Pharmacokinetic/Pharmacodynamic Factors Influencing Emergence of Resistance to Linezolid in an In Vitro Model
- 1 April 2007
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 51 (4), 1287-1292
- https://doi.org/10.1128/aac.01194-06
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-log 10 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.This publication has 28 references indexed in Scilit:
- LINEZOLID-RESISTANT STAPHYLOCOCCUS AUREUS IN TWO PEDIATRIC PATIENTS RECEIVING LOW-DOSE LINEZOLID THERAPYThe Pediatric Infectious Disease Journal, 2006
- BactericidalActivities of Daptomycin, Quinupristin-Dalfopristin, and Linezolidagainst Vancomycin-ResistantStaphylococcus aureusinan In Vitro Pharmacodynamic Model with SimulatedEndocardialVegetationsAntimicrobial Agents and Chemotherapy, 2003
- Linezolid and Vancomycin, Alone and in Combination with Rifampin, Compared with Moxifloxacin against a Multidrug-Resistant and a Vancomycin-Tolerant Streptococcus pneumoniae Strain in an In Vitro Pharmacodynamic ModelAntimicrobial Agents and Chemotherapy, 2003
- Pharmacokinetics and tolerance of single- and multiple-dose oral or intravenous linezolid, an oxazolidinone antibiotic, in healthy volunteersJournal of Antimicrobial Chemotherapy, 2003
- Clinical Pharmacodynamics of Linezolid in Seriously Ill Patients Treated in a Compassionate Use ProgrammeClinical Pharmacokinetics, 2003
- Comparison of Linezolid Activities under Aerobic and Anaerobic Conditions against Methicillin-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococcus faeciumAntimicrobial Agents and Chemotherapy, 2003
- Gene Dosage and Linezolid Resistance in Enterococcus faecium and Enterococcus faecalisAntimicrobial Agents and Chemotherapy, 2002
- In Vitro Activities of Quinupristin-Dalfopristin and Cefepime, Alone and in Combination with Various Antimicrobials, against Multidrug-Resistant Staphylococci and Enterococci in an In Vitro Pharmacodynamic ModelAntimicrobial Agents and Chemotherapy, 2002
- Susceptibility testing with linezolid by different methods, in relation to published 'general breakpoints': J Antimicrob Chemother 2001; 48: 452-454Journal of Antimicrobial Chemotherapy, 2001
- Efficacy of Linezolid in Treatment of Experimental Endocarditis Caused by Methicillin-Resistant Staphylococcus aureusAntimicrobial Agents and Chemotherapy, 2001