What are the new guidelines for treating pulmonary tuberculosis (TB) in patients with and without drug resistance?

New Guidelines for Pulmonary Tuberculosis Treatment

Drug-Susceptible Pulmonary TB

For drug-susceptible pulmonary TB, treat with a 6-month regimen consisting of isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months (intensive phase), followed by isoniazid and rifampin for 4 months (continuation phase). 1, 2, 3

Intensive Phase (First 2 Months)

• Administer isoniazid, rifampin, pyrazinamide, and ethambutol daily 1, 4
• Ethambutol can be omitted only if drug susceptibility testing confirms no isoniazid resistance AND community isoniazid resistance rates are <4% 1, 5
• Daily dosing is strongly recommended over intermittent regimens 1
• Fixed-dose combinations of 2,3, or 4 drugs may provide more convenient administration 1

Continuation Phase (Months 3-6)

• Continue isoniazid and rifampin daily for 4 additional months 1, 3
• This phase can only be initiated after susceptibility to isoniazid and rifampin is confirmed 1
• Treatment should be extended beyond 6 months if the patient remains sputum or culture positive, has cavitary disease, or is HIV-positive 3, 5

Critical Dosing Parameters

• Rifampin: 10 mg/kg daily (maximum 600 mg/day) for adults; 10-20 mg/kg daily (maximum 600 mg/day) for children 3
• Administer rifampin 1 hour before or 2 hours after meals with a full glass of water 3

Isoniazid-Resistant Pulmonary TB

For isoniazid-resistant, rifampin-susceptible TB, add a later-generation fluoroquinolone to a 6-month regimen of rifampin, ethambutol, and pyrazinamide. 1

Recommended Regimen

• Rifampin, ethambutol, pyrazinamide, and a later-generation fluoroquinolone (levofloxacin or moxifloxacin) for 6 months 1
• Levofloxacin is generally preferred over moxifloxacin due to fewer adverse events and less QTc prolongation 6
• Pyrazinamide duration can be shortened to 2 months in selected situations (noncavitary disease, lower bacterial burden, or pyrazinamide toxicity) 1

Alternative Approach

• If pyrazinamide cannot be used, extend treatment to 9-12 months with rifampin, ethambutol, and fluoroquinolone 5

Multidrug-Resistant (MDR) and Rifampin-Resistant (RR) Pulmonary TB

For MDR/RR-TB without fluoroquinolone or bedaquiline resistance, use the BPaLM regimen (bedaquiline, pretomanid, linezolid, moxifloxacin) for 6 months as first-line treatment. 7

Core MDR-TB Regimen Components (When BPaLM Not Available)

The regimen must include at least 4-5 effective drugs based on documented or highly likely susceptibility 1, 8:

Group A Drugs (Include All Three If Possible)

• Later-generation fluoroquinolone (levofloxacin 750-1000 mg daily OR moxifloxacin 400 mg daily) - strong recommendation 1, 8
• Bedaquiline (400 mg daily for 2 weeks, then 200 mg three times weekly for at least 22 weeks, with possible extension beyond 6 months) - strong recommendation 1, 8
• Linezolid (600 mg daily, reducible to 300 mg daily if toxicity occurs) - conditional recommendation 1, 8

Group B Drugs (Add At Least One)

• Clofazimine (100 mg daily) 1, 8
• Cycloserine or terizidone (10-15 mg/kg daily, maximum 1000 mg) 1, 8

Additional Considerations

• Include pyrazinamide when the isolate is not resistant to it 1
• Include ethambutol only when other more effective drugs cannot be assembled to achieve five total drugs 1
• Do NOT include kanamycin or capreomycin - these are specifically recommended against 1, 8, 6
• Do NOT include amoxicillin-clavulanate (except when using a carbapenem), macrolides (azithromycin/clarithromycin), ethionamide/prothionamide, or p-aminosalicylic acid if more effective alternatives are available 1

Injectable Agents (Only When Necessary)

• Use amikacin or streptomycin only when susceptibility is confirmed AND five effective oral drugs cannot be assembled 1, 8
• Always combine carbapenems with amoxicillin-clavulanic acid 1

Treatment Duration for MDR-TB

• Total duration: 18-20 months from treatment start OR 15-17 months after culture conversion, whichever is longer 8
• For pre-XDR-TB and XDR-TB: 15-24 months after culture conversion 1
• Bedaquiline is typically given for 24 weeks (6 months) but may be extended if necessary 8
• Maintain at least 3-4 effective drugs throughout the entire treatment course, even after bedaquiline discontinuation 8

Essential Monitoring and Management Principles

Treatment Adherence

• Directly observed therapy (DOT) is strongly recommended for all TB patients to ensure adherence and prevent resistance development 7, 4
• Use a patient-centered approach tailored to individual circumstances and mutually acceptable to patient and provider 1

Bacteriological Monitoring

• Monitor monthly sputum cultures until negative 7
• For pulmonary TB, 37 of 39 patients (95%) should convert sputum cultures from positive to negative within 2 months of starting treatment 9

Toxicity Monitoring for MDR-TB

• Perform baseline and monthly ECGs to detect QTc prolongation (bedaquiline, clofazimine, fluoroquinolones) 8
• Obtain monthly complete blood counts to detect myelosuppression (linezolid) 8
• Conduct regular visual acuity and color vision assessments to detect optic neuropathy (ethambutol, linezolid) 8
• Instruct patients to report symptoms of hepatotoxicity immediately 7

Critical Pitfalls to Avoid

• Never add a single drug to a failing regimen - this rapidly leads to acquired resistance 1, 6
• Only use drugs to which the isolate has documented or high likelihood of susceptibility 1
• If ≥1% of organisms show resistance to a drug on solid media culture, do not use that drug 1
• Consult a TB expert when drug resistance is suspected or confirmed 1, 4

Special Populations

• HIV-infected patients should be treated with the same regimens but require careful assessment of clinical and bacteriologic response, with treatment prolongation if response is slow or suboptimal 5
• Children should be managed similarly to adults with appropriately adjusted drug doses 5
• Miliary TB, bone/joint TB, or TB meningitis in children requires minimum 12 months of therapy 5

Public Health Responsibility

• Report all suspected and confirmed TB cases to local or state health departments 4
• Perform contact investigations for all active TB cases 1
• Offer treatment for latent TB infection to MDR-TB contacts with 6-12 months of a later-generation fluoroquinolone alone or with a second drug (not pyrazinamide due to toxicity) 1