Linezolid

Mechanism

Amitriptyline, a tricyclic antidepressant, blocks serotonin and norepinephrine reuptake. Linezolid reversibly inhibits MAO. Combined action sharply raises synaptic monoamines, risking serotonin syndrome and hypertensive crisis.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: profuse sweating, tachycardia, hypertension, fever above 38.5 °C. Severe cases progress to seizures, rhabdomyolysis, disseminated intravascular coagulation, and death. First signs appear within hours of concurrent dosing.

Management

The combination is not prescribed. Stop amitriptyline 1–2 weeks before linezolid. If linezolid is urgently needed, switch the patient to mianserin or agomelatine, which lack a strong serotonergic profile. Alternative antibiotics: vancomycin, daptomycin.

Mechanism

Bupropion inhibits dopamine and norepinephrine reuptake. Linezolid reversibly inhibits MAO. Combined action raises monoamine levels, risking hypertensive crisis and seizures (bupropion lowers seizure threshold on its own).

Symptoms

Hypertension, tachycardia, tremor, agitation, headache. Seizures may occur, particularly in patients with prior epilepsy or eating disorders. Serotonin syndrome is less common unless other serotonergics are added.

Management

The combination is not prescribed. Stop bupropion 14 days before linezolid. As a smoking-cessation bridge during antibiotic therapy, use nicotine replacement or varenicline. Alternative antibiotics: vancomycin, daptomycin.

Mechanism

Citalopram (SSRI) raises synaptic serotonin. Linezolid reversibly inhibits MAO. Co-administration sharply amplifies serotonergic transmission. The FDA carries a boxed warning.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: profuse sweating, tachycardia, hypertension, fever above 38.5 °C. Severe cases progress to seizures, rhabdomyolysis, disseminated intravascular coagulation, and death. First signs appear within hours of concurrent dosing.

Management

The combination is not prescribed. Stop citalopram at least 2 weeks before linezolid. Alternative antibiotics: vancomycin, daptomycin, ceftaroline by susceptibility.

Mechanism

Escitalopram (SSRI) raises synaptic serotonin. Linezolid reversibly inhibits MAO. Co-administration sharply amplifies serotonergic transmission. The FDA boxed warning applies to all SSRIs paired with linezolid.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: profuse sweating, tachycardia, hypertension, fever above 38.5 °C. Severe cases progress to seizures, rhabdomyolysis, disseminated intravascular coagulation, and death. First signs appear within hours of concurrent dosing.

Management

The combination is not prescribed. Stop escitalopram at least 2 weeks before linezolid. If urgent antibiotic therapy is needed, use vancomycin, daptomycin, or ceftaroline based on susceptibility.

Mechanism

Fluoxetine (SSRI) raises synaptic serotonin. Linezolid reversibly inhibits MAO. The pair is notable because fluoxetine's active metabolite, norfluoxetine, persists for up to 5 weeks – the serotonergic effect outlasts dosing.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: profuse sweating, tachycardia, hypertension, fever above 38.5 °C. Severe cases progress to seizures, rhabdomyolysis, disseminated intravascular coagulation, and death. First signs appear within hours of concurrent dosing.

Management

The combination is not prescribed. Stop fluoxetine at least 5 weeks before planned linezolid. For acute antibiotic need, use vancomycin or daptomycin. If linezolid is still required, monitor for serotonin syndrome during therapy plus 5 weeks after fluoxetine discontinuation.

Mechanism

Linezolid is a reversible MAO inhibitor with antibacterial activity. IV methylene blue is a reversible MAO-A inhibitor. Two MAO inhibitors together raise the risk of hypertensive crisis and serotonin syndrome even without an SSRI on board.

Symptoms

Hypertensive crisis, tachycardia, severe headache, fever, agitation, confusion. With concomitant serotonergics (SSRI, SNRI, TCA, tramadol), full serotonin syndrome may develop with myoclonus, hyperreflexia, and rhabdomyolysis.

Management

Avoid the combination. For emergency methylene blue use in a patient on linezolid, give for life-threatening indications under ICU monitoring of blood pressure, pulse, and temperature. Pause linezolid if feasible; stop both at the first sign of hypertensive crisis.

Mechanism

Mirtazapine increases serotonin release by blocking presynaptic α2-adrenergic autoreceptors. Linezolid reversibly inhibits MAO. Combined action multiplies serotonergic activity.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: profuse sweating, tachycardia, hypertension, fever above 38.5 °C. Severe cases progress to seizures, rhabdomyolysis, disseminated intravascular coagulation, and death. First signs appear within hours of concurrent dosing.

Management

The combination is not prescribed. Stop mirtazapine at least 2 weeks before linezolid. As bridging therapy during antibiotic course, low-dose trazodone may be used cautiously for sleep. Alternative antibiotics: vancomycin, daptomycin.

Mechanism

Linezolid is an oxazolidinone antibiotic that also reversibly inhibits monoamine oxidase (MAO). Sertraline, a selective serotonin reuptake inhibitor (SSRI), raises synaptic serotonin. Combined action sharply amplifies serotonergic transmission. The FDA carries a boxed warning for this combination.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: profuse sweating, tachycardia, hypertension, fever above 38.5 °C. Severe cases progress to seizures, rhabdomyolysis, disseminated intravascular coagulation, and death. First signs appear within hours of concurrent dosing.

Management

The combination is not prescribed. Stop sertraline at least 2 weeks before starting linezolid (washout). If urgent antibiotic therapy is needed, use vancomycin, daptomycin, or ceftaroline based on susceptibility. If serotonin syndrome has already developed, stop both drugs immediately, start cyproheptadine, and admit for intensive supportive care.

Mechanism

Tramadol is an opioid with serotonin–norepinephrine reuptake inhibition. Linezolid reversibly inhibits MAO. Co-administration causes a sharp rise in synaptic serotonin and risk of serotonin syndrome.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: profuse sweating, tachycardia, hypertension, fever above 38.5 °C. Severe cases progress to seizures, rhabdomyolysis, disseminated intravascular coagulation, and death. First signs appear within hours of concurrent dosing.

Management

The combination is not prescribed. Stop tramadol 24–72 hours before starting linezolid. For analgesia, use paracetamol, NSAIDs (if not contraindicated), or pure opioid agonists such as morphine or oxycodone with no serotonergic activity.

Mechanism

Venlafaxine is a serotonin–norepinephrine reuptake inhibitor (SNRI). Linezolid reversibly inhibits MAO. Combined action raises both serotonin and norepinephrine, risking serotonin syndrome.

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: profuse sweating, tachycardia, hypertension, fever above 38.5 °C. Severe cases progress to seizures, rhabdomyolysis, disseminated intravascular coagulation, and death. First signs appear within hours of concurrent dosing.

Management

The combination is not prescribed. Stop venlafaxine at least 1 week before linezolid. For acute antibiotic need, use vancomycin or daptomycin. After completing linezolid, venlafaxine may resume 24 hours later.