In vitro activity and pharmacodynamics of azithromycin and clarithromycin against Streptococcus pneumoniae based on serum and intrapulmonary pharmacokinetics

Background: Multidrug-resistant strains of Streptococcus pneumoniae are inc reasingly common worldwide, but the clinical significance of their resistan ce to the macrolide antibiotics is controversial. Applying pharmacokinetic and pharmacodynamic principles can assist in the selection of appropriate a ntimicrobial therapy. Objectives: The purpose of this study was to determine the in vitro activit y of penicillin, azithromycin, clarithromycin, and clindamycin against clin ical isolates of S pneumoniae and to evaluate the pharmacodynamics of azith romycin and clarithromycin based on serum and epithelial lining fluid (ELF) concentrations. Methods: The minimum inhibitory concentrations (MICs) of penicillin, azithr omycin, clarithromycin, and clindamycin were determined for 307 isolates of S pneumoniae using broth microdilution. Using serum and ELF concentrations after standard dosing, we calculated the proportion of isolates against wh ich it would be possible to obtain a ratio of azithromycin area under the c urve to MIC greater than or equal to 25 and clarithromycin concentrations t hat exceeded the MIC for greater than or equal to 40% of the dosing interva l. Results: Overall, 19.5%, 25.4%, 25.1%, and 7.2% of the 307 pneumococcal iso lates were resistant to penicillin, azithromycin, clarithromycin, and clind amycin, respectively. However, 71.7% of penicillin-resistant strains were a lso resistant to azithromycin and clarithromycin. Based on serum concentrat ions, clarithromycin achieved its pharmacodynamic target in 76.9% of isolat es, compared with 59.9% for azithromycin. Based on ELF concentrations, clar ithromycin achieved its pharmacodynamic target in 93.5% of isolates, compar ed with 74.6% for azithromycin. Based on ELF concentrations, clarithromycin achieved its pharmacodynamic target in 86.7% of penicillin-resistant isola tes, compared with 28.3% for azithromycin. Conclusions: On the basis of serum and ELF concentrations, clarithromycin a chieved pharmacodynamic targets against a greater proportion of S pneumonia e isolates than did azithromycin. Clinical studies are needed to determine the efficacy of these agents against pneumococci that demonstrate in vitro resistance using current susceptibility breakpoints.