The Mark Coventry Award: Higher Tissue Concentrations of Vancomycin With Low-dose Intraosseous Regional Versus Systemic Prophylaxis in TKA

A Randomized Trial

Abstract

Background

In response to increasing antibiotic resistance, vancomycin has been proposed as an alternative prophylactic agent in TKA. However, vancomycin requires a prolonged administration time, risks promoting further antibiotic resistance, and can cause systemic toxicity. Intraosseous regional administration (IORA) is known to achieve markedly higher antibiotic concentrations than systemic administration and may allow the use of a lower vancomycin dose.

Questions/purposes

We assessed whether low-dose IORA vancomycin can achieve tissue concentrations equal or superior to those of systemic administration in TKA and compared complications between patients treated with IORA and intravenous vancomycin.

Methods

We randomized 30 patients undergoing primary TKA to receive 250 or 500 mg vancomycin via IORA or 1 g via systemic administration. IORA was performed as a bolus injection into a tibial intraosseous cannula below an inflated thigh tourniquet immediately before skin incision. Subcutaneous fat and bone samples were taken during the procedure and antibiotic concentrations measured.

Results

The overall mean tissue concentration of vancomycin in subcutaneous fat was 14 μg/g in the 250-mg IORA group, 44 μg/g in the 500-mg IORA group, and 3.2 μg/g in the systemic group. Mean concentrations in bone were 16 μg/g in the 250-mg IORA group, 38 μg/g in the 500-mg IORA group, and 4.0 μg/g in the systemic group. One patient in the systemic group developed red man syndrome during infusion.

Conclusions

Low-dose IORA vancomycin results in tissue concentrations equal or superior to those of systemic administration. IORA optimizes timing of vancomycin administration, and the lower dose may reduce the risk of systemic side effects while providing equal or enhanced prophylaxis in TKA.

Level of Evidence

Level I, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.

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References

  1. 1.

    Bull AL, Worth LJ, Richards MJ. Impact of vancomycin surgical antibiotic prophylaxis on the development of methicillin-sensitive Staphylococcus aureus surgical site infections: report from Australian Surveillance Data (VICNISS). Ann Surg. 2012;256:1089–1092.

    PubMed  Article  Google Scholar 

  2. 2.

    Burgess DS. Pharmacodynamic principles of antimicrobial therapy in the prevention of resistance. Chest. 1999;115(3 suppl):19S–23S.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Burke JF. The effective period of preventive antibiotic action in experimental incisions and dermal lesions. Surgery. 1961;50:161–168.

    CAS  PubMed  Google Scholar 

  4. 4.

    Butt TD, Bailey JV, Dowling PM, Fretz PB. Comparison of 2 techniques for regional antibiotic delivery to the equine forelimb: intraosseous perfusion vs. intravenous perfusion. Can Vet J. 2001;42:617–622.

    CAS  PubMed Central  PubMed  Google Scholar 

  5. 5.

    Carlsson AK, Lidgren L, Lindberg L. Prophylactic antibiotics against early and late deep infections after total hip replacements. Acta Orthop Scand. 1977;48:405–410.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Classen DC, Evans RS, Pestotnik SL, Horn SD, Menlove RL, Burke JP. The timing of prophylactic administration of antibiotics and the risk of surgical-wound infection. N Engl J Med. 1992;326:281–286.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Collier PE, Rudolph M, Ruckert D, Osella T, Collier NA, Ferrero M. Are preoperative antibiotics administered preoperatively? Am J Med Qual. 1998;13:94–97.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Crawford T, Rodvold KA, Solomkin JS. Vancomycin for surgical prophylaxis? Clin Infect Dis. 2012;54:1474–1479.

    PubMed  Article  Google Scholar 

  9. 9.

    de Lalla F, Novelli A, Pellizzer G, Milocchi F, Viola R, Rigon A, Stecca C, Dal Pizzol V, Fallani S, Periti P. Regional and systemic prophylaxis with teicoplanin in monolateral and bilateral total knee replacement procedures: study of pharmacokinetics and tissue penetration. Antimicrob Agents Chemother. 1993;37:2693–2698.

    PubMed Central  PubMed  Article  Google Scholar 

  10. 10.

    de Lalla F, Viola R, Pellizzer G, Lazzarini L, Tramarin A, Fabris P. Regional prophylaxis with teicoplanin in monolateral or bilateral total knee replacement: an open study. Antimicrob Agents Chemother. 2000;44:316–319.

    PubMed Central  PubMed  Article  Google Scholar 

  11. 11.

    Doyon F, Evrard J, Mazas F, Hill C. Long-term results of prophylactic cefazolin versus placebo in total hip replacement. Lancet. 1987;1:860.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Fletcher N, Sofianos D, Berkes MB, Obremskey WT. Prevention of perioperative infection. J Bone Joint Surg Am. 2007;89:1605–1618.

    PubMed  Article  Google Scholar 

  13. 13.

    Garcia S, Lozano ML, Gatell JM, Soriano E, Ramon R, Sanmiguel JG. Prophylaxis against infection. Single-dose cefonicid compared with multiple-dose cefamandole. J Bone Joint Surg Am. 1991;73:1044–1048.

    CAS  PubMed  Google Scholar 

  14. 14.

    Hasan MY, Kissoon N, Khan TM, Saldajeno V, Goldstein J, Murphy SP. Intraosseous infusion and pulmonary fat embolism. Pediatr Crit Care Med. 2001;2:133–138.

    PubMed  Article  Google Scholar 

  15. 15.

    Healy DP, Sahai JV, Fuller SH, Polk RE. Vancomycin-induced histamine release and “red man syndrome”: comparison of 1- and 2-hour infusions. Antimicrob Agents Chemother. 1990;34:550–554.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  16. 16.

    Heydemann JS, Nelson CL. Short-term preventive antibiotics. Clin Orthop Relat Res. 1986;205:184–187.

    PubMed  Google Scholar 

  17. 17.

    Hidayat LK, Hsu DI, Quist R, Shriner KA, Wong-Beringer A. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med. 2006;166:2138–2144.

    PubMed  Article  Google Scholar 

  18. 18.

    Hill C, Flamant R, Mazas F, Evrard J. Prophylactic cefazolin versus placebo in total hip replacement: report of a multicentre double-blind randomised trial. Lancet. 1981;1:795–796.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Hoddinott C, Lovering AM, Fernando HC, Dixon JH, Reeves DS. Determination of bone and fat concentrations following systemic cefamandole and regional cefuroxime administration in patients undergoing knee arthroplasty. J Antimicrob Chemother. 1990;26:823–829.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Kentner R, Haas T, Gervais H, Hiller B, Dick W. Pharmacokinetics and pharmacodynamics of hydroxyethyl starch in hypovolemic pigs; a comparison of peripheral and intraosseous infusion. Resuscitation. 1999;40:37–44.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Klevens RM, Edwards JR, Tenover FC, McDonald LC, Horan T, Gaynes R. Changes in the epidemiology of methicillin-resistant Staphylococcus aureus in intensive care units in US hospitals, 1992–2003. Clin Infect Dis. 2006;42:389–391.

    PubMed  Article  Google Scholar 

  22. 22.

    Larsson AJ, Walker KJ, Raddatz JK, Rotschafer JC. The concentration-independent effect of monoexponential and biexponential decay in vancomycin concentrations on the killing of Staphylococcus aureus under aerobic and anaerobic conditions. J Antimicrob Chemother. 1996;38:589–597.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Lazzarini L, Novelli A, Marzano N, Timillero L, Fallani S, Viola R, de Lalla F. Regional and systemic prophylaxis with teicoplanin in total knee arthroplasty. J Arthroplasty. 2003;18:342–346.

    PubMed  Article  Google Scholar 

  24. 24.

    Mattson S, Boure L, Pearce S, Hurtig M, Burger J, Black W. Intraosseous gentamicin perfusion of the distal metacarpus in standing horses. Vet Surg. 2004;33:180–186.

    PubMed  Article  Google Scholar 

  25. 25.

    McNamara DR, Steckelberg JM. Vancomycin. J Am Acad Orthop Surg. 2005;13:89–92.

    PubMed  Google Scholar 

  26. 26.

    Murphy E, Spencer SJ, Young D, Jones B, Blyth MJ. MRSA colonisation and subsequent risk of infection despite effective eradication in orthopaedic elective surgery. J Bone Joint Surg Br. 2011;93:548–551.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Nickinson RS, Board TN, Gambhir AK, Porter ML, Kay PR. The microbiology of the infected knee arthroplasty. Int Orthop. 2010;34:505–510.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  28. 28.

    Orlowski JP, Julius CJ, Petras RE, Porembka DT, Gallagher JM. The safety of intraosseous infusions: risks of fat and bone marrow emboli to the lungs. Ann Emerg Med. 1989;18:1062–1067.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Polk RE, Healy DP, Schwartz LB, Rock DT, Garson ML, Roller K. Vancomycin and the red-man syndrome: pharmacodynamics of histamine release. J Infect Dis. 1988;157:502–507.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Ritter MA, Barzilauskas CD, Faris PM, Keating EM. Vancomycin prophylaxis and elective total joint arthroplasty. Orthopedics. 1989;12:1333–1336.

    CAS  PubMed  Google Scholar 

  31. 31.

    Rubio-Martínez L, López-Sanromán J, Cruz AM, Santos M, San Román F. Medullary plasma pharmacokinetics of vancomycin after intravenous and intraosseous perfusion of the proximal phalanx in horses. Vet Surg. 2005;34:618–624.

    PubMed  Article  Google Scholar 

  32. 32.

    Rubio-Martínez LM, López-Sanromán J, Cruz AM, Santos M, Andrés MS, Román FS. Evaluation of safety and pharmacokinetics of vancomycin after intravenous regional limb perfusion in horses. Am J Vet Res. 2005;66:2107–2113.

    PubMed  Article  Google Scholar 

  33. 33.

    Rybak MJ. The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin Infect Dis. 2006;42(suppl 1):S35–S39.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Scheuch BC, Van Hoogmoed LM, Wilson WD, Snyder JR, MacDonald MH, Watson ZE, Steffey EP. Comparison of intraosseous or intravenous infusion for delivery of amikacin sulfate to the tibiotarsal joint of horses. Am J Vet Res. 2002;63:374–380.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Shavit I, Hoffmann Y, Galbraith R, Waisman Y. Comparison of two mechanical intraosseous infusion devices: a pilot, randomized crossover trial. Resuscitation. 2009;80:1029–1033.

    PubMed  Article  Google Scholar 

  36. 36.

    Sivagnanam S, Deleu D. Red man syndrome. Crit Care. 2003;7:119–120.

    PubMed Central  PubMed  Article  Google Scholar 

  37. 37.

    Tenover FC, Moellering RC Jr. The rationale for revising the Clinical and Laboratory Standards Institute vancomycin minimal inhibitory concentration interpretive criteria for Staphylococcus aureus. Clin Infect Dis. 2007;44:1208–1215.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Tobias JD, Ross AK. Intraosseous infusions: a review for the anesthesiologist with a focus on pediatric use. Anesth Analg. 2010;110:391–401.

    PubMed  Article  Google Scholar 

  39. 39.

    Tyllianakis ME, Karageorgos AC, Marangos MN, Saridis AG, Lambiris EE. Antibiotic prophylaxis in primary hip and knee arthroplasty: comparison between cefuroxime and two specific antistaphylococcal agents. J Arthroplasty. 2010;25:1078–1082.

    PubMed  Article  Google Scholar 

  40. 40.

    Yamada K, Matsumoto K, Tokimura F, Okazaki H, Tanaka S. Are bone and serum cefazolin concentrations adequate for antimicrobial prophylaxis? Clin Orthop Relat Res. 2011;469:3486–3494.

    PubMed Central  PubMed  Article  Google Scholar 

  41. 41.

    Young SW, Zhang M, Freeman JT, Vince KG, Coleman B. Higher cefazolin concentrations with intraosseous regional prophylaxis in TKA. Clin Orthop Relat Res. 2013;471:244–249.

    PubMed  Article  Google Scholar 

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Acknowledgments

We thank Irene Zeng MSc (Hons) for her assistance with statistical analysis and the Awhina Trust for their funding support, and we thank Dr Kelly Vince for his advice and guidance on the project. We also thank Vidacare Corp for supplying the intraosseous needles without charge.

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Correspondence to Simon W. Young FRACS.

Additional information

The institution of one or more of the authors (MZ, GAM) received funding from the Awhina Trust (Auckland, New Zealand), a charitable trust with no relationship to the subject of this article.

All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research editors and board members are on file with the publication and can be viewed on request.

Clinical Orthopaedics and Related Research neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDA approval status, of any drug or device before clinical use.

Each author certifies that his or her institution approved the human protocol for this investigation, that all investigations were conducted in conformity with ethical principles of research, and that informed consent for participation in the study was obtained.

Procedures and sample collection were performed at North Shore Hospital, Auckland, New Zealand. Sample analysis was performed at Canterbury Health Laboratories, Christchurch, New Zealand.

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Young, S.W., Zhang, M., Freeman, J.T. et al. The Mark Coventry Award: Higher Tissue Concentrations of Vancomycin With Low-dose Intraosseous Regional Versus Systemic Prophylaxis in TKA. Clin Orthop Relat Res 472, 57–65 (2014). https://doi.org/10.1007/s11999-013-3038-z

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Keywords

  • Vancomycin
  • Teicoplanin
  • Femoral Nerve Block
  • Vancomycin Concentration
  • High Tissue Concentration