PMID- 17242144
OWN - NLM
STAT- MEDLINE
DCOM- 20070801
LR  - 20181113
IS  - 0066-4804 (Print)
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Linking)
VI  - 51
IP  - 4
DP  - 2007 Apr
TI  - Pharmacokinetic/pharmacodynamic factors influencing emergence of resistance to 
      linezolid in an in vitro model.
PG  - 1287-92
AB  - 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.
FAU - Boak, Lauren M
AU  - Boak LM
AD  - Facility for Anti-Infective Drug Development and Innovation, Victorian College of 
      Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria 3052, 
      Australia.
FAU - Li, Jian
AU  - Li J
FAU - Rayner, Craig R
AU  - Rayner CR
FAU - Nation, Roger L
AU  - Nation RL
LA  - eng
PT  - Journal Article
DEP - 20070122
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Acetamides)
RN  - 0 (Oxazolidinones)
RN  - ISQ9I6J12J (Linezolid)
SB  - IM
MH  - Acetamides/*pharmacokinetics/*pharmacology
MH  - Area Under Curve
MH  - Dose-Response Relationship, Drug
MH  - *Drug Resistance, Multiple, Bacterial
MH  - Gram-Positive Bacteria/*drug effects/metabolism
MH  - Linezolid
MH  - Microbial Sensitivity Tests
MH  - Models, Biological
MH  - Oxazolidinones/*pharmacokinetics/*pharmacology
PMC - PMC1855482
EDAT- 2007/01/24 09:00
MHDA- 2007/08/02 09:00
PMCR- 2007/08/01
CRDT- 2007/01/24 09:00
PHST- 2007/01/24 09:00 [pubmed]
PHST- 2007/08/02 09:00 [medline]
PHST- 2007/01/24 09:00 [entrez]
PHST- 2007/08/01 00:00 [pmc-release]
AID - AAC.01194-06 [pii]
AID - 1194-06 [pii]
AID - 10.1128/AAC.01194-06 [doi]
PST - ppublish
SO  - Antimicrob Agents Chemother. 2007 Apr;51(4):1287-92. doi: 10.1128/AAC.01194-06. 
      Epub 2007 Jan 22.