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Significance of tissue levels for prediction of antibiotic efficacy and determination of dosage

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Abstract

Determination of tissue levels is widely thought to provide useful information in the investigation of a new antibiotic, however this assumption is not fully justified. In this paper the following questions are covered. Firstly, the methodological problems encountered in the measurement of antibiotic levels in solid tissues and extravascular fluids are described. Secondly, the difficulties encountered in interpreting tissue concentrations are discussed, given the heterogeneity of distribution of drugs, potential intracellular penetration, binding to tissue proteins and local factors reducing antibacterial activity. Thirdly, the respective importance of animal and human data on tissue levels for prediction of efficacy is analysed. In some animal models it is possible to study the conditions affecting antibacterial activity and to obtain data relevant to the clinical situation. However, the inoculum effect, the metabolism of bacteria, the mechanism of the bactericidal action of drugs and the type of infected tissue are important factors to be taken into account. In humans, data obtained from infected tissue is sparse and contributes little to knowledge. Knowledge of tissue levels may be important for establishing whether data obtained in animals can be applied to humans or not. Fourthly, the importance of tissue levels in determining antibiotic dosages is evaluated. In humans, tissue levels are of limited value in the determination of unitary dose and dosage intervals in relation to the clinical response. Through serum levels of free drug, half-life at the β-phase and rate of in vitro killing are the most important parameters to be considered. Their relative importance depends mainly on the mode of action of the drug. Animal models may be useful for studying this question and the influence of the mode of administration of the drug on tissue levels.

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  1. Médecine Interne, Hôpital Bichat-Claude Bernard, 46 Rue Henri Huchard, and ISERM U13, 75877, Paris 18, France

    C. Carbon

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Carbon, C. Significance of tissue levels for prediction of antibiotic efficacy and determination of dosage. Eur. J. Clin. Microbiol. Infect. Dis. 9, 510–516 (1990). https://doi.org/10.1007/BF01964293

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