What is the relationship between Linezolid (an antibiotic) and Serotonin Syndrome?

From the Guidelines

Linezolid should not be used with serotonergic medications due to the risk of potentially life-threatening serotonin syndrome. Linezolid is an antibiotic that also functions as a monoamine oxidase inhibitor (MAOI), which can increase serotonin levels in the brain. When combined with other medications that increase serotonin (such as SSRIs, SNRIs, TCAs, triptans, certain opioids like tramadol and meperidine, dextromethorphan, St. John's wort, and other MAOIs), dangerous serotonin accumulation can occur. Symptoms of serotonin syndrome include agitation, confusion, hyperthermia, muscle rigidity, tremor, seizures, and autonomic instability.

Key Considerations

• If linezolid treatment is necessary for a patient on serotonergic medications, the serotonergic agent should ideally be discontinued at least 2 weeks before starting linezolid, as suggested by the most recent guideline evidence 1.
• In urgent situations where linezolid must be used, close monitoring for serotonin syndrome is essential, particularly during the first 24-72 hours of treatment.
• After completing linezolid therapy, wait at least 24 hours before restarting serotonergic medications.
• Always consult with pharmacy services when considering linezolid for patients on any potentially interacting medications, as highlighted in the clinical practice guidelines 1.

Mechanism and Risks

• Linezolid's mechanism as a monoamine oxidase inhibitor (MAOI) increases the risk of serotonin syndrome when combined with serotonergic agents, as noted in the study published in the American Journal of Respiratory and Critical Care Medicine 1.
• The risk of serotonin syndrome is a significant concern, and healthcare providers should be aware of the potential for dangerous serotonin accumulation when prescribing linezolid to patients on serotonergic medications.

Clinical Guidance

• The most recent and highest quality study 1 emphasizes the importance of strict clinical monitoring for potential toxicity, including peripheral neuropathy, optic neuritis, anemia, and leukopenia, when using linezolid.
• The guidelines also recommend assessing for visual toxicity after restarting linezolid, and considering a reduced dose of 300 mg daily to avoid recurrent visual toxicity.

From the FDA Drug Label

Potential Serotonergic Interactions Unless patients are carefully observed for signs and/or symptoms of serotonin syndrome, linezolid should not be administered to patients with carcinoid syndrome and/or patients taking any of the following medications: serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), meperidine or buspirone Serotonergic Agents: Co-administration of linezolid and serotonergic agents was not associated with serotonin syndrome in Phase 1,2 or 3 studies Spontaneous reports of serotonin syndrome associated with co-administration of ZYVOX and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported.

The relationship between Linezolid and Serotonin Syndrome is that co-administration of linezolid with serotonergic agents may increase the risk of serotonin syndrome. Patients who are treated with linezolid and concomitant serotonergic agents should be closely observed for signs and symptoms of serotonin syndrome. 2, 2

From the Research

Relationship Between Linezolid and Serotonin Syndrome

• Linezolid is a reversible, nonselective monoamine oxidase inhibitor that can increase the risk of serotonin syndrome when used with serotonergic agents, such as selective serotonin reuptake inhibitors (SSRIs) 3, 4, 5, 6, 7.
• The incidence of linezolid-associated serotonin toxicity is reported to be between 0.54% and 18.2% 6.
• Most cases of serotonin syndrome occurred in patients concurrently receiving SSRIs 3, 4, 6.
• Receipt of multiple agents with serotonergic activity seems to increase the risk of serotonin toxicity 6.
• The onset and resolution of symptoms varied from hours to days 6.

Clinical Management and Recommendations

• Clinicians should obtain complete drug histories to identify patients at risk and strictly monitor drug therapy, including concomitant drugs 4.
• Education about this potential drug interaction and the symptoms of serotonin syndrome is essential for clinicians 4.
• The Food and Drug Administration recommends avoiding the use of linezolid in patients receiving select serotonergic agents, highlighting the need to carefully balance the risk/benefit ratio in this situation 6.
• However, some studies suggest that linezolid may be used concomitantly with SSRIs without a 14-day washout period, with careful monitoring for signs and symptoms of serotonin syndrome 3, 7.

Case Reports and Studies

• A retrospective chart review of 72 patients who received linezolid and an SSRI or venlafaxine within 14 days of each other found that only 2 patients (3%) had a high probability of serotonin syndrome 3.
• A case series reported on two hospitalized patients who developed serotonin syndrome while being treated with linezolid for pedal infections and receiving serotonergic agents for depression 5.
• A retrospective case-control study of 348 patients found that the incidence of serotonin syndrome was low, with no significant difference when linezolid was used alone or in combination with an SSRI or SNRI 7.