How should I treat a patient with drug‑susceptible tuberculosis, including the drug regimen, dosing, duration, monitoring, and special considerations such as low body weight, hepatic impairment, HIV co‑infection, and possible multidrug‑resistant TB?

Treatment of Drug-Susceptible Tuberculosis

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

Initial Drug Regimen

Standard Four-Drug Intensive Phase (First 2 Months)

• Isoniazid (INH): 5 mg/kg up to 300 mg daily (adults); 10-15 mg/kg up to 300 mg daily (children) 3
• Rifampin (RIF): Standard dosing per weight 1
• Pyrazinamide (PZA): Continue for full 2 months 1, 2
• Ethambutol (EMB): Include unless primary isoniazid resistance is documented to be <4% in the community AND the patient has no previous TB treatment, is not from a high drug-resistance prevalence country, and has no known exposure to drug-resistant cases 1, 4

Critical caveat: Ethambutol can only be safely omitted in children whose visual acuity cannot be monitored if all four low-resistance criteria are met; however, most experts include ethambutol regardless due to difficulty ascertaining true resistance prevalence 1

Continuation Phase (Months 3-6)

• Isoniazid and rifampin only for 4 months after confirming drug susceptibility 1, 2
• Continue daily dosing (strongly recommended) or transition to directly observed therapy (DOT) with thrice-weekly dosing after initial 2 weeks in selected low-risk patients 1

Drug Susceptibility Testing and Treatment Modification

Mandatory Testing Protocol

• Perform drug susceptibility testing on the first isolate from all patients with newly diagnosed TB 1, 5
• Repeat testing if cultures remain positive after 3 months of treatment or if clinical evidence of treatment failure exists 1, 5
• Adjust regimen immediately when susceptibility results become available 1

Modification Based on Results

If fully susceptible to INH and RIF: Continue isoniazid and rifampin for total 6 months with pyrazinamide only in first 2 months 1, 5, 4

If isoniazid-resistant but rifampin-susceptible: Add a later-generation fluoroquinolone (levofloxacin or moxifloxacin) to a 6-month regimen of rifampin, ethambutol, and pyrazinamide 1, 2. Pyrazinamide duration can be shortened to 2 months in noncavitary, lower-burden disease or if pyrazinamide toxicity occurs 1

If multidrug-resistant (MDR-TB, resistant to at least INH and RIF): Construct regimen with at least 5 effective drugs including bedaquiline, linezolid, levofloxacin or moxifloxacin, and clofazimine for 15-21 months after culture conversion 1, 2

Monitoring Requirements

Baseline Evaluation

• Sputum smear and culture with drug susceptibility testing 2
• Chest radiograph 2
• HIV testing 2
• Hepatitis B/C screening in patients with risk factors 2
• Baseline liver function tests, complete blood count, serum creatinine 2
• Visual acuity testing if ethambutol is used 1

During Treatment

• Monthly sputum cultures until 2 consecutive specimens are negative 2
• Monthly assessments of weight, adherence, symptom improvement, and adverse effects 2
• Repeat drug susceptibility testing if patient remains culture-positive after 3 months 5, 2
• Monitor for hepatotoxicity, particularly during first 2 months 5
• Reevaluate patients not responding after 3 months of treatment 2

Special Populations

HIV Co-infection

• Use the same 6-month, four-drug regimen as HIV-negative patients 1, 2
• Extend treatment to at least 9 months and for at least 6 months beyond documented culture conversion due to risk of suboptimal response 1, 5, 2
• Substitute rifabutin for rifampin with appropriate dose adjustments when patients receive protease inhibitors or NNRTIs 1, 5
• Screen antimycobacterial drug levels in patients with advanced HIV disease to prevent malabsorption and emergence of MDR-TB 1
• Critically assess clinical and bacteriologic response; prolong therapy if slow or suboptimal response 1, 4

Pregnancy

• Initial regimen should include isoniazid, rifampin, and ethambutol 5, 3
• Do not routinely use pyrazinamide due to inadequate teratogenicity data 5, 2, 3
• Avoid streptomycin as it causes congenital deafness 5, 3

Low Body Weight

• Adjust doses based on actual body weight using standard mg/kg dosing 1
• Consider therapeutic drug monitoring in patients with very low body weight 1

Hepatic Impairment

• Monitor liver function tests closely, especially during first 2 months 5
• If baseline hepatic impairment exists, consider regimens that minimize hepatotoxic drugs or use alternative agents with expert consultation 1
• Never add a single drug to a failing regimen as this leads to acquired resistance 5

Children

• Use same principles as adults with appropriately adjusted doses 1, 4
• Daily dosing: INH 10-15 mg/kg up to 300 mg; intermittent dosing: 20-40 mg/kg up to 900 mg 3
• Ethambutol should be included unless visual acuity cannot be monitored AND all low-resistance criteria are met 1
• Extend treatment to 12 months for miliary TB, bone/joint TB, or tuberculous meningitis 4

Extrapulmonary Tuberculosis

Standard Sites (Peritoneal, Pleural, Lymph Node)

• Use the same 6-month regimen as pulmonary TB 1, 2, 4, 6
• Corticosteroids are not routinely indicated for peritoneal TB 2

Special Sites Requiring Extended Therapy

• Extend to 9-12 months for disseminated disease, miliary disease, bone/joint TB, or tuberculous meningitis 1, 5
• Children with miliary TB, bone/joint TB, or tuberculous meningitis should receive minimum 12 months 4
• Adjunctive corticosteroids benefit tuberculous pericarditis (prevents cardiac constriction) and tuberculous meningitis (decreases neurologic sequelae), especially when administered early 3
• Surgery may be necessary for constrictive pericarditis or spinal cord compression from Pott's disease 3

Directly Observed Therapy (DOT)

Implementation

• DOT should be implemented whenever possible as it is the central element of successful TB management 2, 3
• Consider DOT for all patients, particularly those at risk for nonadherence 1
• Patient noncompliance is a major cause of drug-resistant tuberculosis 3

Dosing Schedules with DOT

• Daily dosing strongly recommended during intensive phase 1, 2
• After initial 2 weeks of daily therapy, can transition to thrice-weekly DOT in patients who are HIV-negative with noncavitary, smear-negative disease (low risk of relapse) 1
• Twice-weekly DOT after initial 2 weeks may be considered only in HIV-negative, low-risk patients when daily or thrice-weekly DOT is difficult to achieve 1

Critical warning: If doses are missed in twice-weekly regimens, therapy becomes equivalent to once-weekly dosing, which is inferior and increases relapse risk 1

Patient-Centered Approaches

• Video-observed treatment for remote monitoring 1, 2
• Transportation vouchers 1
• Convenient clinic hours and locations 1
• Bilingual/bicultural outreach workers 1
• Food stamps, meals, or restaurant coupons as incentives 1
• Social service assistance including substance abuse treatment referrals and housing assistance 1

Common Pitfalls to Avoid

• Never add a single drug to a failing regimen—this creates acquired resistance 5
• Do not delay adjusting treatment after receiving drug susceptibility results 5
• Do not use shortened 4-month fluoroquinolone-containing regimens—they substantially increase relapse rates (RR 3.56 for moxifloxacin regimens, RR 2.11 for gatifloxacin regimens) compared to standard 6-month treatment 7
• Monitor for drug interactions with rifampin, which affects oral contraceptives, anticoagulants, and antiretroviral drugs 5
• Do not omit ethambutol unless all four low-resistance criteria are definitively met, as resistance prevalence is difficult to ascertain accurately 1
• Avoid kanamycin and capreomycin in MDR-TB regimens; use amikacin or streptomycin only when susceptibility is confirmed 1