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Difficulty: EasyPharmacologic Interventions

An ambulatory 58-year-old female presents to her primary care physician for evaluation of a progressing soft tissue infection on her left lower extremity. Her past medical history is significant for hyperlipidemia, for which she takes simvastatin daily. The physician determines that oral antimicrobial therapy is indicated. However, the physician recalls that certain antibiotics strongly inhibit the cytochrome P450 3A4 (CYP3A4) enzyme, which would significantly increase this patient's serum simvastatin levels and elevate her risk of statin-induced myopathy. Which of the following antimicrobial agents possess this specific pharmacokinetic interaction and should either be avoided or require temporary suspension of the statin? (Select all that apply)

  1. ClarithromycinAnswer
  2. B
    Azithromycin
  3. C
    Amoxicillin
  4. ErythromycinAnswer
  5. E
    Doxycycline

Answer

The antimicrobial agents that strongly inhibit cytochrome P450 3A4 and interact with simvastatin are clarithromycin and erythromycin.
Simvastatin is a widely used lipid-lowering agent that undergoes extensive first-pass metabolism in the liver primarily via the cytochrome P450 3A4 (CYP3A4) isoenzyme. Clarithromycin and erythromycin are macrolide antibiotics that act as potent inhibitors of CYP3A4. Concomitant administration of these specific macrolides with simvastatin blocks the statin's metabolism, leading to markedly elevated serum statin concentrations. This accumulation poses a significant, dose-dependent risk of severe adverse effects, most notably myopathy and rhabdomyolysis. When these specific antibiotics are clinically necessary, the statin should be temporarily withheld for the duration of the antibiotic therapy.

Step-by-Step Solution

1
Identify the metabolic pathway of the patient's current medication.
Simvastatin is primarily metabolized by the hepatic enzyme cytochrome P450 3A4 (CYP3A4).
Understanding the baseline metabolism is necessary to predict drug-drug interactions.
2
Evaluate the proposed antimicrobial agents for CYP3A4 inhibition.
Clarithromycin and erythromycin are potent CYP3A4 inhibitors, while azithromycin, amoxicillin, and doxycycline are not.
Strong inhibitors of CYP3A4 will prevent the breakdown of simvastatin, leading to toxic accumulation and an increased risk of myopathy or rhabdomyolysis.

Key Concept

Pharmacokinetic drug-drug interactions involving CYP3A4 inhibitors and statins
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Topics

Pharmacologic Interventions

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