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 10(5) cfu/mouse). Treatment was begun 18 h post infection, with clarithromycin or erythromycin 50 mg/kg subcutaneously (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 less than 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 less than 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.
Bédos
J P
JP
INSERM U.13-Hôpital Claude-Bernard, Paris, France.
Azoulay-Dupuis
E
E
Vallée
E
E
Veber
B
B
Pocidalo
J J
JJ
D000818:Animals; D017291:Clarithromycin / Q000031:analogs & derivatives; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D008168:Lung / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy* / Q000382:microbiology
C056228:14-hydroxyclarithromycin; D004917:Erythromycin; D017291:Clarithromycin