Pharmacology Update
Linezolid (Zyvox): A New Antibiotic for Resistant Gram-Positive Organisms
By William T. Elliott, MD, FACP and James Chan, PharmD, PhD
The oxazolidinones are a new class of anti-microbial agents with a wide range of activity against many important human pathogens including many gram-positive bacteria. The FDA recently approved linezolid (Zyvox—Pharmacia & Upjohn), the first agent in this class. Linezolid is bioavailable both parenterally and orally and is active against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, among others.
Indications
Linezolid is indicated for the treatment of infections in adults caused by designated susceptible microorganisms:
• Vancomycin-resistant Enterococcus faecium including concurrent bacteremia.
• Nosocomial pneumonia caused by S. aureus (methicillin-suspectible and -resistant strains), or Streptococcus pneumoniae (penicillin-susceptible strains only).
• Complicated skin and skin structure infections caused by S. aureus (methicillin-susceptible and -resistant strains), Streptococcus pyogenes, or Streptococcus agalactiae.
• Uncomplicated skin and skin structure infections caused by S. aureus (methicillin-susceptible strains only) or S. pyogenes.
• Community-acquired pneumonia caused by S. aureus (methicillin-suspectible strains only), or S. pneumoniae (penicillin-susceptible strains only).
Combination therapy may be clinically indicated if gram-negative organisms are documented or suspected.
Dosage
For vancomycin-resistant E. faecium infections, including concurrent bacterium, the recommended dose is 600 mg IV or orally every 12 hours for 14-28 consecutive days. For nosocomial pneumonia, community-acquired pneumonia (including concurrent bacteremia), or complicated skin and skin structure infections the dose is 600 mg IV or orally every 12 hours for 10-14 consecutive days. For uncomplicated skin and skin structure infections, the dose is 400 mg orally for 10-14 consecutive days.1 Linezolid may be taken without regard to meals, but high-fat food should be avoided. No dosage adjustment is needed for geriatric patients or those with moderate renal impairment. Two metabolites of linezolid may accumulate in patients with renal impairment and the accumulation increases with the severity of impairment.1
Linezolid is available as injections (2 mg/mL, 100 mL, 200 mL, 300 mg), 400 mg and 600 mg tablets, and powder for oral suspension (100 mg/5 mL, 150 mL).
Potential Advantages
Linezolid is well absorbed after oral administration with bioavailability close to 100%. It may be administered intravenously or orally without dose adjustment.1 This allows for step-down therapy and outpatient treatment. Linezolid is not an inducer of cytochrome P450 isoenzymes and is not detectably metabolism by this system; thus, drug interactions involving P450 system are unlikely.1 In vitro data suggest that linezolid may be more active than either vancomycin or quinupristin/dalfopristin against Enteroccocus faecalis.2
Potential Disadvantages
Linezolid is a reversible nonselective inhibitor of monoamine oxidase. Mean maximum increases in systolic blood pressure of 32-38 mg Hg have been reported in normotensive subjects coadministered with pseudoephedrine (60 mg) or phenylpropanolamine (25 mg) given as two doses four hours apart.1 These changes were seen 2-3 hours after the second dose of pseudoephedrine or phenylpropanolamine and returned to baseline 2-3 hours after peak. Large quantities of foods or beverages with high tyramine content should be avoided.1 The most common side effects are diarrhea (2.8-11%), headache (0.5-11.3%), and nausea (3.4-9.6%).1 Thrombocytopenia has been reported in subjects who were treated with 600 mg every 12 hours for up to 28 days.1 Patients at risk for bleeding, those with pre-existing thrombocytopenia, those concurrently taking medication that may decrease platelets, or those who may require therapy of two weeks or longer should be monitored. The estimated rates of thrombocytopenia were 5% for subjects receiving more than 1 g per day and 3% for those receiving less than 1 g per day.6 Resistant E. faecium has been seen in clinical trials.1 The availability of linezolid as an oral formulation may increase the potential for inappropriate use and lead to resistant strains.
Comments
Linezolid is the first approved member of a new class of antimicrobial agents, the oxazolidinones. These drugs inhibit protein synthesis by binding to bacterial 23 S ribosomal RNA of the 50s subunit. Linezolid is bacteriostatic against enterococci and staphylococci, and bactericidal for the majority of streptococci strains.1,3 It is active against multidrug-resistant enterococci and multi-resistant gram-positive bacteria.2,5 It is active against penicillin-sensitive, intermediate, and resistant S. pneumoniae as well as strains resistant to erythromycin, ceftriaxone, clindamycin, and tetracycline.3 The cure rate based on an intent-to-treat analysis in subjects with documented vancomycin-resistant enterococcal infections with or without bacteremia was 67% (39/58) for the high dose (600 mg every 12 hours) and 52% (24/46) for the low dose (200 mg every 12 hours) when treated for 7-28 days.1 Subjects could receive aztreonam or aminoglycoside if clinically indicated. This study was conducted without a comparator and the FDA’s Antiinfective Drug Advisory Committee has recommended a comparative trial with quinupristin/dalfopristin.4 The cure rate for nosocomial pneumonia based on a modified intent-to-treat analysis was 57% (n = 94) for linezolid and 46% (n = 83) for vancomycin. The cure rate for complicated skin and skin structure infections was 86% (n = 316) for linezolid and 82% (n = 313) for oxacillin.1
Clinical Implications
Linezolid is the second antimicrobial to be recently approved for treatment of vancomycin-resistant E. faecium after quinupristin/dalfopristin (Synercid). There are currently no head-to-head trials between linezolid and quinupristin/dalfopristin. In addition, linezolid is approved for the treatment of methicillin-resistant S. aureus in nosocomial and complicated skin and skin structure infections. The major advantage of linezolid is its oral bioavailability. Linezolid may be a useful alternative to vancomycin and streptogramin (quinu-pritin/dalfopristin) as cross-resistance has not been observed among these classes. Pharmacia & Upjohn is expected to submit additional efficacy data for the treatment of infections due to penicillin-resistant S. pneumoniae in hopes of gaining FDA approval for these indications. The average wholesale cost of linezolid (600 mg twice daily) is about $100 per day for the tablets and about $140 for the injectable.
References
1. Zyvox Product Information. April 2000. Pharmacia & Upjohn Company.
2. Johnson AP, et al. J Antimicrob Chemother 2000;45: 225-230.
3. Clemett D, et al. Drugs 2000;59(4):815-827.
4. FDC Report. The Pink Sheet 2000;62(13):28.
5. Bostic GD, et al. Diagn Microbiol Infect Dis 1998; 30:109-112.
6. FDC Report. The Pink Sheet 2000;62(14):11-12.
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