What is the updated treatment regimen for tuberculosis now that ethambutol has been removed and moxifloxacin has been added?

Updated Tuberculosis Treatment Regimen with Moxifloxacin

Drug-Susceptible Tuberculosis: 4-Month Moxifloxacin Regimen

For eligible adults and adolescents ≥12 years with drug-susceptible pulmonary TB, the WHO now conditionally recommends a 4-month regimen of rifapentine, isoniazid, pyrazinamide, and moxifloxacin (replacing ethambutol), which shortens treatment by 2 months compared to the standard 6-month regimen. 1

Key Eligibility Criteria:

• Age ≥12 years with pulmonary drug-susceptible TB 1
• Non-cavitary or minimal cavitary disease 1
• Low bacillary burden 1
• No severe extrapulmonary TB (excluding CNS, miliary, or spinal TB) 1
• Not pregnant 1

Standard 6-Month Regimen (When 4-Month Not Appropriate):

• Intensive phase (2 months): Isoniazid, rifampin, pyrazinamide, and ethambutol daily 2, 3
• Continuation phase (4 months): Isoniazid and rifampin daily 2, 3
• Ethambutol can be discontinued once drug susceptibility confirms full susceptibility to isoniazid and rifampin 2

Critical Caveat:

Research trials testing 4-month moxifloxacin regimens that simply replaced ethambutol or isoniazid in standard therapy showed significantly increased relapse rates (RR 3.56,95% CI 2.37-5.37) and failed to demonstrate non-inferiority. 4, 5 The successful 4-month regimen uses rifapentine (not rifampin) with moxifloxacin, which is a distinct formulation. 1

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Multidrug-Resistant/Rifampicin-Resistant TB: Moxifloxacin-Containing Regimens

9-Month All-Oral Bedaquiline Regimen (Preferred for Eligible MDR/RR-TB):

For MDR/RR-TB patients without fluoroquinolone resistance, no prior second-line drug exposure >1 month, and no extensive disease, use the 9-month all-oral regimen with moxifloxacin or levofloxacin as the fluoroquinolone component. 1

Intensive Phase (4-6 months):

• Bedaquiline (6 months total) 1
• Moxifloxacin OR levofloxacin (levofloxacin generally preferred due to less QTc prolongation) 1, 6
• Clofazimine 1
• Pyrazinamide 1
• Ethambutol 1
• High-dose isoniazid 1
• Ethionamide (or linezolid 600mg daily for maximum 2 months) 1

Continuation Phase (5 months):

• Moxifloxacin OR levofloxacin 1, 6
• Clofazimine 1, 6
• Pyrazinamide 1, 6
• Ethambutol 1, 6

When to Choose Levofloxacin Over Moxifloxacin:

• Levofloxacin is generally preferred over moxifloxacin because it causes fewer adverse events and less QTc prolongation. 1
• However, moxifloxacin has similar efficacy for treating DR-TB 1
• Avoid levofloxacin in pediatric populations due to musculoskeletal disorder risk 1

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Longer MDR/RR-TB Regimens (18-20 Months)

Drug Classification and Selection:

When 9-month regimens cannot be used (extensive disease, severe extrapulmonary TB, fluoroquinolone resistance, pregnancy, age <14 years), construct an 18-20 month regimen using the WHO drug grouping system. 1

Group A Drugs (Include All Three):

• Levofloxacin OR moxifloxacin (strong recommendation) 1
• Bedaquiline (strong recommendation for ≥18 years; conditional for 6-17 years) 1
• Linezolid (strong recommendation) 1

Group B Drugs (Include At Least One):

• Clofazimine (conditional recommendation) 1
• Cycloserine or terizidone (conditional recommendation) 1

Group C Drugs (Add If Needed):

• Ethambutol (conditional recommendation) 1
• Delamanid (conditional recommendation for ≥3 years) 1
• Pyrazinamide 1
• Imipenem-cilastatin or meropenem with amoxicillin/clavulanate 1
• Amikacin (avoid kanamycin and capreomycin) 1
• Ethionamide or prothionamide 1
• p-aminosalicylic acid 1

Construction Algorithm:

1. Start with all three Group A agents (including moxifloxacin or levofloxacin) 1
2. Add at least one Group B agent 1
3. Ensure minimum of 4 effective drugs in intensive phase 1
4. If only 1-2 Group A agents available, include both Group B agents 1
5. Add Group C agents only if regimen cannot be composed from Groups A and B alone 1

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Special Populations

Pregnant and Lactating Women:

• Use 9-month regimen with linezolid variation instead of ethionamide 1
• Ethionamide is contraindicated in pregnancy 1
• Linezolid has more consolidated safety data during pregnancy 1

Children:

• 9-month all-oral regimen can be used in children of all ages 1
• Bedaquiline now recommended even below 6 years of age 1
• BPaLM regimen not recommended below 14 years due to lack of pretomanid safety data 1
• Prefer levofloxacin over moxifloxacin due to musculoskeletal concerns 1

Isoniazid-Resistant, Rifampicin-Susceptible TB:

• 6 months of rifampicin, ethambutol, pyrazinamide, and levofloxacin (conditional recommendation) 1
• Moxifloxacin can substitute for levofloxacin 1
• Do not add streptomycin or other injectable agents 1

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Critical Monitoring Requirements

Moxifloxacin-Specific Monitoring:

• QTc prolongation monitoring (higher risk than levofloxacin) 1, 6
• Tendinopathy surveillance 6, 2
• Peripheral neuropathy assessment 6, 2

Ethambutol Monitoring (When Retained):

• Optic neuritis screening with regular visual acuity and color vision testing 6, 2
• Dose adjustment in renal impairment 6

Common Pitfall:

Do not assume all 4-month moxifloxacin regimens are equivalent—only the rifapentine-based regimen has demonstrated efficacy, while rifampin-based 4-month regimens with moxifloxacin showed increased relapse rates in clinical trials. 4, 5