Ketolides: an emerging treatment for macrolide-resistant respiratory infections, focusing on S. pneumoniae.
Resistance to antibiotics in community acquired respiratory infections is increasing worldwide. Resistance to the macrolides can be class-specific, as in efflux or ribosomal mutations, or, in the case of erythromycin ribosomal methylase (erm)-mediated resistance, may generate cross-resistance to other related classes. The ketolides are a new subclass of macrolides specifically designed to combat macrolide-resistant respiratory pathogens. X-ray crystallography indicates that ketolides bind to a secondary region in domain II of the 23S rRNA subunit, resulting in an improved structure-activity relationship. Telithromycin and cethromycin (formerly ABT-773) are the two most clinically advanced ketolides, exhibiting greater activity towards both typical and atypical respiratory pathogens. As a subclass of macrolides, ketolides demonstrate potent activity against most macrolide-resistant streptococci, including ermB- and macrolide efflux (mef)A-positive Streptococcus pneumoniae. Their pharmacokinetics display a long half-life as well as extensive tissue distribution and uptake into respiratory tissues and fluids, allowing for once-daily dosing. Clinical trials focusing on respiratory infections indicate bacteriological and clinical cure rates similar to comparators, even in patients infected with macrolide-resistant strains.
Zhanel
George G
GG
MS 673 Microbiology, Department of Clinical Microbiology, Health Sciences Centre, 820 Sherbrook Street, Winnipeg, Manitoba, R3A 1R9, Canada. ggzhanel@pcs.mb.ca
Hisanaga
Tamiko
T
Nichol
Kim
K
Wierzbowski
Aleksandra
A
Hoban
Daryl J
DJ
D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D024901:Drug Resistance, Multiple, Bacterial; D004917:Erythromycin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D048628:Ketolides; D018942:Macrolides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D048628:Ketolides; D018942:Macrolides; D004917:Erythromycin; C405499:cethromycin; C106791:telithromycin