Special Feature
Linezolid: New Agent for Old Bugs
By Uday B. Nanavaty, MD
Gram-positive infections are emerging as the most common nosocomial infections in ICUs across the United States. These gram-positive infections are caused by organisms such as staphylococci, streptococci, and enterococci. Recently, there has been increasing concern about drug resistance among these gram-positive cocci. Colonization and infection with vancomycin-resistant enterococci (VRE) are encountered in almost all ICUs. Methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis are also commonly seen in the ICU environment. Cases of S. aureus with intermediate resistance to vancomycin (VISA) have been reported. Penicillin-resistant Streptococcus pneumoniae are found in up to 25% of cases of community-acquired pneumococcal pneumonias throughout the country.
Thus, resistant gram-positive infections are a common problem in the ICU. Until the introduction of quiniprustin/dalfoprostin, vancomycin was the only agent with reasonable activity against a lot of the organisms causing these infections. There was no satisfactory therapy for VRE infections. Quiniprustin/dalfoprostin and linezolid were both developed specifically for gram-positive infections, and have now been introduced to clinical practice. Linezolid in particular is among the newest additions to the list of FDA-approved antimicrobial agents,1-5 and will surely find increasing use in ICU practice. The drug was developed by Pharmacia and Upjohn and is available with the brand name Zyvox.
History
Linezolid belongs to the oxazolidinone class of drugs. It is a new class of antimicrobial agent, and no other drug from this class has previously been used in clinical practice. Of note, this class of drugs was initially developed for control of bacterial and fungal foliage disease of tomatoes and other plants. Chemical derivatives tried initially were shown to be effective against gram-positive bacteria and Mycobacterium tuberculosis, but were not developed for clinical use due to lethality seen in rats.
Subsequent chemical modifications have resulted in safe and effective compounds, one of which, linezolid, has undergone clinical trials. Although several large clinical trials have been performed in patients with community-acquired pneumonia (CAP), skin- and soft-tissue infections, and nosocomial pneumonia, so far most of the data have only been published in abstract form. Most available information is in review articles citing personal communications by their authors with the company.
Mechanism of Action
Linezolid and other oxazolidinone drugs act by inhibiting protein synthesis in susceptible bacteria. The binding site for protein synthesis inhibition is the 50S ribosomal sub unit. It inhibits the formation of the 30S initiation complex, thereby inhibiting protein synthesis in bacteria at a very early step. This is a unique mechanism, as no other antimicrobial class interferes with this initiator complex formation. Because this class of drugs acts early on translation machinery in bacteria, cross resistance with other classes of drugs is less likely than with other types of antimicrobials. The drug is bacteriostatic rather than bacteriocidal, although the clinical implications of this are not clear, as it has been shown to clear bacterial infections successfully.
Pharmacology
Linezolid is 100% bio-available via the oral route, and can also be administered intravenously via peripheral veins. After an oral dose, peak plasma levels are achieved within one to two hours. Although food affects the maximum concentration of the drug, the area of the curve for plasma concentration over time remains largely unchanged. The minimum plasma levels remain above the minimum inhibitory concentration (MIC) after twice daily dosing in healthy volunteers. Excretion in urine seems to be the primary route of clearance. The drug does undergo nonenzymatic oxidation, mediated via reactive oxygen species, in vivo. This oxidation results in metabolites with low antibacterial activity. The elimination half-life was 4.5-5.5 hours under single dose and steady-state conditions in volunteers.
No dose adjustment is warranted based on age. Also, no dose adjustment is recommended for patients with mild to moderate renal or hepatic dysfunction. Supplemental dosing may be necessary for patients undergoing hemodialysis. The FDA warns against possible interaction with over-the-counter cold remedies. Aztreonam has been administered with linezolid in clinical trials without any untoward interaction.
Laboratory Studies
A large number of bacterial isolates have been tested against linezolid, and its activity has been in general comparable to those of other drugs effective against those bacteria. In vitro data suggest that linezolid is effective against MRSA, VRE (E. faecium and E. faecalis) penicillin-resistant pneumococci, corynebacteria, some gram-negative anaerobes, and mycobacteria. It is slightly less active against Legionella species, Chlamydia pneumoniae, and Haemophilus influenzae. For most of the gram-positive organisms, the minimum inhibitory concentration for 90% of the strains tested (MIC90) was less than 4 mg/mL.
Clinical Studies
Most of the clinical studies proving efficacy and safety of linezolid have only been published in abstract form. Some small case series and single case reports reporting experience with off-label "compassionate use" have also been published in peer-reviewed journals.
The efficacy of linezolid in skin and soft tissue infections has been established with a study involving about 800 patients. In this study linezolid was compared to oxacillin/dicloxacillin. In another study of soft tissue infection, it has been compared to vancomycin with equal efficacy. In outpatients with CAP, linezolid was as effective as cefpodoxime. In hospitalized patients with CAP, linezolid was as effective as intracenous ceftriaxone followed by orally-administered cefpodoxime. Intravenous linezolid at a twice-daily dose of 600 mg achieved clinical cure in 88.6% patients with VRE infections. In a large group of neutropenic patients (88% of whom had E. faecium infections), treated in "compassionate use" protocol, clinical cure was achieved in about 70% of patients. In nosocomial pneumonia, a combination of linezolid and aztreonam was as effective as a combination of vancomycin and aztreonam. At this point, experience with critically ill patients with bacteremia is limited.
Resistance
Two isolates during treatment under "compassionate use" protocols have shown rising MICs against linezolid. Both patients from whom these isolates were recovered had indwelling devices that could not be removed. The clinical implications and mechanisms of this are unknown.
FDA Approval
The FDA has approved the use of linezolid in infections with VRE (E. faecium), including bloodstream infections, hospital-acquired pneumonia, and complicated skin and skin-structure infections. It has also been approved for CAP and uncomplicated skin and skin-structure infections.
Dosage
Currently, the recommended dosage of linezolid is 600 mg, orally or intravenously, twice daily. At present, adjustment for mild-to-moderate hepatic or renal dysfunction is not suggested. No dose adjustment is suggested for elderly patients.
Adverse Effects
The most common side effects have been headache, nausea, diarrhea, and vomiting. To date, the most important laboratory changes have been decreases in blood platelet and white blood cell counts. It is unclear at this point how many patients will be unable to tolerate linezolid for one reason or another. Again of note, there is limited experience with the use of this drug in severely ill bacteremic patients.
Summary (See Table)
Linezolid 1-5 is a new class of antibacterial agent that works by inhibiting the initiation of protein synthesis at a proximal step. The drug can be given either orally or intravenously. So far in clinical studies the drug has had an excellent safety profile, and it appears to be effective in a wide variety of resistant gram-positive infections, including those caused by MRSA and VRE. Judicious use of this drug may lead to a decrease in the spread of resistant gram-positive infections. So far, limited experience is available for its routine use in ICU.
| Table: A Quick Overview of Linezolid | |
| • | An oxazolidinone—a new class of antimicrobials |
| • | Either oral or intravenous administration |
| • | Minimal side effects |
| • | Comparable efficacy against a wide variety of gram-positive infections, including MRSA and VRE |
| • | Dosage is 600 mg twice daily |
| • | No adjustment in mild-to-moderate renal or hepatic dysfunction |
| • | No cross resistance with other agents |
| • | Bacteriostatic |
| • | Limited data on use in ICU |
References
1. Clemett D, Markham A. Linezolid. Drugs 2000;59: 815-827.
2. Dresser LD, Rybak MJ. The pharmacologic and bacteriologic properties of oxazolidinones, a new class of synthetic antimicrobials. Pharmacotherapy 1998; 18:456-462.
3. Lundsrom TS, Sobel JD. Antibiotics for gram positive bacterial infections. Infect Dis Clin North Am 2000; 14:463-474.
4. Chien JW, et al. Use of linezolid, an oxazolidinone, in treatment of multidrug resistant gram positive bacterial infections. Clin Infect Dis 2000;30:146-151.
5. FDA talk paper on Zyvox at www.fda.gov.
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