When should anti‑tuberculosis therapy be initiated in patients with active or latent tuberculosis, including special populations such as pregnant women and those with suspected drug‑resistant disease?

When to Initiate Anti-Tuberculosis Therapy

Begin anti-tuberculosis treatment immediately in any patient with confirmed or suspected active TB disease using a four-drug regimen (isoniazid, rifampin, pyrazinamide, and ethambutol), even before culture results are available, if clinical symptoms, chest radiography, and acid-fast bacilli smears suggest active disease. 1, 2

Active Tuberculosis Disease: Immediate Treatment Indications

Clinical Presentation Requiring Immediate Treatment

• Pulmonary symptoms (persistent cough >3 weeks, hemoptysis, chest pain) combined with constitutional symptoms (fever, night sweats, weight loss, malaise) warrant immediate empiric treatment 2, 3
• Positive acid-fast bacilli smear on sputum examination—do not wait for culture confirmation 4, 1
• Chest radiography showing cavitary lesions, infiltrates, or findings consistent with TB in a symptomatic patient 2, 3
• Known exposure to infectious TB with compatible clinical presentation 2

Mandatory Pre-Treatment Steps (But Do Not Delay Treatment)

• Obtain three sputum samples for acid-fast bacilli smear and mycobacterial culture with drug susceptibility testing before starting therapy 4, 1, 5
• Perform HIV testing on all TB patients within 2 months of diagnosis 4
• Obtain baseline chest radiography 1, 2
• Check baseline liver function tests, renal function, complete blood count, and visual acuity (for ethambutol monitoring) 2

Critical pitfall: Never delay treatment while waiting for culture results if clinical suspicion is high—cultures can take 6-8 weeks, and untreated TB causes significant morbidity and mortality 4, 1

Standard Four-Drug Initial Regimen

Drug Selection Based on Resistance Patterns

• In areas where isoniazid resistance is >4% (which includes most of the United States): Start all four drugs—isoniazid, rifampin, pyrazinamide, and ethambutol 4, 1
• In areas where isoniazid resistance is <4%: Three drugs (isoniazid, rifampin, pyrazinamide) may suffice, but only if the patient has no prior TB treatment, is not from a high-resistance country, and has no known exposure to drug-resistant cases 1
• Ethambutol can only be omitted when all four low-resistance criteria are definitively met—resistance prevalence is often uncertain, so include it unless you have documented local resistance data 1, 5

Treatment Duration

• Intensive phase: 2 months of daily isoniazid, rifampin, pyrazinamide, and ethambutol 4, 1, 2
• Continuation phase: 4 months of daily isoniazid and rifampin (total 6 months) for drug-susceptible disease 1, 2
• Extend to 9 months total if cavitary disease is present on initial chest radiograph and sputum culture remains positive after 2 months 2

Latent Tuberculosis Infection: Treatment Indications

Who Should Receive LTBI Treatment

• Positive tuberculin skin test (TST ≥5 mm induration) in high-risk groups: HIV-infected persons, recent contacts of infectious TB cases, persons with chest radiography showing prior TB, organ transplant recipients, immunosuppressed patients 4
• TST ≥10 mm in recent immigrants from high-prevalence countries, injection drug users, residents/employees of high-risk congregate settings, healthcare workers, children <4 years old 4
• TST ≥15 mm in persons with no known risk factors 4
• Positive interferon-gamma release assay (IGRA) in the same risk groups 6, 7

Exclude Active Disease Before Starting LTBI Treatment

• Perform chest radiography on all persons with positive TST or IGRA 4
• Obtain sputum cultures if chest radiography is abnormal or symptoms are present—do not start LTBI treatment until cultures are negative (may take 6-8 weeks) 4
• Rule out active TB by history, physical examination, and chest radiography before initiating LTBI treatment 4

LTBI Treatment Regimens (Preferred Options)

• Isoniazid plus rifapentine once weekly for 12 weeks (by directly observed therapy) 8, 6
• Rifampin daily for 4 months 4, 8, 6
• Isoniazid plus rifampin daily for 3 months 4, 8
• Isoniazid daily for 9 months (6 months is acceptable but 9 months is preferred for HIV-infected persons and those with radiographic evidence of prior TB) 4, 7

Special Populations

HIV Co-Infection

• Use the same four-drug regimen as HIV-negative patients 1, 5
• Extend treatment to at least 9 months and continue for at least 6 months after documented culture conversion due to higher risk of treatment failure 4, 1, 5
• Substitute rifabutin for rifampin (with dose adjustments) when patients receive protease inhibitors or NNRTIs to avoid drug interactions 4, 5
• Avoid once-weekly continuation regimens in HIV-infected patients due to high failure rates and rifamycin resistance 5

Pregnancy

• Do not delay treatment if active TB is suspected—untreated TB poses greater risk to mother and fetus than treatment 4
• Initial regimen: Isoniazid, rifampin, and ethambutol for 2 months, then isoniazid and rifampin for 7 months (total 9 months) 4
• Avoid pyrazinamide routinely due to inadequate teratogenicity data, though some experts include it when resistance is likely and susceptibility is probable 4
• Avoid streptomycin due to fetal ototoxicity 4, 9
• Add pyridoxine 10 mg daily to prevent peripheral neuropathy 9
• For LTBI in pregnancy: Initiate treatment immediately if HIV-infected or recently infected; for lower-risk pregnant women, some experts recommend waiting until after delivery 4

Children

• Use the same regimen as adults with weight-based dosing 4, 1
• Ethambutol may be omitted only in children whose visual acuity cannot be monitored (<6 years old) and only when all four low-resistance criteria are met 4, 1
• Obtain gastric aspirates (early morning, 3 separate days) in children <10 years who cannot produce sputum—expected yield is 50% 4

Extrapulmonary Tuberculosis

• Use the same 6-month regimen for peritoneal, pleural, and lymph node TB 1, 5
• Extend to 9-12 months for disseminated disease, miliary TB, bone/joint TB, or tuberculous meningitis 4, 1, 5

Drug-Resistant TB Contacts

• Isoniazid-resistant, rifampin-susceptible: Add a fluoroquinolone (levofloxacin or moxifloxacin) to rifampin, ethambutol, and pyrazinamide for 6 months 1, 5
• Multidrug-resistant TB (MDR-TB): Construct a regimen with ≥5 effective drugs including bedaquiline, linezolid, a fluoroquinolone, and clofazimine for 15-21 months after culture conversion 1, 5
• LTBI from MDR-TB exposure: Pyrazinamide plus ethambutol or pyrazinamide plus a quinolone for 6-12 months (immunocompetent contacts may be observed; immunocompromised contacts should be treated for 12 months) 4

Directly Observed Therapy (DOT)

When to Use DOT

• All patients on intermittent dosing (twice-weekly or thrice-weekly) must receive DOT 4, 1
• Daily dosing with DOT should be used whenever feasible, especially for patients at highest risk for nonadherence or progression to disease (HIV-infected persons, recent contacts of infectious cases) 4, 1
• Consider DOT for all patients because predicting adherence is difficult—if local treatment completion rates are <90%, expand DOT use 4

Patient-Centered DOT Strategies

• Video-observed treatment, transportation vouchers, flexible clinic hours, bilingual outreach workers, food incentives, and social-service referrals improve adherence 1

Monitoring and Adjustment

Ongoing Monitoring Requirements

• Monthly sputum cultures until two consecutive specimens are negative 1
• Repeat drug susceptibility testing if cultures remain positive after 3 months of treatment or if clinical evidence of treatment failure emerges 4, 1, 5
• Monthly clinical assessments for adherence, symptom improvement, weight, and adverse effects (hepatitis symptoms: nausea, vomiting, abdominal pain, jaundice) 4, 1
• Reevaluate patients who are smear-positive at 3 months for possible nonadherence or drug-resistant infection 4

When to Adjust Treatment

• Adjust regimen immediately once drug susceptibility results are available 1, 5
• Never add a single new drug to a failing regimen—add at least three new drugs to which susceptibility is likely to prevent further acquired resistance 4, 5
• Consult a TB specialist if treatment failure is suspected or drug resistance is confirmed 4, 6

Key Pitfalls to Avoid

• Do not wait for culture results to start treatment in symptomatic patients with high clinical suspicion 1, 2
• Do not omit ethambutol unless you have documented local isoniazid resistance <4% and the patient meets all four low-resistance criteria 1, 5
• Do not use once-weekly continuation regimens in HIV-infected patients 5
• Do not start LTBI treatment until active TB disease is excluded by chest radiography and, if indicated, negative sputum cultures 4
• Report every case of active TB to the local public health department within 1 week of diagnosis 4
• Place all patients with suspected or confirmed respiratory or laryngeal TB in respiratory isolation until they have three consecutive negative sputum smears on different days and are clinically improving 4