Studies reveal bacterial resistance to widely-prescribed antibiotics is increasing

December 05, 2000

Telithromycin shown active in combating treatment-resistant respiratory tract bacterial infections

Frankfurt, Germany. Bacteria are growing increasingly resistant to the antibiotics widely prescribed to treat respiratory tract infections (RTIs), according to data presented today at the First Annual Resistant Gram Positive Infections conference. Findings from the international surveillance study PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) indicate a high prevalence of global bacterial resistance to penicillin and macrolide antibiotics including erythromycin, clarithromycin and azithromycin. RTIs such as community-acquired pneumonia (CAP), acute bacterial exacerbations of chronic bronchitis (AECB), acute sinusitis and tonsillitis/pharyngitis represent a significant societal burden, causing 50 million deaths globally each year.

Phase III clinical trial data designed to assess the activity of telithromycin against other common RTI drugs were presented at the conference. Studies found that telithromycin may provide a convenient, once-daily, short-course treatment option for select RTIs, including those infections caused by bacteria resistant to available therapies.

"The results of PROTEKT demonstrate the urgent need for new, powerful antibiotics to use in the treatment of common respiratory tract infections," said lead PROTEKT investigator Dr. David Felmingham, Director of GR Micro Ltd., London. "Telithromycin's activity both in the laboratory and in patients indicate that it is a viable treatment option for the millions of people who suffer from these troublesome infections."

Telithromycin is the first in a new family of antibiotics called ketolides, which are a novel addition to the macrolide-lincosamide-streptogramin (MLSb) group. Telithromycin is specifically designed to offer optimal broad-spectrum coverage in both upper and lower RTIs - including those caused by resistant strains - with a short and reliable treatment regimen. Telithromycin combats resistant bacteria by inhibiting the protein synthesis necessary for bacterial reproduction, binding 10 times tighter than macrolides at two different sites on bacterial ribosomes. In vitro data suggest that it has a low propensity to induce bacterial resistance.

PROTEKT Study
PROTEKT data include isolates from countries spanning North America, Europe, Latin America and the Asia Pacific. PROTEKT involves 72 laboratories in 25 countries. It is an ongoing study, where researchers analyze the susceptibility of seven common and atypical community-acquired RTI-causing bacteria to most current treatments including penicillins such as amoxicillin, cephalosporins and commonly used macrolides such as azithromycin and clarithromycin.

The study evaluates the in vitro activity of telithromycin. To date, more than 9,000 clinical isolates of Streptococcus pneumoniae, Streptococcus pyogenes, Moraxella catarrhalis, Haemophilus influenzae, Haemophilus parainfluenzae, Staphylococcus aureus and Legionella pneumophila have been collected from patients with RTIs such as CAP, AECB, otitis media and pharyngitis. Unlike many previous surveillance programs, PROTEKT isolates are sent to a central laboratory and analyzed using standardized tests specifically focusing on determining microbiological activity of telithromycin and other antibiotics.

Results of the study, which included six countries, targeting S. pneumoniae demonstrated a 33% overall resistance to penicillin, with the highest level in South Korea (70%). Resistance to macrolides was more than 50%, overall, rating highest in South Korea (88%). All isolates of S. pneumoniae were susceptible to telithromycin. Beta-lactamase producing isolates of H. influenzae, which deactivate penicillin and related antibiotics by breaking down a part of their structure called a betalactam ring, were most prevalent in South Korea (55%) and were 16% overall. H. parainfluenzae isolates demonstrated lower rates of beta-lactamase production (11% overall). In M. catarrhalis isolates, beta-lactamase production was 95% overall, reaching 100% in Brazil and South Korea.

Comprehensive results and full details of the project, continually updated, are available to the public online at www.protekt.org.

Telithromycin Phase III Clinical Trial Results
Telithromycin Phase III studies comprise data from almost 2,500 patients treated with telithromycin and almost 1,800 patients treated with comparator antibiotics. Telithromycin showed a high level of activity against S. pneumoniae, S. pyogenes, S. aureus, H. influenzae and M. catarrhalis; as well as atypical bacteria such as Chlamydia pneumoniae, Mycoplasma pneumoniae, and L. pneumoniae. In those studies for which side effects were cited, the most common adverse events included diarrhea, nausea, dizziness, and headache.

Community-Acquired Pneumonia (CAP)
Findings from three comparative Phase III studies -- each designed to asses telithromycin activity in the treatment of CAP -- showed that telithromycin once a day is as effective as comparator drugs. A study conducted throughout Europe and South Africa showed that telithromycin once a day was as effective as high dose amoxicillin (1,000 mg) three times a day (94.6% vs. 90.1% clinical cure rate). Another study, conducted in North America, showed comparable efficacy between telithromycin once a day and the macrolide clarithromycin (500 mg) twice a day (88.3% vs. 88.5% clinical cure rate) and a third study, also conducted in North America, demonstrated that telithromycin once a day is as effective as the fluoroquinolone trovafloxacin (200 mg) once a day (91.1% vs. 94.8% clinical cure rate).

Two sub-analyses of data from the North American study demonstrated that telithromycin had a 90% clinical cure rate against S. pneumoniae - the most common cause of CAP. Another sub-analysis of North American and European study data demonstrated that telithromycin is effective against atypical respiratory bacteria including Chlamydia pneumoniae (93.3%), Mycoplasma pneumoniae (96.4%), Legionella pneumoniae (100%), and Coxiella burnetti (80%).

Acute Exacerbation of Chronic Bronchitis (AECB)
Results from two North American studies showed that telithromycin was as effective as comparator antibiotics with a shorter treatment duration in the treatment of chronic bronchitis complicated by a bacterial infection. The first study demonstrated that 800 mg of telithromycin once a day for five days is well tolerated and as effective as cefuroxime axetil 500 mg twice a day for 10 days (89.2% vs. 86.3% clinical cure rate). The second study showed that telithromycin once a day for a five day period is as effective as amoxycillin/clavulanic (amox/clav) acid (500 mg/125 mg, respectively) three times a day for 10 days (86.1% vs. 82.1% clinical cure rate).

Sinusitis
In a North American study conducted to examine clinical and bacteriological efficacy in sinusitis, telithromycin 800 mg once a day for five or 10 days was compared with a 10-day regimen of amoxicillin/clavulanic acid in 790 patients. Telithromycin administered for five days was as effective (75.8% clinical cure rate) as a 10-day course of the comparator (74.6%); and as effective as a 10-day course of telithromycin (74.1% clinical cure rate). Another study of 336 sinusitis patients in Europe and North America confirmed comparable cure rates between the 5-day and 10-day regimens (91.1% vs. 91.0% clinical cure rate). Patients in the study received either 10 days of telithromycin or five days of telithromycin followed by a placebo for five days. Telithromycin-susceptible bacteria isolated from the sinusitis patients included S. pneumoniae, H. influenzae, M. catarrhalis, and S. aureus.

Pharyngitis/Tonsillitis
A study was conducted in Europe to test the clinical efficacy of 800 mg of telithromycin once a day for five days as compared with 500 mg of penicillin V three times a day for 10 days. Patients who took telithromycin only five times had cure rates comparable to those whose regimen included either 20 or 30 doses of penicillin V (telithromycin 94.8% vs. penicillin V 94.1% clinical cure rate). In a second study, conducted in North America, telithromycin taken for only five days demonstrated equivalence in clinical and bacteriological cure to clarithromycin (91.3% vs. clarithromycin 88.1% clinical cure rate), which was taken over the course of 10 days in the treatment of pharyngitis or tonsillitis caused by group A Beta-hemolytic streptococci.

Aventis submitted applications for telithromycin to the U.S. Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products (EMEA) in March 2000. The company is seeking approval for a once-daily dosing regimen for CAP, AECB, and acute sinusitis in patients 18 and older, as well as pharyngitis/tonsillitis in patients age 13 and older; and a short-course treatment regimen (once a day for five days) in all indications except CAP (once a day for seven to 10 days).
-end-
Aventis (NYSE: AVE), a world leader in pharmaceuticals and agriculture, is dedicated to improving life through the discovery and development of innovative products in the fields of prescription drugs, vaccines, therapeutic proteins, crop production and protection, animal health and nutrition. Aventis announced in November 2000 that it intends to focus on pharmaceuticals and plans to divest its activities in agriculture. With its global corporate headquarters in Strasbourg, France, Aventis employs around 95,000 people in more than 120 countries and recorded pro forma sales in 1999 of 20.5 billion euros. Aventis was launched in December 1999 through the merger of Hoechst AG of Germany and Rhône-Poulenc SA of France. For more information: www.aventis.com.

Aventis Pharma AG is the pharmaceutical company of Aventis. Aventis Pharma is dedicated to treating and preventing human disease through the discovery, development, manufacture and sale of innovative pharmaceutical products aimed at satisfying unmet medical needs. Aventis Pharma focuses on important therapeutic areas such as cardiology, oncology, infectious diseases, arthritis, allergies and respiratory disorders, diabetes and the central nervous system disorders. Aventis Pharma has its corporate headquarters in Frankfurt, Germany. Aventis Pharma encompasses Aventis Pasteur, a world leader in vaccines based in Lyon, France, and Aventis Behring, a world leader in therapeutic proteins headquartered in King of Prussia, Pennsylvania, USA.

Statements in this news release other than historical information are forward-looking statements subject to risks and uncertainties. Actual results could differ materially depending on factors such as the availability of resources, the timing and effects of regulatory actions, the strength of competition, the outcome of litigation and the effectiveness of patent protection. Additional information regarding risks and uncertainties is set forth in the current Annual Report on Form 20-F of Aventis on file with the Securities and Exchange Commission.

Ketchum UK

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