Drug Criteria & Outcomes: Telithromycin (Ketek) Formulary Evaluation

Part 1: Mechanism of Action, In Vitro Activity, Resistance Profile, Pharmacokinetics, Indication, and Dosage

ByJennifer Herring

Telithromycin is the first of the ketolides, a new class of antibacterial drugs that are derived from macrolide antibiotics.

Chemical deviations from the macrolides

The only chemical modification necessary to classify a drug as a ketolide is replacement of the a-L-cladinose moiety at position 3 of the 14-membered erythronolide A ring of the macrolide with a keto function. This replacement is thought to increase the acid stability of this class of antibacterials, as well as overcome resistance.

Chemical changes specific to telithromycin are:

  • cycling of the C11-12 positions to form a carbamate ring;
  • imidazo-pyridyl group attachment to the carbamate ring;
  • replacement of a hydroxyl group at position 6 of the erythronolide A ring with a methoxy group.

Mechanism of action

Similar to the macrolides, telithromycin binds to the 70S bacterial ribosome, specifically the 23S rRNA of the 50S ribosomal subunit. As a result, protein synthesis is prohibited secondary to inhibition of translation of the bacterial mRNA. Depending on the nature of the pathogen, this binding results in either bacteriostatic or bactericidal activity.

The primary binding site of the macrolides and ketolides is with domain V of the 23S rRNA, where binding is a result of interactions between the erythronolide A ring of the macrolide/ketolide and several nucleotides within the central loop.

Although their interaction is similar here, each antibacterial also interacts with the hairpin 35 region of domain II. This site, domain II, is where the ketolides differ from the macrolides. The L-cladinose structure of the macrolide does not sufficiently protect the N1 position of A752 nucleotide, thereby leaving it susceptible to chemical modification. Telithromycin, however, fully protects the N1 position of the A752 due to the extension of C11-12. This results in enhanced interaction and binding to domain II. Ultimately, telithromycin is able to maintain its position on the ribosome even after alterations of domain V significantly decrease binding of the erythronolide A ring. This dual binding also enables the drug to overcome resistance caused by modification to one of the sites due to methylation.

Improved resistance profile

Because telithromycin has been derived from the macrolides, it also is susceptible to some of the resistance mechanisms of bacteria, namely constitutive methylation on domain V of the 23S rRNA. This resistance is facilitated by erm genes found on plasmids or chromosomes of resistant bacteria. Unlike the macrolides, however, telithromycin does not induce methylase production. As a result, telithromycin remains effective vs. the inducible methylation. Telithromycin also is effective against mef-controlled efflux, which is the other main mechanism by which bacteria are resistant to macrolides.

In vitro activity

As most respiratory tract infections are caused by Streptoccocus pneumoniae and Haemophillus influenzae, it is pertinent to compare minimum inhibitory concentration (MIC) values of telithromycin (see Table 1, below) to other agents currently being used to treat them. The activity of telithromycin for S. pneumoniae is comparable to that of the other first-line agents, including clarithromycin, amoxicillin/clavulanic acid, trovafloxacin, and amoxicillin. For penicillin-resistant S. pneumoniae (PRSP) and erythromycin-resistant S. pneumoniae (ERSP), telithromycin has been found to have superior in vitro activity vs. the macrolides/azalides. Against H. influenzae, however, telithromycin appears to have less optimal and more variable activity, especially compared to that of trovafloxacin.

Pharmacokinetics

Absorption:

  • Oral bioavailability of telithromycin is 54% in both young and elderly subjects due to an extensive first-pass effect.
  • Neither rate nor extent of absorption is affected by food; therefore, it may be taken without regard to food.

Distribution:

  • Protein binding of telithromycin has been reported as 60-70%.
  • Volume of distribution following intravenous infusion is 2.9 L/kg.
  • Telithromycin concentrates in extracellular tissue, as well as in phagocytic cells, specifically bronchial mucosa, epithelial lining fluid, and alveolar macrophages.
  • Uptake into extracellular tissue, like the macrolides, is enhanced by inflammation and blunted by the lack of it.
  • Pregnancy category C.

Metabolism:

  • Liver metabolizes 37% of dose.
  • Metabolized to four major metabolites, of which RU 76363 retains antibacterial activity at a level four- to 16-fold less than the parent compound.
  • Substrate and inhibitor of CYP3A4.
  • Possible competitive inhibitor of CYP2D6.
  • Possible interactions with drugs metabolized via CYP1A2.

Elimination:

  • 75% feces (unchanged and metabolites).
  • 13% excreted unchanged in urine.
  • No dosage adjustment for hepatic insufficiency.
  • No dosage adjustment for renal insufficiency, although no dose has been established for severe insufficiency (less than 30 mL/min).
  • Effect of dialysis has not been studied.
  • Combined hepatic and renal disease likely would require adjustment.
  • No dosage adjustment necessary based on age alone.

The pharmacokinetics of telithromycin allow for once-daily dosing due to a longer half-life (see Table 2, below), which is similar to that of trovafloxacin. Telithromycin exhibits concentration-dependent killing, also more similar to trovafloxacin than the time-dependent killing of the beta-lactams and some macrolides.

Indication and dosage

Telithromycin is indicated for the treatment of the following infections in patients 18 years old and older:

Acute bacterial exacerbation of chronic bronchitis (AECB) due to Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis.

Acute bacterial sinusitis (ABS) due to Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, or Staphylococcus aureus.

Community-acquired pneumonia (CAP) (of mild-to-moderate severity) due to Streptococcus pneumoniae, (including multidrug-resistant isolates [MDRSP]), Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, or Myco-plasma pneumoniae.

Decreased compliance with medication regimens often is cited as a factor responsible for increasing resistance to current antibiotic therapy.

Telithromycin offers distinct advantages over standard agents, in that the pharmacokinetic profile of telithromycin allows for once-daily dosing (compared to two and three times daily dosing with comparator agents), as well as a shorter duration of treatment (5 days vs. 7-10 days). Table 3, below summarizes the dosage and administration regimens for telithromycin’s three indications. (Editor’s note: Part 2 of this evaluation will continue with a discussion of Clinical Trials, Adverse Events, Drug Interactions, Cost, and Recommendation in the September issue of Drug Criteria & Outcomes.)

By Jennifer Herring, PharmD Candidate, Harrison School of Pharmacy, Auburn (AL) University.