US Pharm. 2006;11:HS-41-HS-42.

Linezolid (Zyvox, Pfizer) is an oxazolidinone antibiotic indicated for the treatment of infections caused by vancomycin-resistant enterococcus, methicillin-resistant Staphylococcus aureus, and other aerobic gram-positive bacteria. Linezolid inhibits protein synthesis of susceptible bacteria by binding to 23S on the 50S subunit of bacterial ribosomal RNA to prevent the formation of the 70S-initiation complex necessary for translation.1 Serious side effects of linezolid therapy include myelosuppression and peripheral neuropathy. However, the side effect profile of linezolid is quite favorable, with gastrointestinal side effects most frequently reported. As linezolid exhibits near 100% oral bioavailability, it does not require dosage conversion from parenteral to oral regimens. Linezolid is metabolized by oxidation and is not a substrate of the cytochrome P450 system. Clearance is primarily nonrenal; thus, dose adjustment in patients with renal dysfunction is not necessary, although two primary metabolites of linezolid may accumulate.1 Thus, linezolid is an attractive antibiotic choice that can easily be used on an inpatient or outpatient basis; however, one must be aware of potential drug interactions.

Linezolid possesses nonspecific monoamine oxidase inhibition. Because serotonin and other catecholamines are metabolized by monoamine oxidase, linezolid may interact with adrenergic, serotonergic, and dopaminergic agents. It may interact with dopamine, pseudoephedrine, selective serotonin reuptake inhibitors (SSRIs) such as paroxetine and fluoxetine, serotonin noradrenergic reuptake inhibitors such as venlafaxine and nefazodone, and other monoamine oxidase inhibitors such as phenelzine and tranylcypromine. Linezolid also interacts with certain foods, such as those containing tyramine (e.g., aged meats, cheeses, beer, wine). Serotonergic agents promote synaptic release of serotonin or inhibit the metabolism or reuptake of serotonin, leading to increased levels in the central nervous system and periphery. Although toxicity from coadministration of linezolid and serotonergic agents is not reported in phase I, II, or III trials,2 multiple case reports describe temporally related linezolid administration and serotonin toxicity manifesting as serotonin syndrome.

Serotonin syndrome occurs when there is excess central nervous system or peripheral serotonergic activity and is characterized by altered mental status, autonomic dysfunction, and neuromuscular abnormalities.3 It can occur with single-drug therapy, multiple-drug therapy, or overdose. Use of recreational drugs, such as 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) and lysergic acid diethylamide (LSD), has also been associated with serotonin syndrome. 2 Symptoms of serotonin syndrome include confusion, restlessness, agitation, coma, seizure, lethargy, hyperthermia, tachycardia, diaphoresis, nausea, vomiting, diarrhea, dilated pupils, hyperreflexia, myoclonus, rigidity, trismus, and death. Laboratory tests may reveal increased white blood cell count, increased creatinine phosphokinase, and decreased serum bicarbonate. Early recognition and withdrawal of the offending agents is essential.3-5 Diagnosis of serotonin syndrome is based on signs and symptoms and medication history.3 Toxicity is treated with supportive care, including mechanical ventilation, external cooling, sedatives, paralytics, anticonvulsants, and antihypertensives. Cyproheptadine, a potent antihistamine and antimuscarine antiserotonergic agent, may be used as adjunctive therapy dosed every one to four hours (maximum daily dose of 32 mg/day.5 After withdrawal of offending medication, followed by supportive therapy and treatment, symptoms usually resolve in 24 to 36 hours. 2

Case reports (Table 1) describe the occurrence of serotonin syndrome in patients initiating linezolid who were already taking serotonergic agents, including citalopram, paroxetine, sertraline, and venlafaxine.




It is recommended in the literature to allow two weeks between discontinuation of a serotonergic agent and initiation of linezolid.5-8 Considering the long half-lives of SSRIs, this recommendation is particularly prudent. For example, fluoxetine has an elimination half-life ranging from one to six days, and an active metabolite, norfluoxetine, may have a half-life as long as 16 days. Because of slow elimination, interactions may occur days to weeks after discontinuation of a serotonergic agent, depending on individual patient clearance. It is imperative that linezolid be initiated cautiously with frequent monitoring in patients with a recent history of serotonergic medications.

Ultimately, the recommendation to delay start of linezolid for two weeks is not clinically realistic. A patient with an active infection requiring linezolid therapy cannot wait two weeks before starting an antibiotic. Dose reduction of the serotonergic agent, although empirically reasonable, is not supported by any data. The most reasonable strategy, also representative of clinical practice, is to use linezolid in patients receiving serotonergic agents when the benefit outweighs the risks. These select patients should be educated on the symptoms of serotonin syndrome and should be closely monitored by their primary caregivers.

Monitoring may include complete blood counts, a chemistry panel (especially serum bicarbonate), renal and hepatic function, mental status, and vital signs.1 Linezolid must be discontinued and not restarted until two weeks after discontinuation of an interacting agent, should serotonin syndrome result from a drug interaction. Awareness of this interaction will prevent serious adverse events and even death.

REFERENCES
1. Zyvox [package insert]. New York, NY: Pfizer; 2005 May.
2. Jones SL, Athan E, O'Brien D. Serotonin syndrome due to co-administration of linezolid and venlafaxine. J Antimicrob Chemother. 2004;54:289-290.
3. Lavery S, Ravi H, McDaniel WW, et al. Linezolid and serotonin syndrome. Psychosomatics. 2001;42:432-434.
4. Gillman PK. Linezolid and serotonin toxicity. Clin Infect Dis. 2003;37:1274-1275.
5. Tahir N. Serotonin syndrome as a consequence of drug-resistant infections: an interaction between linezolid and citalopram. J Am Med Dir Assoc. 2004;5:111-113.
6. Wigen CL, Goetz MB. Serotonin syndrome and linezolid. Clin Infect Dis. 2002;34:1651-1652.
7. Bernard L, Stern R, Lew D, et al. Serotonin syndrome after concomitant treatment with linezolid and citalopram. Clin Infect Dis. 2003;36:1197.
8. Hachem RY, Hicks K, Huen A, et al. Myelosuppression and serotonin syndrome associated with concurrent use of linezolid and selective serotonin reuptake inhibitors in bone marrow transplant recipients. Clin Infect Dis. 2003;37:e8-11.
9. Thomas CR, Rosenberg M, Blythe V, et al. Serotonin syndrome and linezolid. J Am Acad Child Adolesc Psychiatry. 2004;43:790.

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