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Pharmacokinetics and penetration of linezolid into inflamed soft tissue in diabetic foot infections

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

Physiological changes and local and systemic inflammation may affect plasma and tissue pharmacokinetics of antimicrobial agents in diabetics. The aim of the study was to investigate the penetration of linezolid into inflamed areas of infected diabetic foot wounds and the pharmacokinetics in the risk population of diabetics.

Methods

Pharmacokinetics and tissue penetration of linezolid into inflamed diabetic foot infection (DFI) tissue were determined at steady state in 15 patients with diabetes type 2 and DFI following administration of multiple oral doses of 600 mg given every 12 h. Second debridement was performed on days 4–6, 3 h after linezolid administration. Linezolid concentrations were determined in perinecrotic wound tissue of inflamed diabetic foot by high-performance liquid chromatography (HPLC).

Results

A mean maximum plasma concentration (Cmax) in plasma of 14.3 mg/L was attained at a median of 2.0 h [time to reach Cmax (Tmax) range 0.5–6.0 h). Area under the concentration time curve from zero to 12 h (AUC0–12 h) with a mean of 114.1 mg∙h/L and Cmin of 5.4 mg/L were achieved in patients with diabetes mellitus type 2. Penetration of linezolid into inflamed areas of DFI with tissue/plasma ratios of mean 101.7% [95% confidence interval (CI) 56; 148%] produced a mean concentration of 9.6 μg/g (95% CI 7.4; 11.8 μg/g) greater than those predicted to be effective against methicillin-resistant staphylococci [minimum concentration that inhibits 90% of organisms (MIC90) of 4 mg/L]. Tissue/plasma ratios correlated positive with systemic inflammation.

Conclusion

Plasma pharmacokinetics of linezolid in diabetics and adequate levels in inflamed areas of diabetic foot wound suggest that an oral dose of 600 mg bd of linezolid provides effective concentrations for treating methicillin-resistant Staphylococcus aureus (MRSA) in DFI.

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Abbreviations

BMI:

Body mass index

Cmax :

Maximum plasma concentration

Cmin :

Minimum plasma concentration

DFI:

Diabetic foot infection

DFS:

Diabetic foot syndrome

ECG:

12-lead electrocardiogram

EDTA:

Ethylenediamine tetraacetic acid

EOT visit:

End-of-treatment visit

MIC:

Minimum inhibitory concentration

MIC90 :

Minimum concentration that inhibits 90% of organisms

MRSA:

Methicillin-resistant Staphylococcus aureus

PK/PD:

Pharmacokinetic/pharmacodynamic

PO:

Per os

r:

Coefficient of correlation

t 1/2:

Terminal half life

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Acknowledgements

We thank Mrs. K. Kroesche for her skilful analytical assistance and Mrs. A. Bruss for data management. This work was supported in part by a research grant from Pharmacia, Erlangen, Germany.

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Authors and Affiliations

  1. Center of Pharmacology and Toxicology, Institute of Clinical Pharmacology, University of Rostock, Schillingallee 70, 18057, Rostock, Germany

    J. Majcher-Peszynska, G. Haase, R. Mundkowski & B. Drewelow

  2. Department of Surgery, University of Rostock, Rostock, Germany

    M. Saß, A. Pietsch & W. Schareck

  3. Department of Internal Medicine, University of Rostock, Rostock, Germany

    S. Klammt

  4. Institute of Clinical Pharmacology, University of Rostock, Schillingallee 70, 18057, Rostock, Germany

    J. Majcher-Peszynska

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  1. J. Majcher-Peszynska
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Correspondence to J. Majcher-Peszynska.

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Majcher-Peszynska, J., Haase, G., Saß, M. et al. Pharmacokinetics and penetration of linezolid into inflamed soft tissue in diabetic foot infections. Eur J Clin Pharmacol 64, 1093–1100 (2008). https://doi.org/10.1007/s00228-008-0531-5

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  • DOI: https://doi.org/10.1007/s00228-008-0531-5

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