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Antimicrobial Agents and Chemotherapy, April 2007, p. 1287-1292, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.01194-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Pharmacokinetic/Pharmacodynamic Factors Influencing Emergence of Resistance to Linezolid in an In Vitro Model{triangledown}

Lauren M. Boak, Jian Li, Craig R. Rayner,{dagger} and Roger L. Nation*

Facility for Anti-Infective Drug Development and Innovation, Victorian College of Pharmacy, Monash University, Parkville, Victoria, Australia

Received 22 September 2006/ Returned for modification 27 November 2006/ Accepted 8 January 2007

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.

* Corresponding author. Mailing address: Facility for Anti-Infective Drug Development and Innovation, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia. Phone: 61 3 9903 9061. Fax: 61 3 9903 9629. E-mail: Roger.Nation{at}vcp.monash.edu.au

{triangledown} Published ahead of print on 22 January 2007.

{dagger} Present address: Roche Products Limited, Shire Park, Welwyn Garden City, England.

Antimicrobial Agents and Chemotherapy, April 2007, p. 1287-1292, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.01194-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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