Emergency Department Visits
timeFrame: 90 days
measure: Number of participants dying of any cause
timeFrame: 90 days
measure: Number of participants requiring re-operation
timeFrame: 90 days
measure: Number of participants requiring major lower limb amputation
timeFrame: 90 days
Other outcomes:
Locations:
Study officials:
affiliation: London Health Sciences Centre
name: Luc Dubois, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nguyen LL, Brahmanandam S, Bandyk DF, Belkin M, Clowes AW, Moneta GL, Conte MS. Female gender and oral anticoagulants are associated with wound complications in lower extremity vein bypass: an analysis of 1404 operations for critical limb ischemia. J Vasc Surg. 2007 Dec;46(6):1191-1197. doi: 10.1016/j.jvs.2007.07.053.
citation: Giles KA, Hamdan AD, Pomposelli FB, Wyers MC, Siracuse JJ, Schermerhorn ML. Body mass index: surgical site infections and mortality after lower extremity bypass from the National Surgical Quality Improvement Program 2005-2007. Ann Vasc Surg. 2010 Jan;24(1):48-56. doi: 10.1016/j.avsg.2009.05.003. Epub 2009 Jul 19.
citation: Greenblatt DY, Rajamanickam V, Mell MW. Predictors of surgical site infection after open lower extremity revascularization. J Vasc Surg. 2011 Aug;54(2):433-9. doi: 10.1016/j.jvs.2011.01.034. Epub 2011 Mar 31.
citation: Vogel TR, Dombrovskiy VY, Carson JL, Haser PB, Lowry SF, Graham AM. Infectious complications after elective vascular surgical procedures. J Vasc Surg. 2010 Jan;51(1):122-9; discussion 129-30. doi: 10.1016/j.jvs.2009.08.006. Epub 2009 Dec 2.
citation: Culver DH, Horan TC, Gaynes RP, Martone WJ, Jarvis WR, Emori TG, Banerjee SN, Edwards JR, Tolson JS, Henderson TS, et al. Surgical wound infection rates by wound class, operative procedure, and patient risk index. National Nosocomial Infections Surveillance System. Am J Med. 1991 Sep 16;91(3B):152S-157S. doi: 10.1016/0002-9343(91)90361-z.
citation: Turtiainen J, Hakala T. Surgical wound infections after peripheral vascular surgery. Scand J Surg. 2014 Dec;103(4):226-31. doi: 10.1177/1457496913514384. Epub 2014 Apr 15.
citation: Bandyk DF. Vascular surgical site infection: risk factors and preventive measures. Semin Vasc Surg. 2008 Sep;21(3):119-23. doi: 10.1053/j.semvascsurg.2008.05.008.
citation: Pevzner L, Swank M, Krepel C, Wing DA, Chan K, Edmiston CE Jr. Effects of maternal obesity on tissue concentrations of prophylactic cefazolin during cesarean delivery. Obstet Gynecol. 2011 Apr;117(4):877-882. doi: 10.1097/AOG.0b013e31820b95e4.
citation: Ott E, Bange FC, Sohr D, Teebken O, Mattner F. Risk factors associated with surgical site infections following vascular surgery at a German university hospital. Epidemiol Infect. 2013 Jun;141(6):1207-13. doi: 10.1017/S095026881200180X. Epub 2012 Aug 21.
citation: Siracuse JJ, Nandivada P, Giles KA, Hamdan AD, Wyers MC, Chaikof EL, Pomposelli FB, Schermerhorn ML. Prosthetic graft infections involving the femoral artery. J Vasc Surg. 2013 Mar;57(3):700-5. doi: 10.1016/j.jvs.2012.09.049. Epub 2013 Jan 9.
citation: Virkkunen J, Heikkinen M, Lepantalo M, Metsanoja R, Salenius JP; Finnvasc Study Group. Diabetes as an independent risk factor for early postoperative complications in critical limb ischemia. J Vasc Surg. 2004 Oct;40(4):761-7. doi: 10.1016/j.jvs.2004.07.040.
citation: Ramdev P, Rayan SS, Sheahan M, Hamdan AD, Logerfo FW, Akbari CM, Campbell DR, Pomposelli FB Jr. A decade experience with infrainguinal revascularization in a dialysis-dependent patient population. J Vasc Surg. 2002 Nov;36(5):969-74. doi: 10.1067/mva.2002.128297.
citation: Khan NR, Thompson CJ, DeCuypere M, Angotti JM, Kalobwe E, Muhlbauer MS, Camillo FX, Klimo P Jr. A meta-analysis of spinal surgical site infection and vancomycin powder. J Neurosurg Spine. 2014 Dec;21(6):974-83. doi: 10.3171/2014.8.SPINE1445. Epub 2014 Sep 26.
citation: Mohammed S, Pisimisis GT, Daram SP, Bechara CF, Barshes NR, Lin PH, Kougias P. Impact of intraoperative administration of local vancomycin on inguinal wound complications. J Vasc Surg. 2013 Apr;57(4):1079-83. doi: 10.1016/j.jvs.2012.09.073. Epub 2013 Jan 11.
citation: Fleischman AN, Austin MS. Local Intra-wound Administration of Powdered Antibiotics in Orthopaedic Surgery. J Bone Jt Infect. 2017 Jan 1;2(1):23-28. doi: 10.7150/jbji.16649. eCollection 2017.
citation: Ghobrial GM, Cadotte DW, Williams K Jr, Fehlings MG, Harrop JS. Complications from the use of intrawound vancomycin in lumbar spinal surgery: a systematic review. Neurosurg Focus. 2015 Oct;39(4):E11. doi: 10.3171/2015.7.FOCUS15258.
citation: Alcala-Cerra G, Paternina-Caicedo AJ, Moscote-Salazar LR, Gutierrez-Paternina JJ, Nino-Hernandez LM. [Application of vancomycin powder into the wound during spine surgery: systematic review and meta-analysis]. Rev Esp Cir Ortop Traumatol. 2014 May-Jun;58(3):182-91. doi: 10.1016/j.recot.2013.10.004. Epub 2014 Apr 2. Spanish.
citation: Xiong L, Pan Q, Jin G, Xu Y, Hirche C. Topical intrawound application of vancomycin powder in addition to intravenous administration of antibiotics: A meta-analysis on the deep infection after spinal surgeries. Orthop Traumatol Surg Res. 2014 Nov;100(7):785-9. doi: 10.1016/j.otsr.2014.05.022. Epub 2014 Oct 3.
citation: Kang DG, Holekamp TF, Wagner SC, Lehman RA Jr. Intrasite vancomycin powder for the prevention of surgical site infection in spine surgery: a systematic literature review. Spine J. 2015 Apr 1;15(4):762-70. doi: 10.1016/j.spinee.2015.01.030. Epub 2015 Jan 28.
citation: 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 Mar 1;14(3):397-407. doi: 10.1016/j.spinee.2013.10.012. Epub 2013 Oct 30.
citation: 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 May;83(5):816-23. doi: 10.1016/j.wneu.2014.12.033. Epub 2014 Dec 19.
citation: Evaniew N, Khan M, Drew B, Peterson D, Bhandari M, Ghert M. Intrawound vancomycin to prevent infections after spine surgery: a systematic review and meta-analysis. Eur Spine J. 2015 Mar;24(3):533-42. doi: 10.1007/s00586-014-3357-0. Epub 2014 May 18.
citation: Hussain ST. Local application of gentamicin-containing collagen implant in the prophylaxis and treatment of surgical site infection following vascular surgery. Int J Surg. 2012;10 Suppl 1:S5-9. doi: 10.1016/j.ijsu.2012.05.015. Epub 2012 May 29.
citation: Horch R, Kronung G. [Prevention of infection in teflon prostheses for dialysis access. Experiences with a resorbable combined collagen-antibiotic system]. Vasa. 1989;18(1):30-4. German.
citation: Holdsworth J. Treatment of infective and potentially infective complications of vascular bypass grafting using gentamicin with collagen sponge. Ann R Coll Surg Engl. 1999 May;81(3):166-70.
citation: Friberg O, Svedjeholm R, Soderquist B, Granfeldt H, Vikerfors T, Kallman J. Local gentamicin reduces sternal wound infections after cardiac surgery: a randomized controlled trial. Ann Thorac Surg. 2005 Jan;79(1):153-61; discussion 161-2. doi: 10.1016/j.athoracsur.2004.06.043.
citation: Kowalewski M, Pawliszak W, Zaborowska K, Navarese EP, Szwed KA, Kowalkowska ME, Kowalewski J, Borkowska A, Anisimowicz L. Gentamicin-collagen sponge reduces the risk of sternal wound infections after heart surgery: Meta-analysis. J Thorac Cardiovasc Surg. 2015 Jun;149(6):1631-40.e1-6. doi: 10.1016/j.jtcvs.2015.01.034. Epub 2015 Jan 23.
citation: Ruszczak Z, Friess W. Collagen as a carrier for on-site delivery of antibacterial drugs. Adv Drug Deliv Rev. 2003 Nov 28;55(12):1679-98. doi: 10.1016/j.addr.2003.08.007.
citation: Andreas M, Muckenhuber M, Hutschala D, Kocher A, Thalhammer F, Vogt P, Fleck T, Laufer G. Direct sternal administration of Vancomycin and Gentamicin during closure prevents wound infection. Interact Cardiovasc Thorac Surg. 2017 Jul 1;25(1):6-11. doi: 10.1093/icvts/ivx032.