Study of the different release characteristics of antibiotics from patients: A dynamic eluting system to investigate drug release from antibiotic-impregnated calcium sulfate delivery

Background: Antibiotic-impregnated calcium sulfate delivery systems (ACDS) are commonly used to treat chronic osteomyelitis. Our research is to investigate drug release in vitro over a longer period, as a cautious predictor of in vivo release. Methods: The local release behavior of antibiotic in vitro was simulated. The consecutive dynamic eluting experiment was performed based on the pro-operative characteristic of osteomyelitis patients and the determined results of drug concentration in the human drainage tissue fluid (DTF). The concentration of each drug in the receiving solution was detected by ultra-performance liquid chromatography-tandem quadrupole detector mass spectrometry. The ACDS was reviewed by scanning electronic microscopy (SEM) after 48 h, and prepared to be eluted for another examination after 33 days. The mechanism of antibiotic release was analyzed by using the Ritger–Peppas and Weibull equations. Results: The cumulative release rate of vancomycin in a vancomycin-calcium sulfate delivery system (VCDS) was 77.50 % (3.0 mm diameter) and 72.43 % (4.8 mm diameter), while that of the tobramycin in a tobramycin-calcium sulfate delivery system (TCDS) was 88.0 % (3.0 mm diameter) and 84.55 % (4.8 mm diameter). At the 15th day, approximately 27.92% of vancomycin was and 29.35% of tobramycin was released from the local implant in vivo. Using SEM, numerous vancomycin and tobramycin particles were found to be attached to the columnar calcium sulfate crystals at the start of the experiment. The release behavior of the two antibiotics followed a combination of Fickian diffusion and Case II transport mechanisms within the first 48 h, and a Fickian diffusion mechanism during the subsequent time period. The correlation coefficient of tobramycin and vancomycin in vivo and in vitro was 0.9704–0.9949 and 0.9549–0.9782, respectively. Conclusion: A good correlation of the in vivo and in vitro cumulative release rates was observed by comparing the cumulative release rate of drugs in vitro by means of the dynamic eluting model, and in the DTF. Therefore, our study has proved that it is possible to use the dynamic eluting model as a cautious predictor of in vivo release.

[1]  B. Baroli.  From natural bone grafts to tissue engineering therapeutics: Brainstorming on pharmaceutical formulative requirements and challenges. , 2009, Journal of pharmaceutical sciences.

[2]  Christopher Gauland.  Managing Lower-Extremity Osteomyelitis Locally with Surgical Debridement and Synthetic Calcium Sulfate Antibiotic Tablets , 2011, Advances in skin & wound care.

[3]  D. Coomans,et al.  Non-linear mixed effects models for the evaluation of dissolution profiles. , 2002, International journal of pharmaceutics.

[4]  D. Shou,et al.  Rapid quantification of tobramycin and vancomycin by UPLC-TQD and application to osteomyelitis patient samples. , 2014, Journal of chromatographic science.

[5]  C. J. Thompson,et al.  Hydrogenolysis—An Identification Tool , 1967 .

[6]  Nicholas A. Peppas,et al.  A simple equation for description of solute release II. Fickian and anomalous release from swellable devices , 1987 .

[7]  B. Atiyeh,et al.  Duration of post-surgical antibiotics in chronic osteomyelitis: empiric or evidence-based? , 2010, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases.

[8]  R. Hoffmann,et al.  Treatment algorithms for chronic osteomyelitis. , 2012, Deutsches Arzteblatt international.

[9]  Tadashi Kokubo,et al.  How useful is SBF in predicting in vivo bone bioactivity? , 2006, Biomaterials.

[10]  L. Grover,et al.  Comparing the efficacy of three bioceramic matrices for the release of vancomycin hydrochloride. , 2009, Journal of biomedical materials research. Part B, Applied biomaterials.

[11]  K. Kosmidis,et al.  On the use of the Weibull function for the discernment of drug release mechanisms. , 2006, International journal of pharmaceutics.

[12]  H. Hu,et al.  Preparation, characterization and in vitro release study of gallic acid loaded silica nanoparticles for controlled release. , 2013, Pharmazie.

[13]  Changqing Zhang,et al.  Treatment of osteomyelitis and repair of bone defect by degradable bioactive borate glass releasing vancomycin. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[14]  J. Bumgardner,et al.  Preliminary in vitro evaluation of an adjunctive therapy for extremity wound infection reduction: Rapidly resorbing local antibiotic delivery , 2009, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[15]  I. Marriott,et al.  Causative agents of osteomyelitis induce death domain-containing TNF-related apoptosis-inducing ligand receptor expression on osteoblasts. , 2011, Bone.

[16]  Joseph C Wenke,et al.  Effect of various concentrations of antibiotics on osteogenic cell viability and activity , 2011, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[17]  Patty W. Wright,et al.  Acute kidney injury after placement of an antibiotic-impregnated cement spacer during revision total knee arthroplasty. , 2012, The Journal of arthroplasty.

[18]  K. Urabe,et al.  In vitro comparison of elution characteristics of vancomycin from calcium phosphate cement and polymethylmethacrylate , 2009, Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association.

[19]  David A Puleo,et al.  Calcium sulfate: Properties and clinical applications. , 2009, Journal of biomedical materials research. Part B, Applied biomaterials.

[20]  T. Kokubo,et al.  Newly Improved Simulated Body Fluid , 2003 .

[21]  M. McKee,et al.  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 , 2010, Journal of orthopaedic trauma.

[22]  J. Barralet,et al.  Modeling vancomycin release kinetics from microporous calcium phosphate ceramics comparing static and dynamic immersion conditions. , 2008, Acta biomaterialia.

[23]  H. Khalili,et al.  Vancomycin-induced nephrotoxicity: mechanism, incidence, risk factors and special populations. A literature review , 2012, European Journal of Clinical Pharmacology.

[24]  M. Assor.  Noncemented total knee arthroplasty with a local prophylactic anti-infection agent: a prospective series of 135 cases. , 2010, Canadian journal of surgery. Journal canadien de chirurgie.

[25]  J. L. Santos,et al.  Calcium phosphate-mediated gene delivery using simulated body fluid (SBF). , 2012, International journal of pharmaceutics.

[26]  Robin Patel,et al.  Are Anidulafungin or Voriconazole Released from Polymethylmethacrylate In Vitro? , 2011, Clinical orthopaedics and related research.

[27]  S. Bew,et al.  Recent advances in the synthesis of new glycopeptide antibiotics. , 2012, Chemical Society reviews.

[28]  Aldo R Boccaccini,et al.  Bone tissue engineering therapeutics: controlled drug delivery in three-dimensional scaffolds , 2010, Journal of The Royal Society Interface.

[29]  D. Basu,et al.  Local antibiotic delivery systems for the treatment of osteomyelitis - A review , 2009 .

[30]  D. Stead.  Current methodologies for the analysis of aminoglycosides. , 2000, Journal of chromatography. B, Biomedical sciences and applications.