Abstract
Current antimicrobial dosing regimens are designed to maintain active drug levels for most of the dosing interval and are based on 40-y-old observations. With use of numerous multiple-dosing regimens in an animal model, this study is the first to successfully minimize the interdependence between pharmacokinetic parameters and thereby determine, by stepwise multivariate regression analysis, that the time that serum levels exceeded the minimum inhibitory concentration (MIC) was the most significant parameter determining efficacy for beta-lactams and erythromycin against various pathogens, whereas the log area under the curve was the major parameter for aminoglycosides. Optimal dosing intervals were no greater than the time that serum levels exceeded the MIC plus the duration of the postantibiotic effect. Careful application of these concepts should allow other investigators to use more optimally dosed regimens than those previously used in preclinical trials and to design studies to improve on current dosing regimens for humans.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Anti-Bacterial Agents / administration & dosage
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Anti-Bacterial Agents / pharmacokinetics*
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Anti-Bacterial Agents / therapeutic use
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Bacterial Infections / drug therapy*
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Cefazolin / administration & dosage
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Cefazolin / pharmacokinetics
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Cefazolin / therapeutic use
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Erythromycin / administration & dosage
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Erythromycin / pharmacokinetics
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Erythromycin / therapeutic use
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Escherichia coli / drug effects
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Female
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Gentamicins / administration & dosage
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Gentamicins / pharmacokinetics
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Gentamicins / therapeutic use
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Mice
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Mice, Inbred ICR
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Penicillins / administration & dosage
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Penicillins / pharmacokinetics
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Penicillins / therapeutic use
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Pseudomonas aeruginosa / drug effects
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Regression Analysis
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Staphylococcus aureus / drug effects
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Streptococcus pneumoniae / drug effects
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Ticarcillin / administration & dosage
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Ticarcillin / pharmacokinetics
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Ticarcillin / therapeutic use
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Tobramycin / administration & dosage
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Tobramycin / pharmacokinetics
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Tobramycin / therapeutic use
Substances
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Anti-Bacterial Agents
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Gentamicins
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Penicillins
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Erythromycin
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Ticarcillin
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Cefazolin
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Tobramycin