title: Pharmacokinetic/pharmacodynamic factors influencing emergence of resistance to linezolid in an in vitro model.
abstract: Emerging resistance threatens the usefulness of linezolid for the treatment of severe infections caused by multidrug-resistant gram-positive bacteria. Optimal pharmacokinetic (PK)/pharmacodynamic (PD) indices have been described for the antimicrobial efficacy of linezolid (area under the concentration-time curve over 24 h at steady state divided by the MIC, >100; the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state PK conditions, >85). The aim of this study was to investigate the influence of these PK/PD indices on the development of resistance to linezolid by using an in vitro PK/PD model. Four dosage regimens were simulated over 72 h (two intermittent bolus regimens of 600 mg every 12 h [q12h] and 120 mg q12h and two continuous-infusion regimens of 120 mg/24 h and 30 mg/24 h) against four reference strains: methicillin-resistant Staphylococcus aureus (MRSA), heteroresistant vancomycin-intermediate S. aureus (hVISA), vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant Enterococcus faecium (VRE). Linezolid concentrations were measured by high-performance liquid chromatography. Changes in susceptibility were characterized by pre- and posttreatment MIC measurements and population analysis profiles (PAPs). The linezolid concentrations that were achieved closely matched those that were targeted. The simulation with 600 mg q12h provided a >3-log10 reduction in the number of CFU/ml for all four strains, as did the 120-mg-q12h regimen for hVISA and VISA and the 30-mg/24-h continuous infusion for VRE and VISA. After 72 h of exposure to the 120-mg/24-h continuous-infusion simulation, the area under the PAP curve for all strains increased substantially (40 to 178%); increases in the MICs for the MRSA and hVISA strains were observed. The results demonstrate that PK/PD considerations are important in optimizing both antibacterial activity and the development of resistance to linezolid. The potential for resistance development appears to be higher when a constant concentration is maintained in the vicinity of the MIC of the bacteria.
authors.affiliation: Facility for Anti-Infective Drug Development and Innovation, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Boak
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Craig R
authors.initials: CR
authors.lastname: Rayner
authors.forename: Roger L
authors.initials: RL
authors.lastname: Nation
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D024901:Drug Resistance, Multiple, Bacterial; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000378:metabolism; D000069349:Linezolid; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D023303:Oxazolidinones / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D000081:Acetamides; D023303:Oxazolidinones; D000069349:Linezolid