Skip to main content
SpringerLink
Log in

The use of tissue sealants to deliver antibiotics to an orthopaedic surgical site with a titanium implant

  • Original Article
  • Published:
Journal of Orthopaedic Science

Abstract

Background

Orthopaedic surgery is associated with unacceptable infection rates that respond poorly to systemic antibiotics. The objective of this study was to use an animal model for orthopaedic implant infection to examine the ability of a new-generation fibrin tissue sealant to effectively deliver antibiotics to the surgical site.

Methods

The antibiotics cefazolin, fusidic acid or 5-fluorouracil were blended into Vitagel™ tissue sealant. The release rate of the drugs was measured using HPLC methods and bioactivity was measured by the zone of inhibition method with pathogenic Staphylococcus aureus. The antibiotic activity of the drug-loaded sealant was then tested in rats using infected orthopaedic surgical sites (titanium clip on spine). Efficacy was evaluated by residual bacterial counts on clips, clinical observations of infection, and histological findings.

Results

The drugs were released in a controlled manner over 2–4 days. All three antibiotics demonstrated strong antibacterial activity when released from the sealants. None of the treated animals demonstrated systemic illness. Post mortem dissection revealed a well-encapsulated abscess surrounding the titanium clip with erosion of the bony process. Using an inoculum of 1–5 × 103 CFU, treatment with antibiotic-loaded fibrin sealant demonstrated reduced infective swelling and reduced bacterial counts on surgical clip swabs compared to control rats or rats treated with antibiotic only. This model allowed for almost 100 % infectivity with a 0 % mortality rate due to infection, mimicking the clinical features of human implant infection.

Conclusion

The results support the use of antibiotic-loaded commercially available fibrin sealants to prevent infection after implant surgery.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Marrie TJ, Costerton JW. Mode of growth of bacterial pathogens in chronic polymicrobial human osteomyelitis. J Clin Microbiol. 1985;22:924–33.

    PubMed  CAS  Google Scholar 

  2. Petty W, Spanier S, Shuster JJ, Silverthorne C. The influence of skeletal implants on incidence of infection. Experiments in a canine model. J Bone Joint Surg Am. 1985;67:1236–44.

    PubMed  CAS  Google Scholar 

  3. Trampuz A, Zimmerli W. Antimicrobial agents in orthopaedic surgery: prophylaxis and treatment. Drugs. 2006;66:1089–105.

    Article  PubMed  CAS  Google Scholar 

  4. Fujimoto K, Yamamura K, Osada T, Hayashi T, Nabeshima T, Matsushita M, Nishikimi N, Sakurai T, Nimura Y. Subcutaneous tissue distribution of vancomycin from a fibrin glue/Dacron graft carrier. J Biomed Mater Res. 1997;36:564–7.

    Article  PubMed  CAS  Google Scholar 

  5. Nishimoto K, Yamamura K, Fukase F, Kobayashi M, Nishikimi N, Komori K. Subcutaneous tissue release of amikacin from a fibrin glue/polyurethane graft. J Infect Chemother. 2004;10:101–4.

    Article  PubMed  CAS  Google Scholar 

  6. Ueng SW, Yuan LJ, Lee N, Lin SS, Chan EC, Weng JH. In vivo study of biodegradable alginate antibiotic beads in rabbits. J Orthop Res. 2004;22:592–9.

    Article  PubMed  CAS  Google Scholar 

  7. Schlag G, Redl H. Fibrin sealant in orthopaedic surgery. Clin Orthop Relat Res. 1988;227:269–85.

    PubMed  CAS  Google Scholar 

  8. Spotnitz WD, Prabhu R. Fibrin sealant tissue adhesive—review and update. J Long Term Eff Med Implants. 2005;15:245–70.

    Article  PubMed  Google Scholar 

  9. Shireman PK, Greisler HP. Fibrin sealant in vascular surgery: a review. J Long Term Eff Med Implants. 1998;8:117–32.

    PubMed  CAS  Google Scholar 

  10. Mader JT, Stevens CM, Stevens JH, Ruble R, Lathrop JT, Calhoun JH. Treatment of experimental osteomyelitis with a fibrin sealant antibiotic implant. Clin Orthop Relat Res. 2002:58–72.

  11. Tredwell S, Jackson JK, Hamilton D, Lee V, Burt HM. Use of fibrin sealants for the localized, controlled release of cefazolin. Can J Surg. 2006;49:347–52.

    PubMed  Google Scholar 

  12. Woolverton CJ, Huebert K, Burkhart B, MacPhee M. Subverting bacterial resistance using high dose, low solubility antibiotics in fibrin. Infection. 1999;27:28–33.

    Article  PubMed  CAS  Google Scholar 

  13. Poelstra KA, Barekzi NA, Grainger DW, Gristina AG, Schuler TC. A novel spinal implant infection model in rabbits. Spine (Phila Pa 1976). 2000;25:406–10.

  14. Stall AC, Becker E, Ludwig SC, Gelb D, Poelstra KA. Reduction of postoperative spinal implant infection using gentamicin microspheres. Spine (Phila Pa 1976). 2009;34:479–83.

  15. Fluckiger U, Ulrich M, Steinhuber A, Doring G, Mack D, Landmann R, Goerke C, Wolz C. Biofilm formation, icaADBC transcription, and polysaccharide intercellular adhesin synthesis by staphylococci in a device-related infection model. Infect Immun. 2005;73:1811–9.

    Article  PubMed  CAS  Google Scholar 

  16. Ney AL, Kelly PH, Tsukayama DT, Bubrick MP. Fibrin glue-antibiotic suspension in the prevention of prosthetic graft infection. J Trauma. 1990;30:1000–5; discussion 5–6.

    Google Scholar 

  17. Woolverton CJ, Fulton JA, Salstrom SJ, Hayslip J, Haller NA, Wildroudt ML, MacPhee M. Tetracycline delivery from fibrin controls peritoneal infection without measurable systemic antibiotic. J Antimicrob Chemother. 2001;48:861–7.

    Article  PubMed  CAS  Google Scholar 

  18. Zilch H, Lambiris E. The sustained release of cefotaxim from a fibrin-cefotaxim compound in treatment of osteitis. Pharmacokinetic study and clinical results. Arch Orthop Trauma Surg. 1986;106:36–41.

    Article  PubMed  CAS  Google Scholar 

  19. Craig WA, Ebert SC. Continuous infusion of beta-lactam antibiotics. Antimicrob Agents Chemother. 1992;36:2577–83.

    Article  PubMed  CAS  Google Scholar 

  20. Cavanaugh DL, Berry J, Yarboro SR, Dahners LE. Better prophylaxis against surgical site infection with local as well as systemic antibiotics. An in vivo study. J Bone Joint Surg Am. 2009;91:1907–12.

    Article  PubMed  Google Scholar 

  21. Zeller V, Durand F, Kitzis MD, Lhotellier L, Ziza JM, Mamoudy P, Desplaces N. Continuous cefazolin infusion to treat bone and joint infections: clinical efficacy, feasibility, safety, and serum and bone concentrations. Antimicrob Agents Chemother. 2009;53:883–7.

    Article  PubMed  CAS  Google Scholar 

  22. An YH, Friedman RJ. Animal models of orthopaedic implant infection. J Invest Surg. 1998;11:139–46.

    Article  PubMed  CAS  Google Scholar 

  23. Melcher GA, Claudi B, Schlegel U, Perren SM, Printzen G, Munzinger J. Influence of type of medullary nail on the development of local infection. An experimental study of solid and slotted nails in rabbits. J Bone Joint Surg Br. 1994;76:955–9.

    PubMed  CAS  Google Scholar 

  24. Lucke M, Schmidmaier G, Sadoni S, Wildemann B, Schiller R, Stemberger A, Haas NP, Raschke M. A new model of implant-related osteomyelitis in rats. J Biomed Mater Res B Appl Biomater. 2003;67:593–602.

    Article  PubMed  CAS  Google Scholar 

  25. Monzon M, Garcia-Alvarez F, Lacleriga A, Gracia E, Leiva J, Oteiza C, Amorena B. A simple infection model using pre-colonized implants to reproduce rat chronic Staphylococcus aureus osteomyelitis and study antibiotic treatment. J Orthop Res. 2001;19:820–6.

    Article  PubMed  CAS  Google Scholar 

  26. Rissing JP, Buxton TB, Weinstein RS, Shockley RK. Model of experimental chronic osteomyelitis in rats. Infect Immun. 1985;47:581–6.

    PubMed  CAS  Google Scholar 

  27. Johansson A, Svensson O, Blomgren G, Eliasson G, Nord CE. Anaerobic osteomyelitis. A new experimental rabbit model. Clin Orthop Relat Res;1991:297–301.

  28. Deysine M, Rosario E, Isenberg HD. Acute hematogenous osteomyelitis: an experimental model. Surgery. 1976;79:97–9.

    PubMed  CAS  Google Scholar 

  29. Mendel V, Simanowski HJ, Scholz HC, Heymann H. Therapy with gentamicin-PMMA beads, gentamicin-collagen sponge, and cefazolin for experimental osteomyelitis due to Staphylococcus aureus in rats. Arch Orthop Trauma Surg. 2005;125:363–8.

    Article  PubMed  CAS  Google Scholar 

  30. Waiz JM, Avelar RL, Longtine KJ, Carter KL, Mermel LA, Heard SO. Anti-infective external coating of central venous catheters: a randomized trail comparing 5-fluorouracil with chlorohexidene/silver sulfadiazine in preventing catheter colonization. Crit Care Med. 2010;38:2095–102.

    Article  Google Scholar 

  31. Calhoun JH, Mader JT. Antibiotic beads in the management of surgical infections. Am J Surg. 1989;157:443–9.

    Article  PubMed  CAS  Google Scholar 

  32. Penner MJ, Duncan CP, Masri BA. The in vitro elution characteristics of antibiotic-loaded CMW and Palacos-R bone cements. J Arthroplast. 1999;14:209–14.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

Partial funding for these studies was obtained from Angiotech Pharmaceuticals Inc.

Conflict of interest

The authors of this study are not in any conflict of interest with any outside parties. Dr Cashman no longer works for the company Angiotech. The company Angiotech kindly allowed Dr Cashman to work on this project and supplied the sealant material. This project was purely academic in nature and neither Dr Cashman or Angiotech have any financial or commercial interest in this project.

Author information

Authors and Affiliations

  1. Angiotech Pharmaceuticals, 1618 Station Street, Vancouver, BC, V6A 1B6, Canada

    Johanne D. Cashman

  2. Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, V6T 1Z3, Canada

    John K. Jackson, Clement Mugabe, Samuel Gilchrist & Helen M. Burt

  3. Vancouver General Hospital, 855 West 12th Avenue, Vancouver, BC, V5Z 1M9, Canada

    Kate Ball & Stephen Tredwell

Authors
  1. Johanne D. Cashman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John K. Jackson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Clement Mugabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Samuel Gilchrist
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kate Ball
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stephen Tredwell
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Helen M. Burt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John K. Jackson.

About this article

Cite this article

Cashman, J.D., Jackson, J.K., Mugabe, C. et al. The use of tissue sealants to deliver antibiotics to an orthopaedic surgical site with a titanium implant. J Orthop Sci 18, 165–174 (2013). https://doi.org/10.1007/s00776-012-0325-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00776-012-0325-6

Keywords

Search

Navigation