What are the current guidelines for the management of tuberculosis (TB) in a given location, considering factors such as patient age, weight, and human immunodeficiency virus (HIV) co-infection status?

Management of Tuberculosis: Current Guidelines

Initial Treatment Regimen for Drug-Susceptible TB

The preferred treatment for drug-susceptible tuberculosis is 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

Intensive Phase (First 2 Months)

• Four-drug therapy: Isoniazid + Rifampin + Pyrazinamide + Ethambutol 1, 2
• Ethambutol should be included in the initial regimen until drug susceptibility results are available, unless primary isoniazid resistance in the community is <4% 1, 3
• For children too young to be monitored for visual acuity, streptomycin may be substituted for ethambutol 3
• All doses should be given daily—intermittent dosing in the intensive phase should be avoided, especially in HIV-coinfected patients due to increased risk of relapse with acquired rifamycin resistance 4

Continuation Phase (Months 3-6)

• Two-drug therapy: Isoniazid + Rifampin for 4 months 1, 3
• May be given daily or three times weekly under directly observed therapy 1

Alternative Regimens

• A 4-month regimen containing rifapentine is now recommended for eligible individuals with pulmonary TB 2
• For patients who cannot take pyrazinamide, a 9-month regimen of isoniazid and rifampin (with ethambutol until susceptibility known) is acceptable 3
• If isoniazid resistance is demonstrated, rifampin and ethambutol should be continued for a minimum of 12 months 3

Baseline Diagnostic Testing

Microbiological Confirmation

• Obtain at least 3 sputum specimens for acid-fast bacilli (AFB) smear and culture before initiating treatment 1
• At least one baseline specimen should be tested using a rapid molecular test (e.g., nucleic acid amplification test) 1
• Drug susceptibility testing for isoniazid, rifampin, ethambutol, and pyrazinamide must be performed on all initial isolates 1, 5

Additional Baseline Assessments

• Chest radiograph for all patients 1
• HIV testing for all TB patients—this is mandatory regardless of perceived risk 1, 6
• Hepatitis B and C screening for patients with risk factors (injection drug use, birth in Asia or Africa, or HIV infection) 1
• Baseline liver function tests (ALT, AST) 1
• Baseline visual acuity and color discrimination for patients receiving ethambutol 1
• Fasting glucose or hemoglobin A1c for patients with diabetes risk factors 1

Monitoring During Treatment

Microbiological Monitoring

• Monthly sputum smear and culture until 2 consecutive specimens are negative 1
• Repeat drug susceptibility testing if patient remains culture-positive after 3 months of treatment 1
• Patients with positive smears at month 5 should be considered treatment failures 1

Clinical Monitoring

• Monthly weight assessment to adjust medication doses as needed 1
• Monthly assessment of adherence and TB symptoms (cough, fever, fatigue, night sweats) 1
• Monthly monitoring for adverse drug effects including jaundice, dark urine, nausea, vomiting, abdominal pain, fever, rash, anorexia, malaise, neuropathy, and arthralgias 1
• Monthly visual disturbance inquiry and color discrimination tests for patients on ethambutol 1

Laboratory Monitoring

• Liver function tests should be monitored regularly in patients with baseline abnormalities, chronic alcohol consumption, concurrent hepatotoxic medications, viral hepatitis, history of liver disease, or HIV infection 1
• For HIV-positive patients, monitor CD4 count and HIV viral load at least every 3 months 7

Directly Observed Therapy (DOT)

All patients should receive directly observed therapy where a treatment supporter watches medication ingestion. 1

• DOT is particularly critical for patients with social risk factors, HIV coinfection, or suspected poor adherence 8
• Fixed-dose combinations are highly recommended, especially when medication ingestion is not directly observed, as they minimize the opportunity for selective single-drug intake 1, 9

Management of Treatment Interruptions

During Intensive Phase (First 2 Months)

• If interruption <14 days: Continue treatment to complete planned total number of doses (as long as all doses completed within 3 months) 1
• If interruption ≥14 days: Restart treatment from the beginning 1

During Continuation Phase

• If received ≥80% of doses and initially smear-negative: Continue therapy until all doses completed 1
• If received ≥80% of doses and initially smear-positive: Continue therapy until all doses completed, unless consecutive lapse >2 months 1
• If received <80% of doses and lapse <3 months: Restart intensive phase if treatment cannot be completed within recommended timeframe 1
• If received <80% of doses and lapse ≥3 months: Restart therapy from the beginning with new intensive and continuation phases 1

For Patients Lost to Follow-Up

• Resend sputum for AFB smear, culture, and drug susceptibility testing when brought back to therapy 1

Special Populations

HIV-Coinfected Patients

Initiate TB treatment first, before antiretroviral therapy (ART), to reduce risk of immune reconstitution inflammatory syndrome (IRIS) and better manage drug interactions. 8

TB Treatment Modifications

• Use the same 6-month regimen (2 months HRZE, then 4 months HR) 8, 7, 3
• Daily therapy is mandatory—avoid intermittent dosing in the intensive phase 4, 5
• Add pyridoxine (vitamin B6) 25-50 mg daily to all HIV-infected patients on isoniazid to reduce peripheral neuropathy risk 7, 5

Timing of ART Initiation

• For CD4 <50 cells/mm³: Initiate ART within 2 weeks of starting TB treatment 7, 5
• For CD4 >50 cells/mm³: Initiate ART within 8 weeks of starting TB treatment 7, 5
• Treatment for TB should not be delayed while awaiting ART 1

Drug Interactions

• Rifampin interacts significantly with protease inhibitors and non-nucleoside reverse transcriptase inhibitors 8, 9
• Rifabutin 150 mg daily may be substituted for rifampin when ART contains ritonavir or cobicistat 8, 7, 5

Additional Considerations

• Cotrimoxazole prophylaxis should be given to all TB-HIV coinfected patients 1
• HIV-positive patients may have atypical TB presentations with higher rates of extrapulmonary and disseminated disease 8, 9
• Monitor closely for IRIS, which may present as apparent worsening of TB symptoms after ART initiation—treat with corticosteroids if severe 7
• HIV-infected patients have a 14-fold increased risk of drug-induced hepatotoxicity, requiring more frequent liver function monitoring 7

Pregnant Women

• All first-line drugs (rifampin, isoniazid, ethambutol, pyrazinamide) can be used during pregnancy 9
• Streptomycin is contraindicated due to fetal ototoxicity 9
• Add prophylactic pyridoxine 10 mg/day 9

Patients with Diabetes Mellitus

• Use the same drug regimen as non-diabetic patients 9
• Strict blood glucose control is mandatory 9
• Doses of oral hypoglycemic agents may need to be increased due to rifampin interaction 9
• Add prophylactic pyridoxine 9

Patients with Renal Failure

• Dosages must be adjusted according to creatinine clearance, especially for streptomycin, ethambutol, and isoniazid 9
• In acute renal failure, give ethambutol 8 hours before hemodialysis 9

Patients with Pre-existing Liver Disease

• In stable disease with normal liver enzymes, all anti-TB drugs may be used with frequent liver function monitoring 9

Children

• Manage essentially the same as adults using appropriately adjusted doses 3
• A 4-month regimen is now recommended for children with non-severe TB 2
• Children with miliary TB, bone/joint TB, or tuberculous meningitis should receive a minimum of 12 months of therapy 3

Drug-Resistant TB

Assessment for Drug Resistance

• Assess likelihood of drug resistance based on: prior treatment history, exposure to a drug-resistant source case, and community prevalence of drug resistance 1
• Molecular resistance testing should be performed for patients with risk factors for drug resistance 1

Management of MDR-TB

• Multidrug-resistant TB (resistance to at least isoniazid and rifampin) requires specialized treatment with second-line drugs 1
• At least 4 drugs to which organisms are known or presumed susceptible should be used 1
• Treatment duration is typically 18 months 1
• Novel regimens containing bedaquiline, pretomanid, and linezolid with or without moxifloxacin are now recommended 2
• Consultation with an expert in MDR-TB management is mandatory 1, 7
• Never add a single drug to a failing regimen—this leads to further drug resistance 8

Case Reporting and Documentation

• Report all new and retreatment TB cases to local public health authorities within 1 week of diagnosis 1
• Maintain a written record of all medications given, bacteriological response, and adverse reactions for all patients 1
• This is required by law in most jurisdictions 1

Contact Investigation

• Evaluate all close contacts (especially children <5 years and HIV-infected persons) for both latent TB infection and active TB disease 1
• Tuberculin-negative children and adolescents who are close contacts should receive preventive therapy until repeat tuberculin skin test is done 12 weeks after contact 10

Common Pitfalls to Avoid

• Never use single-drug therapy for active TB—this is inadequate and promotes drug resistance 10
• Do not use intermittent dosing in the intensive phase for HIV-coinfected patients 4
• Do not delay TB treatment while awaiting ART initiation in HIV-coinfected patients 1
• Do not rely on chest radiographs alone for monitoring treatment response—sputum microscopy is essential 1
• Do not use tuberculin skin tests or IGRAs to diagnose active TB disease—these are often negative with active disease 5
• Do not assume treatment failure is due to drug resistance without first assessing adherence 1, 9