Prevention of Staphylococcus aureus biofilm formation on metallic surgical implants via controlled release of gentamicin
Author(s)
David J. McMillan,
Cameron Lutton,
Natalie Rosenzweig,
Kadaba S. Sriprakash,
Ben Goss,
Michaela Stemberger,
Michael A. Schuetz,
Roland Steck
ABSTRACT
Implant associated infections are a critical health concern following orthopaedic surgery. Sustained local delivery of antibiotics has been suggested as a means of preventing these infections. Poly(D,L-lactide) (PDLLA) is a biodegradable polymer that has been used to coat implants for the delivery of antibiotics and other bioactive molecules. While effective, these studies show that antibiotics are released in a burst profile. Here we evaluated a method for controlled release of gentamicin from implant surfaces using the palmitate alkyl salt to decrease its solubility in aqueous solution. Steel Kirschner wires (K-wires) were coated with Gentamicin-palmitate (GP)-PDLLA, gentamicin sulphate (GS)-PDLLA or vancomycin sulphate (VS)-PDLLA, and elution of antibiotics from coated K-wires investigated using HPLC/MS/ MS. In contrast to burst antibiotic release from the GS-PDLLA and VS-PDLLA groups, GP was released in a slower sustained manner. Colonisation and initial attachment of Staphylococcus aureus Xen29 to gentamicin-coated K-wires was reduced by 90% when compared to the non-coated control group. However there was no statistical difference in recovery of bacteria from GS or GP groups. Bacteria recovered from VS-PDLLA coated K-wires decreased by 36%. Bioluminescence emitted by S. aureus Xen29 was also reduced over seven days in the antibiotic control groups, demonstrating that growth and biofilm development over the longer term was impaired by antibiotic-PDLLA coating. These results indicate that using alkyl salts of antibiotics may be an effective strategy for controlling the release of antibiotics from implants.
Implant associated infections are a critical health concern following orthopaedic surgery. Sustained local delivery of antibiotics has been suggested as a means of preventing these infections. Poly(D,L-lactide) (PDLLA) is a biodegradable polymer that has been used to coat implants for the delivery of antibiotics and other bioactive molecules. While effective, these studies show that antibiotics are released in a burst profile. Here we evaluated a method for controlled release of gentamicin from implant surfaces using the palmitate alkyl salt to decrease its solubility in aqueous solution. Steel Kirschner wires (K-wires) were coated with Gentamicin-palmitate (GP)-PDLLA, gentamicin sulphate (GS)-PDLLA or vancomycin sulphate (VS)-PDLLA, and elution of antibiotics from coated K-wires investigated using HPLC/MS/ MS. In contrast to burst antibiotic release from the GS-PDLLA and VS-PDLLA groups, GP was released in a slower sustained manner. Colonisation and initial attachment of Staphylococcus aureus Xen29 to gentamicin-coated K-wires was reduced by 90% when compared to the non-coated control group. However there was no statistical difference in recovery of bacteria from GS or GP groups. Bacteria recovered from VS-PDLLA coated K-wires decreased by 36%. Bioluminescence emitted by S. aureus Xen29 was also reduced over seven days in the antibiotic control groups, demonstrating that growth and biofilm development over the longer term was impaired by antibiotic-PDLLA coating. These results indicate that using alkyl salts of antibiotics may be an effective strategy for controlling the release of antibiotics from implants.
Cite this paper
nullMcMillan, D. , Lutton, C. , Rosenzweig, N. , Sriprakash, K. , Goss, B. , Stemberger, M. , Schuetz, M. and Steck, R. (2011) Prevention of Staphylococcus aureus biofilm formation on metallic surgical implants via controlled release of gentamicin. Journal of Biomedical Science and Engineering, 4, 535-542. doi: 10.4236/jbise.2011.48069.
nullMcMillan, D. , Lutton, C. , Rosenzweig, N. , Sriprakash, K. , Goss, B. , Stemberger, M. , Schuetz, M. and Steck, R. (2011) Prevention of Staphylococcus aureus biofilm formation on metallic surgical implants via controlled release of gentamicin. Journal of Biomedical Science and Engineering, 4, 535-542. doi: 10.4236/jbise.2011.48069.
References
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Acta Orthop Belg, 58 Suppl 1, 217-221. [8] Lew D.P., Waldvogel F.A. (2004) Osteomyelitis. Lancet, 364, 369-379. [9] Harris L.G., Richards R.G. (2006) Staphylococci and implant surfaces: a review. Injury, 37 Suppl 2, S3-14. [10] Wenzel R.P. (1991) Epidemiology of Hospital acquired infections. In: Balows Jr, A., Hausler, W.J., Herman, K.L., Isenberg, H.D., Shadomy, H.J., eds. Manual of Clinical Microbiology. Washington D.C.: American Society for Microbiology. [11] Dirschl D.R., Almekinders L.C. (1993) Osteomyelitis. Common causes and treatment recommendations. Drugs, 45, 29-43. [12] An Y.H., Stuart G.W., McDowell S.J., McDaniel S.E., Kang Q., et al. (1996) Prevention of bacterial adherence to implant surfaces with a crosslinked albumin coating in vitro. J Orthop Res, 14, 846-849. [13] Gabriel G.J., Maegerlein J.A., Nelson C.F., Dabkowski J.M., Eren T., et al. (2009) Comparison of facially amphiphilic versus segregated monomers in the design of antibacterial copolymers. Chemistry, 15, 433-439. [14] Peltonen L.I., Kinnari T.J., Aarnisalo A.A., Kuusela P., Jero J. (2007) Comparison of bacterial adherence to polylactides, silicone, and titanium. Acta Otolaryngol, 127, 587-593. [15] Gollwitzer H., Ibrahim K., Meyer H., Mittelmeier W., Busch R., et al. (2003) Antibacterial poly(D,L-lactic acid) coating of medical implants using a biodegradable drug delivery technology. J Antimicrob Chemother, 51, 585-591. [16] Kenawy el R., Worley S.D., Broughton R. (2007) The chemistry and applications of antimicrobial polymers: a state-of-the-art review. Biomacromolecules, 8, 1359-1384. [17] Schmidmaier G., Lucke M., Wildemann B., Haas N.P., Raschke M. (2006) Prophylaxis and treatment of implant-related infections by antibiotic-coated implants: a review. Injury, 37, S105-S112. [18] Schmidmaier G., Wildemann B., Bail H., Lucke M., Fuchs T., et al. (2001) Local Application of Growth Factors (Insulin-Like Growth Factor-1 and Transforming Growth Factor-b1) From Biodegradable Poly(D,L-lactide) Coating of Osteosynthetic Implants Accelerates Fracture Healing in Rats. Bone, 28, 341-350. [19] Vogt S., Ku K.-D., Ege W., Pawlik K., Schnabelrauch M. (2003) Novel Polylactide-Based Release Systems for Local Antibiotic Therapies. Materialwissenschaft und Werkstofftechnik, 34, 1041-1047. [20] Kadurugamuwa J.L., Sin L., Albert E., Yu J., Francis K., et al. (2003) Direct continuous method for monitoring biofilm infection in a mouse model. Infect Immun, 71, 882-890. [21] Xiong Y.Q., Willard J., Kadurugamuwa J.L., Yu J., Francis K.P., et al. (2005) Real-time in vivo bioluminescent imaging for evaluating the efficacy of antibiotics in a rat Staphylococcus aureus endocarditis model. Antimicrob Agents Chemother, 49, 380-387. [22] Periti P., Mini E., Mosconi G. (1998) Antimicrobial prophylaxis in orthopaedic surgery: the role of teicoplanin. J Antimicrob Chemother, 41, 329-340. [23] Schmidmaier G., Lucke M., Wildemann B., Haas N.P., Raschke M. (2006) Prophylaxis and treatment of implant-related infections by antibiotic-coated implants: a review. Injury, 37 Suppl 2, S105-112. [24] Stewart P.S., Costerton J.W. (2001) Antibiotic resistance of bacteria in biofilms. Lancet, 358, 135-138. [25] Felton L.A., O'Donnell P.B., McGinity J.W. (2008) Mechanical properties of polymeric films prepared from aqueous dispersions Drugs and the Pharmaceutical Sciences, 176, 105-128. [26] Hogan J.E. (1995) Film-coating materials [for pharmaceuticals] and their properties In: Cole, G., ed. Pharmaceutical Coating Technology Taylor and Francis. 6-52. [27] Darouiche R., Mansouri M., Zakarevicz D., AlSharif A., Landon G. (2007) In Vivo Efficacy of Antimicrobial- Coated Devices. Journal of Bone and Joint Surgery American, 89, 792-797. [28] Aviv M., Berdicevsky I., Zilberman M. (2007) Gentamicin-loaded bioresorbable films for prevention of bacterial infections associated with orthopedic implants. J Biomed Mater Res A, 83, 10-19. [29] Suuronen R., Pohjonen T., Hietanen J., Lindqvist C. (1998) A 5-year in vitro and in vivo study of the biodegradation of polylactide plates. J Oral Maxillofac Surg, 56, 604-614; discussion 614-605. [30] Leenslag J.W., Pennings A.J., Bos R.R., Rozema F.R., Boering G. (1987) Resorbable materials of poly (L- lactide). VII. In vivo and in vitro degradation. Biomaterials, 8, 311-314. [31] Gustilo R.B., Gruninger R.P., Davis T. (1987) Classification of type III (severe) open fractures relative to treatment and results. Orthopedics, 10, 1781-1788. [32] Sakoulas G., Moise-Broder P.A., Schentag J., Forrest A., Moellering R.C., Jr., et al. (2004) Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol, 42, 2398-2402. [33] Lucke M., Wildemann B., Sadoni S., Surke C., Schiller R., et al. (2005) Systemic versus local application of gentamicin in prophylaxis of implant-related osteomyelitis in a rat model. Bone, 36, 770-778.
[1] Darouiche R.O. (2001) Device-associated infections: a macroproblem that starts with microadherence. Clin Infect Dis, 33, 1567-1572. [2] Darouiche R.O. (2004) Treatment of infections associated with surgical implants. N Engl J Med, 350, 1422-1429. [3] McGraw J.M., Lim E.V. (1988) Treatment of open tibial-shaft fractures. External fixation and secondary intramedullary nailing. J Bone Joint Surg Am, 70, 900-911. [4] Campoccia D., Montanaro L., Arciola C.R. (2006) The significance of infection related to orthopedic devices and issues of antibiotic resistance. Biomaterials, 27, 2331-2339. [5] Wiedel J.D. (2002) Salvage of infected total knee fusion: the last option. Clin Orthop Relat Res, 139-142. [6] Sugarman B., Young E.J. (1989) Infections associated with prosthetic devices: magnitude of the problem. Infect Dis Clin North Am, 3, 187-198. [7] Hughes S.P. (1992) Antibiotic penetration into bone in relation to the immediate management of open fractures: a review. Acta Orthop Belg, 58 Suppl 1, 217-221. [8] Lew D.P., Waldvogel F.A. (2004) Osteomyelitis. Lancet, 364, 369-379. [9] Harris L.G., Richards R.G. (2006) Staphylococci and implant surfaces: a review. Injury, 37 Suppl 2, S3-14. [10] Wenzel R.P. (1991) Epidemiology of Hospital acquired infections. In: Balows Jr, A., Hausler, W.J., Herman, K.L., Isenberg, H.D., Shadomy, H.J., eds. Manual of Clinical Microbiology. Washington D.C.: American Society for Microbiology. [11] Dirschl D.R., Almekinders L.C. (1993) Osteomyelitis. Common causes and treatment recommendations. Drugs, 45, 29-43. [12] An Y.H., Stuart G.W., McDowell S.J., McDaniel S.E., Kang Q., et al. (1996) Prevention of bacterial adherence to implant surfaces with a crosslinked albumin coating in vitro. J Orthop Res, 14, 846-849. [13] Gabriel G.J., Maegerlein J.A., Nelson C.F., Dabkowski J.M., Eren T., et al. (2009) Comparison of facially amphiphilic versus segregated monomers in the design of antibacterial copolymers. Chemistry, 15, 433-439. [14] Peltonen L.I., Kinnari T.J., Aarnisalo A.A., Kuusela P., Jero J. (2007) Comparison of bacterial adherence to polylactides, silicone, and titanium. Acta Otolaryngol, 127, 587-593. [15] Gollwitzer H., Ibrahim K., Meyer H., Mittelmeier W., Busch R., et al. (2003) Antibacterial poly(D,L-lactic acid) coating of medical implants using a biodegradable drug delivery technology. J Antimicrob Chemother, 51, 585-591. [16] Kenawy el R., Worley S.D., Broughton R. (2007) The chemistry and applications of antimicrobial polymers: a state-of-the-art review. Biomacromolecules, 8, 1359-1384. [17] Schmidmaier G., Lucke M., Wildemann B., Haas N.P., Raschke M. (2006) Prophylaxis and treatment of implant-related infections by antibiotic-coated implants: a review. Injury, 37, S105-S112. [18] Schmidmaier G., Wildemann B., Bail H., Lucke M., Fuchs T., et al. (2001) Local Application of Growth Factors (Insulin-Like Growth Factor-1 and Transforming Growth Factor-b1) From Biodegradable Poly(D,L-lactide) Coating of Osteosynthetic Implants Accelerates Fracture Healing in Rats. Bone, 28, 341-350. [19] Vogt S., Ku K.-D., Ege W., Pawlik K., Schnabelrauch M. (2003) Novel Polylactide-Based Release Systems for Local Antibiotic Therapies. Materialwissenschaft und Werkstofftechnik, 34, 1041-1047. [20] Kadurugamuwa J.L., Sin L., Albert E., Yu J., Francis K., et al. (2003) Direct continuous method for monitoring biofilm infection in a mouse model. Infect Immun, 71, 882-890. [21] Xiong Y.Q., Willard J., Kadurugamuwa J.L., Yu J., Francis K.P., et al. (2005) Real-time in vivo bioluminescent imaging for evaluating the efficacy of antibiotics in a rat Staphylococcus aureus endocarditis model. Antimicrob Agents Chemother, 49, 380-387. [22] Periti P., Mini E., Mosconi G. (1998) Antimicrobial prophylaxis in orthopaedic surgery: the role of teicoplanin. J Antimicrob Chemother, 41, 329-340. [23] Schmidmaier G., Lucke M., Wildemann B., Haas N.P., Raschke M. (2006) Prophylaxis and treatment of implant-related infections by antibiotic-coated implants: a review. Injury, 37 Suppl 2, S105-112. [24] Stewart P.S., Costerton J.W. (2001) Antibiotic resistance of bacteria in biofilms. Lancet, 358, 135-138. [25] Felton L.A., O'Donnell P.B., McGinity J.W. (2008) Mechanical properties of polymeric films prepared from aqueous dispersions Drugs and the Pharmaceutical Sciences, 176, 105-128. [26] Hogan J.E. (1995) Film-coating materials [for pharmaceuticals] and their properties In: Cole, G., ed. Pharmaceutical Coating Technology Taylor and Francis. 6-52. [27] Darouiche R., Mansouri M., Zakarevicz D., AlSharif A., Landon G. (2007) In Vivo Efficacy of Antimicrobial- Coated Devices. Journal of Bone and Joint Surgery American, 89, 792-797. [28] Aviv M., Berdicevsky I., Zilberman M. (2007) Gentamicin-loaded bioresorbable films for prevention of bacterial infections associated with orthopedic implants. J Biomed Mater Res A, 83, 10-19. [29] Suuronen R., Pohjonen T., Hietanen J., Lindqvist C. (1998) A 5-year in vitro and in vivo study of the biodegradation of polylactide plates. J Oral Maxillofac Surg, 56, 604-614; discussion 614-605. [30] Leenslag J.W., Pennings A.J., Bos R.R., Rozema F.R., Boering G. (1987) Resorbable materials of poly (L- lactide). VII. In vivo and in vitro degradation. Biomaterials, 8, 311-314. [31] Gustilo R.B., Gruninger R.P., Davis T. (1987) Classification of type III (severe) open fractures relative to treatment and results. Orthopedics, 10, 1781-1788. [32] Sakoulas G., Moise-Broder P.A., Schentag J., Forrest A., Moellering R.C., Jr., et al. (2004) Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol, 42, 2398-2402. [33] Lucke M., Wildemann B., Sadoni S., Surke C., Schiller R., et al. (2005) Systemic versus local application of gentamicin in prophylaxis of implant-related osteomyelitis in a rat model. Bone, 36, 770-778.