J Knee Surg 2021; 34(09): 936-940
DOI: 10.1055/s-0039-3402078
Original Article

Local Vancomycin Concentrations after Intra-articular Injection into the Knee Joint: An Experimental Porcine Study

1   Department of Orthopaedic Surgery, Horsens Regional Hospital, Horsens, Denmark
2   Orthopaedic Research Unit, Aarhus University Hospital, Aarhus N, Denmark
3   Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
,
Maja B. Thomassen
2   Orthopaedic Research Unit, Aarhus University Hospital, Aarhus N, Denmark
3   Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
,
Ole H. Larsen
4   Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus N, Denmark
,
Andrea R. Jørgensen
2   Orthopaedic Research Unit, Aarhus University Hospital, Aarhus N, Denmark
3   Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
,
Maiken Stilling
2   Orthopaedic Research Unit, Aarhus University Hospital, Aarhus N, Denmark
3   Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
5   Department of Orthopaedic Surgery, Aarhus University Hospital, Aarhus N, Denmark
,
Kjeld Søballe
2   Orthopaedic Research Unit, Aarhus University Hospital, Aarhus N, Denmark
3   Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
5   Department of Orthopaedic Surgery, Aarhus University Hospital, Aarhus N, Denmark
,
Pelle Hanberg
1   Department of Orthopaedic Surgery, Horsens Regional Hospital, Horsens, Denmark
2   Orthopaedic Research Unit, Aarhus University Hospital, Aarhus N, Denmark
3   Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
› Author Affiliations

Abstract

Intra-articular injection of vancomycin may be an important antimicrobial prophylactic supplement to systemic administration in the prevention of prosthetic joint infections. In eight female pigs, 500 mg of diluted vancomycin was given by intra-articular injection into the knee joint. Microdialysis was used for dense sampling of vancomycin concentrations over 12 hours in the synovial fluid of the knee joint, and in the adjacent femoral and tibial cancellous bone and subcutaneous tissue. Venous blood samples were obtained as reference. The mean (standard deviation [SD]) peak drug concentration of vancomycin in the synovial fluid of the knee joint was 5,277 (5,668) μg/mL. Only one pig failed to reach a peak drug concentration above 1,000 μg/mL. The concentration remained high throughout the sampling interval with a mean (SD) concentration of 337 (259) μg/mL after 690 minutes. For all extraarticular compartments, the pharmacokinetic parameters (area under the concentration time-curve, peak drug concentration, and time to peak drug concentration) were comparable. The highest extraarticular mean (SD) peak drug concentration of 4.4 (2.3) μg/mL was found in subcutaneous tissue. An intra-articular injection of 500 mg diluted vancomycin was found to provide significant prophylactic mean concentrations for at least 12 hours in the synovial fluid of the knee joint. Correspondingly, the adjacent tissue and plasma concentrations were low but remained stable, signifying low risk of systemic toxic side effects and a slow release or uptake from the synovium to the systemic circulation.



Publication History

Received: 17 November 2019

Accepted: 18 July 2019

Article published online:
30 December 2019

© 2019. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 
  • References

  • 1 Hackett DJ, Rothenberg AC, Chen AF. et al. The economic significance of orthopaedic infections. J Am Acad Orthop Surg 2015; 23 (Suppl): S1-S7
  • 2 Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. ; Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Guideline for prevention of surgical site infection, 1999. Am J Infect Control 1999; 27 (02) 97-132 , quiz 133–134, discussion 96
  • 3 Whiteside LA. Prophylactic peri-operative local antibiotic irrigation. Bone Joint J 2016; 98-B (1, Suppl A): 23-26
  • 4 Bryson DJ, Morris DL, Shivji FS, Rollins KR, Snape S, Ollivere BJ. Antibiotic prophylaxis in orthopaedic surgery: difficult decisions in an era of evolving antibiotic resistance. Bone Joint J 2016; 98-B (08) 1014-1019
  • 5 Bue M, Birke-Sørensen H, Thillemann TM, Hardlei TF, Søballe K, Tøttrup M. Single-dose pharmacokinetics of vancomycin in porcine cancellous and cortical bone determined by microdialysis. Int J Antimicrob Agents 2015; 46 (04) 434-438
  • 6 Bue M, Hanberg P, Tøttrup M. et al. Vancomycin concentrations in the cervical spine after intravenous administration: results from an experimental pig study. Acta Orthop 2018; 89 (06) 683-688
  • 7 Bue M, Tottrup M, Hanberg P. et al. Bone and subcutaneous adipose tissue pharmacokinetics of vancomycin in total knee replacement patients. Acta Orthop 2018; 89 (01) 95-100
  • 8 Sweet FA, Forsthoefel CW, Sweet AR, Dahlberg RK. Local versus systemic antibiotics for surgical infection prophylaxis in a rat model. J Bone Joint Surg Am 2018; 100 (18) e120
  • 9 Young SW, Zhang M, Freeman JT, Mutu-Grigg J, Pavlou P, Moore GA. The Mark Coventry Award: higher tissue concentrations of vancomycin with low-dose intraosseous regional versus systemic prophylaxis in TKA: a randomized trial. Clin Orthop Relat Res 2014; 472 (01) 57-65
  • 10 Elek SD. Experimental staphylococcal infections in the skin of man. Ann N Y Acad Sci 1956; 65 (03) 85-90
  • 11 Roy ME, Peppers MP, Whiteside LA, Lazear RM. Vancomycin concentration in synovial fluid: direct injection into the knee vs. intravenous infusion. J Arthroplasty 2014; 29 (03) 564-568
  • 12 Whiteside LA, Roy ME, Nayfeh TA. Intra-articular infusion: a direct approach to treatment of infected total knee arthroplasty. Bone Joint J 2016; 98-B (1, Suppl A): 31-36
  • 13 Landersdorfer CB, Bulitta JB, Kinzig M, Holzgrabe U, Sörgel F. Penetration of antibacterials into bone: pharmacokinetic, pharmacodynamic and bioanalytical considerations. Clin Pharmacokinet 2009; 48 (02) 89-124
  • 14 Bue M, Hanberg P, Koch J. et al. Single-dose bone pharmacokinetics of vancomycin in a porcine implant-associated osteomyelitis model. J Orthop Res 2018; 36 (04) 1093-1098
  • 15 Hanberg P, Bue M, Birke Sørensen H, Søballe K, Tøttrup M. Pharmacokinetics of single-dose cefuroxime in porcine intervertebral disc and vertebral cancellous bone determined by microdialysis. Spine J 2016; 16 (03) 432-438
  • 16 Stolle LB, Plock N, Joukhadar C. et al. Pharmacokinetics of linezolid in bone tissue investigated by in vivo microdialysis. Scand J Infect Dis 2008; 40 (01) 24-29
  • 17 Tøttrup M, Bue M, Koch J. et al. Effects of implant-associated osteomyelitis on cefuroxime bone pharmacokinetics: assessment in a porcine model. J Bone Joint Surg Am 2016; 98 (05) 363-369
  • 18 Traunmüller F, Schintler MV, Spendel S. et al. Linezolid concentrations in infected soft tissue and bone following repetitive doses in diabetic patients with bacterial foot infections. Int J Antimicrob Agents 2010; 36 (01) 84-86
  • 19 Tøttrup M, Bibby BM, Hardlei TF. et al. Continuous versus short-term infusion of cefuroxime: assessment of concept based on plasma, subcutaneous tissue, and bone pharmacokinetics in an animal model. Antimicrob Agents Chemother 2015; 59 (01) 67-75
  • 20 Joukhadar C, Müller M. Microdialysis: current applications in clinical pharmacokinetic studies and its potential role in the future. Clin Pharmacokinet 2005; 44 (09) 895-913
  • 21 Müller M. Science, medicine, and the future: microdialysis. BMJ 2002; 324 (7337): 588-591
  • 22 Scheller D, Kolb J. The internal reference technique in microdialysis: a practical approach to monitoring dialysis efficiency and to calculating tissue concentration from dialysate samples. J Neurosci Methods 1991; 40 (01) 31-38
  • 23 EUCAST. European Committee on Antimicrobail Susceptibility Testing. 2019 . Aaccessed 6 May 2019 at: https://mic.eucast.org/Eucast2/SearchController/search.jsp?action=performSearch&BeginIndex=0&Micdif=mic&NumberIndex=50&Antib=38&Specium=-1
  • 24 Howlin RP, Brayford MJ, Webb JS, Cooper JJ, Aiken SS, Stoodley P. Antibiotic-loaded synthetic calcium sulfate beads for prevention of bacterial colonization and biofilm formation in periprosthetic infections. Antimicrob Agents Chemother 2015; 59 (01) 111-120
  • 25 Stolle L, Arpi M, H-Jørgensen P, Riegels-Nielsen P, Keller J. Distribution of gentamicin from a Gentacoll sponge measured by in vivo microdialysis. Scand J Infect Dis 2005; 37 (04) 284-287
  • 26 Rathbone CR, Cross JD, Brown KV, Murray CK, Wenke JC. Effect of various concentrations of antibiotics on osteogenic cell viability and activity. J Orthop Res 2011; 29 (07) 1070-1074
  • 27 Shaw KA, Eichinger JK, Nadig N, Parada SA. In vitro effect of vancomycin on the viability of articular chondrocytes. J Orthop Trauma 2018; 32 (03) 148-153
  • 28 Hake ME, Young H, Hak DJ, Stahel PF, Hammerberg EM, Mauffrey C. Local antibiotic therapy strategies in orthopaedic trauma: practical tips and tricks and review of the literature. Injury 2015; 46 (08) 1447-1456
  • 29 Whiteside LA, Roy ME. One-stage revision with catheter infusion of intraarticular antibiotics successfully treats infected THA. Clin Orthop Relat Res 2017; 475 (02) 419-429
  • 30 McNally MA, Ferguson JY, Lau AC. et al. Single-stage treatment of chronic osteomyelitis with a new absorbable, gentamicin-loaded, calcium sulphate/hydroxyapatite biocomposite: a prospective series of 100 cases. Bone Joint J 2016; 98-B (09) 1289-1296
  • 31 Morgenstern M, Vallejo A, McNally MA. et al. The effect of local antibiotic prophylaxis when treating open limb fractures: A systematic review and meta-analysis. Bone Joint Res 2018; 7 (07) 447-456
  • 32 Ferguson J, Diefenbeck M, McNally M. Ceramic biocomposites as biodegradable antibiotic carriers in the treatment of bone infections. J Bone Jt Infect 2017; 2 (01) 38-51
  • 33 Jensen LK, Koch J, Henriksen NL. et al. Suppurative inflammation and local tissue destruction reduce the penetration of cefuroxime to infected bone implant cavities. J Comp Pathol 2017; 157 (04) 308-316