Results of a new international phase 4 study of patients with nosocomial pneumonia due to culture-proven methicillin-resistant Staphylococcus aureus(MRSA) demonstrated that the antibiotic Zyvox (linezolid) achieved a statistically significantly higher clinical success rate compared with vancomycin for the primary endpoint. The ZEPHyR (Linezolid in the treatment of subjects with nosocomial pneumonia proven to be due to methicillin-resistant Staphylococcus aureus) study was the largest ever conducted in this population. These findings will be presented at the 48th Annual Meeting of the Infectious Diseases Society of America in Vancouver.

Investigators from 156 centres worldwide randomised 1,225 patients, of whom 448 patients had proven MRSA nosocomial pneumonia (modified intent-to-treat group); 339 patients also met key protocol criteria at the end of study (per-protocol group) and were included in the primary analysis. Clinical success rates at the end of study were 57.6 percent (95/165) for patients treated with linezolid compared with 46.6 percent (81/174) for patients treated with vancomycin in the per-protocol group, the primary endpoint. These results demonstrated that linezolid achieved a statistically significantly higher clinical success rate compared to vancomycin (95 percent confidence interval for the difference in response rates: 0.5 percent, 21.6 percent; p=0.042). Results were consistent for the per-protocol group at end of treatment and for all MRSA pneumonia subjects (modified intent-to-treat) at end of treatment and end of study. Microbiologic success was also consistent in both the per-protocol and the modified intent-to-treat groups at both end of treatment and end of study.

"Nosocomial pneumonia continues to be a significant cause of illness, and when these infections are due to MRSA, our options are limited, as there are few antibiotics that are effective against this resistant organism," said study investigator Dr. Jean Chastre, Professor of Medicine and Critical Care Medicine, University Paris 6, Réanimation Médicale, Pitié-Salpêtrière Hospital, Paris. "The findings, which show a higher cure rate for linezolid compared with vancomycin, provide important information for physicians who treat nosocomial pneumonia caused by MRSA."

According to the European Centre for Disease Prevention and Control, an estimated 4.1 million patients acquire healthcare-associated infections (HCAI) in the EU every year and there are at least 37,000 deaths occurring as a direct consequence of these infections.1

The 2007 Annual Report of the European Antimicrobial Resistance Surveillance System (EARSS) describes the effectiveness of antibiotics across Europe between 1999 and 2006. The report found high prevalence of MRSA in most European Countries, with large intercountry and intercentre variations. The proportion of S. aureus infections due to MRSA varies from 0% in northern Europe to 50% in southern Europe, and rates of 60% have been reported in some intensive care units (ICU).2 Nosocomial pneumonia caused by resistant pathogens such as MRSA has the potential to become a severe and life-threatening infection. 3, 4

"Pfizer is committed to research in infectious diseases, and data from this large comparative study add to the body of evidence for linezolid in the treatment of MRSA nosocomial pneumonia and reinforce its efficacy in this patient population," said Dr. Mark Kunkel, Executive Director, Clinical Group Lead for Anti-infective Drugs.

Safety data were assessed in all patients who received at least one dose of study drug, the intent-to-treat group (N=1,184). Treatment-related adverse events, serious adverse events and deaths were comparable for linezolid and vancomycin. Adverse events were considered treatment-related for 16.2 percent of linezolid patients and 18.4 percent of vancomycin subjects. Treatment-related adverse events reported in 1 percent or more of linezolid patients were diarrhoea (3.7 percent), rash (2.7 percent), constipation (1.0 percent) and nausea (1.0 percent). Treatment-related adverse events reported in 1 percent or more of vancomycin patients were diarrhoea (4.3 percent), nausea (1.9 percent), rash (1.7 percent), anaemia (1.4 percent) and acute renal failure (1.4 percent). Overall, 208 patients in each group reported serious adverse events; these were considered treatment-related in five linezolid patients and thirteen vancomycin patients. Deaths occurred in 18.3 percent of patients who received linezolid and 19.4 percent of patients who received vancomycin.

More About the ZEPHyR Study

This phase 4, randomized, double-blind, multicenter prospective trial compared the efficacy and safety of linezolid with vancomycin in the treatment of nosocomial pneumonia proven to be caused by MRSA, a serious and difficult-to-treat bacterial infection that is resistant to many antibiotics. The study randomized 1,225 patients between 2004 and 2010. The study was designed as a non-inferiority study with nested superiority, meaning the primary endpoint would be tested for superiority if it met non-inferiority criteria. The primary endpoint was clinical outcome at end of study (7-30 days post end of therapy) in the per-protocol population. Secondary analyses included clinical outcome at end of treatment in the per-protocol population, clinical outcomes in the modified intent-to-treat population at end of study and end of treatment, microbiologic outcomes at end of study and end of treatment in the per-protocol and modified intent-to-treat populations, and safety and tolerability in the intent-to-treat population. Patients were randomized to receive linezolid IV 600 mg every 12 hours or vancomycin 15 mg/kg every 12 hours over the course of seven to 14 days; vancomycin doses could be titrated at the investigator's discretion based on creatinine clearance and vancomycin trough levels.

About Zyvox (linezolid)

Please refer to the Summary of Product Characteristics for further information relating to linezolid 5

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1. European Center for Disease Prevention and Control. Available at here. Accessed September 2010.

2. European Antimicrobial Resistance Surveillance System (EARSS). Accessed October 2010

3. The 2007Annual report of the European Antimicrobial Resistance Surveillance System (EARSS). Available here. Accessed October 2010

4. Kollef MH, Micek ST. Staphylococcus aureus pneumonia: a "superbug" infection in community and hospital settings. Chest. 2005;128:1093-1097.

5. Zyvox® Summary of Product Characteristics. Available here.

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