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Biomaterials and Biomedical Engineering
  Volume 2, Number 3, September 2015 , pages 127-141
 open access

Modified Pharmacokinetic/Pharmacodynamic model for electrically activated silver-titanium implant system
Zhuo Tan, Paul E. Orndorff and Rohan A. Shirwaiker

    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 (R2>0.7). 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.
Key Words
    Pharmacokinetic/Pharmacodynamic model; antimicrobial efficacy; orthopaedic implants; silver oligodynamic iontophoresis; low intensity direct current; parameter characterization; time-kill curves
Zhuo Tan, Rohan A. Shirwaiker: Edward P. Fitts Department of Industrial and Systems Engineering, North Carolina State University, Raleigh, NC 27695, USA

Zhuo Tan, Rohan A. Shirwaiker: Medical Implants and Tissue Engineering (MITE) Lab, North Carolina State University,
Raleigh, NC 27695, USA

Paul E. Orndorff: Department of Population Health and Pathobiology, North Carolina State University,
Raleigh, NC 27607, USA

Rohan A. Shirwaiker: UNC-NCSU Joint Department of Biomedical Engineering, Raleigh, NC 27695, USA

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