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Pharmacokinetic/pharmacodynamic factors influencing emergence of resistance to linezolid in an in vitro model.

Boak LM, Li J, Rayner CR, Nation RL

Facility for Anti-Infective Drug Development and Innovation, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.

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.

Published 26 March 2007 in Antimicrob Agents Chemother, 51(4): 1287-92.
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