What are the recommended drug regimens, doses, and durations for treating drug‑susceptible pulmonary tuberculosis, latent tuberculosis infection, and multidrug‑resistant tuberculosis, including monitoring and special considerations such as pregnancy?

Medications for Tuberculosis

Drug-Susceptible Pulmonary Tuberculosis

For newly diagnosed drug-susceptible pulmonary TB in adults, treat with a 6-month regimen: 2 months of isoniazid, rifampin, pyrazinamide, and ethambutol (intensive phase) followed by 4 months of isoniazid and rifampin (continuation phase), all given daily. 1

Intensive Phase (First 2 Months)

• Isoniazid 5 mg/kg (approximately 300 mg) daily 1, 2
• Rifampin 10 mg/kg daily (600 mg for patients ≥50 kg; 450 mg for <50 kg) 1, 2
• Pyrazinamide 25 mg/kg daily 1
• Ethambutol 15 mg/kg daily 1, 2
• Duration: 56 doses over 8 weeks 1
• Ethambutol can only be omitted if drug susceptibility testing confirms full susceptibility to both isoniazid and rifampin, or if community isoniazid resistance is documented <4% 1

Continuation Phase (Months 3-6)

• Isoniazid 5 mg/kg (approximately 300 mg) daily 1
• Rifampin 10 mg/kg (600 mg) daily 1
• Duration: 126 doses over 18 weeks (4 months) 1

Extended Treatment (9 Months Total)

• Extend continuation phase to 7 months (total 9 months) for patients with both cavitary disease on initial chest radiograph and positive sputum culture at completion of 2 months 1, 2
• Also extend to 9 months for HIV-positive patients not on antiretroviral therapy 1

Pyridoxine Supplementation

• Mandatory pyridoxine 25-50 mg daily for all individuals at risk of peripheral neuropathy: pregnant women, breastfeeding infants, HIV-infected persons, patients with diabetes, alcoholism, malnutrition, chronic renal failure, and older adults 1, 2
• Increase to 100 mg daily if peripheral neuropathy develops 1

Administration and Monitoring

• Directly observed therapy (DOT) is mandatory for all TB patients to ensure completion and prevent resistance 1, 2
• Daily dosing is strongly preferred; when DOT is used, 5-days-per-week is acceptable alternative to 7-days-per-week 1
• Obtain sputum smear and culture at baseline, then monthly until two consecutive specimens are negative 1
• Perform baseline drug-susceptibility testing for isoniazid, rifampin, ethambutol, and pyrazinamide 1

Critical Pitfall

• Never use twice-weekly dosing in HIV-infected patients or those with smear-positive or cavitary disease due to markedly increased risk of failure and relapse 1

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Isoniazid-Resistant Tuberculosis

For isoniazid-resistant TB with rifampin susceptibility, treat with a 6-month regimen of rifampin, ethambutol, pyrazinamide, and a later-generation fluoroquinolone (levofloxacin or moxifloxacin). 3, 4

• Do not add streptomycin or other injectable agents 4
• Pyrazinamide duration can be shortened to 2 months in selected situations (non-cavitary, lower burden disease, or pyrazinamide toxicity) 3

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Multidrug-Resistant Tuberculosis (MDR-TB)

For MDR/rifampin-resistant TB, the preferred regimen is the 6-month all-oral BPaLM regimen (bedaquiline, pretomanid, linezolid, moxifloxacin) for patients without documented resistance to fluoroquinolones or bedaquiline. 4

Shorter All-Oral Regimen (6 Months)

Indicated for MDR/RR-TB patients meeting all criteria: 3

• No previous exposure to second-line TB drugs >1 month
• No fluoroquinolone resistance on drug susceptibility testing
• No extensive pulmonary TB (cavities) or severe extrapulmonary TB (spinal/CNS/miliary)
• Not pregnant
• Age >6 years

Intensive phase (4-6 months):

• Bedaquiline (6 months total: daily for first 2 weeks, then thrice weekly for 22 weeks) 3
• Levofloxacin or moxifloxacin (levofloxacin preferred for fewer adverse events and less QTc prolongation) 3
• Clofazimine 3
• Pyrazinamide 3
• Ethambutol 3
• High-dose isoniazid 3
• Ethionamide 3

Continuation phase (5 months):

• Levofloxacin or moxifloxacin 3
• Clofazimine 3
• Pyrazinamide 3
• Ethambutol 3

Longer Individualized Regimen (18-20 Months)

Required for patients with: 3

• Extensive pulmonary disease
• Severe extrapulmonary TB
• Additional fluoroquinolone resistance
• Prior exposure to second-line medicines >1 month

Drug prioritization (WHO classification): 3

Group A (include at least 3):

• Levofloxacin or moxifloxacin 3
• Bedaquiline 3
• Linezolid 3

Group B (include at least 1):

• Clofazimine 3
• Cycloserine or terizidone 3

Group C (add if needed):

• Ethambutol 3
• Delamanid 3
• Pyrazinamide 3
• Imipenem-cilastatin or meropenem with amoxicillin/clavulanate 3
• Amikacin (or streptomycin) 3
• Ethionamide or prothionamide 3
• p-aminosalicylic acid 3

Minimum of 5 drugs total for longer regimens 3

Drugs to Avoid in MDR-TB

• Do not use kanamycin or capreomycin 3, 4
• Do not use amoxicillin-clavulanate except when patient is receiving a carbapenem 3
• Do not use macrolides (azithromycin, clarithromycin) 3

Active Drug Safety Monitoring (aDSM)

• Mandatory for all MDR-TB patients due to high frequency of severe adverse events 3
• All adverse events must be accurately recorded and managed 3

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Latent Tuberculosis Infection (LTBI)

For Contacts of Drug-Susceptible TB

• Standard regimens include isoniazid for 6-9 months or rifampin-based shorter regimens 5
• Once-weekly isoniazid and rifapentine for 12 weeks by DOT is safe and effective 5

For Contacts of MDR-TB

• Offer treatment for LTBI versus observation alone 3
• Treat with 6-12 months of a later-generation fluoroquinolone alone or with a second drug, based on drug susceptibility of source-case isolate 3

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Special Populations

Pregnancy

• Standard 6-month regimen (isoniazid, rifampin, pyrazinamide, ethambutol) is safe in pregnancy 3
• Avoid streptomycin and other aminoglycosides due to fetal ototoxicity 3
• Ethionamide and prothionamide may be teratogenic and should be avoided 3
• Breastfeeding is safe while taking anti-tuberculosis drugs 3
• Pyridoxine 25-50 mg daily is mandatory 1

HIV Co-infection

• Use the same standard 6-month daily regimen (2 months HRZE / 4 months HR) for HIV-infected patients on antiretroviral therapy 1
• Never use intermittent (twice- or thrice-weekly) regimens in HIV-infected patients due to high relapse and resistance rates 1
• Extend continuation phase by 3 months (total 9 months) if not on antiretroviral therapy 1
• For HIV-positive patients with CD4 <100 cells/mm³, daily therapy is mandatory during intensive phase 2

Diabetes Mellitus

• Use standard regimen with strict blood glucose control 3, 6
• Doses of oral hypoglycemic agents may need to be increased due to rifampin interaction 3, 6
• Prophylactic pyridoxine is indicated 3, 6

Renal Failure

• Rifampin, isoniazid, and pyrazinamide can be given in standard doses 3
• Reduce doses of streptomycin and ethambutol; monitor serum concentrations 3

Liver Disease

• In stable disease with normal liver enzymes, all drugs may be used with frequent monitoring 3, 6
• Baseline and regular liver function tests required in patients with chronic liver disease, alcoholism, chronic active hepatitis, cirrhosis, or hepatitis B/C 3
• Weekly liver function tests for first 2 weeks, then every 2 weeks during first 2 months 3

Children

• Use the same 6-month regimen as adults 3
• Ethambutol can be used without undue fear of side effects 3
• Children with pulmonary TB are rarely infectious as cavitary disease is unusual 3

Extrapulmonary TB

• TB meningitis: Treat for minimum 12 months with rifampin, isoniazid, pyrazinamide, plus either streptomycin or ethambutol for first 2 months 3
• Other extrapulmonary sites (adenitis, bowel, pericarditis, bone/joint): Use standard 6-month regimen 3
• Corticosteroids indicated for pericarditis, stage II-III meningitis, endobronchial disease in children, and spinal TB with cord compression 3, 2

Unconscious Patients

• Administer isoniazid and rifampin as syrup, pyrazinamide as syrup or crushed tablets via nasogastric tube 3
• Alternatively, rifampin and isoniazid can be given by intravenous infusion 3
• Streptomycin given intramuscularly 3