Implants coated with PEG-PPS alone showed a dramatic degree of periprosthetic osteolysis that became evident by POD 7 and progressed over time. In contrast, antibiotic-encapsulated PEG-PPS implants showed no detectable radiographic periprosthetic osteolysis (Fig. 5), consistent with the high efficacy of these coatings in facilitating bacterial clearance from the implants.
Infection after total joint arthroplasty represents a clinically devastating complication that is exceedingly difficult to prevent and treat9,28,29. The difficulty is due to several host and pathogen factors, including a high affinity of bacteria for the foreign implant surface; the formation of biofilm, which blocks the penetration of immune cells and systemic antibiotics; and the emergence of antibiotic-resistant organisms8,9,28-36. Given this, novel strategies are needed to minimize the number of such cases that develop infection.
The present study demonstrated that antibiotics—in this case, vancomycin and tigecycline—can be loaded into a PEG-PPS polymer coating covalently linked to metal implants. These antibiotics can then be passively released over the course of 1 week to maintain therapeutic levels during the perioperative period, or actively induced to release antibiotic more rapidly in the face of a bacterial challenge. This is in stark contrast to the poorly controlled, erratic antibiotic release from PMMA37. The local release of vancomycin and tigecycline from the PEG-PPS coatings resulted in a significantly lower bacterial burden as measured by in vivo bioluminescence imaging, with confirmatory quantification of CFUs isolated from the implants and surrounding bone and joint tissue on POD 21. Interestingly, the tigecycline-loaded PEG-PPS implants achieved a more potent antibacterial effect than did the vancomycin-loaded PEG-PPS and prevented bacterial colonization on 100% of the implants.
The PEG-PPS coating is unique, as it consists of an inner layer of polymer covalently linked to the implant and self-assembled outer layers that allow for an active release. This release, triggered by the bacterially induced hyperinflammatory state, can drive the diffusion of antibiotic. These unique properties have the potential to protect the implant from bacterial adherence and biofilm formation as can occur through direct contamination intraoperatively, or seeding of the implant from transient bacteremia or infected hematoma formation during the acute postoperative period1,9,28,29,34-36.
In our study, the tigecycline-encapsulated PEG-PPS coating was particularly effective in preventing any colonization of bacteria on the implant surface (as evidenced by 0 CFUs cultured from the implant) as well as significantly reducing the CFUs isolated from the surrounding bone and joint tissue. The enhanced efficacy of tigecycline versus vancomycin-coated implants requires further investigation. However, a possible explanation for the increased efficacy is that tigecycline has preferential uptake in rodent and human bone compared with vancomycin38-40. Additional studies should evaluate the efficacy of these antibiotic polymer coatings at higher concentrations, of combinations of antibiotics (such as the synergistic effect of adding rifampin, which has enhanced therapeutic effect against periprosthetic joint infection in cases of implant retention41-44), or of these antibiotic polymers in combination with intravenous prophylactic perioperative antibiotics.
An important limitation of this coating is that it is designed to be short-acting and biodegradable and, therefore, will only be effective in preventing infection seeded during surgery or in the immediate postoperative period. It will not be present for sources of infection due to hematogenous spread occurring after the postoperative period at any point during the lifetime of the implant. Its absorption is presumed to be advantageous, as it does not impact osseointegration or provide an additional surface for bacterial adherence, which are important for the long-term biocompatibility of the implant. Additionally, this coating was designed to completely elute from the implant by 14 days. As the coating is made by a layering technique, a longer-duration PEG-PPS coating is easily achievable by adding more layers.
Despite these limitations, we believe that this novel PEG-PPS implant coating is an effective tool to deliver various antibiotics or even combinations of antibiotics locally during the perioperative period. This coating is versatile in that it can be loaded with many different antibiotics or antimicrobials, has a passive-release mechanism to consistently ensure levels above the desired MIC to prevent the development of antibiotic resistance, and has an active-release mechanism that responds to the presence of bacteria with increased antibiotic release. Additionally, the coating is completely biodegradable and can be easily applied to implants of all shapes and sizes. In summary, “smart” antimicrobial implant coatings, such as the PEG-PPS coating described in this study, have great potential to minimize the incidence of postoperative infection following arthroplasty.
Investigation performed at the University of California, Los Angeles, Los Angeles, California
1. Illingworth KD, Mihalko WM, Parvizi J, Sculco T, McArthur B, el Bitar Y, Saleh KJ. How to minimize infection and thereby maximize patient outcomes in total joint arthroplasty: a multicenter approach: AAOS exhibit selection. J Bone Joint Surg Am. 2013 ;95(8):e50.
2. Lentino JR. Prosthetic joint infections: bane of orthopedists, challenge for infectious disease specialists. Clin Infect Dis. 2003 ;36(9):1157–61. Epub 2003 Apr 14.
3. Best JT. Revision total hip and total knee arthroplasty. Orthop Nurs. 2005 ;24(3):174–9; quiz 180-1.
4. Blom AW, Brown J, Taylor AH, Pattison G, Whitehouse S, Bannister GC. Infection after total knee arthroplasty. J Bone Joint Surg Br. 2004 ;86(5):688–91.
5. Bozic KJ, Kurtz SM, Lau E, Ong K, Vail TP, Berry DJ. The epidemiology of revision total hip arthroplasty in the United States. J Bone Joint Surg Am. 2009 ;91(1):128–33.
6. Jafari SM, Coyle C, Mortazavi SM, Sharkey PF, Parvizi J. Revision hip arthroplasty: infection is the most common cause of failure. Clin Orthop Relat Res. 2010 ;468(8):2046–51.
7. Kurtz S, Ong K, Lau E, Mowat F, Halpern M. Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Joint Surg Am. 2007 ;89(4):780–5.
8. Del Pozo JL, Patel R. Clinical practice. Infection associated with prosthetic joints. N Engl J Med. 2009 ;361(8):787–94.
9. Zimmerli W, Trampuz A, Ochsner PE. Prosthetic-joint infections. N Engl J Med. 2004 ;351(16):1645–54.
10. Kruckenhauser EM, Nogler M, Coraça-Huber D. Use of lavage fluids in arthroplasty to prevent postoperative infections. Drug Res (Stuttg). 2014 ;64(3):166–8. Epub 2013 Aug 28.
11. Qadir R, Ochsner JL, Chimento GF, Meyer MS, Waddell B, Zavatsky JM. Establishing a role for vancomycin powder application for prosthetic joint infection prevention-results of a wear simulation study. J Arthroplasty. 2014 ;29(7):1449–56. Epub 2014 Feb 12.
12. Alijanipour P, Heller S, Parvizi J. Prevention of periprosthetic joint infection: what are the effective strategies? J Knee Surg. 2014 ;27(4):251–8. Epub 2014 May 3.
13. Shirai T, Tsuchiya H, Nishida H, Yamamoto N, Watanabe K, Nakase J, Terauchi R, Arai Y, Fujiwara H, Kubo T. Antimicrobial megaprostheses supported with iodine. J Biomater Appl. 2014 ;29(4):617–23. Epub 2014 Jun 9.
14. Fulkerson E, Valle CJ, Wise B, Walsh M, Preston C, Di Cesare PE. Antibiotic susceptibility of bacteria infecting total joint arthroplasty sites. J Bone Joint Surg Am. 2006 ;88(6):1231–7.
15. Salgado CD, Dash S, Cantey JR, Marculescu CE. Higher risk of failure of methicillin-resistant Staphylococcus aureus prosthetic joint infections. Clin Orthop Relat Res. 2007 ;461:48–53.
16. Walls RJ, Roche SJ, O’Rourke A, McCabe JP. Surgical site infection with methicillin-resistant Staphylococcus aureus after primary total hip replacement. J Bone Joint Surg Br. 2008 ;90(3):292–8.
17. Howden BP, Davies JK, Johnson PD, Stinear TP, Grayson ML. Reduced vancomycin susceptibility in Staphylococcus aureus, including vancomycin-intermediate and heterogeneous vancomycin-intermediate strains: resistance mechanisms, laboratory detection, and clinical implications. Clin Microbiol Rev. 2010 ;23(1):99–139.
18. Aslam S, Trautner BW, Ramanathan V, Darouiche RO. Combination of tigecycline and N-acetylcysteine reduces biofilm-embedded bacteria on vascular catheters. Antimicrob Agents Chemother. 2007 ;51(4):1556–8. Epub 2007 Jan 12.
19. Cafiso V, Bertuccio T, Spina D, Purrello S, Stefani S. Tigecycline inhibition of a mature biofilm in clinical isolates of Staphylococcus aureus : comparison with other drugs. FEMS Immunol Med Microbiol. 2010 ;59(3):466–9. Epub 2010 May 19.
20. Cai Y, Wang R, Liang B, Bai N, Liu Y. Systematic review and meta-analysis of the effectiveness and safety of tigecycline for treatment of infectious disease. Antimicrob Agents Chemother. 2011 ;55(3):1162–72. Epub 2010 Dec 20.
21. Brand AM, de Kwaadsteniet M, Dicks LM. The ability of nisin F to control Staphylococcus aureus infection in the peritoneal cavity, as studied in mice. Lett Appl Microbiol. 2010 ;51(6):645–9. Epub 2010 Oct 11.
22. Faust N, Varas F, Kelly LM, Heck S, Graf T. Insertion of enhanced green fluorescent protein into the lysozyme gene creates mice with green fluorescent granulocytes and macrophages. Blood. 2000 ;96(2):719–26.
23. Pribaz JR, Bernthal NM, Billi F, Cho JS, Ramos RI, Guo Y, Cheung AL, Francis KP, Miller LS. Mouse model of chronic post-arthroplasty infection: noninvasive in vivo bioluminescence imaging to monitor bacterial burden for long-term study. J Orthop Res. 2012 ;30(3):335–40. Epub 2011 Aug 11.
24. Bernthal NM, Stavrakis AI, Billi F, Cho JS, Kremen TJ, Simon SI, Cheung AL, Finerman GA, Lieberman JR, Adams JS, Miller LS. A mouse model of post-arthroplasty Staphylococcus aureus joint infection to evaluate in vivo the efficacy of antimicrobial implant coatings. PLoS One. 2010 ;5(9):e12580.
25. Bernthal NM, Pribaz JR, Stavrakis AI, Billi F, Cho JS, Ramos RI, Francis KP, Iwakura Y, Miller LS. Protective role of IL-1β against post-arthroplasty Staphylococcus aureus infection. J Orthop Res. 2011 ;29(10):1621–6. Epub 2011 Mar 28.
26. Bernthal NM, Taylor BN, Meganck JA, Wang Y, Shahbazian JH, Niska JA, Francis KP, Miller LS. Combined in vivo optical and μCT imaging to monitor infection, inflammation, and bone anatomy in an orthopaedic implant infection in mice. J Vis Exp. 2014 ;(92):e51612.
27. Cho JS, Pietras EM, Garcia NC, Ramos RI, Farzam DM, Monroe HR, Magorien JE, Blauvelt A, Kolls JK, Cheung AL, Cheng G, Modlin RL, Miller LS. IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice. J Clin Invest. 2010 ;120(5):1762–73. Epub 2010 Apr 1.
28. Darouiche RO. Treatment of infections associated with surgical implants. N Engl J Med. 2004 ;350(14):1422–9.
29. Trampuz A, Widmer AF. Infections associated with orthopedic implants. Curr Opin Infect Dis. 2006 ;19(4):349–56.
30. Miller LS, Pietras EM, Uricchio LH, Hirano K, Rao S, Lin H, O’Connell RM, Iwakura Y, Cheung AL, Cheng G, Modlin RL. Inflammasome-mediated production of IL-1beta is required for neutrophil recruitment against Staphylococcus aureus in vivo. J Immunol. 2007 ;179(10):6933–42.
31. Antoci V Jr, King SB, Jose B, Parvizi J, Zeiger AR, Wickstrom E, Freeman TA, Composto RJ, Ducheyne P, Shapiro IM, Hickok NJ, Adams CS. Vancomycin covalently bonded to titanium alloy prevents bacterial colonization. J Orthop Res. 2007 ;25(7):858–66.
32. Kurtz SM, Lau E, Schmier J, Ong KL, Zhao K, Parvizi J. Infection burden for hip and knee arthroplasty in the United States. J Arthroplasty. 2008 ;23(7):984–91. Epub 2008 Apr 10.
33. Bozic KJ, Ries MD. The impact of infection after total hip arthroplasty on hospital and surgeon resource utilization. J Bone Joint Surg Am. 2005 ;87(8):1746–51.
34. Stoodley P, Nistico L, Johnson S, Lasko LA, Baratz M, Gahlot V, Ehrlich GD, Kathju S. Direct demonstration of viable Staphylococcus aureus biofilms in an infected total joint arthroplasty. A case report. J Bone Joint Surg Am. 2008 ;90(8):1751–8.
35. Sheehan E, McKenna J, Mulhall KJ, Marks P, McCormack D. Adhesion of Staphylococcus to orthopaedic metals, an in vivo study. J Orthop Res. 2004 ;22(1):39–43.
36. Nishimura S, Tsurumoto T, Yonekura A, Adachi K, Shindo H. Antimicrobial susceptibility of Staphylococcus aureus and Staphylococcus epidermidis biofilms isolated from infected total hip arthroplasty cases. J Orthop Sci. 2006 ;11(1):46–50.
37. van de Belt H, Neut D, Schenk W, van Horn JR, van Der Mei HC, Busscher HJ. Staphylococcus aureus biofilm formation on different gentamicin-loaded polymethylmethacrylate bone cements. Biomaterials. 2001 ;22(12):1607–11.
38. Ji AJ, Saunders JP, Amorusi P, Wadgaonkar ND, O’Leary K, Leal M, Dukart G, Marshall B, Fluhler EN. A sensitive human bone assay for quantitation of tigecycline using LC/MS/MS. J Pharm Biomed Anal. 2008 ;48(3):866–75. Epub 2008 Jul 6.
39. Landersdorfer CB, Bulitta JB, Kinzig M, Holzgrabe U, Sörgel F. Penetration of antibacterials into bone: pharmacokinetic, pharmacodynamic and bioanalytical considerations. Clin Pharmacokinet. 2009;48(2):89–124.
40. Rodvold KA, Gotfried MH, Cwik M, Korth-Bradley JM, Dukart G, Ellis-Grosse EJ. Serum, tissue and body fluid concentrations of tigecycline after a single 100 mg dose. J Antimicrob Chemother. 2006 ;58(6):1221–9. Epub 2006 Sep 29.
41. Lora-Tamayo J, Euba G, Ribera A, Murillo O, Pedrero S, García-Somoza D, Pujol M, Cabo X, Ariza J. Infected hip hemiarthroplasties and total hip arthroplasties: differential findings and prognosis. J Infect. 2013 ;67(6):536–44. Epub 2013 Aug 7.
42. Maaloum Y, Meybeck A, Olive D, Boussekey N, Delannoy PY, Chiche A, Georges H, Beltrand E, Senneville E, d’Escrivan T, Leroy O. Clinical spectrum and outcome of critically ill patients suffering from prosthetic joint infections. Infection. 2013 ;41(2):493–501. Epub 2012 Oct 25.
43. Widmer AF, Gaechter A, Ochsner PE, Zimmerli W. Antimicrobial treatment of orthopedic implant-related infections with rifampin combinations. Clin Infect Dis. 1992 ;14(6):1251–3.
44. Zimmerli W, Widmer AF, Blatter M, Frei R, Ochsner PE; Foreign-Body Infection (FBI) Study Group. Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. JAMA. 1998 ;279(19):1537–41.
45. Prabhakara R, Harro JM, Leid JG, Keegan AD, Prior ML, Shirtliff ME. Suppression of the inflammatory immune response prevents the development of chronic biofilm infection due to methicillin-resistant Staphylococcus aureus. Infect Immun. 2011 ;79(12):5010–8. Epub 2011 Sep 26.