Are clarithromycin and azithromycin (macrolide antibiotics) interchangeable in the treatment of Mycobacterium Avium Complex (MAC) based on sensitivity testing?

Clarithromycin and Azithromycin Are Clinically Interchangeable for MAC Treatment When Macrolide-Susceptible

While clarithromycin and azithromycin demonstrate equivalent microbiologic efficacy against macrolide-susceptible MAC, azithromycin is preferred due to superior tolerability and fewer drug interactions, though clarithromycin remains an acceptable alternative when azithromycin is unavailable or not tolerated. 1

Key Evidence on Interchangeability

Equivalent Microbiologic Efficacy

• No clinically significant differences exist between azithromycin and clarithromycin in sputum culture conversion at 6 months, end of therapy, or sustained conversion after treatment 1
• No difference in acquisition of macrolide resistance between the two agents 1
• Both demonstrate activity as monotherapy and as part of multi-drug regimens administered daily or three times weekly 1
• Limited direct comparison studies show no significant difference in microbiologic efficacy or tolerability, though a nonsignificant trend toward lower tolerability for clarithromycin was observed 1

Critical Distinction: Sensitivity Testing Applies to the Macrolide Class

Macrolide susceptibility testing predicts treatment success for MAC pulmonary disease as a class effect - susceptibility to one macrolide generally indicates susceptibility to both 1. The 2020 ATS/ERS/ESCMID/IDSA guidelines recommend baseline susceptibility testing for macrolides without distinguishing between clarithromycin and azithromycin 1.

Why Azithromycin Is Preferred (But Not Required)

Practical Advantages Favoring Azithromycin

• Fewer drug-drug interactions mediated by the cytochrome P450 system compared to clarithromycin 1
• Critical rifamycin interaction differences: Azithromycin serum concentrations are affected less by concurrent rifampicin or rifabutin than clarithromycin 1
• Bidirectional interaction with rifabutin and clarithromycin leads to increased rifabutin concentrations (but not rifampicin), which has been associated with uveitis 1
• Lower pill burden with once-daily dosing 1
• Possibly lower costs 1
• Better perceived tolerability by expert panels 1

When Clarithromycin Is Acceptable

Clarithromycin is an acceptable alternative when azithromycin is not available or not tolerated 1. The conditional recommendation for azithromycin over clarithromycin (very low certainty of evidence) indicates these agents are clinically interchangeable from an efficacy standpoint 1.

Critical Clinical Caveats

Both Agents Require Companion Drugs

• Macrolide monotherapy or inadequate companion drugs dramatically increases resistance risk 2
• Macrolide resistance developed in only 4% of patients receiving the recommended two companion drugs (ethambutol plus rifamycin) regardless of whether clarithromycin or azithromycin was used 2
• Risk factors for resistance include macrolide monotherapy or combination with quinolone only (76% of resistant cases) 2

Macrolide Resistance Consequences

• Sputum culture conversion rates plummet from approximately 80% with macrolide-susceptible MAC to only 5-36% with macrolide-resistant disease 1
• Macrolide-resistant MAC requires aggressive therapy including injectable aminoglycosides for >6 months and often surgical resection (79% conversion rate) versus 5% conversion without such therapy 2
• One-year mortality in culture-positive macrolide-resistant patients was 34% compared to 0% in those who converted 2

Monitoring Considerations

• Both azithromycin and clarithromycin have been associated with QTc prolongation and sudden death 1
• Electrocardiographic monitoring may be considered when concurrent QTc-prolonging medications are used 1
• However, systematic reviews show no increase in cardiac disorders or mortality compared with placebo 1

Practical Algorithm for Selection

Start with azithromycin for newly diagnosed macrolide-susceptible MAC due to fewer drug interactions, especially when rifamycins are co-administered 1

Switch to clarithromycin if:

• Azithromycin is unavailable 1
• Patient experiences intolerable side effects with azithromycin 1
• No rifabutin is being used (eliminating the key drug interaction concern) 1

Do not switch between agents based on susceptibility testing alone - if the isolate is macrolide-susceptible, either agent is appropriate from an efficacy standpoint 1