Pharmacokinetics of antibiotics in tissues and tissue fluids: a review

The majority of bacterial infections occur outside the vascular compartment and, thus, considerable interest has been devoted to studies of antibiotic concentrations in different tissues. This review deals with the pharmacokinetics of antibiotics in tissues where the drug is distributed by passive diffusion. It is not always recognized that tissue levels of antibiotics represent the means of different concentrations in the major tissue compartments: interstitial fluid, cells and blood capillaries. Non-lipophilic drugs, such as beta-lactam antibiotics, which do not penetrate cells, are confined to the extracellular fluid volume, which constitutes approximately 20% of the tissue. Consequently, whole tissue levels are low. Conversely, drugs that penetrate and accumulate in cells may well yield tissue levels exceeding the serum levels. Since most bacterial infections start and progress in the interstitial fluid, whole tissue levels are therapeutically meaningless, but are nevertheless often compared to the MICs of bacteria. For protein-bound drugs, the lower albumin concentrations in extracellular fluids is another important factor that may lead to erroneous conclusions regarding the ability of an antibiotic to distribute into tissues. Different models have been developed to study antibiotic levels in the interstitial fluid. The geometry of the tissue fluid compartment (ratio of surface area to volume: SA/V) has been recognized as one of the most important determinants of antibiotic pharmacokinetics in these models. In healthy tissues (high SA/V) similar concentrations are found in serum and tissue fluid. Although limited information is available regarding antibiotic pharmacokinetics in infected tissues, it seems that in acute bacterial infections, the most relevant concentrations to relate to pharmacodynamic parameters are the unbound levels of the drug in serum.