Vancomycin-laden calcium phosphate-calcium sulfate composite allows bone formation in a rat infection model

English version

Autoři: K. Keely Boyle ^aff001; Branden Sosa ^aff002; Liza Osagie ^aff003; Kathleen Turajane ^aff002; Mathias P. G. Bostrom ^aff002; Xu Yang ^aff002
Působiště autorů: University at Buffalo, Buffalo, New York, United States of America ^aff001; Hospital for Special Surgery, New York, New York, United States of America ^aff002; Royal Free Hospital, London, England, United Kingdom ^aff003
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0222034

Souhrn

Objective

Local antibiotic delivery systems with differing chemical and mechanical properties have been developed to assist in the management of osteomyelitis. We investigated the bone conductive and resorptive capabilities of a calcium phosphate-calcium sulfate (CaP/CaS) composite compared with commercially available polymethylmethacrylate (PMMA). In addition, we compared the in vivo preventative and treatment efficacies of both biomaterials in a proven osteomyelitis model.

Methods

Sixty-four, male Sprague-Dawley rats were inoculated with 10 μl of 1.5 x 10⁸ CFU/ml of Staphylococcus aureus in a surgically drilled defect in the right proximal tibia. Infected animals were randomly allocated into prevention and treatment groups with 32 rats each. In the prevention group, the defect was filled with a plug containing either PMMA or CaP/CaS immediately after the inoculation. In the treatment group, the infected defects were irrigated, debrided, and filled with either a PMMA or CaP/CaS plug. Both CaP/CaS and PMMA were impregnated with 10% weight of vancomycin. Rats were sacrificed 6 weeks after cement insertion. Infection was detected by bacterial culture and histological analysis. Bone formation in the defect was assessed with micro-computed tomography and histology.

Results

No bacteria were detected in any group. Both the prevention and treatment groups using CaP/CaS had significantly more bone volume fraction, bone area, and cartilage area than the PMMA groups.

Conclusions

When loaded with 10% of vancomycin, CaP/CaS and PMMA have the same efficacy for treatment and prevention of osteomyelitis. CaP/CaS enhances bone defect healing through improved bone remodeling in our osteomyelitis rat model.

Klíčová slova:

Biology and life sciences – Physical sciences – Chemistry – Anatomy – Medicine and health sciences – Chemical compounds – Salts – Sulfates – Microbiology – Materials science – Materials – Critical care and emergency medicine – Pharmacology – Infectious diseases – Bacterial diseases – Rheumatology – Microbial control – Antimicrobials – Antibiotics – Drugs – Musculoskeletal system – Skeleton – Trauma medicine – Traumatic injury – Bone fracture – Connective tissue diseases – Osteomyelitis – Vancomycin – Composite materials – Binders – Cements

Zdroje

1. Pollak AN, Jones AL, Castillo RC, Bosse MJ, MacKenzie EJ, Group LS. The relationship between time to surgical debridement and incidence of infection after open high-energy lower extremity trauma. J Bone Joint Surg Am. 2010;92(1):7–15. doi: 10.2106/JBJS.H.00984 20048090

2. McKee MD, Li-Bland EA, Wild LM, Schemitsch EH. A prospective, randomized clinical trial comparing an antibiotic-impregnated bioabsorbable bone substitute with standard antibiotic-impregnated cement beads in the treatment of chronic osteomyelitis and infected nonunion. J Orthop Trauma. 2010;24(8):483–90. doi: 10.1097/BOT.0b013e3181df91d9 20657257.

3. Gustilo RB, Anderson JT. Prevention of infection in the treatment of one thousand and twenty-five open fractures of long bones: retrospective and prospective analyses. J Bone Joint Surg Am. 1976;58(4):453–8. 773941.

4. Keating JF, Simpson AH, Robinson CM. The management of fractures with bone loss. J Bone Joint Surg Br. 2005;87(2):142–50. 15736731.

5. Buchholz HW, Elson RA, Heinert K. Antibiotic-loaded acrylic cement: current concepts. Clin Orthop Relat Res. 1984;(190):96–108. 6386264.

6. Gogia JS, Meehan JP, Di Cesare PE, Jamali AA. Local antibiotic therapy in osteomyelitis. Semin Plast Surg. 2009;23(2):100–7. doi: 10.1055/s-0029-1214162 20567732

7. Scott CP, Higham PA, Dumbleton JH. Effectiveness of bone cement containing tobramycin. An in vitro susceptibility study of 99 organisms found in infected joint arthroplasty. J Bone Joint Surg Br. 1999;81(3):440–3. 10872362.

8. Patzakis MJ, Mazur K, Wilkins J, Sherman R, Holtom P. Septopal beads and autogenous bone grafting for bone defects in patients with chronic osteomyelitis. Clin Orthop Relat Res. 1993;(295):112–8. 8403634.

9. McKee MD, Wild LM, Schemitsch EH, Waddell JP. The use of an antibiotic-impregnated, osteoconductive, bioabsorbable bone substitute in the treatment of infected long bone defects: early results of a prospective trial. J Orthop Trauma. 2002;16(9):622–7. 12368641.

10. Borrelli J Jr., Prickett WD, Ricci WM. Treatment of nonunions and osseous defects with bone graft and calcium sulfate. Clin Orthop Relat Res. 2003;(411):245–54. doi: 10.1097/01.blo.0000069893.31220.6f 12782881.

11. Nelson CL, McLaren SG, Skinner RA, Smeltzer MS, Thomas JR, Olsen KM. The treatment of experimental osteomyelitis by surgical debridement and the implantation of calcium sulfate tobramycin pellets. J Orthop Res. 2002;20(4):643–7. doi: 10.1016/S0736-0266(01)00133-4 12168649.

12. Gitelis S, Brebach GT. The treatment of chronic osteomyelitis with a biodegradable antibiotic-impregnated implant. J Orthop Surg (Hong Kong). 2002;10(1):53–60. doi: 10.1177/230949900201000110 12401922.

13. Turner TM, Urban RM, Gitelis S, Kuo KN, Andersson GB. Radiographic and histologic assessment of calcium sulfate in experimental animal models and clinical use as a resorbable bone-graft substitute, a bone-graft expander, and a method for local antibiotic delivery. One institution’s experience. J Bone Joint Surg Am. 2001;83-A Suppl 2(Pt 1):8–18. doi: 10.2106/00004623-200100021-00003 11685848.

14. Urban RM, Turner TM, Hall DJ, Infanger S, Cheema N, Lim TH. Healing of large defects treated with calcium sulfate pellets containing demineralized bone matrix particles. Orthopedics. 2003;26(5 Suppl):s581–5. 12755230.

15. Blaha JD. Calcium sulfate bone-void filler. Orthopedics. 1998;21(9):1017–9. 9769049.

16. Thomas DB, Brooks DE, Bice TG, DeJong ES, Lonergan KT, Wenke JC. Tobramycin-impregnated calcium sulfate prevents infection in contaminated wounds. Clin Orthop Relat Res. 2005;441:366–71. doi: 10.1097/01.blo.0000181144.01306.b0 16331028.

17. Walsh WR, Morberg P, Yu Y, Yang JL, Haggard W, Sheath PC, et al. Response of a calcium sulfate bone graft substitute in a confined cancellous defect. Clin Orthop Relat Res. 2003;(406):228–36. doi: 10.1097/01.blo.0000030062.92399.6a 12579023.

18. Kelly CM, Wilkins RM, Gitelis S, Hartjen C, Watson JT, Kim PT. The use of a surgical grade calcium sulfate as a bone graft substitute: results of a multicenter trial. Clin Orthop Relat Res. 2001;(382):42–50. doi: 10.1097/00003086-200101000-00008 11154003.

19. Moore DC, Chapman MW, Manske D. The evaluation of a biphasic calcium phosphate ceramic for use in grafting long-bone diaphyseal defects. J Orthop Res. 1987;5(3):356–65. doi: 10.1002/jor.1100050307 3040949.

20. Joosten U, Joist A, Frebel T, Brandt B, Diederichs S, von Eiff C. Evaluation of an in situ setting injectable calcium phosphate as a new carrier material for gentamicin in the treatment of chronic osteomyelitis: studies in vitro and in vivo. Biomaterials. 2004;25(18):4287–95. doi: 10.1016/j.biomaterials.2003.10.083 15046919.

21. Zelken J, Wanich T, Gardner M, Griffith M, Bostrom M. PMMA is superior to hydroxyapatite for colony reduction in induced osteomyelitis. Clin Orthop Relat Res. 2007;462:190–4. doi: 10.1097/BLO.0b013e3180ca9521 17514008.

22. Adams K, Couch L, Cierny G, Calhoun J, Mader JT. In vitro and in vivo evaluation of antibiotic diffusion from antibiotic-impregnated polymethylmethacrylate beads. Clin Orthop Relat Res. 1992;(278):244–52. 1563160.

23. Mackey D, Varlet A, Debeaumont D. Antibiotic loaded plaster of Paris pellets: an in vitro study of a possible method of local antibiotic therapy in bone infection. Clin Orthop Relat Res. 1982;(167):263–8. 7094471.

24. An YH FR. Animal models of orthopedic implant infection. Journal Investigative Surgery. 1998.

25. Ding M, Odgaard A, Hvid I. Accuracy of cancellous bone volume fraction measured by micro-CT scanning. J Biomech. 1999;32(3):323–6. doi: 10.1016/s0021-9290(98)00176-6 10093033.

26. Nazarian A, von Stechow D, Zurakowski D, Muller R, Snyder BD. Bone volume fraction explains the variation in strength and stiffness of cancellous bone affected by metastatic cancer and osteoporosis. Calcif Tissue Int. 2008;83(6):368–79. doi: 10.1007/s00223-008-9174-x 18946628.

27. Swiontkowski MF, Hanel DP, Vedder NB, Schwappach JR. A comparison of short- and long-term intravenous antibiotic therapy in the postoperative management of adult osteomyelitis. J Bone Joint Surg Br. 1999;81(6):1046–50. 10615984.

28. Barie PS. Breaking with tradition: evidence-based antibiotic prophylaxis of open fractures. Surg Infect (Larchmt). 2006;7(4):327–9. doi: 10.1089/sur.2006.7.327 16978075.

29. Rohilla M, Saldanha K, Waseem M. Early versus delayed surgical treatment of open tibial fractures: effect on the rates of infection and need of secondary surgical procedures to promote bone union. Injury. 2006;37(1):85–6; author reply 6–7. doi: 10.1016/j.injury.2005.06.059 16384557.

30. Cho SH, Song HR, Koo KH, Jeong ST, Park YJ. Antibiotic-impregnated cement beads in the treatment of chronic osteomyelitis. Bull Hosp Jt Dis. 1997;56(3):140–4. 9361913.

31. Gristina AG, Naylor P, Myrvik Q. Infections from biomaterials and implants: a race for the surface. Med Prog Technol. 1988;14(3–4):205–24. 2978593.

32. Mayberry-Carson KJ, Tober-Meyer B, Smith JK, Lambe DW Jr., Costerton JW. Bacterial adherence and glycocalyx formation in osteomyelitis experimentally induced with Staphylococcus aureus. Infect Immun. 1984;43(3):825–33. 6199302

33. Hashmi MA, Norman P, Saleh M. The management of chronic osteomyelitis using the Lautenbach method. J Bone Joint Surg Br. 2004;86(2):269–75. 15046445.

34. Costerton JW, Stewart PS, Greenberg EP. Bacterial biofilms: a common cause of persistent infections. Science. 1999;284(5418):1318–22. doi: 10.1126/science.284.5418.1318 10334980.

35. Achermann Y, Goldstein EJ, Coenye T, Shirtliff ME. Propionibacterium acnes: from commensal to opportunistic biofilm-associated implant pathogen. Clin Microbiol Rev. 2014;27(3):419–40. doi: 10.1128/CMR.00092-13 24982315

36. Leid JG, Shirtliff ME, Costerton JW, Stoodley P. Human leukocytes adhere to, penetrate, and respond to Staphylococcus aureus biofilms. Infect Immun. 2002;70(11):6339–45. doi: 10.1128/IAI.70.11.6339-6345.2002 12379713

37. Ceri H, Olson ME, Stremick C, Read RR, Morck D, Buret A. The Calgary Biofilm Device: new technology for rapid determination of antibiotic susceptibilities of bacterial biofilms. J Clin Microbiol. 1999;37(6):1771–6. 10325322

38. Bowyer GW, Cumberland N. Antibiotic release from impregnated pellets and beads. J Trauma. 1994;36(3):331–5. doi: 10.1097/00005373-199403000-00008 8145311.

39. Sanicola SM, Albert SF. The in vitro elution characteristics of vancomycin and tobramycin from calcium sulfate beads. J Foot Ankle Surg. 2005;44(2):121–4. doi: 10.1053/j.jfas.2005.01.006 15768360.

40. Chang W, Colangeli M, Colangeli S, Di Bella C, Gozzi E, Donati D. Adult osteomyelitis: debridement versus debridement plus Osteoset T pellets. Acta Orthop Belg. 2007;73(2):238–43. 17515238.

41. Hanssen AD. Local antibiotic delivery vehicles in the treatment of musculoskeletal infection. Clin Orthop Relat Res. 2005;(437):91–6. doi: 10.1097/01.blo.0000175713.30506.77 16056032.