Abstract
Background
The aim of this study was to prepare poly(d,l-lactide-co-glycolide) (PLGA) microspherical implants containing teicoplanin (TCP) using a double emulsion solvent evaporation method and to evaluate its efficacy for the local treatment of chronic osteomyelitis.
Methods
The particle size and distribution, morphological characteristics, thermal behaviour, drug content, encapsulation efficiency and in vitro release assessments of the formulations were carried out. Sterile TCP–PLGA microspheres were implanted in the proximal tibia of rats with methicillin resistant Staphylococcus aureus (MRSA) osteomyelitis. After 3 weeks of treatment, bone samples were analysed with a microbiological assay and evaluated histopathologically.
Results
Microspheres between the size ranges of 2.01 and 3.91 μm were obtained. Production yield of all formulations was found to be higher than 82% and encapsulation efficiencies of 33.6–69.8% were obtained. DSC thermogram showed that the TCP was in an amorphous state in microspheres. In vitro drug release studies had indicated that the drug release rate of microspheres was decreased upon increasing the polymer:drug ratio. Based on the in vivo data, rats treated with implants and intramuscular injection showed 1.7 × 103 ± 1.3 × 103 and 5.8 × 104 ± 5.3 × 104 colony forming unit of MRSA in 1 g bone samples (CFU/g), respectively (P < 0.01).
Conclusions
The in vitro and in vivo studies had shown that the TCP–PLGA microspheres were effective for the treatment of chronic osteomyelitis in an animal experimental model. Hence, these microspheres may be potentially useful in the clinical setting with the need for further investigation for optimal dosing of TCP–PLGA microspheres.
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References
Lew DP, Waldvogel FA (2004) Osteomyelitis. Lancet 364:369–379. doi:10.1016/S0140-6736(04)16727-5
Yenice I, Calis S, Atilla B et al (2003) In vitro/in vivo evaluation of the efficiency of teicoplanin-loaded biodegradable microparticles formulated for implantation to infected bone defects. J Microencapsul 20:705–717. doi:10.1080/0265204031000154179
Compere EL, Metzger WI, Mitra RN (1972) The treatment of pyogenic bone and joint infections by closed irrigation (circulation) with a non-toxic detergent and one or more antibiotics. J Bone Joint Surg Am 54-A:1227–1234
Mackey D, Varlet A, Debeaumont D (1982) 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 167:263–268
Adams K, Couch L, Cierny G et al (1992) In vitro and in vivo evaluation of antibiotic diffusion from antibiotic-impregnated polymethacrylate beads. Clin Orthop Relat Res 278:244–252
Kawanabe K, Okada Y, Matsusue Y et al (1998) Treatment of osteomyelitis with antibiotic-soaked porous glass ceramic. J Bone Joint Surg Br 80:527–530. doi:10.1302/0301-620X.80B3.8576
Mendel V, Simanovski HJ, Scholz HC et al (2005) Therapy with gentamycin-PMMA beads, gentamycin-collagen sponge, and cefazolin for experimental osteomyelitis due to Staphylococcus aureus in rats. Arch Orthop Trauma Surg 125:363–368. doi:10.1007/s00402-004-0774-2
Cevher E, Orhan Z, Mülazımoğlu L et al (2006) Characterization of biodegradable chitosan microspheres containing vancomycin and treatment of experimental osteomyelitis caused by methicillin-resistant Staphylococcus aureus with prepared microspheres. Int J Pharm 317:127–135. doi:10.1016/j.ijpharm.2006.03.014
Orhan Z, Cevher E, Mülazımoğlu L et al (2006) The preparation of ciprofloxacin hydrochloride-loaded chitosan and pectin microspheres: their evaluation in an animal osteomyelitis model. J Bone Joint Surg Br 88:270–275. doi:10.1302/0301-620X.88B2.16328
Teupe C, Meffert R, Wincler S et al (1992) Ciprofloxacin- impregnated poly-L-Lactic acid drug carrier: new aspects of a resorbable drug delivery system in local antimicrobial treatment of bone infections. Arch Orthop Trauma Surg 112:33–35. doi:10.1007/BF00431041
Ramchandani M, Robinson D (1998) In vitro and in vivo release of ciprofloxacin from PLGA 50–50 implants. J Control Release 54:167–175. doi:10.1016/S0168-3659(97)00113-2
Brogden RN, Peters DH (1994) Teicoplanin. A reappraisal of its antimicrobial activity, pharmacokinetic properties and therapeutic efficacy. Drugs 47:823–854. doi:10.2165/00003495-199447050-00008
Campoli-Richards DM, Brogden RN, Faulds D (1990) Teicoplanin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential. Drugs 40:449–486. doi:10.2165/00003495-199040030-00007
Wilson APR, Taylor B, Treasure T et al (1998) Antibiotic prophylaxis in cardiac surgery: serum and tissue levels of teicoplanin, flucloxacillin and tobramycin. J Antimicrob Chemother 21:201–212. doi:10.1093/jac/21.2.201
Le Frock JL, Ristuccia AM, the Teicoplanin Bone, Joint Cooperative Study Group (1999) Teicoplanin in the treatment of bone and joint infections: an open study. J Infect Chemother 5:32–39. doi:10.1007/s101560050005
Benita S, Benoit JP, Puisieux F et al (1984) Characterisation of drug loaded poly (D, L-lactide) microspheres. J Pharm Sci 73:1721–1724. doi:10.1002/jps.2600731215
Riva E, Ferry N, Cometti A et al (1987) Determination of teicoplanin in human plasma and urine by affinity and reversed-phase high-performance liquid chromatography. J Chromatogr A 421:99–110. doi:10.1016/0378-4347(87)80383-3
Council Directive 86/609/EEC (1986) European Convention for the protection of vertebrate animals used for experimental and other scientific purposes. Off J C Eur Comm L 358:1–48
Chapter 71, Sterility Tests, The United State Pharmacopeia/The National Formulary, USP30/NF25, Vol. 1 (2007) The United State pharmacopeial convention, Rockville, pp 97–102
Norden CW (1970) Experimental osteomyelitis. I: a description of the model. J Infect Dis 122:410–418
O’Reilly T, Mader JT (1999) Rat model of bacterial osteomyelitis of the tibia. In: Zak O, Sande MA (eds) Handbook of animal models of infection: experimental model in antimicrobial chemotherapy. Academic Press, San Diego, pp 560–575
Rissing JP (1990) Animal models of osteomyelitis. Knowledge, hypothesis, and speculation. Infect Dis Clin North Am 4:377–390
Cevher E, Orhan Z, Sensoy D et al (2007) Sodium fusidate-poly(D, L-lactide-co-glycolide) microspheres: preparation, characterization and in vivo evaluation of their effectiveness in the treatment of chronic osteomyelitis. J Microencapsul 24:577–595. doi:10.1080/02652040701472584
Lazarettos J, Efstathopoulos N, Papagelopoulos PJ et al (2004) A bioresorbable calcium phosphate delivery system with teicoplanin for treating MRSA osteomyelitis. Clin Orthop Relat Res 423:253–258. doi:10.1097/01.blo.0000127422.06956.35
Wang G, Liu SJ, Ueng SWN, Chan EC (2004) The release of cefazoline and gentamicin from biodegradable PLA/PGA beads. Int J Pharm 273:203–212. doi:10.1016/j.ijpharm.2004.01.010
Rushton N (1997) Applications of local antibiotic therapy. Eur J Surg 578:27–30
Gürsel I, Korkusuz F, Türesin F et al (2001) In vivo application of biodegradable controlled antibiotic release systems for the treatment of implant-related osteomyelitis. Biomaterials 22:73–80. doi:10.1016/S0142-9612(00)00170-8
Popham GJ, Mangino P, Seligson D et al (1991) Antibiotic impregnated beads. Part II. Factors in antibiotic selection. Orthop Rev 20:331–337
Henry SL, Galloway KP (1995) Local antibiotic therapy for the management of orthopaedic infections. Pharmacokinetic considerations. Clin Pharmacokinet 29:36–45. doi:10.2165/00003088-199529010-00005
Walenkamp GH (2001) Gentamicin PMMA beads and other local antibiotic carriers in two-stage revision of total knee infection: a review. J Chemother 13 Spec No 1(1):66–72
Schaison G, Graninger W, Bouza E (2000) Teicoplanin in the treatment of serious infection. J Chemother 12(suppl 5):26–33
Castro C, Evora C, Baro M et al (2005) Two-month ciprofloxacin implants for multibacterial bone infections. Eur J Pharm Biopharm 60:401–406. doi:10.1016/j.ejpb.2005.02.005
Karp JM, Shoichet MS, Davies JE (2003) Bone formation on two-dimensional poly(D, L-lactide-co-glycolide) (PLGA) films and three-dimensional PLGA tissue engineering scaffolds in vitro. J Biomed Mater Res A 64:388–396. doi:10.1002/jbm.a.10420
Ghiselli R, Cirioni O, Giacometti A et al (2008) Comparative efficacy of topical versus systemic teicoplanin in experimental model of wound infections. J Surg Res 144:74–81. doi:10.1016/j.jss.2007.02.051
Ismael F, Bléton R, Saleh-Mghir A et al (2003) Teicoplanin-containing cement spacers for treatment of experimental Staphylococcus aureus joint prosthesis infection. Antimicrob Agents Chemother 47:3365–3367. doi:10.1128/AAC.47.10.3365-3367.2003
Fernández A, Cabellos C, Tubau F et al (2005) Experimental study of teicoplanin, alone and in combination, in the therapy of cephalosporin-resistant pneumococcal meningitis. J Antimicrob Chemother 55:78–83. doi:10.1093/jac/dkh496
Griffith D, Dudley DM (2007) Animal models of infection for the study of antibiotic pharmacodynamics. In: Nightingale CH, Ambrose PG, Drusano GL, Murakawo T (eds) Antimicrobial pharmacodynamics in theory and clinical practice. Informa Healthcare USA Inc, New York, pp 78–102
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Orhan, Z., Cevher, E., Yıldız, A. et al. Biodegradable microspherical implants containing teicoplanin for the treatment of methicillin-resistant Staphylococcus aureus osteomyelitis. Arch Orthop Trauma Surg 130, 135–142 (2010). https://doi.org/10.1007/s00402-009-0886-9
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DOI: https://doi.org/10.1007/s00402-009-0886-9