The wobbly status of ketolides: where do we stand?

Ketolides are erythromycin A derivatives with a keto group replacing the cladinose sugar and an aryl-alkyl group attached to the lactone macrocycle. The aryl-alkyl extension broadens its antibacterial spectrum to include all pathogens responsible for community-acquired pneumonia (CAP): Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis as well as atypical pathogens (Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila). Ketolides have extensive tissue distribution, favorable pharmacokinetics (oral, once-a-day) and useful anti-inflammatory/immunomodulatory properties. Hence, they were considered attractive additions to established oral antibacterials (quinolones, β-lactams, second-generation macrolides) for mild-to-moderate CAP. The first ketolide to be approved, Sanofi-Aventis' telithromycin (RU 66647, HMR 3647, Ketek®), had tainted clinical development, controversial FDA approval and subsequent restrictions due to rare, irreversible hepatotoxicity that included deaths. Three additional ketolides progressed to non-inferiority clinical trials vis-à-vis clarithromycin for CAP. Abbott's cethromycin (ABT-773), acquired by Polymedix and subsequently by Advanced Life Sciences, completed Phase III trials, but its New Drug Application was denied by the FDA in 2009. Enanta's modithromycin (EDP-420), originally codeveloped with Shionogi (S-013420) and subsequently by Shionogi alone, is currently in Phase II in Japan. Optimer's solithromycin (OP-1068), acquired by Cempra (CEM-101), is currently in Phase III. Until this hepatotoxicity issue is resolved, ketolides are unlikely to replace established antibacterials for CAP, or lipoglycopeptides and oxazolidinones for gram-positive infections.