The Clinical Relevance of Protein Binding and Tissue Concentrations in Antimicrobial Therapy

The relevance of protein binding, molecular size and lipophilicity to tissue penetration of antimicrobials is discussed, and the clinical relevance of tissue penetration of these agents is assessed. In order to assess the relevance of any factor on the clinical outcome of a group of infections it is necessary to obtain some form of dose response; i.e. the dose has to be (intentionally or otherwise) titrated down until negative responses are seen. Information on clinical failures tends not to be reported, hence useful data are difficult to obtain. The relevance of protein binding to the microbiological activity of a drug is important and the use of some highly bound agents in readily assessable diseases is illustrated with a few examples: the poor efficacy of fusidic acid in gonorrhoea, when high failure rates are found with doses of 2g; ceftriaxone in gonorrhoea, at doses (25mg) with which one would expect cures, is associated with significant failures; the failure of cefoperazone in serious illness can be related to the degree of protein binding. The degree of tissue penetration (protein binding apart) is related to clinical efficacy in urinary tract infections (where ample evidence is available), chest infections (where the data are somewhat fewer but probably convincing) and meningitis where experimental data are firm but clinical information less readily available.