Advanced SearchSearch Tips
Modified Pharmacokinetic/Pharmacodynamic model for electrically activated silver-titanium implant system
facebook(new window)  Pirnt(new window) E-mail(new window) Excel Download
 Title & Authors
Modified Pharmacokinetic/Pharmacodynamic model for electrically activated silver-titanium implant system
Tan, Zhuo; Orndorff, Paul E.; Shirwaiker, Rohan A.;
Silver-based systems activated by low intensity direct current continue to be investigated as an alternative antimicrobial for infection prophylaxis and treatment. However there has been limited research on the quantitative characterization of the antimicrobial efficacy of such systems. The objective of this study was to develop a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model providing the quantitative relationship between the critical system parameters and the degree of antimicrobial efficacy. First, time-kill curves were experimentally established for a strain of Staphylococcus aureus in a nutrientrich fluid environment over 48 hours. Based on these curves, a modified PK/PD model was developed with two components: a growing silver-susceptible bacterial population and a depreciating bactericidal process. The test of goodness-of-fit showed that the model was robust and had good predictability (>). The model demonstrated that the current intensity was positively correlated to the initial killing rate and the bactericidal fatigue rate of the system while the anode surface area was negatively correlated to the fatigue rate. The model also allowed the determination of the effective range of these two parameters within which the system has significant antimicrobial efficacy. In conclusion, the modified PK/PD model successfully described bacterial growth and killing kinetics when the bacteria were exposed to the electrically activated silver-titanium implant system. This modeling approach as well as the model itself can also potentially contribute to the development of optimal design strategies for other similar antimicrobial systems.
Pharmacokinetic/Pharmacodynamic model;antimicrobial efficacy;orthopaedic implants;silver oligodynamic iontophoresis;low intensity direct current;parameter characterization;time-kill curves;
 Cited by
Anima, Nanda and Saravanan, M. (2009), "Biosynthesis of silver nanoparticles from Staphylococcus aureus and its antimicrobial activity against MRSA and MRSE", Nanomed. Nanotech. Biol. Med., 5(4), 452-456. crossref(new window)

Baranyi, J. and Roberts, T.A. (1994), "A dynamic approach to predicting bacterial growth in food", Int. J. Food Microbiol., 23(3), 277-294. crossref(new window)

Berbari, E., Hanssen, A., Duffy, M., Steckelberg, J., Ilstrup, D., Harmsen, W. and Osmon, D. (1998), "Risk factors for prosthetic joint infection: case-control study", Clin. Infect. Dis., 27(5), 1247-1254. crossref(new window)

Carlsson, L., Rostlund, T., Albrektsson, B., Albrektsson, T. and Branemark, P. (1986), "Osseointegration of titanium implants", Acta Orthop. Scand., 57(4), 285-289. crossref(new window)

Craig, W.A. (1995), "Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins", Diagn. Microbiol. Infect. Dis., 22(1), 89-96. crossref(new window)

Czock, D. and Keller, F. (2007), "Mechanism-based pharmacokinetic-pharmacodynamic modeling of antimicrobial drug effects", J. Pharmacokinet. Pharmacodyn., 34(6), 727-751. crossref(new window)

Darouiche, R.O. (1999), "Anti-infective efficacy of silver-coated medical prostheses", Clin. Infect. Dis., 29(6), 1371-1377. crossref(new window)

Derendorf, H. and Meibohm, B. (1999), "Modeling of pharmacokinetic/pharmacodynamic (PK/PD) relationships: Concepts and perspectives", Pharm. Res., 16(2), 176-185. crossref(new window)

Emsley, J. (2001). Nature's Building Blocks: An A-Z Guide to the Elements, Oxford, Oxford University Press.

Feng, Q.L., Wu, J., Chen, G.Q., Cui, F.Z., Kim, T.N. and Kim, J.O. (2000), "A mechanistic study of the antibacterial effect of silver ions on Escherichia coli and Staphylococcus aureus", J. Biomed. Mater. Res. A, 52(4), 662-668. crossref(new window)

Fuller, T.A., Wysk, R.A., Charumani, C., Kennett, M., Sebastiennelli, W.J., Abrahams, R., Shirwaiker, R.A., Voigt, R.C. and Royer, P. (2010), "Developing an engineered antimicrobial/prophylactic system using electrically activated bactericidal metals", J. Mater. Sci. Mater. Med., 21(7), 2103-2114. crossref(new window)

Gustafsson, I., Lowdin, E., Odenholt, I. and Cars, O. (2001), "Pharmacokinetic and pharmacodynamic parameters for antimicrobial effects of cefotaxime and amoxicillin in an in vitro kinetic model", Antimicrob. Agents Chemother., 45(9), 2436-2440. crossref(new window)

Harris Williams & Co. (2011), Orthopedic Implants-A Global Market Overview, Hyderabad, India, Industry Experts.

Le Guehennec, L., Soueidan, A., Layrolle, P. and Amouriq, Y. (2007), "Surface treatments of titanium dental implants for rapid osseointegration", Dent. Mater., 23(7), 844-854. crossref(new window)

Liu, P., Rand, K.H., Obermann, B. and Derendorf, H. (2005), "Pharmacokinetic-pharmacodynamic modelling of antibacterial activity of cefpodoxime and cefixime in in vitro kinetic models", Int. J. Antimicrob. Agents, 25(2), 120-129. crossref(new window)

Loh, J.V., Percival, S.L., Woods, E.J., Williams, N.J. and Cochrane, C.A. (2009), "Silver resistance in MRSA isolated from wound and nasal sources in humans and animals", Int. Wound J., 6(1), 32-38. crossref(new window)

Marshall, S., Macintyre, F., James, I., Krams, M. and Jonsson, N.E. (2006), "Role of mechanistically-based pharmacokinetic/pharmacodynamic models in drug development: a case study of a therapeutic protein", Clin. Pharmacokinet., 45(2), 177-197. crossref(new window)

Nielsen, E.I., Viberg, A., Lowdin, E., Cars, O., Karlsson, M.O. and Sandstrom, M. (2006), "Semimechanistic Pharmacokinetic/Pharmacodynamic model for assessment of activity of antibacterial agent from time-kill curve experiments", Antimicrob. Agents Chemother., 51(1), 128.

Samberg, M.E., Tan, Z., Monteiro-Riviere, N.A., Orndorff, P.E. and Shirwaiker, R.A. (2013), "Biocompatibility analysis of an electrically-activated silver-based antibacterial surface system for medical device applications", J. Mater. Sci. Mater. Med., 24(3), 755-760. crossref(new window)

Shirwaiker, R.A., Samberg, M.E., Cohen, P.H., Wysk, R.A. and Monteiro-Riviere, N.A. (2013), "Nanomaterials and synergistic low-intensity direct current (LIDC) stimulation technology for orthopedic implantable medical devices", WIREs Nanomed. Nanobiotechnol., 5(3), 191-204. crossref(new window)

Shirwaiker, R.A., Wysk, R.A., Kariyawasam, S., Carrion, H. and Voigt, R.C. (2011), "Micro-scale fabrication and characterization of a silver-polymer-based electrically activated antibacterial surface", Biofabrication, 3(1), 015003. crossref(new window)

Shirwaiker, R.A., Wysk, R.A., Kariyawasam, S., Voigt, R.C., Carrion, H. and Nembhard, H. (2014), "Interdigitated silver-polymer-based antibacterial surface system activated by oligodynamic iontophoresis - An empirical characterization study", Biomed. Microdevices, 16(1), 1-10. crossref(new window)

Strohala, R., Schellingb, M., Takacsc, M., Jureckac, W., Gruberd, U. and Offner, F. (2005), "Nanocrystalline silver dressings as an efficient anti-MRSA barrier: a new solution to an increasing problem", J. Hosp. Infect., 60(3), 226-230. crossref(new window)

Tan, Z., Ganapathy, A., Orndorff, P.E. and Shirwaiker, R.A. (2015), "Effects of cathode design parameters on in vitro antimicrobial efficacy of electrically-activated silver-based iontophoretic system", J. Mater. Sci. Mater. Med., 26(1), 1-10.

Tan, Z., Xu, G. and Shirwaiker, R.A. (2014), "In vitro quantitative analysis on the antimicrobial performance of the dual-metal implant system", IIE Annual Conference and Expo, Montreal.

Tsvetkov, V.V. (1995), "Corrosion-resistant titanium alloys", Pharm. Chem. J., 29(8), 564-566. crossref(new window)

Vaddady, P.K., Lee, R.E. and Meibohm, B. (2010), "In vitro pharmacokinetic/pharmacodynamic models in anti-infective drug development: focus on TB", Future Med. Chem., 2(8), 1355-1369. crossref(new window)

Virk, A. and Osmon, D. (2001), "Prosthetic joint infection", Curr. Treat Option. Infect Dis., 351(16), 287-300.

Wang, Z., Butner, J.D., Cristini, V. and Deisboeck, T.S. (2015), "Integrated PK-PD and agent-based modeling in oncology", J. Pharmacokinet. Pharmacodyn., doi:10.1007/s10928-015-9403-7. crossref(new window)

Wiedel, J. (2002), "Salvage of infected total knee fusion: the last option", Clin. Orthop. Relat. Res., 404, 139-142. crossref(new window)

Wysk, R.A., Sebastianelli, W.J., Shirwaiker, R.A., Bailey, G.M., Charumani, C., Kennett, M., Kaucher, A., Abrahams, R., Fuller, T.A., Royer, P., Voigt, R.C. and Cohen, P.H. (2010), "Prophylactic bactericidal orthopedic implants - animal testing study", J. Biomed. Sci. Eng., 3(9), 917-926. crossref(new window)