The use of ketolides in treatment of upper respiratory tract infections

Abstract

Recent surveillance studies suggest that the incidence of resistance to macrolide antibiotics in common community-acquired respiratory tract pathogens, particularly Streptococcus pneumoniae and Streptococcus pyogenes, is increasing and limiting the usefulness of these drugs. The ketolides, of which telithromycin is the first to be available for clinical use (but not yet in the United States), represent a new class of antibacterials developed specifically to combat respiratory tract pathogens that have acquired resistance to macrolides. The ketolides possess innovative structural modifications, a 3-keto group and a large N-substituted C11, C12-carbamate side chain. This novel structure allows ketolides, which are inhibitors of protein synthesis, to exert a more effective interaction with domain II of the 23S rRNA, enhancing binding to bacterial ribosomes and allowing binding to macrolide-lincosamide-streptogramin B-resistant ribosomes. This novel chemical structure also promotes greater stability of telithromycin in acid conditions, providing the potential for greater stability in gastric fluid and at cellular/tissue levels. Early clinical trials support the bacteriologic and clinical efficacy of telithromycin in the treatment of upper respiratory tract infections (RTIs) such as streptococcal pharyngitis and acute sinusitis, including infections caused by macrolide-resistant S. pneumoniae and S. pyogenes. Common adverse side effects associated with telithromycin are predominantly gastrointestinal, usually of mild to moderate severity, and rarely involve withdrawal of the drug. Telithromycin represents an attractive option for the empiric treatment of upper RTIs, especially as resistance to macrolides is likely to continue to increase.

Susceptibility of clinical methicillin-resistant Staphylococci isolates to new antibiotics

“…Reports of resistance to glycopeptides first appeared in Japan [13] and the U.S [39]; other countries reported resistance to vancomycin or intermediate strains. These increasing rates of resistance demonstrate the need for new antibiotics [14,44]. In the last ten years, broadspectrum antibiotics such as daptomycin, linezolid, Tigecycline is a tetracycline-derivative antibiotic that has a broad spectrum.…”

Pharmacodynamic Activity of Telithromycin at Simulated Clinically Achievable Free-Drug Concentrations in Serum and Epithelial Lining Fluid against Efflux ( mefE )-Producing Macrolide- Resistant Streptococcus pneumoniae for Which Telithromycin MICs Vary

“…The second mechanism, which results in macrolide efflux, is coded by the mefA or mefE genes (6,9,29,33). Efflux is macrolide specific (14-and 15-membered macrolides only) and does not affect the lincosamide or streptogramins (28,32). Note that ermB-positive S. pneumoniae strains generally exhibit high-level (MIC 90 Ն 64 g/ml) macrolide resistance, while mefA-or mefE-positive S. pneumoniae strains exhibit low-to moderate-level resistance (MIC 90 4 g/ml) (6, 9, 29, 33).…”

“…Presently, in North America, mefE-positive S. pneumoniae is more common than ermB-positive S. pneumoniae and mefE strains make up the majority of macrolideresistant S. pneumoniae strains (6, 9). In many European countries, ermB-positive S. pneumoniae strains are more prevalent (28,32).Although reports associating macrolide-resistant S. pneumoniae with macrolide clinical failure in the treatment of community-acquired respiratory infections are available, they are not that common (24).Ketolides are a new class of semisynthetic agents derived from erythromycin A and are designed specifically to combat respiratory tract pathogens that have acquired resistance to macrolides (5,7,8,11,22,26,32). The main structural difference between ketolides and the macrolides is the lack of Lcladinose sugar at position 3 of the erythronolide A ring and its replacement with a 3-keto group (28,33).…”

“…Presently, in North America, mefE-positive S. pneumoniae is more common than ermB-positive S. pneumoniae and mefE strains make up the majority of macrolideresistant S. pneumoniae strains (6, 9). In many European countries, ermB-positive S. pneumoniae strains are more prevalent (28,32).…”

“…Ketolides are a new class of semisynthetic agents derived from erythromycin A and are designed specifically to combat respiratory tract pathogens that have acquired resistance to macrolides (5,7,8,11,22,26,32). The main structural difference between ketolides and the macrolides is the lack of Lcladinose sugar at position 3 of the erythronolide A ring and its replacement with a 3-keto group (28,33).…”