Dose regimen optimization of cephalothin for surgical prophylaxis against Staphylococcus aureus and coagulase negative staphylococci in dogs by pharmacokinetic/pharmacodynamic modeling.

First generation cephalosporins such cephalothin of cefazolin are indicated for antimicrobial prophylaxis for clean and clean contaminated surgical procedures because its antimicrobial spectrum, relative low toxicity and cost. Anesthesia and surgery could alter the pharmacokinetic behavior of different drugs administered perioperative by many mechanisms that affect distribution, metabolism or excretion processes. Intravenous administration of the antimicrobial within 30 and 60 min before incision is recommended in order to reach therapeutic serum and tissue concentrations and redosing is recommended if the duration of the procedure exceeds two half-life of the antimicrobial. To the author's knowledge there are no pharmacokinetic studies of cephalothin in dogs under anesthesia/surgery conditions. The aim of this study was (1) to evaluate the pharmacokinetics of cephalothin in anesthetized dogs undergoing ovariohysterectomy by a nonlinear mixed-effects model and to determine the effect of anesthesia/surgery and other individual covariates on its pharmacokinetic behavior; (2) to determine the MIC and conduct a pharmacodynamic modeling of time kill curves assay of cephalothin against isolates of Staphylococcus spp. isolated from the skin of dogs; (3) to conduct a PK/PD analysis by integration of the obtained nonlinear mixed-effects models in order to evaluate the antimicrobial effect of changing concentrations on simulated bacterial count; and (4) to determine the PK/PD endpoints and PK/PDco values in order to predict the optimal dose regimen of cephalothin for antimicrobial prophylaxis in dogs. Anesthesia/surgery significantly reduced cephalothin clearance by 18.78%. Based on the results of this study, a cephalothin dose regimen of 25 mg/kg q6h by intravenous administration showed to be effective against Staphylococcus spp. isolates with MIC values ≤2 µg/mL and could be recommended for antimicrobial prophylaxis for clean surgery in healthy dogs.

3D-Printed Gastroretentive Tablets Loaded with Niclosamide Nanocrystals by the Melting Solidification Printing Process (MESO-PP).

Niclosamide (NICLO) is a recognized antiparasitic drug being repositioned for Helicobacter pylori. The present work aimed to formulate NICLO nanocrystals (NICLO-NCRs) to produce a higher dissolution rate of the active ingredient and to incorporate these nanosystems into a floating solid dosage form to release them into the stomach slowly. For this purpose, NICLO-NCRs were produced by wet-milling and included in a floating Gelucire l3D printed tablet by semi-solid extrusion, applying the Melting solidification printing process (MESO-PP) methodology. The results obtained in TGA, DSC, XRD and FT-IR analysis showed no physicochemical interactions or modifications in the crystallinity of NICLO-NCR after inclusion in Gelucire 50/13 ink. This method allowed the incorporation of NICLO-NCRs in a concentration of up to 25% w/w. It achieved a controlled release of NCRs in a simulated gastric medium. Moreover, the presence of NICLO-NCRs after redispersion of the printlets was observed by STEM. Additionally, no effects on the cell viability of the NCRs were demonstrated in the GES-1 cell line. Finally, gastroretention was demonstrated for 180 min in dogs. These findings show the potential of the MESO-PP technique in obtaining slow-release gastro-retentive oral solid dosage forms loaded with nanocrystals of a poorly soluble drug, an ideal system for treating gastric pathologies such as H. pylori.