Relationship of high tissue concentrations of azithromycin to bactericidal activity and efficacy in vivo

Measurement of killing kinetics of azithromycin against strains of Streptococcus pneumoniae and Klebsiella pneumoniae in vitro showed that it had a limited bacteri-cidal activity (> 90 % kill) for the first eight hours of incubation, but developed complete bactericidal activity (> 99-9 % kill) by 24 h incubation. Since high and sustained tissue levels of azithromycin occur in animals and humans, it was proposed that it might produce a bactericidal effect in vivo. This was demonstrated in a lung infection model in mice, designed to mimic the in-vitro killing studies. A 25 mg/kg dose of azithromycin given 24 h before intranasal challenge reduced the recoverable Str. pneumoniae population by> 99-9%, in comparison with untreated controls. Erythromycin did not produce a bactericidal effect at 100 mg/kg, and roxithromycin only reduced the viable count by 96%, at a dose of 50 mg/kg. Against a K. pneumoniae lung infection, a 50 mg/kg dose of azithromycin reduced the bacterial count by 99%. The bactericidal effect was correlated with lung tissue concentrations of azithromycin. In a proliferating Escherichia coli paper disc infec-tion model, extravascular fluid concentrations of azithromycin were correlated with a 99-9 % reduction in bacterial count, while corresponding serum concentrations were always less than the MIC. Dosing with azithromycin eradicated Haemophilia inftuenzae from the bulk (middle ear) of gerbils, as was not the case with erythrc-mycin and roxithromycin. This effect was correlated with the antibiotic concentra-tion in bulla lavage