linezolid and Body-Weight

The objective of the present retrospective observational study carried out in patients receiving a standard dosage of linezolid and undergoing routine therapeutic drug monitoring (TDM) was to assess the interindividual variability in plasma exposure, to identify the prevalence of attainment of optimal pharmacodynamics, and to define if an intensive program of TDM may be warranted in some categories of patients. Linezolid plasma concentrations (trough [C(min)] and peak [C(max)] levels) were analyzed by means of a high-performance liquid chromatography (HPLC) method, and daily drug exposure was estimated (daily area under the plasma concentration-time curve [AUC(24)]). The final database included 280 C(min) and 223 C(max) measurements performed in 92 patients who were treated with the fixed 600-mg dose every 12 h (q12h) intravenously (n = 58) or orally (n = 34). A wide variability was observed (median values [interquartile range]: 3.80 mg/liter [1.75 to 7.53 mg/liter] for C(min), 14.70 mg/liter [10.57 to 19.64] for C(max), and 196.08 mg·h/liter [144.02 to 312.10 mg·h/liter] for estimated AUC(24)). Linezolid C(min) was linearly correlated with estimated AUC(24) (r(2) = 0.85). Optimal pharmacodynamic target attainment (defined as C(min) of ≥2 mg/liter and/or AUC(24)/MIC(90) ratio of >80) was obtained in about 60 to 70% of cases, but potential overexposure (defined as C(min) of ≥10 mg/liter and/or AUC(24) of ≥400 mg·h/liter) was documented in about 12% of cases. A significantly higher proportion of cases with potential overexposure received cotreatment with omeprazole, amiodarone, or amlodipine. Our study suggests that the application of TDM might be especially worthwhile in about 30% of cases with the intent of avoiding either the risk of dose-dependent toxicity or that of treatment failure.

Topics: Acetamides; Adult; Aged; Anti-Bacterial Agents; Body Weight; Drug Monitoring; Female; Humans; Linezolid; Male; Middle Aged; Oxazolidinones; Retrospective Studies

The pharmacokinetics and distribution into bone tissue of ceftobiprole in uninfected New Zealand White rabbits were determined after subcutaneous administration of the prodrug ceftobiprole medocaril. Serum exposure (maximum concentration of the drug in serum, trough concentration, area under the concentration-time curve) to ceftobiprole at 20 and 80 mg/kg was dose proportional, and there was no accumulation of ceftobiprole following repeated (every 6 h [q6h]) injections of the antibiotic. Ceftobiprole titers in the tibial matrix and marrow were 3.2 +/- 1.3 microg/g and 11.2 +/- 6.5 microg/g, respectively, in uninfected animals treated with 20 mg/kg of the antibiotic and 13.4 +/- 7.3 microg/g and 66.3 +/- 43.2 microg/g, respectively, in uninfected animals treated with 80 mg/kg of the antibiotic. No differences in ceftobiprole titers were observed between right and left tibiae for either bone matrix or marrow. The efficacies of 4 weeks of treatment with ceftobiprole (40 mg/kg administered subcutaneously [s.c.] q6h), vancomycin (30 mg/kg administered s.c. q12h), or linezolid (60 mg/kg administered orally q8h) were compared, using a rabbit model of methicillin-resistant Staphylococcus aureus tibial osteomyelitis. After treatment with ceftobiprole, the bacterial titers in all infected left tibiae from evaluable rabbits were below the level of detection, whereas only 73% of infected left tibiae from vancomycin- or linezolid-treated animals had bacterial titers below the level of detection; the mean titers of ceftobiprole were 3 to 5 times higher in infected left tibiae than in uninfected right tibiae. These results indicate that ceftobiprole provided effective parenteral treatment of osteomyelitis in this rabbit model.

Topics: Animals; Body Weight; Cephalosporins; Disease Models, Animal; Methicillin Resistance; Microbial Sensitivity Tests; Osteomyelitis; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Tibia