ketolide

Ketolides are a class of semi-synthetic antibiotics derived from macrolides. They are characterized by replacement of one sugar moiety with a keto group, which gives the class its name, and by the addition of an extended lipophilic side chain that improves binding to the bacterial ribosome. The first member to reach clinical use was telithromycin, and other compounds such as cethromycin and solithromycin have been studied in various development programs.

Mechanism of action and spectrum: Ketolides bind to the 50S ribosomal subunit and inhibit protein synthesis, with high-affinity interaction with the 23S rRNA. This enables activity against bacteria that have developed macrolide resistance through MLS_B methylation, and provides robust activity against many respiratory pathogens. They are generally active against Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and atypical pathogens such as Mycoplasma pneumoniae, while showing variable activity against other Gram-negative organisms.

Pharmacokinetics and clinical use: Most ketolides are available in oral formulations, with some also offered by intravenous administration. They are largely metabolized in the liver via hepatic enzymes and can interact with other drugs through cytochrome P450 pathways. Clinically, ketolides have been used for respiratory tract infections, including community-acquired pneumonia, acute bacterial sinusitis, and bronchitis, particularly as alternatives when macrolide resistance limits the effectiveness of older agents.

Safety and regulatory status: Telithromycin, the first ketolide approved for clinical use, has been associated with rare but serious liver injury and other adverse effects, leading to regulatory warnings and restricted use in many regions. Several other ketolides faced safety concerns and limited development. As a result, the role of ketolides in therapy remains cautious, with ongoing research into safer and more tolerable compounds.