Linezolid bested vancomycin for treatment of nosocomial pneumonia due to
MRSA
IDSA
48th Annual Meeting
Linezolid had an end-of-study success rate that was more than 10% higher
than vancomycin in patients with nosocomial or health care-associated pneumonia
due to Methicillin-resistant Staphylococcus aureus, according to
findings presented at the 48th Annual Meeting of the Infectious Diseases
Society of America.
Jean E. Chastre, MD, of the Reanimation Medicale,
Pitie-Salpetriere Hospital in Paris, France, presented the results of the
phase-4 randomized, double–blind trial that was conducted in 156 centers
worldwide, including 90 sites in the US.
The aim was to compare the efficacy and safety of linezolid with
vancomycin in nosocomial or healthcare–associated pneumonia due to proven
MRSA, according to the results.
There were 1,225 adult participants randomly assigned in a 1:1 ratio to
IV linezolid 600 mg twice a day or vancomycin 15 mg/kg twice
a day. The treatment period was seven to 14 days. Patients were evaluated for
safety and efficacy at the end of treatment and at the end of the study, which
was determined to be 7 to 30 days after the end of treatment.
Protocols
The non-inferiority trial had a nested superiority hypothesis. The
researchers conducted three analyses: intention-to-treat (ITT); modified ITT
(mITT), which involved patients with proven MRSA nosocomial pneumonia; and, per
protocol, which included patients in the mITT group who met key protocol
criteria.
The primary endpoint was the clinical outcome at the end of study in the
per-protocol group. Secondary endpoints included the clinical outcome at the
end of treatment, microbiologic outcome at the end of study and
end-of-treatment outcomes in the mITT group as well as ITT safety and
tolerability.
“We defined cure as the resolution of all signs and symptoms of
pneumonia,” Chastre said. “We defined improvement as improvement of
two or more clinical signs of pneumonia, and failure as persistence or
progression of infection.”
Among 1,184 patients who were treated, 38% were evaluable in the mITT
analysis and 29% were evaluable in the per-protocol group at the end of the
study. The two groups were comparable regarding baseline characteristics and
clinical parameters.
The mean per-protocol APACHE-II scores were 17.2 among patients
receiving linezolid and 17.4 among patients receiving vancomycin. Sixty-seven
percent of linezolid patients and 74% of vancomycin patients in the
per-protocol analysis were ventilated.
Results
Results indicated that 57.6% of patients in the linezolid group and
46.6% of patients in the vancomycin group achieved end-of-study success. This
resulted in both non-inferiority (95% CI, 0.5%, 21.6%) and statistical
superiority (P=.042).
“This is an absolute difference of 11 percentage points,”
Chastre said. “Based on our pre-specified plan, linezolid was not only
non-inferior but superior to vancomycin.”
Chastre said that secondary endpoints were consistent with primary
endpoint results. “We saw statistical superiority for success rates in
several categories, including 83% for linezolid and 70% for vancomycin in the
end-of-treatment per-protocol analysis. In the mITT group, it was 80% vs. 68%
in favor of linezolid.”Chastre also noted statistically significant
superiority for linezolid in eradicating the pathogen, 80% vs. 61%.
“There were 54 deaths and 145 serious adverse events — five of
which were treatment-related — in the linezolid arm and 59 deaths and 141
serious adverse events — 13 of which were treatment-related — in the
vancomycin arm over 60 days of follow-up,” Chastre said.
There were 1,471 adverse events among 378 patients in the linezolid arm
and 1,580 adverse events reported by 410 patients receiving vancomycin. There
were 168 treatment-related adverse events among 97 linezolid patients and 192
treatment-related adverse events among 108 vancomycin patients.
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