Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Diseases Society of America 46th Annual Meeting

Washington, DC / October 25-28, 2008

In recent years, rates of infection with methicillin-resistant Staphylococcus aureus (MRSA) have grown substantially. In addition, MRSA is no longer confined to the hospital or institutional setting, and community-acquired (CA)-MRSA infections have become, if not common, alarmingly frequent, according to infectious disease experts.

The cause of their concern is that the clinician’s arsenal contains only a few weapons that are still effective against methicillin-resistant micro-organisms, and heavy reliance on these agents is likely to accelerate the development of S. aureus “superbugs” that are resistant to second-line agents such as the tricyclic glycopeptide vancomycin. The emergence of vancomycin-resistant staphylococci and enterococci highlights the need for new antimicrobial drugs that show good activity against MRSA and other pathogenic micro-organisms.

International Surveillance

Among the agents in late-stage development for MRSA and for methicillin-susceptible S. aureus (MSSA) is the investigational lipoglycopeptide telavancin, structurally related to vancomycin. It has rapid bactericidal action and has shown good activity against Gram-positive pathogens, including MRSA and MSSA.

To test the activity of telavancin against contemporary isolates of Gram-positive pathogens, Dr. Thomas R. Fritsche, Director, JMI Laboratories, North Liberty, Iowa, and colleagues collected more than 10,000 non-duplicate clinical isolates from North America, Europe, the Asia-Pacific region and Latin America.

Findings showed that the antibiotic was highly potent against isolates collected during 2007 on four continents. The agent inhibited all samples of S. aureus, 45.1% of which were resistant to oxacillin, as well as coagulase-negative strains, 78% of which were oxacillin-resistant, at a minimum inhibitory concentration (MIC) of <u><</u>0.5 µg/mL. It also inhibited 98% of Enterococcus faecalis strains, 2.4% of which were vancomycin-resistant, and 61% of E. faecium strains, 43.4% of which were vancomycin-resistant, again at MIC values <u><</u>0.5 µg/mL.

For the vancomycin-resistant strains of enterococci, 26.8% had telavancin MIC values of <u><</u>1 µg/mL and 76.6% had MIC values of <u><</u>2 µg/mL. The MIC values were <u><</u>0.25 µg/mL for all Streptococcus pneumoniae strains, b-hemolytic streptococci, and viridians group strep. Strains of S. pneumoniae and viridians group strep that were not susceptible to penicillin remained susceptible to telavancin. The novel agent was also more potent than either vancomycin or teicoplanin at inhibiting all strains of Corynebacterium species, with MIC values of <u><</u>0.06 µg/mL, compared with <u><</u>0.5 µg/mL for vancomycin and <u><</u>4 µg/mL for teicoplanin.

CANWARD 2007 Analysis of Isolates

In a substudy of the ongoing CANWARD 2007 surveillance study (Antimicrobial Resistance in Canadian Hospitals), investigators from Diagnostic Services of Manitoba Inc. and the University of Manitoba, Winnipeg, examined 7881 isolates from 12 sentinel hospitals across Canada.

The samples came from patients attending hospital clinics, emergency rooms, medical/surgical wards, and intensive care units. Each centre was asked to submit one pathogen per patient per infection site from blood, respiratory specimens, urine, and wound or intravenous (i.v.) sites. In all, 3473 Gram-positive cocci were obtained. Investigators determined susceptibilities to telavancin and comparators with Clinical and Laboratory Standards Institute (CLSI) broth microdilution, and calculated MIC₅₀ and MIC₉₀ values for telavancin and vancomycin.

“What we found was that telavancin had comparable activity to daptomycin and superior activity to vancomycin,” reported Kim A. Nichol, Diagnostic Services of Manitoba Inc., in a poster presentation session.

Specifically, the investigators found that telavancin was more active in vitro than vancomycin against 74 CA-MRSA isolates and 290 hospital-acquired (HA)-MRSA isolates. For both CA and HA isolates, the MIC₅₀/MIC₉₀ values for telavancin were 0.25 and 0.25, respectively, compared with 1/1 for vancomycin. It also showed more potent in vitro activity against S. pneumoniae, MSSA, and Enterococcus isolates, investigators reported.

Activity Evaluation

The ATTAIN I and II (Assessment of Telavancin for Hospital-Acquired Pneumonia) clinical trials were methodologically identical phase III, double-blind, randomized studies comparing telavancin and vancomycin in patients with HA pneumonia (HAP) that was either suspected of or documented as being caused by Gram-positive pathogens.

From patients with HAP enrolled in the ATTAIN trials, scientist Kevin M. Krause, San Francisco, California, and colleagues examined activity of telavancin, vancomycin, daptomycin, teicoplanin, clindamycin, ciprofloxacin, erythromycin and sulfamethoxazole-trimethoprim against Gram-positive isolates.

Out of a total of 738 aerobic isolates from 1089 patients who yielded a respiratory pathogen at baseline, S. aureus species were the most frequently isolated Gram-positive pathogens, found in 88% of the samples; of these, 63% were MRSA strains. The second-most frequently isolated pathogen were S. pneumoniae strains, found in 7% of samples, one-third of which were resistant to penicillin.

The results showed that telavancin and daptomycin were both potent inhibitors of MRSA, with MIC₉₀ values of 0.5 µg/mL each, followed by vancomycin 1 µg/mL, linezolid and teicoplanin 2 µg/mL each, with other agents at 4 µg/mL or above. The authors noted that telavancin’s activity was not affected by methicillin resistance.

They also found that all species of S. pneumoniae had MIC90 values for telavancin <u><</u>0.06 µg/mL. However, it had generally higher MIC₉₀ values for E. faecalis at 1 µg/mL than for S. aureus or S.peumoniae.

ATTAIN Clinical Results

In the ATTAIN trials, the largest studies ever performed in HAP, a total of 1532 patients were randomly assigned to receive either telavancin 10 mg/kg i.v. every 24 hours or vancomycin 1 g i.v. every 12 hours for seven to 21 days. The primary end point was cure, defined as a complete resolution of the signs and symptoms of pneumonia, with no progression on repeat radiographic imaging at a test-of-cure visit seven to 14 days after the last dose of study drug was delivered; failure was defined as persistence or progression of pneumonia or relapse after end of therapy, cessation of study medication due to lack of efficacy, or death after three or more days, attributable to the primary infection, and indeterminate status.

The clinical cure rates for all microbiologically evaluable patients with S. aureus infections were 84% on telavancin compared with 74% on vancomycin, with an absolute difference of 10% (95% CI: 0.7-19.2). “Telavancin rendered numerically superior results to vancomycin in the sickest category of patients: those with high APACHE [Acute Physiology and Chronic Health Evaluation] scores, with high Clinical Pulmonary Infection Scores, with acute respiratory distress syndrome, with bacteremia, and the elderly,” reported Dr. Ethan Rubinstein, Sellers Professor of Research in Medicine and Head, Section of Infectious Diseases, University of Manitoba.

Of patients with MRSA who received telavancin, 82% were cured, compared with 74% on vancomycin (absolute difference 7.9%; 95% CI: -3.5 to 19.3). For patients with methicillin-susceptible infections, the cure rates were 88% and 75%, respectively (absolute difference 12.2%, two-sided CI: 4.2 to 28.8).

Adverse event profiles were similar for both groups. The most common treatment-emergent adverse events were diarrhea, anemia, hypokalemia, constipation, and decubitus ulcer.

According to investigators, findings suggest that telavancin could be a good option for empirical therapy of patients with HAP suspected of being caused by Gram-positive organisms.

The ATTAIN Study Group members also presented details of an analysis of the efficacy of telavancin on HAP caused by S. aureus strains with varying degrees of susceptibility to vancomycin. They found that the clinical cure rate with telavancin was numerically higher than with vancomycin for all subgroups, and that for the subgroup of patients infected with S. aureus strains with vancomycin MIC <u>></u>1 µg/mL, telavancin produced significantly higher clinical cure rates at 86% vs. 74%, respectively (P<0.05).

Summary

Keeping ahead of ever-evolving micro-organisms will require continual drug development to find new agents with broader spectra of action against both Gram-positive and Gram-negative organisms. Experts agree that even with effective, rapidly bactericidal agents such as telavancin, it will be necessary to continually monitor for the emergence of resistant strains.

Note: At press time, telavancin is not available for use in Canada.