Category: Critical Care
Linezolid, an antimicrobial agent in the oxazolidinone class, often used to cover MRSA and/or VRE, is a reversible MAOI that increases the risk of serotonin syndrome, particularly when administered with other serotonergic agents.
In 2011, the US FDA issued a warning against concomitant use of Linezolid and other serotonergic agents, particularly SSRIs and SNRIs. When use of linezolid is absolutely indicated, an appropriate washout period prior to initiation was recommended.
Based on published reports and retrospective reviews, the incidence of linezolid-associated serotonin toxicity is between 0.54% and 18.2%.
A study published in the Journal of Clinical Psychopharmacology in Oct 2017 examined the incidence of serotonin syndrome with combined use of linezolid and SSRIs/SNRIs compared with linezolid alone and though there was a trend toward increased incidence in patients on SSRI/SNRIs, the authors were unable to find a statistically significant difference.
-Study was retrospective
-Incidence of serotonin syndrome in both groups was very low: 1/87 (1.1%) in Linezolid + SSRI/SNRI group compared to 1/261 (0.4%) in Linezolid alone group.
-Patients in “Linezolid alone” group were not on SSRIs or SNRIs, but were allowed to be on other serotonergic medications.
Despite this study, there are many (>30) case reports of Linezolid-associated serotonin syndrome in patients taking other serotonergic agents.
Cyproheptadine (the “antidote”) is an H1 antagonist and nonspecific serotonin antagonist. A single case study published in 2016, reported successful use of cyproheptadine for prophylaxis against serotonin toxicity in a patient with schizophrenia, depression, and severe osteomyelitis requiring treatment with linezolid while on fluoxetine.
Risk of linezolid-associated serotonin syndrome may be lower than previously thought, however, it is still not recommended for use in patients taking concomitant serotonergic agents without an appropriate washout period.
In case of resistant infection with no other antibiotic treatment options, the risks and benefits of concomitant administration must be weighed seriously and providers must familiarize themselves with and be vigilant in watching for signs/symptoms of serotonin toxicity.
In situations where use of linezolid is unavoidable in patients on concomitant serotonergic agents, prophylactic cyproheptadine may be considered.
Karkow DC, Kauer JF, Ernst EJ. Incidence of Serotonin Syndrome With Combined Use of Linezolid and Serotonin Reuptake Inhibitors Compared With Linezolid Monotherapy. J Clin Psychopharmacol. 2017;37(5):518-523. doi:10.1097/JCP.0000000000000751.
Deardorff OG, Khan T, Kulkarni G, Doisy R, Loehr C. Serotonin Syndrome: Prophylactic Treatment With Cyproheptadine. Prim Care Companion CNS Disord. 2016;18(4). doi:10.4088/PCC.16br01966.
Woytowish MR, Maynor LM. Clinical Relevance of Linezolid-Associated Serotonin Toxicity. Ann Pharmacother. 2013;47(3):388-397. doi:10.1345/aph.1R386.
Ramsey TD, Lau TT, Ensom MH. Serotonergic and Adrenergic Drug Interactions Associated with Linezolid: A Critical Review and Practical Management Approach. Ann Pharmacother. 2013;47(4):543-560. doi:10.1345/aph.1R604.