Ketolides in the treatment of respiratory infections

The ketolides are a new class of macrolides specifically designed to combat respiratory tract pathogens that have acquired resistance to macrolides. The ketolides are semi-synthetic derivatives of the 14-membered macrolide erythromycin A. There are currently two ketolides in the late stages of clinical development in the US (telithromycin [HMR-364, Kelek; Aventis] and ABT-773 [Abbot Laboratories]), as well as newer compounds in earlier stages of testing. Ketolides have a mechanism of action very similar to that of erythromycin A. They potently inhibit protein synthesis by interacting close to the peptidyl transferase site of the bacterial 50S ribosomal subunit. Ketolides bind to ribosomes with higher affinity than macrolides. The ketolides exhibit good activity against Gram-positive and some Gram-negative aerobes and have are active against macrolide-resistant Streptococcus species, including most mef A and erm B strains of Streptococcus pneumoniae. Ketolides have pharmacokinetics which allow once-daily dosing and extensive tissue distribution with very high uptake into respiratory tissues and fluids relative to serum. Evidence suggests the ketolides are primarily metabolised by the cytochrome P450 (CYP) enzyme system in the liver and that elimination is a combination of biliary, hepatic and urinary excretion. Clinical trial data are only available for telithromycin and have focused on respiratory tract infections (RTIs) including community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB), sinusitis and streptococcal pharyngitis. Bacteriological and clinical cure rates have been similar to comparators. Ketolides have similar safety profiles to the newer macrolides. In summary, early clinical trials support the clinical efficacy of the ketolides in common RTIs, including activity against macrolide-resistant pathogens.