Telithromycin Tablets (Ketek)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

The FDA has approved Telithromycin, the first Ketolide antibiotic. Ketolides are semisynthetic derivatives of the macrolide erythromycin that have activity against a wide spectrum of respiratory bacterial pathogens including multi-drug resistant Streptococcus pneumoniae. Telithromycin, which is a once-a-day oral tablet, is marketed by Aventis as Ketek.

Indications

Telithromycin is approved for the treatment of acute bacterial exacerbation of chronic bronchitis caused by Streptococcus pneumoniae, Haemophilius influenzae, or Moraxella catarrhalis; acute bacterial sinusitis caused by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, or Staphylococcus aureus; and community acquired pneumoniae (CAP) of mild to moderate severity caused by Streptococcus pneumoniae (including multi-drug resistant isolates), Hemophilus influenzae, Moraxella catarrhalis, Chlamydophilia pneumoniae, or Mycoplasma pneumoniae.1

Dosage

The recommended dose for acute bacterial exacerbation of chronic bronchitis or acute bacterial sinusitis is 800 mg once daily for 5 days. The recommended dose for community-acquired pneumonia of mild-to-moderate severity is 800 mg once daily for 7 to 10 days. Telithromycin can be taken with or without food.1

Telithromycin is supplied as 400 mg tablets.

Potential Advantages

Telithromycin has shown in vitro activity and clinical efficacy against multi-drug resistant S pneumoniae.1-6 It also appears to have low potential to select for or induce macrolide lincosamide streptogramin B (MLSb) resistance.

Potential Disadvantages

The most common side effects were diarrhea (13.3%) and nausea (8.1%). Telithromycin is a substrate and inhibitor of CYP 3A4. Potent inhibitors increase the bioavailability of telithromycin, and the bioavailability of certain substrates of CYP 3A4 (eg, simvastatin, midazolam) are increased. Telithromycin has the potential to prolong QTc, and should be avoided in patients at risk. Exacerbations of myasthenia gravis and visual disturbances (eg, blurred vision, diplopia, problems with accommodation) have been reported.1 Strains of S pneumonia, resistant to telithromycin, have been demonstrated in vitro.1

Comments

Telithromycin, while derived from erythromycin, has higher binding affinity to ribosomes than erythromycin. It is active with dose dependent bactericidal activity against common respiratory bacterial pathogens including atypical/intracellular pathogens and drug resistant strains of S pneumoniae. Concentrations exceeding the MIC90 are achieved in bronchial mucosa and epithelial lining fluid.7 Clinical cure rates of telithromycin (800 mg daily) were comparable to comparators such as clarithromycin (1000 mg daily), trovafloxacin (200 mg daily), and amoxicillin (3000 mg daily) for community acquired pneumonia; amoxicillin/clavulanate (1500/375 mg daily) and cefuroxime axetil (500 mg daily) for acute bacterial sinusitis; and cefuroxime, amoxicillin/clavulanate, and clarithromycin for acute exacerbation of chronic bronchitis.1,2 Clinical cure has also been reported in a limited number of infections caused by multi-drug resistant S pneumoniae. These include isolates resistant to 2 or more of the following: penicillin, 2nd generation cephalosporins, macrolides, tetracycline, and trimethoprim/sulfamethoxazole.1 Overall clinical cure ranged from 85-91% in these resistant pathogens.1,2 Bacterial eradication of erythromycin or penicillin resistant S pneumonia in CAP was 92% (67/73) for telithromycin compared to 70% (7/10) for pooled comparators.2 Telithromycin is generally well tolerated with diarrhea and nausea as the most common side effects. Exacerbations of myasthenia gravis and visual disturbances have been reported. The cost of telithromycin was not available at the time of this review.

Clinical Implications

Epidemiologic data indicate that bacterial resistance to commonly used antibiotics such as penicillin and erythromycin is increasing.8 Penicillin resistant S pneumonia represents over half the isolates in many regions of the United States, erythromycin-resistant strains ranges from 23-41%, and penicillin and erythromycin resistance ranges from 13-30%. Telithromcyin appears to be an effective antibiotic for these resistant bacteria. It must, however, be prescribed judiciously to minimize development of bacterial resistance as resistant strains have been demonstrated in vitro.

Dr. Elliott and Dr. Chan are editors of Internal Medicine Alert. This article was published in the May 2004 issue.

References

1. Ketek Product Information. Aventis Pharmaceutical Inc. March 2004.

2. Zhanel GG, et al. The Ketolides: A Critical Review. Drugs. 2002;62:1771-1804.

3. Balfour JAB, et al. Telithromycin. Drugs. 2001;61:815-829.

4. Buchanan P, et al. J Allergy Clin Immunol. 2002;109(1) supplement S289.

5. Clark JP, et al. Ketolides: A New Class of Antibacterial Agents for Treatment of Community-Acquired Respiratory Tract Infections in a Primary Care Setting. Mayo Clin Proc. 2003;78:1113-1124.

6. Low DE, et al. Clinical and Bacteriological Efficacy of the Ketolide Telithromycin Against Isolates of Key Respiratory Pathogens: A Pooled Analysis of Phase III Studies. Clin Microbiol Infect. 2004;10:27-36.

7. Khair OA, et al. Lung concentrations of Telithromycin After Oral Dosing. J Antimicrob Chemother. 2001;47: 837-840.

8. Dunbar LM. Current Issues in the Management of Bacterial Respiratory Tract Disease: The Challenge of Antibacterial Infection. Am J Med Sci. 2003;326: 360-368.