1: Expert Opin Pharmacother. 2008 Feb;9(2):267-83. Ketolides: pharmacological profile and rational positioning in the treatment of respiratory tract infections. Van Bambeke F, Harms JM, Van Laethem Y, Tulkens PM. Université Catholique de Louvain, Faculté de Médecine, Unité de Pharmacologie Cellulaire et Moléculaire, UCL7370 Avenue Mounier 73, 1200 Brussels, Belgium. francoise.vanbambeke@uclouvain.be Ketolides differ from macrolides by removal of the 3-O-cladinose (replaced by a keto group), a 11,12- or 6,11-cyclic moiety and a heteroaryl-alkyl side chain attached to the macrocyclic ring through a suitable linker. These modifications allow for anchoring at two distinct binding sites in the 23S rRNA (increasing activity against erythromycin-susceptible strains and maintaining activity towards Streptococcus pneumoniae resistant to erythromycin A by ribosomal methylation), and make ketolides less prone to induce methylase expression and less susceptible to efflux in S. pneumoniae. Combined with an advantageous pharmacokinetic profile (good oral bioavailability and penetration in the respiratory tract tissues and fluids; prolonged half-life allowing for once-a-day administration), these antimicrobial properties make ketolides an attractive alternative for the treatment of severe respiratory tract infections such as pneumonia in areas with significant resistance to conventional macrolides. For telithromycin (the only registered ketolide so far), pharmacodynamic considerations suggest optimal efficacy for isolates with minimum inhibitory concentration values < or = 0.25 mg/l (pharmacodynamic/pharmacokinetic breakpoint), calling for continuous and careful surveys of bacterial susceptibility. Postmarketing surveillance studies have evidenced rare, but severe, side effects (hepatotoxicity, respiratory failure in patients with myasthenia gravis, visual disturbance and QTc prolongation in combination with other drugs). On these bases, telithromycin indications have been recently restricted by the US FDA to community-acquired pneumonia, and caution in patients at risk has been advocated by the European authorities. Should these side effects be class related, they may hinder the development of other ketolides such as cethromycin (in Phase III, but on hold in the US) or EDP-420 (Phase II). PMID: 18201149 [PubMed - in process] Related Links The ketolides: a critical review. [Drugs. 2002] PMID:12149046 [Multicenter study in southern South America of the in vitro activity of telithromycin in strains with defined resistance phenotypes isolated from community-acquired respiratory infections] [Rev Esp Quimioter. 2001] PMID:11753448 Use of cethromycin, a new ketolide, for treatment of community-acquired respiratory infections. [Expert Opin Investig Drugs. 2008] PMID:18321237 Ketolides: an emerging treatment for macrolide-resistant respiratory infections, focusing on S. pneumoniae. [Expert Opin Emerg Drugs. 2003] PMID:14661991 Review of macrolides and ketolides: focus on respiratory tract infections. [Drugs. 2001] PMID:11324679