Abstract
Objectives
Traditional therapy of staphylococcal osteomyelitis is ineffective in producing complete sterilization of infected bones due to the formation of the Staphylococcus aureus biofilms. The aim of this study was to develop a new drug-delivery system of antibiotics for treatment of chronic experimental osteomyelitis.
Methods
In the current work, cationic liposomal gentamicin was prepared and impregnated in calcium sulfate (CS), and tested for anti-biofilm activities in vitro and in vivo.
Results and conclusions
The combination of liposomal gentamicin and CS showed initial burst-release of active liposomal gentamicin and had continuous-release (12 days). Liposomal gentamicin released from CS had the same anti-biofilm activity with the liposomal gentamicin prepared freshly. Meanwhile, both agents were more effective relative to free gentamicin at low drug concentration. Therapeutic trials with antibiotics given intravenously revealed that free gentamicin for 14 days was ineffective in sterilizing bone. Treatment with liposomal gentamicin for 14 days resulted in recovery of 33.3% of treated animals, which was the lower slightly than the result treated with implantation of gentamicin-impregnated CS (66.7%). Complete sterilization of bone tissues on cultures (100% cure) was obtained only in the group of liposomal gentamicin-impregnated CS treated for 14 days. The new drug-delivery system was effective in preventing biofilm infection in a contaminated defect, and it could also be used clinically for bacterial infections in the conditions like plaque formation or in arresting biofilm formation in the implanted devices or dead bone of osteomyelitis.
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References
Berestein GL (1987) Liposomes as carriers of antimicrobial agents. Antimicrob Agents Chemother 31:675–678
Ceri H, Olson ME, Stremick C, Read RR, Morck D, Buret A (1999) The Calgary biofilm device: new technology for rapid determination of antibiotic susceptibilities of bacterial biofilms. J Clin Microbiol 37:1771–1776
Chang W, Colangeli M, Colangeli S, Di Bella C, Gozzi E, Donati D (2007) Adult osteomyelitis: debridement versus debridement plus Osteoset T pellets. Acta Orthop Belg 73:238–243
Costerton JW, Stewart PS, Greenberg EP (1999) Bacterial biofilms: a common cause of persistent infections. Science 284:1318–1322. doi:10.1126/science.284.5418.1318
Dunne WM Jr (2002) Bacterial adhesion: seen any good biofilms lately? Clin Microbiol Rev 15:155–166. doi:10.1128/CMR.15.2.155-166.2002
Eng RH, Padberg FT, Smith SM, Tan EN, Cherubin CE (1991) Bactericidal effects of antibiotics on slowly growing and nongrowing bacteria. Antimicrob Agents Chemother 35:1824–1828
Faber C, Stallmann HP, Lyaruu DM, de Blieck JM, Bervoets TJ, van Nieuw Amerongen A, Wuisman PI (2003) Release of antimicrobial peptide Dhvar-5 from polymethylmethacrylate beads. J Antimicrob Chemother 51:1359–1364. doi:10.1093/jac/dkg258
Furneri PM, Fresta M, Puglisi G, Tempera G (2000) Ofloxacinloaded liposomes: in vitro activity and drug accumulation in bacteria. Antimicrob Agents Chemother 44:2458–2464. doi:10.1128/AAC.44.9.2458-2464.2000
Hienz SA, Sakamoto H, Flock JI, Mörner AC, Reinholt FP, Heimdahl A, Nord CE (1995) Development and characterization of a new model of hematogenous osteomyelitis in the rat. J Infect Dis 171:1230–1236
Illera JC, González Gil A, Silván G, Illera M (2000) The effects of different anaesthetic treatments on the adreno-cortical functions and glucose levels in NZW rabbits. J Physiol Biochem 56:329–336
Ince A, Schütze N, Hendrich C, Jakob F, Eulert J, Löhr JF (2007) Effect of polyhexanide and gentamycin on human osteoblasts and endothelial cells. Swiss Med Wkly 137:139–145
Jones MN (2005) Use of liposomes to deliver bactericides to bacterial biofilms. Methods Enzymol 391:211–228. doi:10.1016/S0076-6879(05)91013-6
Kadry AA, Al-Suwayeh SA, Abd-Allah AR, Bayomi MA (2004) Treatment of experimental osteomyelitis by liposomal antibiotics. J Antimicrob Chemother 54:1103–1108. doi:10.1093/jac/dkh465
Kim HJ, Jones MN (2004) The delivery of benzyl penicillin to Staphylococcus aureus biofilms by use of liposomes. J Liposome Res 14:123–139. doi:10.1081/LPR-200029887
Kim HJ, Michael GE, Jones MN (1999) The adsorption of cationic liposomes to S. aureus biofilms. Colloids Surf A Physicochem Eng Asp 149:561–570
Lambe DW Jr, Ferguson KP, Mayberry-Carson KJ, Tober-Meyer B, Costerton JW (1991) Foreign-body-associated experimental osteomyelitis induced with Bacteroides fragilis and Staphylococcus epidermidis in rabbits. Clin Orthop Relat Res 266:285–294
Matl FD, Obermeier A, Repmann S, Friess W, Stemberger A, Kuehn KD (2008) New anti-infective coatings of medical implants based on lipid-like drug carriers. Antimicrob Agents Chemother (Epub ahead of print)
Moghimi SM, Porter CJ, Illum L, Davis SS (1991) The effect of poloxamer-407 on liposome stability and targeting to bone marrow: comparison with polystyrene microspheres. Int J Pharm 68:121–126. doi:10.1016/0378-5173(91)90134-A
Morgan JR, Williams KE (1980) Preparation and properties of liposome-associated gentamicin. Antimicrob Agents Chemother 17:544–548
Norden CW (1971) Experimental osteomyelitis. II. Therapeutic trials and measurement of antibiotic levels in bone. J Infect Dis 124:565–571
Norden CW (1975) Experimental osteomyelitis. IV. Therapeutic trials with rifampin alone and in combination with gentamicin, sisomicin, and cephalothin. J Infect Dis 132:493–499
Norden CW (1983) Experimental chronic staphylococcal osteomyelitis in rabbits: treatment with rifampin alone and in combination with other antimicrobial agents. Rev Infect Dis 5:S491–S494
Norden CW, Keleti E (1980) Treatment of experimental staphylococcal osteomyelitis with rifampin and trimethoprim, alone and in combination. Antimicrob Agents Chemother 17:591–594
Norden CW, Keleti E (1980) Experimental osteomyelitis caused by Pseudomonas aeruginosa. J Infect Dis 141:71–75
Norden CW, Shaffer M (1983) Treatment of experimental chronic osteomyelitis due to S. aureus with gentamicin and rifampin. J Infect Dis 147:352–357
Norden CW, Shinners E (1985) Ciprofloxacin as therapy for experimental osteomyelitis caused by Pseudomonas aeruginosa. J Infect Dis 151:291–294
Norden CW, Shinners E, Niederriter K (1986) Clindamycin treatment of experimental chronic osteomyelitis due to S. aureus. J Infect Dis 153:956–959
Power ME, Olson ME, Domingue PA, Costerton JW (1990) A rat model of S. aureus chronic osteomyelitis that provides a suitable system for studying the human infection. J Med Microbiol 33:189–198
Ravaoarinoro M, Toma E, Agbaba O, Morisset R (1993) Efficient entrapment of amikacin and teicoplanin in liposomes. J Drug Target 1:191–195. doi:10.3109/10611869308996076
Schafer JA, Hovde LB, Rotschafer JC (2006) Consistent rates of kill of Staphylococcus aureus by gentamicin over a 6-fold clinical concentration range in an in vitro pharmacodynamic model (IVPDM). J Antimicrob Chemother 58:108–111. doi:10.1093/jac/dkl216
Schiffelers R, Storm G, Bakker-Woudenberg I (2001) Liposome-encapsulated aminoglycosides in pre-clinical and clinical studies. J Antimicrob Chemother 48:333–344. doi:10.1093/jac/48.3.333
Spagnolo N, Greco F, Rossi A, Ciolli L, Teti A, Posteraro P (1993) Chronic staphylococcal osteomyelitis: a new experimental rat model. Infect Immun 61:5225–5230
Stallmann HP, Faber C, Slotema ET, Lyaruu DM, Bronckers AL, Amerongen AV, Wuisman PI (2003) Continuous-release or burst-release of the antimicrobial peptide human lactoferrin 1-11 (hLF1-11) from calcium phosphate bone substitutes. J Antimicrob Chemother 52:853–855. doi:10.1093/jac/dkg443
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This study was supported by Scientific Technical Department of Yunnan province, China.
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Hui, T., Yongqing, X., Tiane, Z. et al. Treatment of osteomyelitis by liposomal gentamicin-impregnated calcium sulfate. Arch Orthop Trauma Surg 129, 1301–1308 (2009). https://doi.org/10.1007/s00402-008-0782-8
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DOI: https://doi.org/10.1007/s00402-008-0782-8