Telithromycin: new agent for community-acquired RTIs

February 2005

The most common pathogens causing community-acquired respiratory tract infections include Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. There has been a steady increase in penicillin-resistant S. pneumoniae over the past decade. The overall rate of resistance has started to level off in the past few years. However, there is a worrisome trend in that the proportion of high-level resistance has now surpassed the level of intermediate resistance. This could have implications for treatment outcomes. Additionally, macrolide resistance to S. pneumoniae has also been steadily increasing, making outpatient treatment decisions difficult for clinicians.

Telithromycin (Ketek, Sanofi-Aventis) is a new antibacterial agent approved by the FDA in April 2004 and actively marketed during the third quarter of 2004. This column will highlight the similarities and differences of telithromycin when compared with the macrolides.

Structure activity relationships

The base structure for macrolides is the macrolactone ring, with the therapeutically important macrolides comprised of 14-, 15- and 16-member rings. Structural alterations to natural erythromycin A have included the addition of various side chains to enhance acid stability and/or increase antibacterial activity and the insertion of additional molecules in the 14-member macrolactone ring to produce 15- or 16- member rings. The semisynthetic macrolides have broader antibacterial spectrums and improved acid stability, which have resulted in several clinically important macrolides, such as azithromycin (Zithromax, Pfizer) and clarithromycin. This base structure has been further altered to produce the ketolides, which are considered a distinct chemical class of agents.

The ketolides have several key structural modifications when compared with the macrolides. At position 3, the L-cladinose moiety was replaced with a keto group, thus giving the name ketolides; agents with a cladinose group at this position are known as macrolides. The removal of the cladinose group improves the activity against erythromycin-resistant isolates and avoids the potential for induction of macrolide-lincosamide-streptogramin group B (MLS_ß) resistance. The methoxy group at position 6 is similar to clarithromycin and affords excellent acid stability. The carbamate side chain at positions C11 and 12 improves the ribosomal binding affinity, contributing to the improved activity against MLS_ß-resistant bacteria.

The macrolides and ketolides block bacterial protein synthesis by binding to the 50S ribosomal subunit near the peptidyl transferase center located on Domain V. The carbamate side chain of telithromycin gives an additional binding site within the 23S rRNA found on Domain II. This additional binding site is credited with telithromycin’s improved antibacterial spectrum.

Spectrum of activity

Telithromycin is active against the common respiratory pathogens with little collateral damage to our indigenous flora. This is important in limiting the adverse effects of antimicrobials on the environmental ecology. Telithromycin is very active against both penicillin-sensitive and penicillin-resistant S. pneumoniae, with greater potency than the common macrolides. Most notable is telithromycin’s retention of activity against macrolide-resistant strains of S. pneumoniae, including both erm resistance and mef resistance, with little change in the minimum inhibitory concentration (MIC) values.

Telithromycin has activity against H. influenzae and M. catarrhalis similar to that of azithromycin, which is known to be the most active macrolide against these pathogens. The atypical pathogens Chlamydia, Mycoplasma and Legionella are at least as sensitive or more sensitive to telithromycin when compared with azithromycin and clarithromycin.

Telithromycin is rapidly and completely absorbed from the gastrointestinal (GI) tract but undergoes first-pass metabolism, yielding a systemic bioavailability of 57%. This is not affected by food.

Telithromycin is extensively distributed to the respiratory tissues, with concentrations in the tonsils, epithelial lining fluid and alveolar macrophages that far exceed the concentrations found in the serum. Additionally, telithromycin’s concentrations in white blood cells far exceed that achieved in the serum. This may give an advantage to carrying the drug to the site of infection and in treating intracellular organisms.

Telithromycin undergoes hepatic metabolism to four major metabolites. Approximately one-half of the metabolism is mediated by the cytochrome P450 system (3A and 1A isoenzymes), and the other half occurs through other metabolic pathways. The primary route of elimination of the metabolites is through the feces. Small portions of telithromycin are eliminated as the parent drug in the feces (<10%) and the urine (<15%). The elimination of telithromycin is not affected by hepatic impairment or renal insufficiency due to increasing the clearance through compensatory mechanisms; therefore, no dosage adjustments are necessary. Additionally, no adjustments are necessary in the elderly, despite a 30% increase in area under the curve (AUC) seen in this population.

Telithromycin is a bactericidal agent that exhibits concentration-dependent killing. Its pharmacodynamic profile is best described by the C_max:MIC and AUC:MIC ratios.

Adverse effects

Telithromycin has been used in more than 9 million people worldwide with no significant adverse effects reported. In clinical trials, telithromycin was well tolerated with a rate of adverse effects similar to that of the comparator agent. Most adverse effects were considered mild to moderate, with the most common reactions being diarrhea, nausea, vomiting, headache, dizziness and blurred vision. Less than 1% of patients discontinued telithromycin due to GI intolerance.

Prior to telithromycin’s approval, an additional safety study was completed with more than 12,000 patients receiving telithromycin. The overall rate of adverse reactions was 15%, with diarrhea, nausea, headache and dizziness being the most common complaints. Blurred vision was not found in this study as it had been in the previous clinical trials. The blurred vision is reported to be a delay in accommodation, which is similar to what is found with other commonly prescribed medications.

Drug interactions

Telithromycin has the potential to cause several drug interactions due to its metabolism through the cytochrome P450 enzyme system, but nothing has been documented. When telithromycin is used with triphasic contraceptives, the AUC of the contraceptive is increased, with no effect shown on telithromycin; this interaction is not considered to be significant. The concurrent use of telithromycin and the lipid-lowering agents simvastatin (Zocor, Merck), atorvastatin (Lipitor, Pfizer) and lovastatin (Mevacor, Merck) is recommended to be avoided due to the increase AUC of the statin, which could increase the potential for myopathy. However, in the large safety study, there were a significant number of patients on both telithromycin and one of these statins, and no adverse effects from the interaction were reported. Health care professionals should use their judgment in assessing the significance of this drug interaction. Telithromycin has also been studied with concurrent use of warfarin, and no significant drug interaction was found. However, one should always be cautious when adding additional agents to a stable warfarin therapy due to the potential for bleeding.

Clinical uses

Telithromycin has been studied in more than 4,500 patients enrolled in 14 phase-3 clinical trials (10 controlled and four uncontrolled) for the treatment of acute bacterial sinusitis, acute exacerbations of chronic bronchitis and mild to moderate community-acquired pneumonia. Telithromycin demonstrated equivalent clinical cure rates in all of the comparative trials.

Five days of telithromycin was compared with 10 days for the treatment of acute bacterial sinusitis. The five-day regimen was found to have equivalent clinical cure rates to the 10-day course of treatment. In other sinusitis studies, five days of telithromycin was found to be equivalent in clinical cure rates when compared with 10-day courses of either amoxicillin-clavulanate or cefuroxime. For acute exacerbations of chronic bronchitis, five days of telithromycin was compared with a 10-day treatment of amoxicillin-clavulanate, cefuroxime or clarithromycin. Telithromycin demonstrated equivalence in clinical cure rates to the comparator agent.

The mild-to-moderate community-acquired pneumonia studies compared 10 days of telithromycin to 10 days of either amoxicillin (1,000 mg three times daily) or clarithromycin and demonstrated equivalent clinical cure rates. An additional community-acquired pneumonia study of telithromycin vs. trovafloxacin (Trovan, Pfizer) was stopped prematurely due to trovafloxacin’s withdrawal from the market. However, at the time of study discontinuation, the clinical cure rates of telithromycin were equivalent to those of trovafloxacin.

Telithromycin is FDA approved for the treatment of acute exacerbations of chronic bronchitis and acute bacterial sinusitis at a dose of 800 mg once daily for five days and mild to moderate community-acquired pneumonia at a dose of 800 mg once daily for seven to 10 days.

Telithromycin is a welcome addition to the antibacterial armamentarium. It has been shown to be safe and effective in treating common community acquired respiratory tract infections and has little potential for development of resistance.

For more information:

• Douthwaite S. Structure-activity relationships of ketolides vs. macrolides. Clin Microbiol Infect. 2001;7(supp 3):11-17.
• Drusano G. Pharmacodynamic and pharmacokinetic considerations in antimicrobial selection: focus on telithromycin. Clin Microbiol Infect. 2001;7(suppl 3):24-29.

• Marianne Billeter, PharmD, BCPS, Clinical Pharmacology Specialist, Infectious Diseases, Ochsner Clinic Foundation, New Orleans.