What is the 4th agent to add to a regimen of levofloxacin (Levo), azithromycin (Azithro), and ethambutol for the treatment of Nontuberculous Mycobacteria (NTM) infections?

Fourth Agent for NTM Treatment Regimen with Levofloxacin, Azithromycin, and Ethambutol

For a regimen containing levofloxacin, azithromycin, and ethambutol for nontuberculous mycobacterial (NTM) infections, amikacin is the recommended fourth agent to add, particularly for patients with cavitary, extensive nodular/bronchiectatic disease, or macrolide-resistant MAC. 1

Treatment Regimen Considerations

Standard Regimens for MAC Pulmonary Disease

• For nodular/bronchiectatic MAC disease, a three-drug regimen of azithromycin (or clarithromycin), rifampin (or rifabutin), and ethambutol is typically recommended, administered three times weekly 1
• For fibrocavitary or severe nodular/bronchiectatic disease, a daily regimen is preferred with the addition of amikacin or streptomycin early in therapy 1
• For refractory MAC disease (culture-positive after 6 months of therapy), amikacin liposome inhalation suspension or parenteral amikacin (or streptomycin) should be added 1

Fourth Agent Options

Preferred Option:

• Amikacin (IV or inhalation): Most commonly recommended fourth agent for more severe or refractory NTM infections 1
  • Dosing: 10-15 mg/kg daily IV (adjusted according to drug level monitoring) or 590 mg daily via liposome inhalation suspension 1
  • Monitoring: Drug level monitoring recommended (trough <5 mg/L; peak with daily dosing 35-45 μg/mL) 1
  • Caution: Associated with ototoxicity in approximately one-third of patients after 15 weeks of therapy 1

Alternative Options:

• Clofazimine: Alternative drug for patients intolerant to first-line drugs 1
• Moxifloxacin: Can be considered if levofloxacin is not already in the regimen 1, 2
• Linezolid: Alternative for drug-resistant or treatment-refractory cases 1
• Bedaquiline: Some experts would consider for difficult-to-treat cases 1

Special Considerations

Treatment Duration

• Treatment should continue until sputum cultures remain negative for 12 consecutive months while on therapy 3, 4
• Monthly sputum cultures should be obtained to monitor treatment response 3

Cautions and Monitoring

• Never use macrolide monotherapy due to risk of developing macrolide resistance 1, 3
• A two-drug regimen of macrolide with only ethambutol may be inadequate for preventing resistance, especially in fibrocavitary disease 3
• Close monitoring for drug toxicities is essential, particularly:
  • Aminoglycoside-related ototoxicity and nephrotoxicity 1
  • Ethambutol-related ocular toxicity 1
  • QT prolongation with fluoroquinolones 5

Treatment Challenges

• NTM treatment regimens are generally poorly tolerated with high rates of adverse events 5, 6
• Extended treatment duration leads to adherence challenges 4, 6
• Drug-drug interactions are common, especially in elderly patients with comorbidities 4

Treatment Algorithm

1. Assess disease severity:

   • Nodular/bronchiectatic (less severe): Consider if amikacin is needed
   • Cavitary/fibrocavitary (more severe): Add amikacin 1
   • Macrolide-resistant: Add amikacin 1

2. Choose amikacin formulation:

   • For severe disease: IV amikacin (10-15 mg/kg/day) 1
   • For refractory disease: Consider amikacin liposome inhalation suspension (590 mg/day) 1
   • For less severe disease requiring a fourth agent: Consider intermittent (3x weekly) IV amikacin 1

3. Monitor for toxicity:

   • Audiometry before treatment and at regular intervals 1
   • Renal function monitoring 1
   • Drug level monitoring (trough <5 mg/L) 1

4. Adjust based on response:

   • If clinical improvement and culture conversion: Continue regimen
   • If no improvement after 6 months: Consider surgical resection for localized disease 1, 4