Pharmacokinetics and Pharmacodynamics of High-Dose Piperacillin-Tazobactam in Obese Patients.

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/m2 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.

Novel microcomposite implant for the controlled delivery of antibiotics in the treatment of osteomyelitis following total joint replacement.

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.

A simple and rapid RP-HPLC method for the simultaneous determination of piperacillin and tazobactam in human plasma.

A rapid and sensitive reverse phase HPLC (RP-HPLC) method for the simultaneous quantitation of piperacillin and tazobactam in human plasma has been developed and validated. The method utilizes a novel, simple and rapid solid phase extraction step, which results in an improved extraction yield of analytes from human plasma, as well as significantly reduced interference from serum components at low UV wavelength detection compared to previously published liquid-liquid extraction methods. Chromatographic separation was carried out on a Hypersil ODS C18, 3µm column using an acetonitrile-trifluoroacetic acid-water gradient elution with dual wavelength quantitation at 254nm for piperacillin and 218nm for tazobactam. Linear relationships between peak area and drug concentration were obtained in the range of 1.0-200µg/mL for piperacillin and 0.78-50µg/mL for tazobactam, with r2=0.9997 and 0.9994 respectively. The assay proved to be sensitive (with a lower limit of quantitation of 1µg/mL for piperacillin and 0.78µg/mL for tazobactam), specific (no interference from plasma components at either 218nm or 254nm), and reproducible (both intra- and inter- day coefficients of variation were ≤6%). With a total process/assay time of less than 30min, the method provides a simple, precise and reproducible assay for monitoring piperacillin and tazobactam plasma levels that can be readily adapted for routine clinical use.

Characterization of protein degradation in serum-based lubricants during simulation wear testing of metal-on-metal hip prostheses.

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.