In VitroAntibacterial Activity of Modithromycin, a Novel 6,11-Bridged Bicyclolide, against Respiratory Pathogens, Including Macrolide-Resistant Gram-Positive Cocci

Abstract

ABSTRACTThein vitroactivities of modithromycin against Gram-positive and -negative respiratory pathogens, including macrolide-resistant cocci with different resistance mechanisms, were compared with those of other macrolide and ketolide agents. MICs were determined by the broth microdilution method. All 595 test strains used in this study were isolated from Japanese medical facilities. Theerm(ribosome methylase) and/ormef(efflux pump) gene, which correlated with resistance to erythromycin as well as clarithromycin and azithromycin, was found in 81.8%, 21.3%, and 23.2% ofStreptococcus pneumoniae,Streptococcus pyogenes, and methicillin-susceptibleStaphylococcus aureus(MSSA) strains, respectively. Modithromycin showed MIC90s of 0.125 μg/ml against these three cocci, including macrolide-resistant strains. In particular, the MIC of modithromycin againstermB-carryingS. pyogeneswas ≥32-fold lower than that of telithromycin. The activities of modithromycin as well as telithromycin were little affected by the presence ofmefAormefEin both streptococci. Against Gram-negative pathogens, modithromycin showed MIC90s of 0.5, 8, and 0.031 μg/ml againstMoraxella catarrhalis,Haemophilus influenzae, andLegionellaspp., respectively. The MICs of modithromycin againstM. catarrhalisandH. influenzaewere higher than those of telithromycin and azithromycin. However, modithromycin showed the most potent anti-Legionellaactivity among the macrolide and ketolide agents tested. These results suggested that the bicyclolide agent modithromycin is a novel class of macrolides with improved antibacterial activity against Gram-positive cocci, including telithromycin-resistant streptococci and intracellular Gram-negative bacteria of theLegionellaspecies.