Telithromycin: the first ketolide antimicrobial

Telithromycin is the first of the ketolide antibacterials to receive US Food and Drug Administration (FDA) approval for clinical use. It is approved for the treatment of community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB), and acute maxillary sinusitis (AMS) in adults.

This article reviews the mechanism of action, in vitro antimicrobial activity, pharmacokinetics and pharmacodynamics, clinical efficacy, safety, and drug-interaction profile of telithromycin.

Relevant studies were identified through a search of the English-language literature indexed on MEDLINE (1990-March 2005) using the terms telithromycin and HMR 3647, a review of the reference lists of identified articles, and a review of the briefing document prepared by the manufacturer of telithromycin for presentation to the FDA Anti-infective Drugs Advisory Committee. A search of abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy (2001-2004) also was performed.

The results of in vitro susceptibility studies suggest that telithromycin provides coverage against the key respiratory pathogens, both typical and atypical. In addition, telithromycin may be useful against multidrug-resistant strains of Streptococcus pneumoniae and against Haemophilus influenzae, irrespective of beta-lactamase production. In randomized, double-blind, comparative trials (against amoxicillin, amoxicillin/clavulanate, cefuroxime axetil, clarithromycin, moxifloxacin, or trovafloxacin), telithromycin had comparable efficacy to its comparators in the empiric treatment of CAP (4 studies), AECB (3 studies), and AMS (3 studies). Telithromycin is dosed at 800 mg (two 400-mg tablets) QD in community-acquired respiratory tract infections (RTIs). No dose adjustment is required in the elderly, patients with mild to moderate renal insufficiency, or patients with hepatic insufficiency. The majority of adverse events associated with telithromycin were mild to moderate, with gastrointestinal effects (diarrhea, nausea, vomiting) being the most commonly reported, followed by headache and dizziness. Telithromycin has been associated with elevations in hepatic transaminases and prolongation of the electrocardiographic QTc interval, although the significance of these findings is not known. Telithromycin is also a strong inhibitor of and substrate for the cytochrome P450 (CYP) 3A4 isozyme. Therefore, it is important to monitor for potential drug interactions with medications that prolong the QTc interval or are metabolized by the CYP system.

Telithromycin appears to be a useful option for the empiric treatment of community-acquired RTIs in adults. It may be particularly useful in the outpatient setting in areas with high rates of penicillin- and macrolide-resistant S pneumoniae; it may also be an alternative agent for patients who are allergic to beta-lactams and live in areas with a high prevalence of multidrug-resistant S pneumoniae or for those who have failed to respond to beta-lactam- or macrolide-based therapy.