Interpretation of Antibiotic Concentration Ratios Measured in Epithelial Lining Fluid

In spite of the development and wide use of antibiotics, pneumonia is still the leading cause of infection-related mortality worldwide (101), and antibiotic resistance in the major pathogens of pneumonia has become more frequent during the past several decades. In order to defeat and prevent antibiotic resistance, antibiotics need to be used based on pharmacokinetics (PK) and pharmacodynamics (PD) (6, 10, 35). With regard to the PK/PD of antibiotics, considerable effort has been devoted to directly measure the concentrations of antibiotics at infection sites, because the distributions of antibiotics may be different among a variety of tissues. However, even beyond the fact that these measurements are carried out in normal tissues, the techniques used for the measurement are variable in accuracy and reproducibility and the interpretation of their results is hindered by many confounding factors (74, 75). For pulmonary infections, concentrations of antibiotics in epithelial lining fluid (ELF) for extracellular pathogens and in alveolar macrophage (AM) cells for intracellular pathogens are thought to reflect antibiotic activity in pneumonia. Antibiotics whose concentrations are high at these extravascular sites, such as macrolides and fluoroquinolones, tend to be promoted for treatment of pulmonary infection over antibiotics like betalactams and aminoglycosides, even though clinical trials do not show differences in clinical outcome or even bacteriological response. In fact, it is less clear why the ratios of ELF to plasma concentrations are diverse between antibiotics and even between members of the same antibiotic class. The measured ELF-to-plasma concentration ratios may differ based on physicochemical characteristics intrinsic to the molecules. And also, as the ELF concentration of antibiotics is commonly measured by bronchoalveolar lavage (BAL), technical factors or errors in the method of measurement may create these differences. It is believed that these factors need to be clarified before the concept of ELF concentration should be connected to antibiotic outcomes such as bacterial eradication or clinical response. In the current review, data from published human studies were extracted and analyzed to interpret ELF concentrations of antibiotics measured by BAL, considering possible confounding factors.