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 g/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 g/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.

A Novel Ketolide, RBx 14255, with Activity against Multidrug-Resistant Streptococcus pneumoniae

“…In vitro activities similar to those of RBx 14255 were reported for cethromycin (ABT-773), another ketolide, and telithromycin against many resistant phenotypes, including activity against penicillin and macrolide-resistant Gram-positive bacteria (29). In a study by Sato et al (30), modithromycin (EDP-420, EP-013420, S-013420), a novel 6,11- pneumoniae, and the in vitro activities were comparable to those of our fluoroketolide, RBx 14255. Solithromycin is currently being developed in phase 3 clinical trials at Cempra, Inc., for the oncedaily oral treatment of mild to moderate community-acquired bacterial pneumonia (CABP), and phase 2 clinical trial results were recently reported (21).…”

Efficacy and Safety of Liposomal Clarithromycin and Its Effect on Pseudomonas aeruginosa Virulence Factors

“…There are several molecular mechanisms by which bacteria, including P. aeruginosa, resist the action of macrolide, including target site modification by methylation and/or mutation that prevents the binding of antibiotics to their target molecules and inactivation of the drugs or efflux (23)(24)(25).…”

The Chemistry of Peptidyltransferase Center-Targeted Antibiotics: Enzymatic Resistance and Approaches to Countering Resistance

“…The so-called bicyclolides introduce a second heterocycle between the 6 and 11 or 6 and 3 positions (73, 74). The 6, 11-bicyclolide modithromycin (Figure 1) exhibits improved in vitro efficacy against erm + strains of S. pyogenes showing idiosyncratic resistance to telithromycin (75). Another area of development unrelated to resistance is the alteration of the alkyl-arm to one containing an azetidine (azetidinyl ketolides in Figure 1).…”