Medical Inspection – Health Blog

The substitution of a 3-keto function in lieu of the alpha-L-cladinose at position 3 of the erythronolide A ring, along with the addition of an imidazolyl and pyridylring through a butyl chain in lieu of the C11-12 carbamate, chemically differentiate telithromycin from the macrolide group of antimicrobials.

The C11-12 linkage allows telithromycin to bind 10 times more tightly than erythromycin and six times more tightly than canadian clarithromycin to wild-type ribo-somes.15 Telithromycin binds 20 times more tightly than generic erythromycin or clarithromycin to bacterial ribosomes with domain V modifications (which show evidence of MLSB resistance). The 3-keto group allows telithromycin to bind to the ribosomal target without causing expression of MLSB resistance in inducible strains. Telithromycin has not been shown to induce resistance to it-self.
These substitutions demonstrate effects on pharmacokinetic stability and spectrum of activity, allowing telithro-mycin to bind more tightly to two distinct regions on the RNA ribosomal subunit. This dual binding not only augments antibacterial potency but also decreases bacterial resistance caused by alterations to one of the target sites by methylation, as seen in MLSB-resistance phenotypes.

Telithromycin works by inhibiting bacterial protein synthesis by binding to domains II and V of 23S recombinant RNA (rRNA) of the 50S ribosomal sub-unit.8,10 In the presence of resistance caused by bacterial methylases that alter the domain V binding site of telith-romycin, activity is still retained against gram-positive cocci (S. pneumoniae) by binding to domain II. Telithromycin is active against aerobic gram-positive, aerobic gram-negative, and anaerobic bacteria and other microorganisms (Table 4).

Table 4 Microorganisms Against Which Telithromycin Is Active in Vitro

EFFICACY

The Dunbar Study

Dunbar et al. conducted a randomized, double-blind, double-dummy, parallel-group study to compare the efficacy and tolerability of telithromycin 800 mg once daily with high-dose clarithromycin 500 mg twice daily for the treatment of CAP in adults 18 years of age or older. Each regimen was taken for 10 days.

To be eligible for enrollment in this study, patients had to have acute CAP with two or more clinical signs and symptoms associated with CAP as well as a chest film to confirm the presence of an infiltrate. Patients were excluded if they had neoplastic lung disease; progress the telithromycin group of patients was an impressive 88.3%; the rate for the clarithromycin group was 88.5% (Table 5). None of the isolates in this study were resistant to telithromycin, whereas 10.5% of the isolates, including 9.8% of S. pneumoniae were resistant to clarithromycin.

Table 5 Clinical Cure Rates at Post-therapy Check-up (17-24 Days after Start of Treatment)

Telithromycin exhibited exceptional clinical efficacy in elderly patients, in high-risk patients, and in those with para-pneumonic bacteremia. However, a slightly higher incidence of diarrhea was reported with telithromycin than with clarithromycin.

Significant differences in tolerability included taste perversion and headache, which were observed more frequently with clarithromycin; nausea, vomiting, and dizziness occurred more often with telithromycin.

The Luterman Study

Luterman and colleagues conducted a randomized, double-blind, three-arm, parallel-group multicenter trial of 754 patients 18 years of age or older who were experiencing clinical symptoms of acute maxillary sinusitis. The goal was to determine the efficacy and tolerability of five-day and 10-day courses of telithromycin with a 10-day course of generic amoxicillin/clavulanic acid (e.g., Augmentin®, GlaxoSmithKline).

Eligibility requirements for this study included clinical symptoms of acute maxillary sinusitis for less than 28 days and proof of a maxillary sinus infection confirmed by x-ray examination. Patients were excluded if they had a prolonged QT-interval syndrome, a progressively fatal illness, severe hypokalemia, a history of drug or alcohol abuse, renal or hepatic impairment, a history of chronic or recurrent sinusitis, and cystic fibro-sis. Pregnant and lactating women, immunocompromised individuals, and those who had received antibiotic therapy within seven days prior to the study were also excluded.

The patients were randomly assigned, on a 1:1:1 basis, to receive one of these regimens:

• telithromycin 800 mg once in the morning for five days, followed by placebo for five days
• telithromycin 800 mg once in the morning for 10 days

Patients in the telithromycin groups also received a placebo at midday and in the evening.

The efficacy variable was the clinical outcome at the time-of-cure (TOC) visit (17-24 days after initiation of therapy) and at the late post-therapy visit (31-45 days after the initiation of therapy). This schedule ensured a more definite measurement of efficacy and identification of early relapses.

In each treatment group, the clinical cure rate was 75%, indicating therapeutic equivalence among the three groups. All three groups of patients achieved a 70% cure rate during the post-therapy visit.

Diarrhea and nausea were the most common adverse drug events (ADEs) reported in each group. The ECG recordings indicated small mean changes in the QT interval that were within the limits of normal variability in each group.

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• Telithromycin (Ketek): TREATMENT OPTIONS
• Telithromycin (Ketek): ETIOLOGY
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