Drug Criteria & Outcomes
Review of linezolid (Zyvox)
The first oxazolidinone-class antimicrobial
Introduction
Linezolid (Zyvox, Pharmacia), the first of the oxazolidinone-class antimicrobials, has recently been approved by the Food and Drug Administration (FDA). The oxazolidinones, first described in 1987, possess a unique mechanism of action that accounts for utility of linezolid in multi-drug-resistant gram-positive infections. These agents produce disruption of protein synthesis of gram-positive organisms by binding to the 50S ribosomal subunit to inhibit formation of the 70S bacterial initiation complex, thus preventing bacterial growth and replication. Additionally, linezolid, as a representative of the oxazolidinones, generates only low levels of spontaneous resistance mutations with serial passage of plated staphylococci and enterococci.
Linezolid is indicated for vancomycin-resistant Enterococcus faecium infections, nosocomial pneumonia caused by Staphylococcus aureus (methicillin-sensitive or methicillin-resistant strains), or Streptococcus pneumoniae (penicillin-sensitive strains only). Linezolid also is indicated for complicated skin/skin structure infections caused by S. aureus (both methicillin-sensitive and methicillin-resistant), Streptococcus pyogenes, or Steptococcus agalactiae, as well as for uncomplicated skin/skin structure infections caused by S. aureus (methicillin-sensitive strains only) or S. pyogenes. Additionally, linezolid is indicated for community-acquired pneumonia caused by S. pneumoniae (penicillin-susceptible strains only), including cases with concurrent bacteremia or S. aureus (methicillin-susceptible strains only).
In general, the spectrum of activity of linezolid includes most clinically relevant aerobic gram-positive bacteria and extends to some anaerobes and atypicals. With few exceptions, linezolid has minimal activity against gram- negative aerobes.
Efficacy
FDA approval of linezolid was supported by evaluations involving more than 4,000 patients. However, the majority of data is available only in abstract form or in case series or case reports. Results from several randomized trials are available in summary in the product monograph. One study described in the monograph (n = 145) indicated cure rates of 67% and 52% with high-dose (600 mg twice daily) and low-dose (200 mg twice daily) linezolid, respectively, for the treatment of VRE. The product monograph also provides results of treatment with linezolid 600 mg twice daily compared to vancomycin for the treatment of nosocomial pneumonia; microbiologic cure rates were comparable for the two drugs (n = 396).2
Safety
Adverse events reported in the product monograph include diarrhea (4.3%), nausea (3.4%), headache (2.2%), taste disturbances (1.2%), vaginal moniliasis (1.2%), and abnormal liver function tests (1.1%). These data represent treatment experience with 2,046 patients. However, in one large compassionate-use trial involving 500 patients, the rate of adverse events was 36.3%, with drug discontinuation in 11.4%. The events were classified as "serious" in 5.6%. Among the serious events, thrombocytopenia was the most common, occurring in 1.6% of cases, followed by a reduction in hemoglobin/hematocrit (1.4%).
Drug interactions
Linezolid is metabolized primarily by oxidation of the morpholine ring. It is not detectably metabolized by the cytochrome P450. It is not an inducer or inhibitor of the clinically significant cytochrome P450 isoenzymes. Linezolid exhibits nonselective, weak, reversible monoamine oxidase (MAO) inhibitory potential; the product monograph notes potential interactions with adrenergic or serotonergic agents.
Dosing and administration
Linezolid is available as a tablet, oral suspension, and intravenous injection formulation. Recommended dosing is 600 mg, either IV or orally, every 12 hours for all indications except uncomplicated skin and skin-structure infections, for which the dose is 400 mg (orally only) every 12 hours. No dose adjustment is needed when switching from IV to oral dosing. The recommended treatment duration is 10-28 days, depending on indication. No dosage adjustments are needed for mild-to-moderate hepatic insufficiency or renal insufficiency.
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