The ketolides: a critical review.
Ketolides are a new class of macrolides designed particularly to combat respiratory tract pathogens that have acquired resistance to macrolides. The ketolides are semi-synthetic derivatives of the 14-membered macrolide erythromycin A, and retain the erythromycin macrolactone ring structure as well as the D-desosamine sugar attached at position 5. The defining characteristic of the ketolides is the removal of the neutral sugar, L-cladinose from the 3 position of the ring and the subsequent oxidation of the 3-hydroxyl to a 3-keto functional group. The ketolides presently under development additionally contain an 11, 12 cyclic carbamate linkage in place of the two hydroxyl groups of erythromycin A and an arylalkyl or an arylallyl chain, imparting in vitro activity equal to or better than the newer macrolides. Telithromycin is the first member of this new class to be approved for clinical use, while ABT-773 is presently in phase III of development. Ketolides have a mechanism of action very similar to erythromycin A from which they have been derived. 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 aerobes and some Gram-negative aerobes, and have excellent activity against drug-resistant Streptococcus pneumoniae, including macrolide-resistant (mefA and ermB strains of S. pneumoniae). Ketolides such as telithromycin display excellent pharmacokinetics allowing once daily dose administration and extensive tissue distribution relative to serum. Evidence suggests the ketolides are primarily metabolised in the liver and that elimination is by a combination of biliary, hepatic and urinary excretion. Pharmacodynamically, ketolides display an element of concentration dependent killing unlike macrolides which are considered time dependent killers. Clinical trial data are only available for telithromycin and have focused on respiratory infections including community-acquired pneumonia, acute exacerbations of chronic bronchitis, sinusitis and streptococcal pharyngitis. Bacteriological and clinical cure rates have been similar to comparators. Limited data suggest very good eradication of macrolide-resistant and penicillin-resistant S. pneumoniae. As a class, the macrolides are well tolerated and can be used safely. Limited clinical trial data suggest that ketolides have similar safety profiles to the newer macrolides. Telithromycin interacts with the cytochrome P450 enzyme system (specifically CYP 3A4) in a reversible fashion and limited clinically significant drug interactions occur. In summary, clinical trials support the clinical efficacy of the ketolides in upper and lower respiratory tract infections caused by typical and atypical pathogens including strains resistant to penicillins and macrolides. Considerations such as local epidemiology, patterns of resistance and ketolide adverse effects, drug interactions and cost relative to existing agents will define the role of these agents. The addition of the ketolides in the era of antibacterial resistance provides clinicians with more options in the treatment of respiratory infections.
Zhanel
George G
GG
Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. ggzhanel@pcs.mb.ca
Walters
Michael
M
Noreddin
Ayman
A
Vercaigne
Lavern M
LM
Wierzbowski
Aleksandra
A
Embil
John M
JM
Gin
Alfred S
AS
Douthwaite
Stephen
S
Hoban
Daryl J
DJ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D001424:Bacterial Infections / Q000188:drug therapy*; D001682:Biological Availability; D002986:Clinical Trials as Topic; D004347:Drug Interactions; D017850:Economics, Pharmaceutical; D006207:Half-Life; D006801:Humans; D018942:Macrolides; D008826:Microbial Sensitivity Tests; D012141:Respiratory Tract Infections / Q000188:drug therapy*; D014018:Tissue Distribution
D000900:Anti-Bacterial Agents; D018942:Macrolides