How does azithromycin interact with other medications, particularly in patients with pre-existing conditions such as liver or kidney disease?

Azithromycin Drug Interactions and Effects on Other Medications

Azithromycin has a favorable interaction profile compared to other macrolides because it does not inhibit the cytochrome P450 enzyme system, but it still carries significant risks for QT prolongation when combined with other arrhythmogenic drugs, can potentiate warfarin effects, and may increase levels of P-glycoprotein substrates like cyclosporine. 1

Key Pharmacokinetic Characteristics

Azithromycin metabolism is not affected by the CYP450 system, making it safer than clarithromycin or erythromycin when used with protease inhibitors, NNRTIs, and other CYP450-dependent drugs. 1

• Azithromycin can be used safely with antiretroviral drugs without concerns of cytochrome-mediated drug interactions, unlike other macrolides 1
• It inhibits P-glycoprotein efflux protein, leading to increased concentrations of P-gp substrates 1
• No dose adjustment is needed for renal impairment, as renal clearance plays an insignificant role in elimination 2

Critical Cardiac Interactions (QT Prolongation Risk)

The most dangerous interaction involves QT prolongation and risk of torsades de pointes, particularly when azithromycin is combined with hydroxychloroquine or other QT-prolonging agents. 1

High-Risk Cardiac Combinations to Avoid:

• Amiodarone: increased risk of QT prolongation 1
• Disopyramide: increased risk of QT prolongation 1
• Methadone: possible increased risk of QT prolongation 1
• Antiemetics (domperidone, metoclopramide, 5HT3 antagonists): increased risk of QT prolongation 1
• Tyrosine kinase inhibitors (TKIs): avoid with drugs like cabozantinib, ceritinib, crizotinib, nilotinib, osimertinib, vandetanib, vemurafenib 1
• Arsenic trioxide: contraindicated due to additive QT effects 1
• Antidepressants (citalopram, escitalopram): contraindicated 1

Monitoring Requirements for Cardiac Safety:

• Baseline ECG required before starting azithromycin 1
• Repeat ECG at 2 weeks and after adding any new QT-prolonging medication 1
• Evaluate for electrolyte disturbances (hypokalemia, hypomagnesemia) that increase arrhythmia risk 1

Immunosuppressant Interactions

Azithromycin increases cyclosporine and tacrolimus levels through P-glycoprotein inhibition, requiring close therapeutic drug monitoring. 1

• Cyclosporine: blood concentrations should be closely monitored when used with azithromycin 1
• Tacrolimus: case reports document raised tacrolimus concentrations; monitor levels 1
• Colchicine: possible increased colchicine levels and toxicity; monitor for nausea, vomiting, diarrhea, myopathy, and pancytopenia 1

Anticoagulant Interactions

Azithromycin can potentiate warfarin's anticoagulant effect despite not inhibiting CYP450, with effects potentially delayed 4-8 days after completing azithromycin. 2, 3

• Prothrombin times should be carefully monitored during and after azithromycin therapy in patients on warfarin 2
• The mechanism is not fully understood but is clinically significant 3
• Periodic INR monitoring is recommended throughout azithromycin course and for up to 8 days after completion 3

Other Significant Drug Interactions

Digoxin:

• Increased digoxin levels may occur; monitor digoxin concentrations 1

Antacids:

• Aluminum- and magnesium-containing antacids reduce azithromycin absorption 1, 2
• Take azithromycin 2 hours apart from antacids 1

Statins:

• Although azithromycin lacks CYP3A4 inhibition, case reports document interactions with statins 1
• Monitor for myopathy symptoms when combining with statins 1

Ergot Derivatives:

• Ergotism has been precipitated by coadministration with some macrolides 1

Special Considerations for Patients with Liver or Kidney Disease

Hepatic Impairment:

Azithromycin is principally eliminated via the liver and should be used with extreme caution in patients with impaired hepatic function, particularly those with prior cholestatic jaundice from azithromycin. 4, 2

• History of cholestatic jaundice or hepatic dysfunction from prior azithromycin use is an absolute contraindication 4
• Monitor liver function tests (LFTs) sporadically throughout treatment 1
• Azithromycin can cause severe hepatotoxicity including fulminant hepatitis and life-threatening liver failure 1, 5, 6

Renal Impairment:

• Caution should be exercised when GFR <10 mL/min, though no specific dose adjustment is typically required 2
• Azithromycin elimination is not significantly affected by renal function 2

Monitoring Requirements During Azithromycin Therapy

Baseline and periodic monitoring should include ECG, liver function tests, renal function, complete blood count, and audiometry. 1

• ECG: baseline, 2 weeks, and after adding any QT-prolonging medication 1
• LFTs, U&Es, and FBC: monitor sporadically throughout treatment 1
• Audiometry: baseline and intermittently during treatment, particularly in elderly patients at higher doses 1
• Digoxin levels: if applicable 1
• Cyclosporine/tacrolimus levels: if applicable 1
• INR/prothrombin time: if on warfarin 2, 3

Common Pitfalls to Avoid

• Do not assume azithromycin is interaction-free simply because it lacks CYP450 inhibition—P-glycoprotein interactions and QT effects remain clinically significant 1
• Do not overlook the delayed warfarin interaction—effects may manifest 4-8 days after azithromycin completion 3
• Do not combine azithromycin with hydroxychloroquine without ECG monitoring and electrolyte assessment 1
• Do not rechallenge patients who experienced prior azithromycin-related hepatotoxicity 4
• Do not ignore ototoxicity risk, particularly in elderly patients receiving higher doses or prolonged therapy 1