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A size exclusion high performance liquid chromatography (SEC-HPLC) method has been developed which is capable of separation and quantitation of bovine serum albumin (BSA) and bovine serum globulin (BSG) components of serum-based lubricant (SBL) solutions. This allowed characterization of the stability profiles of these proteins when acting as lubricants during hip wear simulation, and identification of wear-specific mechanisms of degradation. Using cobalt-chromium metal-on-metal (MOM) hip joints, it was observed that BSA remained stable for up to 3 days (215K cycles) of wear testing after which the protein degraded in a fairly linear fashion. BSG on the other hand, began to degrade immediately and in a linear fashion with a rate constant of 5% per day. Loss of both proteins occurred via the formation of high molecular weight aggregates which precipitated out of solution. No fragmentation of the polypeptide backbone of either protein was observed. Data obtained suggest that protein degradation was not due to microbial contamination, denaturation at the air-water interface, or frictional heating of articulating joint surfaces in these studies. We conclude that the primary source of protein degradation during MOM simulation testing occurs via high shear rates experienced by SBL solutions at articulating surfaces, possibly coupled with metal-protein interactions occurring as new and reactive metal surfaces are generated during wear testing. The development of this analytical methodology will allow new studies to clarify the role of SBL solutions in wear simulation studies and the interactions and lubricating properties of serum proteins with prosthetic surfaces other than MOM.

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Background and Objective Standard piperacillin-tazobactam (P-T) dosing may be suboptimal in obesity, but high-dose regimens have not been studied. We prospectively evaluated the pharmacokinetics and pharmacodynamics of standard-and high-dose P-T in obese adult inpatients. Methods Those receiving standard-dose P-T with BMI ≥ 30 kg/m 2 weighing 105-139 kg or ≥ 140 kg were given up to 6.75 g or 9 g every 6 h, respectively. Patients were monitored closely for safety. Elimination phase blood samples were drawn for 28 patients on standard and high doses to calculate the pharmacokinetic values using a one-compartment model. The likelihood of pharmacodynamic target attainment (100% fT > 16/4 mg/L) on various P-T regimens was calculated using each patient's own pharmacokinetic values. Results Piperacillin and tazobactam half-lives ranged from 0.5-10.6 to 0.9-15.0 h, while volumes of distribution ranged from 13.6-54.8 to 11.5-60.1 L, respectively. Predicted dose requirements for target attainment ranged from 2.25 g every 6 h in hemodialysis patients to a 27 g/24-h continuous infusion in a patient with a short P-T half-life. An amount of 4.5 g every 6 h would have met the target for only 1/12 (8%) patients with creatinine clearance ≥ 80 mL/min and 13/28 (46%) for all enrolled patients. One patient (3%) experienced an adverse event deemed probably related to high-dose P-T. Conclusion Some patients required high P-T doses for target attainment, but dosing requirements were highly variable. Doses up to 6.75 g or 9 g every 6 h may be tolerable; however, studies are needed to see if high dosing, prolonged infusions, or real-time therapeutic drug monitoring improves outcomes in obese patients. Clinical trial registration (clinicaltrials.gov) NCT01923363.

The objective of this study was to develop a novel microcomposite implant to be used in the treatment of osteomyelitis following total joint arthroplasty, with the dual purpose of releasing high local concentrations of antibiotic to eradicate the infection while providing adequate mechanical strength to maintain the dynamic or static spacer. Vancomycin‐loaded microcomposite implants were fabricated by incorporating drug‐loaded microparticles comprised of mesoporous silica into commonly employed polymethylmethacrylate (PMMA) bone cement, to yield a final drug loading of 10% w/w. In vitro release kinetics at 37°C were monitored by reverse‐phase high‐performance liquid chromatography, and compared to the release kinetics of current therapy implants consisting of drug alone incorporated at 10% w/w directly into PMMA bone cement. Results demonstrated a sevenfold improvement in the elution profile of microcomposite systems over current therapy implants. In vivo delivery of vancomycin to bone from microcomposite implants (70% of payload) was significantly higher than that from current therapy implants (approx. 22% of payload) and maintained significantly higher bone concentrations for up to 2 weeks duration. The elastic modulus showed no statistical difference between microcomposite implants and current standard therapy implants before drug elution, and maintenance of acceptable strength of microcomposite implants postdrug elution. These results demonstrate that we have developed a novel microcomposite spacer that will release continuously high antibiotic concentrations over a prolonged period of time, offering the possibility to eliminate infection and avoid the emergence of new resistant bacterial strains, while maintaining the requisite mechanical properties for proper space maintenance and joint fixation.