Macrolides and Ketolides

The macrolides and ketolides represent a class of antibacterial agents with activities against most Gram-positive and selected Gram-negative as well as atypical pathogens including penicillin-resistant microorganisms. Erythromycin, clarithromycin, and azithromycin, the most extensively used macrolides in North America, and the only approved ketolide telithromycin have demonstrated efficacy and safety in a variety of clinical conditions and have been approved for use in both upper and lower-respiratory tract infections as well as skin and skin structure and genital infections. The introduction of clarithromycin and azithromycin provided the medical community with macrolide agents with not only increased pathogen coverage but also a significant improvement in adverse event profile when compared with the first macrolide agent, erythromycin. However, the global increase in macrolide-resistant Streptococcus pneumoniae is limiting their use. The ketolide telithromycin has great promise with efficacy to treat multidrug-resistant S. pneumoniae but its use has been significantly limited due to a number of serious safety issues which have surfaced since approval. Cethromycin is the only ketolide in late stage development. This chapter will provide a comprehensive review of these agents regarding the following aspects: in vitro antibacterial activity, mechanism of action, mechanism of resistance, pharmacokinetic and pharmacodynamic profile, clinical use, and safety issues. Future directions and challenges for the discovery and development of new macrolides and ketolides are also discussed.