Delivering antibacterials to the lungs: considerations for optimizing outcomes.

Abstract

An important determinant of clinical outcome of a lower respiratory tract infection may be sterilization of the infected lung, which is also dependent on sustained antibacterial concentrations achieved in the lung. For this reason, recently there has been increased interest in measuring the concentration of antimicrobial agents at different potential sites of infection in the lung. Levels of antibacterials are now measured in bronchial mucosa, epithelial lining fluid (ELF) and alveolar macrophages, as well as in sputum. Penicillins and cephalosporins reach only marginal concentrations in bronchial secretions, whereas fluoroquinolones and macrolides have been shown to achieve high concentrations. The extent of penetration of different antibacterials into the bronchial mucosa is relatively high. This is also true for beta-lactams, although their tissue concentrations never reach blood concentrations. Antibacterials penetrate less into the ELF than into the bronchial mucosa, but fluoroquinolones appear to concentrate more into alveolar lavage than into bronchial mucosa. Pulmonary pharmacokinetics is a very useful tool for describing how drugs behave in the human lung, but it does not promote an understanding of the pharmacological effects of a drug. More important, instead, is the correlation between pulmonary disposition of the drug and its minimum inhibitory concentration (MIC) values for the infectious agent. The addition of bacteriological characteristics to in vivo pharmacokinetic studies has triggered a 'pharmacodynamic approach'. Pharmacodynamic parameters integrate the microbiological activity and pharmacokinetics of an anti-infective drug by focusing on its biological effects, particularly growth inhibition and killing of pathogens. Drugs that penetrate well and remain for long periods at the pulmonary site of infection often induce therapeutic responses greater than expected on the basis of in vitro data. However, although the determination of antibacterial concentrations at the site of infection in the lung has been suggested to be important in predicting the therapeutic efficacy of antimicrobial treatment during bacterial infections of the lower respiratory tract, some studies have demonstrated that pulmonary bacterial clearance is correlated more closely to concentrations in the serum than to those in the lung homogenates, probably because they better reflect antibacterial concentration in the interstitial fluid.