Ketolides: A novel class of antibiotics

September 2001

Macrolide antibiotics are recommended as first-line choices for empiric therapy for community-acquired pneumonia because of their broad spectrum. They are also used with parenteral ß-lactams for the treatment of community-acquired pneumonia (CAP) in patients who require hospitalization. Unfortunately, increasing resistance of many bacterial species to ß-lactams and macrolides limits the efficacy of these agents. The ketolides are a new class of semisynthetic macrolide antibiotics. They have been developed to counteract growing resistance.

Ketolides are a novel class of 14-membered ring macrolides characterized by the substitution of the -L-cladinose moiety with a 3-keto group, the addition of a methoxy group at the 6-position, and the extension of the carbamate group at the 11/12-position. Alterations of the 14-membered macrolide ring structure increase acid stability. This improves the affinity of the ketolides for the bacterial ribosome, and increase potency against macrolide-resistant bacteria. Telithromycin is the first of this new class of antibiotics. In June of 2001, Aventis Pharmaceuticals was given an approvable letter by the FDA after review of telithromycin. It will be marketed under the brand name Ketek when it’s licensed.

Mechanism of action

Similar to other macrolides, ketolides inhibit protein synthesis by binding to the bacterial 50S ribosomal subunit. Both erythromycin and telithromycin bind to bacterial ribosomes through interactions with nucleotides in domains 2 and 5 of 23S rRNA. The substitution of nucleotides within domain 5 is the major cause of resistance with some pathogens. The extension of the macrolide structure at the 11/12 position increases the affinity of telithromycin for the bacterial ribosome tenfold over that of erythromycin to domain 2. This increased binding allows telithromycin to overcome many macrolide resistant pathogens that commonly cause community-acquired infections.

Spectrum of activity

The ketolides have a spectrum of activity similar to the macrolides. They have been shown to have excellent activity against a wide range of gram-positive organisms, including macrolide resistant strains. In vitro, telithromycin was active against strains of Streptococcus pneumoniae that were resistant to other macrolides including erythromycin, clarithromycin (Biaxin, Abbott), and azithromycin (Zithromax, Pfizer). It was more active than azithromycin or erythromycin against S. pyogenes, and was 64 times more active than either agent against 66 oxacillin-susceptible strains of Staphylococcus aureus. In general, methicillin/oxacillin-resistant strains of S. aureus have been shown to be resistant to telithromycin.

Telithromycin has similar activity to azithromycin and clarithromycin against Moraxella catarrhalis isolates, but greater activity than clarithromycin against Haemophilus influenzae.

Its efficacy is similar to that of azithromycin and erythromycin against M. pneumoniae and Chlamydia pneumoniae. Activity against Legionella is higher than that of erythromycin. Moderate susceptibility, which is higher than with clarithromycin, is seen against mycobacterium species including Mycobacterium avium, M. bovis, M. paratuberculosis, and M. ulcerans. Strains of M. africanum, M. bovis, M. simiae and M. tuberculosis are resistant to telithromycin.

A pharmacokinetic analysis of telithromycin was conducted in 18 healthy men in a single-center randomized, open-label, single and multiple dose, 3-way crossover study. Subjects were randomized to receive a daily dose of 400 mg, 800 mg or 1,600 mg orally for 7 days separated by a washout period of 7 days. Plasma and urine samples were collected for screening throughout the treatment period. Regardless of the dose, telithromycin was rapidly absorbed and reached a maximum concentration after a median of 1 hour (range 0.5-4 hours). Following a single dose of 400 mg, 800 mg or 1,600 mg, 7.6%, 13.0%, and 19.0%, respectively, was excreted in the urine. Telithromycin is also excreted 13% via the feces and 37% by the liver.

The major active metabolite of telithromycin is RU 76363. It is fourfold to 16-fold less active than the parent compound in vitro. Modest accumulation of both the parent compound and the metabolite was seen after 7 days of dosing, with the AUC values reaching 1.5 times those achieved after a single dose. The oral absolute bioavailability of telithromycin is 57%, and is not affected by food.

Safety

In general, telithromycin was well tolerated during the trial by Namour et al. Adverse reactions were similar to those commonly experienced with other macrolides. Most adverse reactions were mild to moderate and included diarrhea, nausea and gastrointestinal upset. One patient developed severe vomiting and diarrhea during the 1,600 mg daily phase of the trial and was withdrawn from the study. No deaths or serious adverse events were reported during the trial, although the sample size was small. Significant prolongation of the QTc interval was not observed.

Drug interactions

Telithromycin is a competitive inhibitor of CYP3A4. Concomitant administration with drugs that are metabolized by CYP3A4 such as simvastatin and midazolam (Versed, Roche) may increase their plasma concentrations. Telithromycin also undergoes elimination through the CYP3A4. When given with strong CYP3A4 inhibitors like ketoconazole (Nizoral, Janssen) and itraconazole (Sporanox, Janssen), the AUC of telithromycin may increase up to twofold. Telithromycin does not appear to affect the pharmacokinetics or pharmacodynamics of warfarin. Telithromycin’s bioavailability is not affected when given with rimantadine or aluminum/magnesium hydroxide.

Dosage and administration

The telithromycin minimum inhibitory concentration for S. pneumoniae, M. catarrhalis, and H. influenzae, which inhibited 90% of the isolates are <0.06, 0.03, and 2 mg/l, respectively. Following 7 days of dosing with telithromycin 800 mg given once daily, the C_max and C₂₄ values were 2.27 and 0.070 mg/l. A daily dose of 800 mg should therefore provide plasma levels which are sufficient to maintain activity against common respiratory pathogens.

Indication

The FDA has recommended approval for telithromycin for CAP, acute bacterial exacerbations of chronic bronchitis and acute bacterial sinusitis. The FDA has not recommended telithromycin for tonsillitis or pharyngitis, and has issued a non-approvable letter for those indications. Unlike azithromycin and clarithromycin, telithromycin has not sought approval for certain sexually transmitted diseases or for otitis media. Both intravenous and pediatric formulations are currently in development.

Summary

Telithromycin represents the first in a novel class of antibiotics. It has a broad spectrum of activity that includes macrolide-resistant strains of bacteria. While this agent may appear to be an attractive new option for empiric therapy for community-acquired respiratory tract infections, its complete role in therapy is yet to be defined. In areas of high S. pneumoniae resistance, the use of telithromycin may be more appropriate. Proper use of this new class of antibiotics, like all classes of antibiotics, will be paramount in slowing the development of resistance and ensuring future efficacy.

For more information:

• Balfour JA, Figgitt DP. Telithromycin. Drugs. 2001; 61(6):815-829.
• Zhanel GG, Dueck M, Hoban DJ, et al Review of macrolides and ketolides. Focus on respiratory tract infections. Drugs. 2001;61(4):443-498.
• Namour F, Wessels DH, Pascual MH, et al. Pharmacokinetics of the new ketolide telithromycin (HMR 3647) administered in ascending single and multiple doses Antimicrob Agents Chemother. 2001;45(1):170-5.
• Boswell FJ, Andrews JM, Ashby JP, et al. The in-vitro activity of HMR 3647, a new ketolide antimicrobial agent. J Antimicrob Chem. 1998;42:703-9.