What are the risks and precautions when using macrolides (macrolide antibiotics) and statins (HMG-CoA reductase inhibitors) together?

Risks and Precautions When Using Macrolides and Statins Together

Concomitant use of macrolide antibiotics with statins that are extensively metabolized by CYP3A4 (lovastatin or simvastatin) is contraindicated due to the increased risk of myopathy, including potentially fatal rhabdomyolysis. 1

Key Interactions and Risks

Mechanism of Interaction

• Macrolide antibiotics (particularly clarithromycin and erythromycin) inhibit the cytochrome P-450 3A4 isozyme, which metabolizes certain statins, leading to increased statin blood levels and risk of toxicity 2
• Macrolides also inhibit hepatic uptake transporters OATP1B1 and OATP1B3, further increasing statin exposure 3
• The interaction severity depends on the specific statin and macrolide used 4

Risk Stratification by Statin Type

• High risk (contraindicated with clarithromycin): Lovastatin and simvastatin - can experience >5-fold increase in plasma concentration when combined with macrolides 3, 1
• Moderate risk: Atorvastatin - experiences 2-4 fold increase in plasma concentration 3
• Lower risk: Pravastatin (limit to 40mg daily), pitavastatin (withhold or reduce dose) 3
• Minimal risk: Fluvastatin and rosuvastatin - minimal interaction with macrolides 3

Risk Stratification by Macrolide Type

• High risk: Clarithromycin, erythromycin, telithromycin - strong CYP3A4 inhibitors 4
• Lower risk: Azithromycin - generally considered safer to use with statins, though rare cases of interaction have been reported 4, 5

Patient Risk Factors for Adverse Events

• Advanced age (especially >80 years) 6
• Female sex and small body frame 7, 6
• Multisystem disease, particularly chronic renal insufficiency 7, 6
• Polypharmacy (multiple medications) 7, 6
• Concomitant use of other medications that affect statin metabolism 7
• Higher statin doses increase risk of adverse effects 6
• Genetic factors: SLCO1B1 polymorphism can reduce hepatic uptake of statins, increasing risk 5

Clinical Manifestations of Statin-Macrolide Interaction

• Mild: Non-specific muscle aches or joint pains (myalgia) without significant CK elevation 2
• Moderate: Muscle pain with mild-to-moderate CK elevations 2
• Severe: Myositis with muscle weakness, pain, and CK elevations >10 times upper limit of normal 2
• Life-threatening: Rhabdomyolysis with myoglobinuria and acute renal failure 2, 8

Management Recommendations

For Patients Already on Statins Who Need Macrolide Therapy

1. For lovastatin or simvastatin users:

   • Temporarily discontinue statin during macrolide course and for 2 days after completion 1, 3
   • Consider switching to a non-macrolide antibiotic if clinically appropriate 3

2. For atorvastatin users:

   • Temporarily discontinue or reduce dose during macrolide therapy 3
   • Monitor for muscle symptoms 2

3. For pravastatin, fluvastatin, or rosuvastatin users:

   • Can generally continue therapy with caution 3
   • Limit pravastatin to 40mg daily when used with erythromycin or clarithromycin 9
   • Monitor for muscle symptoms 2

For Patients on Macrolides Who Need Statin Therapy

• Select rosuvastatin, fluvastatin, or pravastatin as preferred options 3
• Avoid initiating lovastatin or simvastatin 1

Monitoring Recommendations

• Assess for muscle symptoms before starting combined therapy 6
• Instruct patients to report muscle pain, tenderness, or weakness immediately 2
• Consider baseline CK measurement in high-risk patients 6
• Obtain CK measurements when patients report muscle symptoms 6
• Discontinue statin if severe myopathy develops or CK >10x ULN 2

Common Pitfalls to Avoid

• Failing to recognize that the interaction risk varies significantly between different statins and macrolides 3, 4
• Overlooking that symptoms of myopathy may develop during or even after completion of macrolide therapy 10
• Assuming azithromycin is completely safe with all statins - while it has lower risk, interactions are still possible, especially in genetically susceptible individuals 5
• Continuing high-dose statin therapy during macrolide treatment without appropriate monitoring 2

Remember that while the absolute risk of severe myopathy with statin-macrolide combinations is relatively low, the consequences of rhabdomyolysis can be severe, including acute renal failure and potentially death 8, 10.