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).