title: In vitro antibacterial activity of modithromycin, a novel 6,11-bridged bicyclolide, against respiratory pathogens, including macrolide-resistant Gram-positive cocci.
abstract: The in vitro activities 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. The erm (ribosome methylase) and/or mef (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% of Streptococcus pneumoniae, Streptococcus pyogenes, and methicillin-susceptible Staphylococcus aureus (MSSA) strains, respectively. Modithromycin showed MIC(90)s of 0.125 μg/ml against these three cocci, including macrolide-resistant strains. In particular, the MIC of modithromycin against ermB-carrying S. pyogenes was ≥ 32-fold lower than that of telithromycin. The activities of modithromycin as well as telithromycin were little affected by the presence of mefA or mefE in both streptococci. Against Gram-negative pathogens, modithromycin showed MIC(90)s of 0.5, 8, and 0.031 μg/ml against Moraxella catarrhalis, Haemophilus influenzae, and Legionella spp., respectively. The MICs of modithromycin against M. catarrhalis and H. influenzae were higher than those of telithromycin and azithromycin. However, modithromycin showed the most potent anti-Legionella activity 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 the Legionella species.
authors.affiliation: Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Ota-ku, Tokyo 143-8540, Japan. takafumi.satou@shionogi.co.jp
authors.forename: Takafumi
authors.initials: T
authors.lastname: Sato
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tateda
authors.forename: Soichiro
authors.initials: S
authors.lastname: Kimura
authors.forename: Morihiro
authors.initials: M
authors.lastname: Iwata
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Ishii
authors.forename: Keizo
authors.initials: K
authors.lastname: Yamaguchi
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000737:chemistry* / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006095:Gram-Positive Cocci / Q000187:drug effects*; D006193:Haemophilus influenzae / Q000187:drug effects; D048628:Ketolides / Q000737:chemistry / Q000494:pharmacology; D007875:Legionella / Q000187:drug effects; D044128:Legionella longbeachae / Q000187:drug effects; D016952:Legionella pneumophila / Q000187:drug effects; D018942:Macrolides / Q000737:chemistry* / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D001936:Moraxella catarrhalis / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013297:Streptococcus pyogenes / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D001952:Bridged-Ring Compounds; C520838:EDP 420; D048628:Ketolides; D018942:Macrolides; C106791:telithromycin