title: Efficacy of cethromycin, a new ketolide, against Streptococcus pneumoniae susceptible or resistant to erythromycin in a murine pneumonia model.
abstract: Cethromycin is a ketolide with in vitro activity against macrolide-sensitive and -resistant strains of Streptococcus pneumoniae. We compared its in vivo efficacy to erythromycin in a mouse model of acute pneumonia induced by two virulent clinical strains: a serotype 3 susceptible strain (P-4241) (MICs: erythromycin, 0.03 microg/ml; cethromycin, 0.015 microg/ml) and a serotype 1 strain resistant to erythromycin (P-6254; phenotypically MLSB constitutive) (MICs: erythromycin, 1,024 microg/ml; cethromycin, 0.03 microg/ml). Immunocompetent mice were infected with 10(5) CFU of each strain. Six treatments given either subcutaneously (s.c.) or per os (p.o.) at 12-h intervals were initiated at 6 or 12 h after infection. Against P-4241, cethromycin given s.c. at 25 or 12.5 mg/kg protected 100% of the animals, with lungs and blood completely cleared of bacteria. Given p.o., cethromycin maintained its efficacy with 100 and 86% survival at 25 and 12.5 mg/kg, respectively. Erythromycin, given s.c. at 50 or 37.5 mg/kg, provided 50 and 38% survival rates, respectively. Against P-6254, cethromycin was effective at 25 mg/kg (100% survival) regardless of the administration route, whereas only 25 and 8% of animals survived after a 75-mg/kg erythromycin treatment given s.c. and p.o., respectively. The serum protein binding levels of cethromycin were 94.8 and 88.5% after doses of 12.5 and 25 mg/kg, respectively. The higher in vivo activity of cethromycin compared to erythromycin could be explained by favorable pharmacokinetic/pharmacodynamic indexes against P-6254 but not against P-4241.
authors.affiliation: EA 3964, Faculté de Médecine de l'Université Paris VII, France. eazoulay@bichat.inserm.fr
authors.forename: E
authors.initials: E
authors.lastname: Azoulay-Dupuis
authors.forename: J
authors.initials: J
authors.lastname: Mohler
authors.forename: J P
authors.initials: JP
authors.lastname: Bédos
authors.forename: C
authors.initials: C
authors.lastname: Barau
authors.forename: B
authors.initials: B
authors.lastname: Fantin
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D004917:Erythromycin / Q000493:pharmacokinetics / Q000494:pharmacology*; D048628:Ketolides / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000302:isolation & purification*
chemical_list: D000900:Anti-Bacterial Agents; D048628:Ketolides; D004917:Erythromycin; C405499:cethromycin