What is tuberculosis and its treatment?

Tuberculosis: Disease Overview and Treatment

Tuberculosis (TB) is a chronic bacterial infection caused by Mycobacterium tuberculosis that requires multi-drug combination therapy for 6 months minimum to cure the individual patient and prevent transmission to others. 1

What is Tuberculosis?

TB is an infectious disease that remains a leading cause of death worldwide, with approximately 10.6 million new cases and 1.6 million deaths annually. 1, 2 The infection can present in two forms:

• Latent TB infection (LTBI): Asymptomatic, noncommunicable infection where approximately 5-10% of untreated individuals will progress to active disease 2
• Active TB disease: Symptomatic infection requiring immediate treatment, most commonly affecting the lungs but can involve any organ system 1, 3

Poverty and HIV coinfection are major drivers of TB transmission and disease progression. 4, 1

Treatment Objectives

The three critical goals of TB therapy are: 1

1. Rapidly reduce actively growing bacilli to decrease disease severity, prevent death, and halt transmission
2. Eradicate persisting bacilli to achieve durable cure and prevent relapse after treatment completion
3. Prevent acquisition of drug resistance during therapy by using multiple drugs simultaneously

Standard Treatment for Drug-Susceptible TB

For drug-susceptible pulmonary and extrapulmonary TB, initiate a 4-drug regimen consisting of isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months (intensive phase), followed by isoniazid and rifampin for 4 months (continuation phase). 1, 5, 6, 3

Initial Intensive Phase (2 months):

• Isoniazid (INH): 5 mg/kg daily (max 300 mg) in adults 6
• Rifampin (RIF): 10 mg/kg daily (max 600 mg) in adults 7
• Pyrazinamide (PZA): per weight-based dosing 5
• Ethambutol (EMB): per weight-based dosing 1

Continuation Phase (4 months):

• Isoniazid and Rifampin only 1

When to Omit Ethambutol

Ethambutol can be excluded from the initial regimen only if ALL of the following criteria are met: 3

• Primary isoniazid resistance is less than 4% in the community
• Patient has no previous TB treatment
• Patient is not from a country with high drug resistance prevalence
• Patient has no known exposure to a drug-resistant case

If any of these conditions are not met, include ethambutol until drug susceptibility results are available. 3

Alternative Regimens

9-Month Regimen

For patients who cannot or should not take pyrazinamide, use isoniazid and rifampin for 9 months, with ethambutol included initially until susceptibility results are available. 3 If isoniazid resistance is demonstrated, continue rifampin and ethambutol for a minimum of 12 months. 3

4-Month Rifapentine-Based Regimen

The WHO conditionally recommends a 4-month regimen of rifapentine, isoniazid, pyrazinamide, and moxifloxacin for eligible persons aged 12 years and older with pulmonary drug-susceptible TB. 1 This represents a significant recent advance in shortening treatment duration.

Special Populations

Pregnant Women

• Use isoniazid and rifampin as the backbone regimen 6
• Add ethambutol unless primary isoniazid resistance is unlikely 6
• Avoid streptomycin (causes congenital deafness) 6
• Avoid routine pyrazinamide use due to inadequate teratogenicity data 6

Children

Manage children essentially the same as adults using appropriately adjusted drug doses. 3 However, children with miliary TB, bone/joint TB, or tuberculous meningitis should receive a minimum of 12 months of therapy. 6, 3

HIV-Infected Patients

Use the same 6-month, 4-drug regimen as for HIV-negative patients. 1, 3 However, critically assess clinical and bacteriologic response, as therapy may need to be prolonged on a case-by-case basis if response is slow or suboptimal. 3 Be aware of significant drug interactions between rifamycins and antiretroviral agents, particularly protease inhibitors and NNRTIs. 1

Extrapulmonary Tuberculosis

General Approach

Treat extrapulmonary TB with the same 6-month regimen used for pulmonary disease. 1, 3 However, specific sites require special consideration:

Tuberculous Meningitis

• Use the standard 4-drug intensive phase for 2 months, then continue isoniazid and rifampin for 7-10 additional months (total 9-12 months). 1
• Add adjunctive corticosteroids: Prednisone 60 mg/day for 4 weeks, then 30 mg/day for 4 weeks, 15 mg/day for 2 weeks, and 5 mg/day for the final week (children: 1 mg/kg with proportionate tapering) 1
• Corticosteroids decrease neurologic sequelae and are most beneficial when started early 1

Tuberculous Pericarditis

• Use the standard 6-month regimen plus adjunctive corticosteroids 1
• Prednisone dosing: Same tapering schedule as for meningitis (60→30→15→5 mg/day over 11 weeks for adults) 1
• Corticosteroids reduce mortality risk and prevent cardiac constriction 1

Pleural Tuberculosis

• Use the standard 6-month regimen 1
• Corticosteroids may provide faster symptom resolution but do not prevent residual pleural thickening 1

Miliary, Bone/Joint TB in Children

• Extend treatment to 12 months minimum 6, 3

Directly Observed Therapy (DOT)

All patients should receive directly observed therapy, where a healthcare provider or responsible person watches the patient ingest each dose of medication. 1, 8 This is the most effective method to ensure adherence and prevent treatment failure and drug resistance. 8, 3

DOT is particularly critical for: 8

• Patients with previous treatment interruption
• Patients lost to follow-up who are re-engaged
• All complex cases

Monitoring During Treatment

Bacteriologic Monitoring

• Collect sputum for AFB smear and culture at baseline, after 2 months of treatment, and at treatment completion 1
• If cultures remain positive after 2-3 months of treatment, this indicates increased risk of relapse and potential treatment failure 1, 8
• Monitor sputum cultures monthly until two consecutive specimens are culture-negative in patients with treatment interruption 8

Clinical Monitoring

• Assess adherence and TB symptoms at each visit 8
• Monitor weight monthly and adjust medication doses accordingly 8
• Teach patients to recognize drug toxicity symptoms and report them promptly 1

Drug Susceptibility Testing

Perform drug susceptibility testing for isoniazid, rifampin, ethambutol, and pyrazinamide on all initial isolates. 1, 8 This is essential for detecting drug resistance and guiding appropriate therapy.

Management of Treatment Interruption

If Interruption <2 Months with Prior Good Adherence

Resume the original regimen and extend total treatment duration by the length of interruption. 8

If Interruption >2 Months or Cultures Positive After 3 Months

• Presume treatment failure 8
• Collect specimens for culture and drug susceptibility testing before modifying therapy 8
• Never add a single drug to a failing regimen—this rapidly leads to acquired resistance 8
• Add at least three new drugs to which susceptibility can be inferred 8
• For seriously ill patients or those with positive AFB smears, start empirical retreatment immediately without waiting for susceptibility results 8

Drug-Resistant Tuberculosis

Multidrug-resistant TB (MDR-TB), defined as resistance to at least isoniazid and rifampin, requires individualized treatment based on drug susceptibility testing and consultation with a TB expert. 1, 8, 3, 2 Treatment must use second-line drugs including fluoroquinolones (moxifloxacin, levofloxacin), linezolid, clofazimine, bedaquiline, pretomanid, and delamanid. 1, 4

Public Health Coordination

Because TB has significant public health implications, assign each patient a public health case manager who develops an individualized case management plan addressing specific barriers to adherence. 1 This plan should address:

• Transportation needs (provide vouchers) 8
• Housing instability 8
• Substance abuse treatment referrals 8
• Language barriers 8
• Convenient clinic hours and locations 8
• Incentives such as food stamps, meals, or grocery coupons 8

Common Pitfalls to Avoid

• Never initiate treatment with fewer than 4 drugs when drug resistance cannot be excluded 1
• Never add a single drug to a failing regimen—always add at least 3 new drugs 8
• Never use intermittent dosing (twice weekly) with doses >600 mg rifampin—this causes flu syndrome, hematologic reactions, and renal failure 7
• Never interrupt daily dosing intentionally—this can cause rare renal hypersensitivity reactions 7
• Never delay empirical treatment in seriously ill patients while awaiting diagnostic confirmation 1
• Never assume patients lost to follow-up will return on their own—deploy outreach workers for aggressive field visits 8
• Never fail to warn patients that rifampin causes orange discoloration of body fluids and permanently stains soft contact lenses 7
• Never forget to administer pyridoxine (vitamin B6) to malnourished patients, alcoholics, and diabetics receiving isoniazid 6