Special Feature
Linezolid (Zyvox)—A New Antimicrobial in the Fight Against Antimicrobial Resistance
By Thomas G. Schleis, MS, RPh
Linezolid is the first in a class of synthetic antibiotics known as oxazolidinones. It has been shown to be effective against vancomycin-resistant strains of Enterococcus faecium, Staphylococcus aureus (including methicillin-resistant strains), Streptococcus agalactiae, penicillin-resistant strains of Streptococcus pneumoniae, and Streptococcus pyogenes in in vitro and clinical infections. Linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process. Linezolid is bacteriostatic against enterococci and staphylococci and bactericidal for the majority of strains of streptococci. Because it inhibits bacterial protein synthesis by a mechanism different from other antibacterial agents, cross-resistance between linezolid and other agents is felt to be unlikely.
When administered either intravenously or orally every 12 hours, linezolid exhibits a half-life of approximately five hours with maximum plasma concentrations reached approximately 1-2 hours after dosing. Bioavailability from the oral formulations is approximately 100%, resulting in the same dosing either orally or intravenously. Linezolid can be administered without regard to meals.
Linezolid is rapidly distributed to well-perfused tissues. The ratio of linezolid in saliva relative to plasma is 1.2:1 and for sweat relative to plasma was 0.55:1. The concentration-independent plasma protein binding of linezolid is approximately 31% and it exhibits a volume of distribution of 40-50 liters in healthy adults.
Linezolid is primarily metabolized by oxidation of the morpholine ring, resulting in two inactive metabolites. Nonrenal clearance accounts for approximately 65% of the total clearance of linezolid, with approximately 30% of the dose appearing in the urine as linezolid, 40% as metabolite B, and 10% as metabolite A. While there is accumulation of metabolites of linezolid in patients with renal impairment, the clinical significance of this is unknown. As a result of this and other information, no dosage adjustments are suggested in patients with renal or hepatic insufficiency, or for elderly patients. There are limited data on treatment of pediatric patients with linezolid and it does not have FDA approval for that patient population.
Linezolid is indicated for adult patients with the following:
• Vancomycin-resistant E. faecium;
• Nosocomial pneumonia caused by S. aureus or S. pneumoniae (penicillin-susceptible strains);
• Complicated skin infections caused by S. aureus, S. pyogenes, or S. agalactiae;
• Uncomplicated skin infections caused by S. aureus (methicillin-susceptible strains) or S. pyogenes;
• Community-acquired pneumonia caused by S. pneumoniae (penicillin-susceptible strains) or S. aureus (methicillin-susceptible strains).
The most common adverse reactions in patients treated with linezolid were diarrhea, headache, and nausea. Other adverse events reported were oral and vaginal moniliasis, hypertension, dyspepsia, localized abdominal pain, pruritus, and tongue discoloration.
Pseudomembranous colitis and thrombocytopenia have been reported in patients receiving linezolid. While pseudomembranous colitis can occur with most antimicrobials, thrombocytopenia is more specific to linezolid and platelet counts should be monitored in patients who are at increased risk for bleeding.
Even more specific to linezolid is its ability to inhibit monoamine oxidase. This can potentially result in a number of drug-drug and drug-food interactions. Medications and foods with which interactions may occur include: adrenergic agents; sympathomimetic agents; vasopressors; dopaminergic agents; serotonergic agents; monoamine oxidase inhibitors (e.g., Nardil and Parnate); selective serotonin reuptake inhibitors (e.g., Prozac, Paxil, Zoloft, Celexa, Luvox, and Effexor); and foods high in tyramine (e.g., aged cheeses, smoked meats, sauerkraut, tap beers, red wines, soy sauce, etc.).
Dosages of linezolid for various indications are:
• Vancomycin-resistant E. faecium infections—600 mg IV or po q 12 hours for 14-28 days;
• MRSA—600 mg IV or po q 12 hours;
• Nosocomial or community-acquired pneumonia—600 mg IV or po q 12 hours for 10-14 days;
• Complicated skin infections—600 mg IV or po q 12 hours for 10-14 days;
• Uncomplicated skin infections—400 mg po q 12 hours for 10-14 days.
Linezolid is available as ready-to-use injections of 200, 400, and 600 mg; oral tablets of 400 and 600 mg; and an oral suspension of 100 mg/5 mL in 240-mL bottles. The average wholesale pricing (AWP) for each dose of the 600-mg injectable is $71.88 and for the 600-mg tablet is $53.12.
Like the recently released Synercid (dalfopristin/ quinupristin), the main interest in linezolid will be in the treatment of infections due to vancomycin-resistant E. faecium and resistant organisms when other antimicrobials are contraindicated. Most clinicians will limit its use in other areas due to the high cost of therapy and to avoid the potential of resistance development.
Most notable for linezolid is the potential for drug-food interactions due to its inhibition of monoamine oxidase. The true significance and incidence of interactions is not known and the manufacturer of linezolid, Pharmacia & Upjohn, can only suggest the likelihood of occurrences at this time. In our practice we had one incident of hypertension with a patient on Zoloft receiving linezolid, but have not completed our investigation into what role, if any, linezolid may have played. Nevertheless, it is an area that requires caution when prescribing linezolid, as many patients may not provide complete and factual information as to medications they are taking.
Fortunately, we now have two antibiotics that are potentially effective against vancomycin-resistant organisms, allowing us to maintain a fragile control over the problem of bacterial resistance.
Linezolid is indicated for adult patients with which of the following?
a. Vancomycin-resistant E. faecium
b. Complicated skin infections caused by S. aureus, S. pyogenes, or S. agalactiae
c. Uncomplicated skin infections caused by S. aureus (methicillin-susceptible strains) or S. pyogenes
d. Community-acquired pneumonia caused by S. pneumoniae (penicillin-susceptible strains) or S. aureus (methicillin-susceptible strains)
e. All of the above
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