CLINICAL EFFICACY STUDIES

At present, 10 large-scale, international phase III clinical trials have been completed, encompassing almost 4,300 patients with a range of RTIs; almost 2,500 were treated with telithromycin and about 1,800 were treated with comparator antibiotics. Telithromycin’s efficacy was assessed in RTIs such as CAP, in acute exacerbations of chronic bronchitis (AECB), in acute sinusitis, and in pharyngitis/tonsillitis.

Community-Acquired Pneumonia

In an uncontrolled, open-label phase III study, 240 adults (between 18 and 79 years of age) with a confirmed diagnosis of CAP received oral telithromycin 800 mg once daily for seven to 10 days. Diagnosis of CAP was based on chest x-ray findings and the presence of two classical CAP symptoms. Despite the fact that 21.5% of patients had relatively severe infections (Fine score>3), the clinical cure rates were 92.9% in the intent-to-treat (ITT) population and 79.6% in the per protocol (PP) population. Eradication rates for causative pathogens at the post-therapy visit were 82.7% in the PP population and 85.5% in the ITT population, with particularly high rates of 88.9% for infections caused by S. pneumoniae.

Three comparative phase III studies were also carried out to assess telithro-mycin’s efficacy and safety with comparator antimicrobials. A study conducted throughout Europe and South Africa randomized 404 adult patients with a confirmed diagnosis of acute mild to moderate CAP to oral telithromycin 800 mg once daily or oral amoxicillin 1,000 mg three times daily for 10 days. Telithromycin proved to be as effective as high-dose (94.6% vs 90.1% clinical cure rates) and these rates were maintained in patients with severe disease, documented pneumococcal bac-teremia, and patients with infections caused by atypical organisms. Bacteriological outcomes favored telithromycin in both the ITT population (satisfactory for 79% of telithromycin-treated patients vs. 73% of those on amoxicillin) and in the PP population (satisfactory for 90% vs. 87.5%, respectively, at the post-therapy visit).

Another study, conducted in North and South America and encompassing 448 adult patients with confirmed CAP, demonstrated comparable clinical efficacy between oral telithromycin 800 mg once daily and oral  twice daily, both for 10 days, with clinical cure rates of 88.3% and 88.5%, respectively. Among the pathogens isolated, 87.3% were eradicated by telithromycin and 96.4% were eradicated by clarithromycin at the test-of-cure visit in the PP population. In a third study, carried out in Canada, the U.S., and Africa, 228 adult patients with acute CAP were randomized to oral telithromycin 800 mg once daily or oral trovafloxacin 200 mg once daily, for seven to 10 days. As in the previous studies, telithromycin proved to be equivalent in efficacy to the comparator drug (trovafloxacin) in achieving a clinical cure in adults with CAP (91.1% vs. 94.8% clinical cure rates). Bacteriological eradication rates in the test-of-cure populations were 94.1% in those treated with telithromycin and 100% in those who received trovafloxacin.

In a sub-analysis of the 755 telithromycin-treated patients with CAP in the three multicenter, randomized, double-blind comparator studies and the one multicenter, uncontrolled, open-label study, 35 patients had documented bacteremia at baseline. Thirty of patients were deemed evaluable; 26 of those had bacteremias attributable to S. pneumoniae, including three penicillin-resistant (MIC>2 mg/L) and two ery-thromycin A-resistant (MIC>1 mg/L) strains. The clinical cure rate was 90%, with a rate of 88.5% in those with confirmed pneu-mococcal bacteremias. The bacteriological efficacy rate was 90% for all pathogens and 88.5% for S. pneumoniae. In another sub-analysis of this group of patients, administration of oral telithromycin 800 mg once daily for seven to 10 days was shown to provide excellent clinical cure rates for patients with CAP caused by atypical pathogens including Chlamydia pneumoniae (74/81 or 91.4%), Mycoplasma pneumoniae (174/190 or 91.6%), Legionella pneumoniae (4/4 or 100%), and Coxiella burnetii (4/5 or 80%).

Acute Exacerbation of Chronic Bronchitis

In an international, multicenter study, 324 adult patients with a history of bronchitis and chronic obstructive pulmonary disease (COPD) and presenting with AECB, presumably caused by bacterial infection, were randomly assigned to oral telithromycin 800 mg once daily for five days or amoxicillin/clavulinic acid 500 mg/125 mg three times daily for 10 days. The purpose was to assess the clinical and bacteriological efficacy and safety of telithromycin compared to amoxicillin/ clavulinic acid in the treatment of AECB. Telithromycin once daily for five days was as effective as a standard 10-day course of drug amoxicillin/clavulinic acid, with clinical cure rates of 86.1% versus 82.1%, and bacteriological eradication rates of 69.2% and 70%, respectively, among the PP population at post-therapy. In a second study, carried out in North America, a five-day regimen of oral telithromycin 800 mg once daily was equivalent in clinical efficacy to a 10-day regimen of oral cefur-oxime axetil 500 mg twice daily in 495 adult outpatients with AECB. The clinical cure rates were 89.2% and 86.3%, respec-tively. Satisfactory bacteriological outcome at the test-of-cure visit was achieved in 87.9% of telithromycin treated patients and 86% of those on cefuroxime axetil, with identified causative organisms.

Sinusitis

Two international, multicenter phase III clinical trials were performed to evaluate the efficacy and safety of telithromycin against comparator antimicrobials or as a five- or 10-day regimen for the treatment of adult patients with acute maxillary sinusitis (AMS). In one study, 336 patients with community-acquired AMS were randomized to a five-day course of telithromycin 800 mg once daily or a 10-day course of telithromycin of the same dose. A pre-therapy sinus tap was conducted for bacteriological assessment. A five-day course was shown to be as effective as a 10-day course of treatment for AMS, with comparable cure rates of 91.1% and 91%. In total, 92% of patients receiving five-day telithro-mycin and 89.9% of those treated with the 10-day course had a satisfactory bacteriological outcome at the post-therapy visit.

By comparison, 93.3% (28/30) of S. pneumoniae were presumed eradicated in the five-day arm and 89.3% (25/28) were presumed eradicated in the 10-day arm. In the second study, in 790 patients with AMS, telithromycin 800 mg daily for five days was as effective clinically as a 10-day course of amoxicillin/clavulinic acid 500/125 mg three times daily or a 10-day regimen of telithromycin 800 mg once daily, with clinical cure rates of 75.8%, 74.6%, and 74.1%, respectively. Satisfactory bacteriological outcome in the PP population of the three groups was 85.7% in both telithromycin groups and 75% in those treated with amox-icillin/clavulinic acid. buy antibiotics canada

Pharyngitis/Tonsillitis

Because penicillin is currently the treatment of choice for group A-hemolytic streptococcal (GABHS) pharyngitis/tonsillitis, a multicenter, European phase III trial was carried out to compare the efficacy and safety of oral telithromycin 800 mg once daily for five days, and five days of placebo versus oral penicillin V 500 mg three times daily for 10 days, in 396 adult patients with a presumed diagnosis of GABHS pharyngitis/tonsillitis. Patients who took telithromycin only five times had clinical cure rates comparable to a standard 10-day course of penicillin comprised of 30 doses (94.8% vs. 94.1%).

In the PP population, bacteriological eradication rates at the post-therapy visit were 84.3% in patients treated with telithromycin and 89.1% for those who received penicillin V. In a second study, conducted in North America, 463 adolescent and adult (13-81 years) patients with GABHS pharyngitis/ tonsillitis were randomly assigned to oral telithromycin 800 mg once daily for five days or oral clarithromycin 250 mg twice daily for 10 days. In the 285 patients who were evaluable post-therapy, the five-day telithromycin regimen was equivalent in efficacy to the standard 10-day course of clarithromycin in eradicating GABHS in patients 13 years of age or older with acute pharyngitis/tonsillitis, with clinical cure rates of 92.7% versus 91.7% and bacteriological eradication rates of 91.3% versus 88.1%, respectively.

ADVERSE EVENTS

Telithromycin is generally well-tolerated. Among the 1,899 patients who took part in the controlled phase III clinical trials and were treated with telithromycin 800 mg once daily for five or seven to 10 days, approximately 35% experienced adverse events. Adverse reactions that were judged by investigators to be at least possibly drug-related and occurring in more than 1% of all telithromycin-treated patients were diarrhea (12.9%), nausea (7.3%), dizziness (3.0%), vomiting (2.6%), and headache (2.1%). Similarly, in the 240 patients enrolled in the uncontrolled CAP study and who received at least one dose of study medication, the most frequent adverse events considered to be possibly drug-related were abnormal liver function tests (11.3%), an event known to be associated with CAP; diarrhea (7.5%); and nausea (4.6%). The majority of adverse events were mild to moderate in both the controlled and uncontrolled studies and rarely led to treatment discontinuation. Most discontinuation in the telithromycin groups resulted from adverse gastrointestinal effects, primarily diarrhea (1%), nausea (1%), and vomiting (1%). Finally, no differences were seen in the occurrence of clinically noteworthy abnormal values between treatment with telithromycin and any of the comparator antimicrobials administered in the controlled studies.