A Review of New Antibiotic Telithromycin (KETEK)

Telithromycin was approved by the Food and Drug Administration (FDA) in April 2004 for the treatment of mild to moderate community acquired pneumonia, acute bacterial exacerbation of chronic bronchitis, and acute bacterial sinusitis. The chemical structure of telithromycin, which is classed as a ketolide, is similar to the macrolide drug family, which includes erythromycin, clarithromycin and azithromycin.

Telithromycin is approved by the FDA for treatment of community acquired pneumonia due to multi-drug resistant Streptococcus pneumoniae (MDRSP). MDRSP includes penicillin-resistant S. pneumoniae and those bacteria that are also resistant to two or more of the following antibiotics: penicillin, second generation cephalosporins, the macrolides mentioned above, tetracyclines, and trimethoprim/sulfamethoxazole (BACTRIM, SEPTRA, COTRIM). Levofloxacin, a fluoroquinolone, is currently approved for treatment against S. pneumoniae resistant to penicillin; however, there is no agent other than telithromycin approved for treatment against S. pneumoniae resistant to erythromycin or to any other macrolide in the U.S. at this time.

Telithromycin has undergone a long drug approval process with the FDA. The makers of telithromycin, Aventis Pharmaceuticals, submitted the new drug application (NDA) in March of 2000. The drug went through two advisory committee reviews because of efficacy and safety issues before it was approved in April of 2004. Since 2001, telithromycin has been marketed in Germany, Spain, Italy, Brazil, and Mexico. It is also marketed in Canada and the United Kingdom.

In the original application, Aventis requested approval to market for four indications: tonsillopharyngitis (tonsillitis), acute worsening of bronchitis, sinusitis, and community acquired pneumonia. Tonsillopharyngitis was not approved by the FDA based on the agency’s guidelines for the efficacy of first line claims for antibiotics. The clinical success rate must be at least 85%, according to the FDA’s guidelines, for a first line claim. Telithromycin failed to show the 85% success rate for the treatment of tonsillopharyngitis. Interestingly, the rule of thumb did not apply to the other three indications that were later approved.

The Anti-infective Drug Advisory Committee was unable to make a unanimous decision about the efficacy and safety of telithromycin. Some members believed there was insufficient evidence to prove the efficacy of telithromycin for the treatment of acute worsening of chronic bronchitis, since one of the leading causes of the illness, the bacteria Haemophilus influenzae, was only 60% to 77% eradicated by the drug. Furthermore, one member even questioned the efficacy of the other drugs compared to telithromycin in clinical studies, which led to her disapproval for all three indications:

... the data at hand does not establish the efficacy of the comparators [drug being compared to telithromycin]...without data in front of us establishing the efficacy of the comparators, the data in front of us does not establish efficacy of this drug [telithromycin].

The committee was also split in its decision about the effectiveness of telithromycin against MDRSP. Telithromcyin cure rates were 90% for erythromycin resistant S. pneumoniae, 70% for penicillin resistant S. pneumoniae, and 68.8% for penicillin plus erythromycin resistant S. pneumoniae. The evidence of its efficacy for patients with MDRSP and severe infection was based on a small number of patients and it demands further evaluation.

Most of the adverse effect profile for telithromycin is similar to the other macrolides, mainly headache, dizziness, nausea, and diarrhea. But, telithromycin also has a risk for heart, liver, and eye toxicity. Data from a large U.S. safety study, number 3014, was submitted to the FDA following the first approvable letter. However, the major weaknesses of the trial was its design, which may have led to an underestimation of reported adverse events, and limited the collection and completeness of information about each adverse drug reaction.

Telithromycin causes QT prolongation, and the prolongation increases with increasing dose of the drug. QT prolongation may develop into a life threatening heart rhythm disturbance known as torsades de pointes. Two cases of torsades de pointes were reported at the Anti-infective Drug Advisory Committee meeting and the events were suspected to be drug related. QT prolongation is also reported with some macrolides and fluoroquinolone antibiotics.

Another concern with telithromycin, liver toxicity, is reported with macrolides as well. At the time of the January 8, 2003 advisory committee meeting, the FDA had received 54 reports of liver adverse event reports with telithromycin from countries in which the drug had been marketed, of which, 19 were categorized as serious.

Blurred vision that significantly impaired patients’ ability to perform daily activities was reported during clinical trials. The visual disturbances mainly occurred in women and the young. Visual side effects occurred 1 to 3 hours after a dose and the effect lasted up to 20 hours. From countries in which the drug was first marketed the FDA has received reports of 167 visual adverse events, of which 42 were categorized as serious. Telithromycin appears to cause more visual disturbances compared to macrolides already on the market.

Other concerns with telithromycin include vasculitis (inflammation of blood vessels) and worsening of myasthenia gravis, which has resulted in one fatality.

Telithromycin has shown to be no more effective than other antibiotics: amoxicillin, cefuroxime, clarithromycin, and trovafloxacin. Furthermore, the adverse effect profile is no better than macrolides already on the market, it is possibly less safe and there is a higher risk for drug interactions. The only factor that sets telithromycin apart from the rest is the FDA-approved use for treatment against macrolide resistant S. pneumoniae. The clinical importance of macrolide resistance is up for debate. Although there is an increase in macrolide resistant pneumococci in the U.S., the number of clinical failures has not risen.

Research has found no difference in deaths for pneumonia patients infected with drug sensitive or resistant bacteria after controlling for other risk factors, except, patients with resistant bacteria have a more prolonged hospital stay. The guidelines established by the Infectious Diseases Society of America states, “... a macrolide plus a beta lactam is recommended for initial empiric treatment of outpatients in whom resistance is an issue and for hospitalized patients.” In addition, experts believe the type of macrolide resistance found in the United States may be overcome by increasing the dose of the drug.

Some may feel very excited at the development of a “new” antibiotic and a “new” drug class and may argue that there is a need for more drugs. We would argue that we do not need more drugs, we need better drugs, and telithromycin is a drug that should not have been approved by the FDA.

We agree with the editors of the highly respected French prescription drug journal Prescrire International who stated “that telithromycin is a needless addition to the other macrolides.”

What You Can Do:

Numerous other, safer antibiotics are approved to treat the same infections as this drug, including other forms of erythromycin.