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Difficulty: HardPsychopharmacology and Psychological Therapies

A 45-year-old woman is evaluated on the medical ward by the psychiatric consultation-liaison service due to acute-onset agitation and confusion. The patient has a history of major depressive disorder, which has been well controlled on sertraline 150 mg daily for the past two years, and poorly controlled type 2 diabetes mellitus. She was admitted three days ago for a severe diabetic foot infection. Deep tissue cultures grew Vancomycin-resistant Enterococcus faecium (VRE). Yesterday, her intravenous antibiotics were discontinued, and she was transitioned to a targeted oral antibiotic therapy to facilitate hospital discharge. This morning, she became rapidly disoriented and restless. Temperature is 38.6°C (101.5°F), blood pressure is 165/95 mm Hg, pulse is 128/min, and respirations are 20/min. Physical examination reveals a diaphoretic, flushed woman who is unable to answer questions coherently. Her pupils are dilated (6 mm bilaterally). Neurologic examination is notable for 4+ deep tendon reflexes in the lower extremities, spontaneous myoclonus, and sustained bilateral ankle clonus. Which of the following pharmacologic actions of the newly initiated antibiotic is most directly responsible for this patient's current clinical state?

  1. Inhibition of monoamine oxidaseAnswer
  2. B
    Blockade of central dopamine receptors
  3. C
    Antagonism of central muscarinic receptors
  4. D
    Inhibition of cytochrome P450 3A4
  5. E
    Activation of skeletal muscle ryanodine receptors

Answer

Inhibition of monoamine oxidase
This patient's presentation of altered mental status, autonomic instability (fever, tachycardia, hypertension, diaphoresis), and profound neuromuscular hyperactivity (myoclonus, hyperreflexia, sustained clonus) represents the classic triad of serotonin syndrome. The patient was already taking sertraline, a selective serotonin reuptake inhibitor (SSRI). The abrupt onset of symptoms followed the initiation of a targeted oral antibiotic for Vancomycin-resistant Enterococcus (VRE). Linezolid is an oxazolidinone antibiotic frequently used for VRE and methicillin-resistant Staphylococcus aureus (MRSA) infections. A critical pharmacological characteristic of linezolid is its structural similarity to monoamine oxidase inhibitors (MAOIs), which gives it weak, reversible, nonselective MAOI activity. When administered with an SSRI, linezolid inhibits the enzymatic degradation of serotonin while the SSRI inhibits its reuptake. This leads to a massive accumulation of synaptic serotonin and precipitates serotonin syndrome. Concurrent use of linezolid and serotonergic antidepressants is contraindicated.

Step-by-Step Solution

1
Identify the patient's acute toxidrome from the clinical presentation.
The patient has altered mental status, autonomic instability (fever, tachycardia, hypertension, diaphoresis), and neuromuscular hyperactivity (hyperreflexia, myoclonus, clonus).
This triad is the classic clinical presentation of serotonin syndrome.
2
Determine the inciting pharmacological trigger.
The patient was stable on sertraline (an SSRI) and developed the syndrome shortly after starting a new oral antibiotic for VRE.
Linezolid is a primary oral treatment option for VRE infections and is known to cause severe drug interactions.
3
Identify the mechanism by which the antibiotic caused this syndrome.
Linezolid possesses weak, reversible nonselective monoamine oxidase inhibitor (MAOI) activity.
Combining an MAOI (linezolid) with an SSRI (sertraline) prevents the breakdown and reuptake of serotonin, leading to a massive accumulation of serotonin in the central nervous system, precipitating serotonin syndrome.

Key Concept

Linezolid has off-target monoamine oxidase inhibitor (MAOI) properties and can precipitate life-threatening serotonin syndrome when co-administered with serotonergic agents like SSRIs.
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Topics

Psychopharmacology and Psychological Therapies

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