In vitro and in vivo antibacterial activities of the tricyclic ketolide TE-802 and its analogs

Abstract

The in vitro and in vivo antibacterial activities of tricyclic ketolides (TKs: TE-802, TE-806, TE-935, TE-943) have been compared with those of clarithromycin (CAM), azithromycin (AZM) and rokitamycin (RKM). TKs were active against not only erythromycin (EM)-susceptible organisms; aerobic Gram-positive bacteria, some Gram-negative bacteria, anaerobic bacteria and Mycoplasma pneumoniae, but also EM-resistant Staphylococcus aureus (inducible macrolide-resistant strains) as well as EM-resistant Streptococcus pneumoniae (efflux-resistant strains). The therapeutic efficacies of TKs against systemic infections and respiratory tract infection (RTI) caused by Gram-positive bacteria in mice are superior to those of CAM and AZM. The peak plasma levels (Cmax, po) of TE-802 in mice were equal to that of CAM, but the plasma area under the concentration-time curve (AUC24hours) was 4.7 times that for CAM. The plasma Cmax (po) value for TE-802 in monkey was equal to that of CAM, whereas the AUC8hours value was three-fourths that of CAM. The pharmacokinetics of TE-802 are similar to those of AZM in mice and monkeys, suggesting the potential for once-daily administration in humans.