Will resistance to ketolides develop in Streptococcus pneumoniae?

Recent data from surveillance studies suggest that levels of resistance to macrolide, lincosamide and streptograminB (MLSB) antibacterials in respiratory tract pathogens, particularly Streptococcus pneumoniae, are rising and limiting the usefulness of these drugs. New agents that do not select for resistance are essential to safeguard the future of antibacterial efficacy. The ketolides, of which telithromycin is the first to be registered for clinical use, represent a new class of antibacterials developed specifically for optimal empirical treatment of respiratory tract infections (RTIs). Although derived chemically from macrolides, the ketolides, which possess innovative structural modifications, form a unique class in the macrolide family. A keto function at position 3 of the erythronolide A ring replaces the L-cladinose moiety, generating a class of compounds that, unlike 14- and 15-membered ring macrolides, will not induce MLSB resistance in vitro. A large aromatic N-substituted C11,12-carbamate side chain allows a more effective interaction with domain II of the 23S rRNA, enhancing binding to bacterial ribosomes and allowing binding to MLSB-resistant ribosomes. This novel structure allows ketolides to exert intrinsic activity against respiratory tract pathogens, avoid induction of MLSB resistance, and retain activity against MLS(B)-resistant strains. Furthermore, ketolides have a low potential to select for resistance and cross-resistance both in vitro and in vivo, making them an attractive option for the empirical treatment of RTIs.