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Pharmacokinetic/Pharmacodynamic Modelling of AntibacterialsIn VitroandIn VivoUsing Bacterial Growth and Kill KineticsThe Minimum Inhibitory Concentration versus Stationary Concentration

 

作者: Johan W Mouton,   Alexander A Vinks,  

 

期刊: Clinical Pharmacokinetics  (ADIS Available online 2005)
卷期: Volume 44, issue 2  

页码: 201-210

 

ISSN:0312-5963

 

年代: 2005

 

出版商: ADIS

 

关键词: Antibacterials, pharmacokinetics;Ceftazidime, pharmacokinetics;Meropenem, pharmacokinetics;Tobramycin, pharmacokinetics;Pharmacokinetic pharmacodynamic relationships;Pharmacokinetic modelling;Pharmacodynamic modelling

 

数据来源: ADIS

 

摘要:

BackgroundThe minimum inhibitory concentration (MIC) is thein vitroreference value to describe the activity of an antibacterial against micro-organisms. It does not represent the dynamic effect of the antimicrobial at any point in time, but rather the total antimicrobial effect over the incubation period at a fixed concentration.ObjectiveTo explore the concentration-effect relationship of antimicrobial concentrations against micro-organisms in relation to the MIC.MethodsTime-kill curves were generated for ceftazidime, meropenem and tobramycin againstPseudomonas aeruginosa. The Hill equation with variable slope was fit to the time-kill data, and mathematical models of growth and kill were explored with reference to the MIC.ResultsWith declining concentrations, bacterial killing will decrease until a specific threshold concentration is reached. This concentration, at which bacteria are neither killed nor able to grow, is named the stationary concentration (SC) and is not equal to the MIC. Pharmacokinetic/pharmacodynamic simulations over a range of kill rates, growth rates and slope factors showed that for β-lactam antibacterials, the SC is close to the MIC value, which may explain why concentrationsin vivoneed to be above the MIC, while regrowth of bacteria occurs when concentrations decline below the MIC. For concentration-dependent antibacterials, such as aminoglycosides and quinolones, the SC is shown to be markedly different from the MIC and, in general, is much lower.ConclusionThe MIC is not a good pharmacodynamic parameter to characterise the concentration effect relationship of a given antimicrobial. For ‘concentration independent’ antimicrobials the SC is likely to be close to the MIC, but may be much lower for ‘concentration dependent’ antimicrobials, and may explain subMIC effects.

 

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