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.

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]

    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