Intracellular Pharmacokinetics of Antibacterials and Their Clinical Implications

The intracellular pharmacokinetics of the different classes of antimicrobials into surrogate markers of tissue accumulation (alveolar macrophages and/or total alveolar cells collected by means of bronchoalveolar lavage or peripheral white blood cells) was reviewed. The aim of this review was to discuss the clinical implications of the intracellular pharmacokinetics of antibacterials, either from the therapeutic or toxicological perspective. The different pharmacokinetic behaviour of antimicrobials within cells is mainly related to their physicochemical properties (hydrophilicity and lipophilicity), and may have several clinical implications. Therapeutic efficacy against intracellular pathogens has been correlated mainly with the intracellular concentrations achieved by the different antimicrobial agents. This is relevant especially for macrolides, tetracyclines, fluoroquinolones and rifampicin in the treatment of bacterial infections such as Legionella pneumophila pneumonia, Mycoplasma pneumoniae pneumonia, non-gonococcal urethritis and chronic staphylococcal infections. Additionally, intracellular accumulation of antibacterials was correlated with the possibility of causing organ-specific toxicity, as in the case of aminoglycosides in regard to the risk of nephrotoxicity. Finally, it should be kept in mind that intracellular accumulation may also represent a drug reservoir in the case of lipophilic antimicrobials. This may become extremely relevant from the clinical standpoint when treating critically ill patients with sepsis with antibacterials. The pathophysiology of sepsis may explain why it is necessary to start therapy with an increased loading dose of hydrophilic antimicrobials to promptly achieve therapeutically effective concentrations.