The occurrence of an implant-associated infection (IAI) with the formation of a persisting bacterial biofilm remains a major risk following orthopedic biomaterial implantation. Yet, progress in the fabrication of tunable and durable implant coatings with sufficient bactericidal activity to prevent IAI has been limited. Here, an electrospun composite coating was optimized for the combinatorial and sustained delivery of antibiotics. Antibiotics-laden poly(e-caprolactone) (PCL) and poly'1q' (lactic-co glycolic acid) (PLGA) nanofibers were electrospun onto lattice structured titanium (Ti) implants. In order to achieve tunable and independent delivery of vancomycin (Van) and rifampicin (Rif), we investigated the influence of the specific drug-polymer interaction and the nanofiber coating composition on the drug release profile and durability of the polymer-Ti interface. We found that a bi-layered nanofiber structure, produced by electrospinning of an inner layer of [PCL/Van] and an outer layer of [PLGA/Rif], yielded the optimal combinatorial drug release profile. This resulted in markedly enhanced bactericidal activity against planktonic and adherent Staphylococcus aureus for 6 weeks as compared to single drug delivery. Moreover, after 6 weeks, synergistic bacterial killing was observed as a result of sustained Van and Rif release. The application of a nanofiber-filled lattice structure successfully prevented the delamination of the multi-layer coating after press-fit cadaveric bone implantation. This new lattice design, in conjunction with the multi-layer nanofiber structure, can be applied to develop tunable and durable coatings for various metallic implantable devices. This is particularly appealing to tune the release of multiple antimicrobial agents over a period of weeks to prevent early and delayed onset JAI.

Background and objective External evaluation is an important issue in the population pharmacokinetic analysis of antibiotics. The purpose of this review was to summarize the current approaches and status of external evaluations and discuss the implications of external evaluation results for the future individualization of dosing regimens. Methods We systematically searched the PubMed and EMBASE databases for external evaluation studies of population analysis and extracted the relevant information from these articles. A total of 32 studies were included in this review. Results Vancomycin was investigated in 17 (53.1%) articles and was the most studied drug. Other studied drugs included gentamicin, tobramycin, amikacin, amoxicillin, ceftaroline, meropenem, fluconazole, voriconazole, and rifampicin. Nine (28.1%) studies were prospective, and the sample size varied widely between studies. Thirteen (40.6%) studies evaluated the population pharmacokinetic models by systematically searching for previous studies. Seven (21.9%) studies were multicenter studies, and 27 (84.4%) adopted the sparse sampling strategy. Almost all external evaluation studies of antibiotics (93.8%) used metrics for prediction-based diagnostics, while relatively fewer studies were based on simulations (46.9%) and Bayesian forecasting (25.0%). Conclusion The results of external evaluations in previous studies revealed the poor extrapolation performance of existing models of prediction- and simulation-based diagnostics, whereas the posterior Bayesian method could improve predictive performance. There is an urgent need for the development of standards and guidelines for external evaluation studies.