What drugs interfere with linezolid (an oxazolidinone antibiotic)?

Drugs That Interfere with Linezolid

Linezolid should not be administered concurrently with serotonergic agents (including SSRIs, SNRIs, and tricyclic antidepressants), MAO inhibitors, sympathomimetic drugs, or dopaminergic agents due to the risk of serious adverse reactions including serotonin syndrome and hypertensive crisis. 1, 2

Major Drug Interactions with Linezolid

Serotonergic Medications

• Selective serotonin reuptake inhibitors (SSRIs) such as citalopram, escitalopram, fluoxetine, paroxetine, and sertraline should be avoided due to risk of serotonin syndrome 3, 1
• Serotonin and norepinephrine reuptake inhibitors (SNRIs) including desvenlafaxine, duloxetine, levomilnacipran, and venlafaxine can cause serious adverse reactions when combined with linezolid 3
• Tricyclic antidepressants (amitriptyline, amoxapine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine) can interact with linezolid's MAOI properties 3
• Meperidine and buspirone are contraindicated with linezolid 1
• Serotonin 5-HT1 receptor agonists (triptans) should not be administered with linezolid 1

Monoamine Oxidase Inhibitors

• Other MAOIs (phenelzine, isocarboxazid, selegiline, tranylcypromine) should not be used within two weeks of linezolid therapy 1
• Bupropion (which inhibits dopamine and norepinephrine reuptake) should be avoided with linezolid due to risk of hypertensive reactions 4

Sympathomimetic and Vasopressive Agents

• Pseudoephedrine, phenylephrine, amphetamines, midodrine, and clonidine can cause hypertensive crisis when combined with linezolid 3
• Epinephrine, norepinephrine, and other vasopressive agents are contraindicated unless blood pressure is closely monitored 1
• Albuterol, salmeterol, and terbutaline (sympathomimetic bronchodilators) may interact with linezolid 3

Dopaminergic Agents

• Dopamine and dobutamine should not be administered with linezolid unless patients are monitored for potential increases in blood pressure 1

Opioid Medications

• Meperidine, methadone, tramadol, oxycodone, hydrocodone, morphine, codeine, and fentanyl can cause serious adverse reactions with linezolid 3

Mechanism of Interactions

Linezolid is a reversible, non-selective monoamine oxidase inhibitor (MAOI) that can lead to:

• Increased serotonin levels when combined with serotonergic agents, potentially causing serotonin syndrome 2, 5
• Potentiation of sympathomimetic effects when combined with adrenergic agents, leading to hypertensive crisis 1

Clinical Manifestations of Interactions

Serotonin Syndrome

• Mental status changes, confusion, and agitation 5, 6
• Neuromuscular abnormalities including tremors, myoclonus, hyperreflexia, and incoordination 6
• Autonomic instability with tachycardia and hypertension 5
• Can progress to severe cases with fever, seizures, arrhythmias, and unconsciousness 4

Hypertensive Crisis

• Severe elevation in blood pressure 1
• Risk is particularly high in patients with uncontrolled hypertension, pheochromocytoma, or thyrotoxicosis 2, 1

Management Recommendations

• Carefully weigh risks and benefits before prescribing linezolid to patients on serotonergic medications 7
• Consider alternative antibiotics when possible for patients on interacting medications 7
• If linezolid must be used, discontinue interacting medications (particularly SSRIs) before starting linezolid 7
• Monitor patients closely for signs of serotonin syndrome or hypertensive crisis, especially during the first days of therapy 8
• Be aware that some SSRIs (particularly fluoxetine) have long half-lives and may require longer washout periods 7

Special Considerations

• Recent research suggests the risk of serotonin syndrome with concurrent antidepressant use may be lower than previously thought, particularly in older patients, but vigilance is still warranted 9
• The FDA label explicitly contraindicates linezolid with serotonergic agents, MAOIs, sympathomimetics, and dopaminergic agents unless close monitoring is possible 1
• Patients with pre-existing conditions like uncontrolled hypertension are at higher risk for adverse reactions 2, 1

Other Important Linezolid Precautions

• Monitor complete blood counts weekly in patients receiving linezolid for longer than 2 weeks due to risk of myelosuppression 2
• Watch for peripheral neuropathy and optic neuritis with prolonged use (typically after 12-20 weeks) 2
• Be alert for hyperlactatemia and lactic acidosis with extended therapy 2