Linezolid (Zyvox®, Pfizer) is a synthetic antibacterial agent belonging to the oxazolidinones class of antimicrobial agents. It is licensed for the treatment of nosocomial- and community-acquired pneumonia and for complicated or uncomplicated skin and skin structure infections caused by methicillin or vancomycin resistant gram-positive bacteria.

A clinical trial in adult patients with catheter-related gram-positive bloodstream infections showed a higher mortality rate in the linezolid arm [78/363 (21.5%)] versus the comparator drugs [58/363 (16.0%)] at 84 days post-study admission with an estimated odds ratio of 1.426 [95% CI 0.970–2.098] based on results from logistic regression. The study was an open-label, randomised, comparator-controlled phase 3 study of intravenous/oral linezolid (600mg q12h) versus comparator [intravenous vancomycin (1g q12h) or intravenous oxacillin (2g q6h) followed by oral dicloxacillin (500mg q6h)] with a treatment duration of 7 to 28 days.

While causality has not been established, the observed mortality imbalance occurred primarily in linezolid-treated patients in whom either gram-negative pathogens, mixed gram-negative and gram-positive pathogens, or no pathogen were identified at baseline. Patients randomised to linezolid who had only a gram-positive infection at baseline, including the subgroup of patients with gram-positive bacteraemia experienced a survival rate similar to the comparator group.

From the company's analysis of the mortality data, a major finding was a lower than predicted mortality incidence in the comparator group and a greater overall incidence of gram-negative bloodstream infections in the linezolid group with a higher mortality in the linezolid patients who had gram-negative infections.

The company also noted that the antibiotic treatment for patients with gram-negative infection who died was assessed as inadequate in both arms of the study and may have been a contributing factor to the overall number of deaths in the study.

Arising from this study, HSA is working with the company to update the safety information in the local package insert of Zyvox® to include the findings of this study to remind healthcare professionals that linezolid has no clinical activity against gram-negative pathogens and is not approved for the treatment of gram-negative infections or for the treatment of patients with catheter-related bloodstream infections. Specific gram-negative therapy is required if a concomitant gram-negative pathogen is documented or suspected.