What are the alternative macrolide (mac) therapies for patients intolerant or resistant to initial macrolide treatment, such as clarithromycin (Biaxin) or azithromycin (Zithromax)?

Alternative Macrolide Therapy for MAC Pulmonary Disease

If a patient cannot tolerate azithromycin or clarithromycin, switch to the other macrolide—this is the primary alternative strategy, as both drugs have equal efficacy but different side effect profiles. 1

Primary Alternative: Switch Between Macrolides

Azithromycin to Clarithromycin (or vice versa)

• Studies demonstrate that patients intolerant to one macrolide can successfully switch to the other. 1
• Azithromycin is preferred initially due to better tolerance, fewer drug interactions, lower pill burden, and once-daily dosing. 1
• Clarithromycin causes bitter taste, nausea, and elevated hepatic enzymes, particularly at higher doses (1000 mg twice daily). 1
• Azithromycin side effects include gastrointestinal distress, though less frequent than with clarithromycin. 2
• When azithromycin is unavailable or not tolerated, clarithromycin is an acceptable alternative with equal efficacy. 1

Clinical Evidence for Switching

• Two case reports document successful treatment completion after switching from clarithromycin to azithromycin due to rash and edema. 2
• Both patients achieved successful treatment outcomes without adverse events after the switch. 2

When Macrolides Cannot Be Used At All

For Macrolide-Resistant MAC Disease

Add parenteral aminoglycosides (amikacin or streptomycin) to the regimen for at least 2-3 months, combined with adequate companion medications. 1

• Parenteral amikacin or streptomycin should be included in the initial treatment regimen for:

  • Cavitary disease 1
  • Advanced/severe bronchiectatic disease 1
  • Macrolide-resistant MAC pulmonary disease 1

• Aminoglycosides must be paired with adequate companion medications (ethambutol, rifampicin, and possibly clofazimine) to prevent emergence of resistance. 1

For Treatment-Refractory Disease

Add amikacin liposome inhalation suspension (ALIS) to guideline-based therapy after 6 months of treatment failure. 1

• ALIS is FDA-approved for treatment-refractory MAC pulmonary disease (defined as remaining culture-positive after ≥6 months of guideline-based therapy). 1
• Randomized controlled trials demonstrate efficacy and safety of ALIS when added to guideline-based therapy. 1
• Do not use inhaled amikacin or ALIS as part of initial treatment regimen for newly diagnosed MAC. 1

Alternative Companion Drugs

Second-Line Agents

Alternative drugs for patients intolerant of or resistant to first-line drugs include: 1

• Clofazimine 1
• Moxifloxacin 1
• Linezolid 1
• Some experts would consider bedaquiline or tedizolid 1

Important Caveat

• Clofazimine has been associated with adverse clinical outcomes in MAC treatment and should be used cautiously. 1
• High-dose clarithromycin (1000 mg twice daily) is associated with higher mortality and should not be used. 1

Critical Pitfalls to Avoid

Loss of Macrolide from Regimen

• Removing the macrolide from the treatment regimen is associated with markedly reduced sputum culture conversion rates and higher mortality. 1
• Macrolide susceptibility is a consistent predictor of treatment success for pulmonary MAC. 1
• Therefore, every effort should be made to maintain a macrolide in the regimen through switching between azithromycin and clarithromycin. 1

Drug Interactions

• Clarithromycin has more drug interactions than azithromycin, particularly with protease inhibitors and rifamycins. 1
• Consider these interactions when selecting between macrolides for patients on complex medication regimens. 1

Monitoring Requirements

• Baseline audiometry testing should be performed before starting aminoglycosides, with repeat interval testing during therapy. 1
• Patients should be instructed on signs of ototoxicity and vestibular toxicity (unsteady gait, tinnitus, diminished hearing). 1
• Discontinue or decrease aminoglycoside dosage if signs of toxicity occur. 1