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Penetration of Antibacterials into Bone

Pharmacokinetic, Pharmacodynamic and Bioanalytical Considerations

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Abstract

Antibacterials play a key role in the treatment of bone infections and appropriate surgical prophylaxis. The rate and extent of penetration of antimicrobials into bone has been assessed and shown to be important for successful treatment in numerous studies. However, no recent review or critical evaluation of the analytical techniques is available. This review compares established and new sample preparation and analytical methods to measure bone concentrations.

We performed a systematic literature search in MEDLINE, EMBASE, conference abstracts and references from published articles on bone penetration of antibacterials. This article focuses on the standardization of drug analysis in bone, the extent and rate of bone penetration of antibacterials, and the design, evaluation and reporting techniques of pharmacokinetic studies of bone penetration. The focus is on studies conducted between 1998 and 2007, since a previous review was published in 1999. WinNonlin® Professional version 5.0.1 software was used for statistics.

Very different methods for sample preparation, drug analysis, data handling and reporting have been employed in bone penetration studies. There is substantial variability in the reported mean bone penetration between drugs and between different studies of the same drug. Quinolones, macrolides and linezolid have mean bone:serum concentration ratios that are commonly between 0.3 and 1.2, and higher ratios have been found for azithromycin (bone concentration in mg/kg of total bone). The ratios are usually between 0.15 and 0.3 for cephalosporins and glycopeptides, and between 0.1 and 0.3 for penicillins. Cephalosporins and penicillins have shown significantly lower (p<0.05) concentration ratios than linezolid. For 20 of 25 different drugs, the ratios were higher for cancellous bone than for cortical bone.

The available data show a larger extent of bone penetration for quinolones, macrolides and linezolid than for β-lactams. The bone penetration of penicillins and cephalosporins was significantly lower than that of linezolid. Guidelines on sample preparation, drug analysis, study design and pharmacokinetic evaluation of bone penetration studies are vitally needed.

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Acknowledgements

Drs Cornelia Landersdorfer and Jürgen Bulitta now work at the Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA.

No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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  1. IBMP — Institute for Biomedical and Pharmaceutical Research, Paul-Ehrlich-Str. 19, D-90562, Nürnberg-Heroldsberg, Germany

    Cornelia B. Landersdorfer, Jürgen B. Bulitta, Martina Kinzig &  Fritz Sörgel

  2. Institute of Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Germany

    Ulrike Holzgrabe

  3. Department of Pharmacology, University of Duisburg-Essen, Essen, Germany

    Fritz Sörgel

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  1. Cornelia B. Landersdorfer
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Landersdorfer, C.B., Bulitta, J.B., Kinzig, M. et al. Penetration of Antibacterials into Bone. Clin Pharmacokinet 48, 89–124 (2009). https://doi.org/10.2165/00003088-200948020-00002

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