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

Linezolid is a reversible, non-selective monoamine oxidase inhibitor (MAOI) (linezolid SmPC), and the Spanish carbamazepine SmPC contraindicates carbamazepine with MAOIs; the US label does not recommend the combination and calls the grounds theoretical (US carbamazepine label). Both drugs suppress the bone marrow: linezolid causes anaemia, leukopenia, thrombocytopenia and pancytopenia, with risk rising with treatment length (linezolid SmPC), and carbamazepine lowers white cell and platelet counts and is rarely linked to agranulocytosis and aplastic anaemia (carbamazepine SmPC). As a strong inducer of liver enzymes, carbamazepine may lower linezolid exposure; the clinical significance is unknown (US linezolid label).

Symptoms

Weakness, pallor and breathlessness on exertion (anaemia), frequent infections and fever (leukopenia), bruising and bleeding (thrombocytopenia). Linezolid-related bone marrow suppression is more likely with courses longer than 10–14 days and in older patients (linezolid SmPC).

Management

The combination is contraindicated by the Spanish carbamazepine SmPC, which contraindicates carbamazepine with monoamine oxidase inhibitors (MAOIs) and requires MAOIs to be stopped at least 2 weeks before carbamazepine is started (carbamazepine SmPC). The linezolid SmPC describes linezolid as a reversible, non-selective MAOI (linezolid SmPC), while the linezolid labels do not mention carbamazepine. The FDA wording is softer: carbamazepine with MAOIs is not recommended on theoretical grounds (US carbamazepine label). If linezolid is still given to a patient on carbamazepine, check a full blood count with platelets weekly: the linezolid SmPC requires this for all patients and asks for especially close monitoring when other drugs that lower haemoglobin or platelets are taken (linezolid SmPC). If significant bone marrow suppression develops, stop linezolid unless continuing it is absolutely necessary (linezolid SmPC).

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

Linezolid is a reversible MAO inhibitor. Dextromethorphan is a weak serotonin reuptake inhibitor and sigma-1 agonist. The combination produces synaptic serotonin accumulation and serotonin syndrome.

Symptoms

Within hours of co-administration: agitation, confusion, tachycardia, hypertension, hyperthermia, tremor, myoclonus, hyperreflexia. Severe cases – seizures, coma, rhabdomyolysis.

Management

The AEMPS label for dextromethorphan lists linezolid among contraindicated combinations. Avoid dextromethorphan for the linezolid course (typically 7–14 days). Alternative antitussives: guaifenesin or honey for nocturnal cough. If dextromethorphan was already taken, stop linezolid; serotonin syndrome resolves within 24 hours.

Mechanism

Linezolid is a reversible monoamine oxidase (MAO) inhibitor. Duloxetine (SNRI) raises synaptic serotonin and norepinephrine. Co-administration: serotonin syndrome (FDA safety alert 2011, fatal cases reported).

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.

Management

The AEMPS label for duloxetine says linezolid must not be given to patients on duloxetine. The combination is not prescribed. Stop duloxetine at least 5 days before starting linezolid. For urgent antibiotic therapy: vancomycin, daptomycin, or 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 monoamine oxidase (MAO) inhibitor. Fluvoxamine (SSRI) raises synaptic serotonin. Co-administration: serotonin syndrome, fatal cases reported (FDA safety alert).

Symptoms

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, fever.

Management

The AEMPS label for fluvoxamine lists the combination with linezolid as contraindicated. The combination is not prescribed. Stop fluvoxamine at least 2 weeks before linezolid. For urgent antibiotic therapy: vancomycin, daptomycin, or ceftaroline by susceptibility.

Mechanism

Linezolid is a reversible MAO inhibitor. With meperidine – serotonin syndrome.

Symptoms

Hyperthermia, myoclonus.

Management

Combination contraindicated.

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 used: the FDA label for mirtazapine contraindicates it with MAO inhibitors, including linezolid, and within 14 days of stopping them. A planned linezolid course starts about 2 weeks after the last mirtazapine dose, the interval given in the mirtazapine SmPC. If linezolid is needed urgently, mirtazapine is stopped before the first antibiotic dose and the patient is watched for serotonin syndrome throughout the course. Mirtazapine is restarted no earlier than 14 days after the last linezolid dose. Trazodone is not a bridge: its FDA label also contraindicates linezolid. For gram-positive infections vancomycin or daptomycin are chosen, as they do not inhibit MAO.

Mechanism

Besides its antibacterial action, linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO), so it belongs to the MAO inhibitors (linezolid SmPC). The US Food and Drug Administration (FDA) morphine labels warn that MAO inhibitors may potentiate the effects of morphine, including respiratory depression, coma and confusion, and that MAO inhibitor interactions with opioids may present as serotonin syndrome or opioid toxicity. The linezolid SmPC also reports serotonin syndrome when linezolid was combined with serotonergic drugs, including opioids.

Symptoms

Increasing drowsiness, confusion, slow and shallow breathing, up to coma (FDA morphine labels). Signs of serotonin syndrome: agitation, high fever, heavy sweating, tremor, muscle jerks and rigidity, exaggerated reflexes, impaired thinking and coordination (linezolid labels).

Management

The combination is contraindicated. Spanish SmPCs for oral morphine contraindicate morphine with monoamine oxidase (MAO) inhibitors and within two weeks of stopping them, and the linezolid SmPC classes linezolid as an MAO inhibitor. The US Food and Drug Administration (FDA) morphine labels set the same 14-day ban and name linezolid among MAO inhibitors. The linezolid SmPC contraindicates its use with serotonergic drugs, opioids included, unless the combination is absolutely necessary. If it cannot be avoided, the patient is closely watched for signs of serotonin syndrome: cognitive dysfunction, high fever, exaggerated reflexes, poor coordination; if they appear, stopping one or both drugs is considered (linezolid SmPC).

Mechanism

Linezolid is a reversible MAO inhibitor. Combined with phenelzine causes cumulative MAO inhibition and fatal serotonin syndrome with tyramine load.

Symptoms

Hypertensive crisis, hyperthermia, myoclonus.

Management

Combination contraindicated. Alternative antibiotic: vancomycin or daptomycin for MRSA.

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

Cumulative MAO inhibition (irreversible tranylcypromine + reversible linezolid). Severe serotonin syndrome with tyramine load.

Symptoms

Hypertensive crisis, hyperthermia.

Management

Combination contraindicated.

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.

Mechanism

Linezolid mildly prolongs QT, additively with amiodarone. Clinically significant arrhythmia is rare, but risk is higher with hypokalaemia, hypomagnesaemia, and bradycardia.

Symptoms

QT prolongation on ECG. Dizziness, syncope, palpitations. Rarely: polymorphic ventricular tachycardia (torsades de pointes). Risk is higher with hypokalaemia, hypomagnesaemia, bradycardia, and ischaemic heart disease.

Management

For short linezolid courses (10–14 days), check ECG before start and one week in. Keep potassium and magnesium in the upper half of the normal range. In atrial fibrillation with prior ventricular arrhythmia, alternatives: vancomycin or daptomycin.

Mechanism

Linezolid is a reversible MAO inhibitor. It can potentiate sympathomimetic effects of tyramine-containing foods, but the effect on amlodipine is weak.

Symptoms

Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.

Management

The combination is acceptable for short linezolid courses with blood pressure monitoring. In hypovolaemia or with the first dose: increased orthostatic hypotension risk. The main linezolid combination risk is serotonin syndrome with SSRI/SNRI (see those pairs).

Mechanism

Linezolid does not inhibit the CYP3A4 enzyme and is not expected to change the levels of drugs cleared through it (linezolid SmPC), so atorvastatin levels are not expected to rise. The risk lies elsewhere: rhabdomyolysis has been reported with linezolid (linezolid SmPC), and atorvastatin itself can damage muscle, up to rhabdomyolysis (atorvastatin SmPC). The labels give no data on the combination itself.

Symptoms

Muscle pain, tenderness, cramps or weakness, sometimes with fever and malaise, dark urine and raised creatine kinase in blood tests (linezolid and atorvastatin labels).

Management

The linezolid SmPC asks for caution in patients with risk factors for rhabdomyolysis (linezolid SmPC), and atorvastatin can itself cause rhabdomyolysis (atorvastatin SmPC). Linezolid does not inhibit CYP3A4, so the atorvastatin label's lower maximum dose for drugs that raise atorvastatin levels does not apply to it (linezolid and atorvastatin labels). Ask the patient to report muscle pain, cramps or weakness at once, especially with fever or malaise. If they occur, measure creatine kinase; stop atorvastatin if it is more than 5 times the upper limit of normal or if rhabdomyolysis is suspected (atorvastatin SmPC). At signs of rhabdomyolysis, stop linezolid as well and start appropriate treatment (linezolid SmPC).

Mechanism

Besides its antibacterial action, linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO), so it belongs to the MAO inhibitors (linezolid SmPC). The bisoprolol SmPC warns that MAO inhibitors, except MAO-B inhibitors, increase the blood pressure-lowering effect of beta-blockers but also raise the risk of hypertensive crises (bisoprolol SmPC).

Symptoms

Excessive drop in blood pressure: dizziness, weakness, feeling faint. The opposite reaction is also possible: a hypertensive crisis with a sharp rise in blood pressure and severe headache (bisoprolol SmPC).

Management

The combination is not prohibited, but the bisoprolol SmPC lists monoamine oxidase (MAO) inhibitors, except MAO-B inhibitors, among combinations that need assessment: blood pressure may either fall or rise sharply (bisoprolol SmPC). The linezolid SmPC describes linezolid as a non-selective MAO inhibitor (linezolid SmPC). So blood pressure and wellbeing are watched during a linezolid course in a patient on bisoprolol. In uncontrolled hypertension, linezolid is given only where blood pressure can be closely monitored (linezolid SmPC).