tedizolid and Bacterial-Infections

Oxazolidinones are synthetic antibiotics with bacteriostatic activity against Gram-positive pathogens. Linezolid, the first marketed oxazolidinone, has shown also activity against Mycobaterium tuberculosis, including multidrug-resistant and extensively drug-resistant strains. Recently, a second agent of this class (tedizolid) has been approved for the treatment of acute bacterial skin and skin structure infections, and other oxazolidinones are under active investigation in clinical trials.. In the present review, we consider factors that affect oxazolidinones pharmacokinetics and their role in reducing the effectiveness of these drugs and increasing the risk of drug-related adverse events. Furthermore, we review the potential role of strategies aimed at individualizing drug doses. A MEDLINE PubMed search for articles published from January 1990 to November 2015 was completed matching the terms oxazolidinones, linezolid, or tedizolid with pharmacokinetics, therapeutic drug monitoring, pharmacology or clinical trials. Moreover, additional studies were identified from the reference list of retrieved papers.. Consistent evidence is now available showing that therapeutic drug monitoring and guided individual dose optimization of linezolid is justified and feasible in clinical practice to improve tolerability and possibly response to therapy. The role of individualized drug dosing regimens for other oxazolidinones remains to be proven.

Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; Dose-Response Relationship, Drug; Drug Monitoring; Humans; Linezolid; Oxazolidinones; Precision Medicine; Tetrazoles

The continued ability to treat bacterial infections requires effective antibiotics. The development of new therapeutics is guided by knowledge of the mechanisms of action of and resistance to these antibiotics. Continued efforts to understand and counteract antibiotic resistance mechanisms at a molecular level have the potential to direct development of new therapeutic strategies in addition to providing insight into the underlying biochemical functions impacted by antibiotics. The interaction of antibiotics with the peptidyltransferase center and adjacent exit tunnel within the bacterial ribosome is the predominant mechanism by which antibiotics impede translation, thus stalling growth. Resistance enzymes catalyze the chemical modification of the RNA that composes these functional regions, leading to diminished binding of antibiotics. This review discusses recent advances in the elucidation of chemical mechanisms underlying resistance and driving the development of new antibiotics.

Topics: Acetamides; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Binding Sites; Drug Resistance, Multiple, Bacterial; Erythromycin; Humans; Linezolid; Methylation; Oxazolidinones; Peptidyl Transferases; Protein Biosynthesis; Ribosomes; RNA, Ribosomal, 23S; Tetrazoles

Two open-label, single-dose, parallel-group studies were conducted to characterize the pharmacokinetics of the novel antibacterial tedizolid and the safety of tedizolid phosphate, its prodrug, in renally or hepatically impaired subjects. Tedizolid pharmacokinetics in subjects with severe renal impairment without dialysis support was compared with that of matched control subjects with normal renal function. Effects of hemodialysis on tedizolid pharmacokinetics were determined in a separate cohort of subjects undergoing long-term hemodialysis. Effects of hepatic impairment on tedizolid pharmacokinetics were determined in subjects with moderate or severe hepatic impairment and compared with those of matched control subjects with normal hepatic function. Each participant received a single oral (hepatic impairment) or intravenous (renal impairment) dose of tedizolid phosphate at 200 mg; hemodialysis subjects received two doses (separated by 7 days), before and after dialysis, in a crossover fashion. The pharmacokinetics of tedizolid was similar in subjects with severe renal impairment and controls (∼8% lower area under the concentration-time curve [AUC], with a nearly identical peak concentration) and in subjects undergoing hemodialysis before and after tedizolid phosphate administration (∼9% lower AUC, with a 15% higher peak concentration); <10% of the dose was removed during 4 h of hemodialysis. Tedizolid pharmacokinetics was only minimally altered in subjects with moderate or severe hepatic impairment; the AUC was increased approximately 22% and 34%, respectively, compared with that of subjects in the control group. Tedizolid phosphate was generally well tolerated in all participants. These results suggest that tedizolid phosphate dose adjustments are not necessary in patients with any degree of renal or hepatic impairment. (This study has been registered at ClinicalTrials.gov under registration numbers NCT01452828 [renal study] and NCT01431833 [hepatic study].).

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Area Under Curve; Bacterial Infections; Cross-Over Studies; Female; Humans; Kidney; Kidney Failure, Chronic; Liver; Liver Diseases; Male; Middle Aged; Organophosphates; Oxazoles; Oxazolidinones; Prodrugs; Renal Dialysis; Tetrazoles; Young Adult

Topics: Anti-Bacterial Agents; Bacterial Infections; Female; Humans; Ideal Body Weight; Kidney Failure, Chronic; Male; Oxazolidinones; Renal Dialysis; Tetrazoles