Prophylactic and therapeutic activities of azithromycin in a mouse model of pneumococcal pneumonia.
Azithromycin is a new acid-stable 15-membered-ring macrolide that exhibits an extended half-life and excellent tissue distribution, including distribution in the lung. We compared its in vivo activity with that of erythromycin using two models of Streptococcus pneumoniae pneumonia, namely, a model of acute infection in Swiss mice and a model of subacute infection in C57BL/6j mice. Female mice were infected by oral delivery into the trachea of 10(5) CFU of a virulent serotype 3 strain of S. pneumoniae (P 4241). Prophylactic and therapeutic treatments were given orally (p.o.) or subcutaneously (s.c.) by various regimens. In the model of subacute infection, a single dose of azithromycin, 25 mg/kg, given p.o. 7 h before infection protected 92% of the mice, while erythromycin was completely ineffective. In the model of acute infection, a single dose of azithromycin, 50 mg/kg, given s.c. 24 h prior to challenge protected 80% of the mice, whereas only 35% of the mice survived with erythromycin, 50 mg/kg, 1 h before challenge. Therapy, which was studied exclusively in the model of subacute infection, was initiated 48 h postinfection. Two doses of 12.5 mg/kg given p.o. 12 h apart resulted in 80% survival of mice treated with azithromycin versus 7% survival of mice treated with erythromycin. Pulmonary clearance of bacteria was consistent with the survival rates. Two doses (25 mg/kg) of azithromycin given s.c. at 48 and 65 h after infection led to complete clearance of bacteria from the lungs and blood, whereas erythromycin-treated mice remained bacteremic. The pharmacokinetics of azithromycin account for its superior efficacy against S. pneumoniae pneumonia relative to the efficacy of erythromycin.
Azoulay-Dupuis
E
E
Hôpital Claude Bernard, Institut National de la Santé et de la Recherche Médicale U.13, Paris, France.
Vallée
E
E
Bedos
J P
JP
Muffat-Joly
M
M
Pocidalo
J J
JJ
D000818:Animals; D017963:Azithromycin; D001769:Blood / Q000382:microbiology; D004353:Drug Evaluation, Preclinical; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D008168:Lung / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control
D004917:Erythromycin; D017963:Azithromycin