INDIVIDUAL EFFICACY OF CLARITHROMYCIN-(A-56268) AND ITS MAJOR HUMAN METABOLITE 14-HYDROXY CLARITHROMYCIN-(A-62671) IN EXPERIMENTAL PNEUMOCOCCAL PNEUMONIA IN THE MOUSE

In man, clarithromycin (A-56268) is metabolized to a 14-hydroxy derivative (14-OH clarithromycin, A-62671); this metabolite is absent in mice. An experimental mouse model was used to compare the efficacy of clarithromycin versus 14-OH clarithromycin in pneumococcal pneumonia by treatment with either the parent drug or its 14-OH metabolite alone. Four groups of 15 mice were infected intra-tracheally with a virulent strain of Streptococcus pneumoniae serotype 3 (approximately 105 cfu/mouse). Treatment was begun 18 h post infection, with clarithromycin or erythromycin 50 mg/kg βubcutaneously (sc) bd, 14-OH clarithromycin 25 mg/kg sc bd or antibiotic free saline sc bd for 24 or 48 h. Survival rates ten days after one day of treatment with clarithromycin, 14-OH clarithromycin, erythromycin, or saline were 53%, 60%, 27% and 0% respectively. After two days treatment the rates were 100%, 100%, 53% (P < 0·01) and 0% respectively. Thirty-six h after two doses, 14-OH clarithromycin demonstrated superior intra-pulmonary killing activity to erythromycin (2·7±0·4 vs 6·6±0·8 log10 cfu/mL lung homogenate) (P < 0·001) and comparable activity to clarithromycin (3·6 ±1·3 log10 cfu/mL). These results show that clarithromycin (50 mg/kg sc) and 14-OH clarithromycin (25 mg/kg sc) have similar in vivo efficacy in a mouse model, in which the 14-OH metabolite is not produced from clarithromycin. This suggests that in man, the clinical efficacy of clarithromycin is not impaired by metabolism to 14-OH clarithromycin, which achieves serum concentrations in man of approximately 1 mg/L after multiple doses of clarithromycin 500 mg po. © 1992 by The British Society for Antimicrobial Chemotherapy.