If a patient is on caspofungin, linezolid, and Metronidazole (Flagyl), should they remain on their Bupropion (Wellbutrin), Trazodone, and Escitalopram?

Discontinue Escitalopram Immediately; Consider Holding or Discontinuing Other Psychiatric Medications

Linezolid is a weak monoamine oxidase inhibitor (MAOI) that is contraindicated with serotonergic agents like escitalopram, trazodone, and potentially bupropion due to the serious risk of serotonin syndrome, which can be fatal. 1

Critical Drug Interaction: Linezolid + Escitalopram

• Escitalopram MUST be discontinued immediately due to documented cases of near-fatal serotonin syndrome when combined with linezolid 2
• Serotonin syndrome can develop within 24-48 hours of combining these medications and presents with mental status changes (confusion, agitation), neuromuscular hyperactivity (tremors, clonus, hyperreflexia, muscle rigidity), and autonomic instability (hypertension, tachycardia, diaphoresis) 1
• Advanced symptoms include fever, seizures, arrhythmias, and unconsciousness leading to death 1
• MAOIs, including linezolid, should be avoided in combination with any other serotonergic drug 1

High-Risk Interaction: Linezolid + Trazodone

• Trazodone should be discontinued as it is both a selective serotonin reuptake inhibitor and 5-HT2A/5-HT2C receptor antagonist 3
• The combination poses significant risk for serotonin syndrome given trazodone's serotonergic properties 1
• Multiple case reports document serotonin syndrome with linezolid and various SSRIs including sertraline, paroxetine, citalopram, and fluoxetine 4, 5

Moderate Concern: Linezolid + Bupropion

• Bupropion may be continued with close monitoring, as it has no appreciable serotonergic activity and primarily affects norepinephrine and dopamine 3
• However, caution is warranted as linezolid has weak MAOI properties that could theoretically interact with noradrenergic agents 1
• Monitor for hypertension, agitation, and autonomic instability 1

Clinical Management Algorithm

Immediate actions:

• Stop escitalopram immediately 4, 2
• Stop trazodone immediately 1
• Consider holding bupropion or continue with intensive monitoring 3

Monitoring requirements (first 24-48 hours):

• Assess for confusion, agitation, myoclonus, tremor, hyperreflexia, muscle rigidity 1
• Monitor vital signs for hypertension, tachycardia, tachypnea, fever 1
• Check for diaphoresis, shivering, diarrhea 1

Duration considerations:

• Do NOT restart serotonergic agents until linezolid is completed AND a 14-day washout period has elapsed 4
• If serotonin syndrome develops, discontinue all serotonergic agents and provide supportive care with continuous cardiac monitoring 1

Evidence Quality Note

While one retrospective analysis suggested low incidence (3%) of serotonin syndrome with concomitant linezolid and SSRI use 6, multiple case reports document severe and near-fatal outcomes 4, 5, 2. The guideline-level evidence clearly states this combination should be avoided 1, and the potential for fatal outcomes mandates prioritizing patient safety over the retrospective data.

Common Pitfall to Avoid

Do not assume that because the patient has been on these medications for a short time without symptoms that they are safe to continue—serotonin syndrome can develop at any point during concomitant therapy and may present suddenly 1, 4. The risk persists throughout the entire duration of linezolid therapy 1.