Telithromycin

The treatment of respiratory tract infections (RTIs) continues to be an international challenge; RTIs are associated with considerable morbidity and mortality in both developed and developing countries. Globally, lower RTIs accounted for 4.3 million premature deaths in 1990.

A major barrier to the confident prescribing of empiric therapies for RTIs is the increasing resistance worldwide among respiratory tract pathogens to existing antimicrobial agents. Although the clinical impact of penicillin-resistant Streptococcus pneumoniae (S. pneumoniae) has been controversial in non-meningococ-cal respiratory infections, the usefulness of penicillin against this pathogen can be reduced by the progressive development of resistance. Even more worrisome is the fact that penicillin-resistant S. pneumo-niae strains are often resistant to other K-lactams and the macrolides.
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Figure 1 Used with permission from Aventis

Figure 1. Used with permission from Aventis

The macrolide-linosamide-strepto-gramin (MLSB) group of antimicrobials are clinically valuable drugs, particularly for the treatment of RTIs, which can be caused by S. pneumoniae as well as by “atypical” pathogens like Mycoplasma pneumoniae. Resistance of S. pneumoniae to these antimicrobials, however, is increasing on an international scale. From 1997 to 1998, non-susceptible rates ranged from 9% in the United Kingdom to 74% in China. Of most recent concern is the emergence, noted in some studies, of occasional resistance to fluoroquinolones. Resistance is associated with the increased use of these agents.

Figure 2. Used with permission from Aventis

Figure 2. Used with permission from Aventis

Telithromycin (Ketek, Aventis) is the first of a new family of semisynthetic anti­microbials known as the ketolides. Chemically derived from the macrolides, this novel antibiotic has been specifically developed to overcome the problem of increasing resistance to the antimicrobials in the MLSb group, and is characterized by a broad microbiological spectrum, a unique mechanisms of action, and a favorable resistance profile. Most importantly, it possesses good in vitro activity against most of the common respiratory pathogens, including S. pneumoniae that are resistant to beta-lactams or macrolides. If, however, the strains resistant to macrolides carry the ermB gene, many of those strains will also be resistant to telithromycin.
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CHEMISTRY AND PHARMACOLOGY

Chemically, telithromycin is designated 11,12-dideoxy-3-de [(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribo-hexo-pyranosyl) oxy] 6-0-methyl-3-oxo-12, 11-[oxycarbonyl[(4-[4-(3-pyridinyl)-1 H-imi-dazol-1-yl]butyl]imino]]erythromycin. Its empirical formula is C43H65-N5O10 and its molecular weight is 812.03. Telithromycin is a white to off-white crystalline powder.

Figure 3. Used with permission from Aventis

Figure 3. Used with permission from Aventis

Although telithromycin is chemically related to the macrolide and retains some of its favorable properties, such as a good safety profile, this new ketolide is differentiated from the macrolides by several innovative features. These features enable it to overcome most MLSB resistance, offer a low potential to select for resistance in vitro, avoid the induction of cross-resistance to members of the MLSB group of antimicrobials, and offer a broad spectrum of antimicrobial activity (Figure 1). generic cialis uk

Figure 4. Used with permission from Aventis

Figure 4. Used with permission from Aventis

One of the main chemical differences in telithromycin is the presence of a 3-keto group in place of the neutral sugar C3-cladinose moiety, which was long thought to be important for the antimicrobial activity of the macro-lides. The replacement of the cladinose sugar with a keto group has not caused a loss of activity, but rather has been linked to improved activity against erythromycin-resistant S. pneumoniae strains and is associated with the ketolide’s inability to induce MLSB resistance in vitro (Figures 2 and 3). Also, the presence of a methoxy group at C6 provides excellent stability in an acidic environment, a factor that has important implications for oral bioavailabili-ty and for activity in the acidic environment of respiratory tract cells and tissues. In addition, an alkyl/arylcarbonate extension at positions C11,12 of the lactone ring increases telithromycin’s affinity for ribosomes, resulting in enhanced antibacterial activity and possibly accounting for its ability to overcome MLSB resistance. This modification of target ribosomal binding sites also has been suggested as a reason for telithromycin’s low potential to select for resistance (Figure 4).