Tuberculosis, Active

Timothy R. Sterling, M.D.

PATHOGENS

  • Mycobacterium tuberculosis
  • Mycobacterium bovis

CLINICAL

  • Pulmonary TB: cough > 2 wks, fever, night sweats, weight loss, hemoptysis, SOB, chest pain
  • Disseminated TB: fevers, weight loss, organ involvement.
  • CXR: upper lobe infiltrate(s) classic (often cavitary); atypical presentations especially in children or if HIV+; hilar adenopathy.
  • Diagnostics:
    • Sputum AFB smear: ~50% sensitive
    • AFB culture: ~80% sensitive
    • PCR (e.g., Xpert MTB/RIF, MTB/RIF Ultra, MTB/XDR): best sensitivity in sputum with positive AFB smear; less sensitive in smear-negative or extrapulmonary TB specimens.
    • Tuberculin skin test (Mantoux, PPD) and IFN-gamma release assays (e.g., QuantiFERON-Gold, T.SPOT.TB): cannot distinguish the active disease from latent infection; either can be negative in >25% with active infection.

DIAGNOSIS

  • Culture: gold standard; it also allows for determining drug susceptibility.
  • AFB smear: indicates infectiousness in respiratory specimens, i.e., AFB smear-positive is more infectious than smear-negative.
  • Amplification methods:
    • Xpert MTB/RIF, MTB/RIF Ultra: highly sensitive and specific for detecting TB and RIF resistance directly in sputum.
      • It can be used on extrapulmonary samples but with lower sensitivity due to lower bacillary burden.
      • Xpert MTB/RIF Ultra: more sensitive than standard Xpert MTB/RIF and recommended by WHO.
    • PCR (nucleic acid amplification) tests can be performed directly on clinical specimens in untreated patients.
      • Sensitive in smear + pulmonary patients.
      • Less sensitive in smear-negative and extra-pulmonary specimens due to a lower bacillary burden.
  • WHO recommends line probe assays (e.g., Genotype MTBDR (Hain Lifescience) to detect MDR-TB (multidrug-resistant TB; resistance to at least INH +RIF) in resource-limited settings. Hain test can be used directly on clinical specimens rather than waiting for culture.
  • The FDA has approved IFN-gamma release assays (QuantiFERON-Gold, T.SPOT.TB) for diagnosing TB infection and disease, but they cannot distinguish between latent infection and disease.

TREATMENT

Adults

  • For drug-susceptible TB, typically four drugs are used for 8 weeks; then, using susceptibilities, reduce to 2 or 3 drugs (usually INH + RIF) used for the balance of duration.
  • Initial therapy: four-drug therapy standard (RIPE), all are oral and dosed daily.
    • RIF 10mg/kg (600mg max)
    • INH 5mg/kg (300mg max)
    • PZA 15-30mg/kg (2g max)
    • EMB 15-25mg/kg (1.6g max)
    • Vitamin B6 (pyridoxine) 50mg
  • HIV: Rifampin can be given with efavirenz; can use rifabutin in place of rifampin in persons on HIV-1 protease inhibitors, integrase inhibitors, NNRTI, and methadone.
    • Rifampin can be given with raltegravir but must increase the raltegravir dose to 800 mg twice daily. Rifampin can also be given with dolutegravir, but dolutegravir dosing must be increased to 50 mg twice-daily.
  • Check drug susceptibilities when available.
    • Treat with at least two drugs to which M. tb is susceptible.
  • Duration: determined by the site of disease response to therapy.
    • The usual duration 6 mos for drug-susceptible TB, but use 9 mos if cavitary disease and cx (+) after 2 mos.
    • For meningitis treatment, see Meningitis, TB
    • Bone/joint TB: longer duration typical, usually 9-12 months
  • Alternative 4-month regimen can be considered for persons > 12 years old with drug-susceptible pulmonary TB.
    • The regimen consists of 8 weeks of daily rifapentine (RPT), INH, PZA, and moxifloxacin (MOX, 400 mg), followed by 9 weeks of daily treatment with RPT, INH, and MOX.
  • Refer to the local health department so the patient can receive directly observed therapy (DOT).
  • Dosing less frequently than daily is possible but must be done via DOT.
  • Drug-resistant TB: consult TB or infectious diseases expert for guidance.
    • See 2019 WHO guidelines and ATS/CDC/ERS/IDSA Clinical Practice Guidelines. Two options: 18-20 months (longer) or 9-12 months (shorter) regimens. Limited evidence.

Children

  • Similar to adults, a 4-drug regimen is used initially, then trimmed to a 2-drug minimum when susceptibilities are available.
  • Initial therapy: four drugs (RIPE), all oral and once daily.
    • RIF 10-20mg/kg (600mg max)
    • INH 10-15mg/kg (300mg max)
    • PZA 15-30mg/kg (2g max)
    • EMB 15-20mg/kg (1g max)
    • Pyridoxine 50mg
  • After the first 2 months of treatment, it can decrease to INH + RIF if drug-susceptible (or presumed source case has drug-susceptible TB if culture and susceptibilities are unknown for the child).
  • Use EMB only to monitor visual acuity (e.g., usually, age > 8 yrs).
  • Can use rifabutin in place of rifampin in persons on HIV protease inhibitors, integrase inhibitors, and NNRTI. Dose adjustments are necessary.
  • Check drug susceptibilities; treat with at least 2 drugs to which M. tb is susceptible.
  • The disease site determines Rx duration, response to therapy (see Adult section above).
  • Refer to the local health department so the patient can receive DOT.
  • Dosing less frequently than daily is possible but must be done via DOT.

Infection Control

  • TB isolation: cough > 2 weeks + abnormal CXR.
    • Can discontinue if 3 sputum samples (expectorated or induced) are AFB smear-negative.
      • Three expectorated can be within 24 hours if one specimen is from early AM.
    • Can also discontinue respiratory isolation if 2 sputum samples are Xpert-negative
    • If AFB smear-positive or on TB treatment, can discontinue infection control after 2 weeks of treatment, clinical improvement, and AFB smear-negative.
  • Special concerns exist if the patient will be transferred to a high-risk setting or concern for drug-resistant organisms (e.g., nursing home, homeless shelter, contact with immunocompromised persons).

Selected Drug Comments

Drug

Recommendation

Rifabutin

It can be used in place of rifampin, drug interactions to a lesser extent than with rifampin (e.g., less likely to precipitate methadone withdrawal).

Ethambutol

Least potent of first-line agents but must be in regimen until susceptibilities are known. Visual/color acuity testing is needed if continued long-term.

Pyrazinamide

Hepatotoxicity and hyperuricemia are possible.

Rifampin

Essential for 6-month "short-course" therapy. Many drug interactions. It may cause LFT abnormalities, especially cholestatic pictures.

Isoniazid

Hepatotoxicity and peripheral neuropathy are possible; the risk of the latter decreases with the use of pyridoxine (vitamin B6).

FOLLOW UP

  • Refer all cases to the local health department for treatment and contact investigation.
  • DOT is preferred for both adults and children.
  • If adverse drug reactions prompt change in 4- or later 2-drug therapy, this is best done in close consultation with a health expert in TB or infectious diseases.

OTHER INFORMATION

  • Guidelines based on ATS/CDC Guidelines.
    • This includes the recommendation to extend treatment to 9 mos if cavitary disease plus cx + after 2 months.
  • MDR-TB should be managed in consultation with an expert in resistant TB disease.
  • HIV-infected patients w/ TB:
    • Concerns for drug interactions, immune reconstitution inflammatory syndrome (IRIS), and drug toxicity. Manage in consultation with experts.
    • If CD4 < 50, initiation of ART within 2 weeks of starting TB therapy decreases the risk of AIDS-defining events and death and is therefore recommended.
  • In some situations, diagnosis is only apparent with negative cultures after response to therapy (may occur 10-20%+ of TB patients depending on presentation).
    • It may need to be treated empirically, especially in severely ill (e.g., TB meningitis), before obtaining a definite diagnosis.

Pathogen Specific Therapy

Pathogen

First-Line Agent

Second-Line Agent

M. tuberculosis

isoniazid
rifampin
pyrazinamide
ethambutol

streptomycin
capreomycin
moxifloxacin
ethionamide
para-aminosalicylic acid

cycloserine

bedaquiline

Basis for recommendation

  1. Carr W, Kurbatova E, Starks A, et al. Interim Guidance: 4-Month Rifapentine-Moxifloxacin Regimen for the Treatment of Drug-Susceptible Pulmonary Tuberculosis - United States, 2022. MMWR Morb Mortal Wkly Rep. 2022;71(8):285-289.  [PMID:35202353]

    Comment: The four-month option for adolescents and adults is now part of the potential regimen, shortening from six months. A 4-month regimen containing rifapentine (RPT), moxifloxacin (MOX), isoniazid (INH), and pyrazinamide (PZA) was as effective as the standard 6-month regimen for tuberculosis (TB) treatment.

  2. Nahid P, Mase SR, Migliori GB, et al. Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline. Am J Respir Crit Care Med. 2019;200(10):e93-e142.  [PMID:31729908]

    Comment: An oral regimen is possible for MDR Tb, however, certainty in the evidence was judged to be very low, because the data came from observational studies with significant loss to follow-up and imbalance in background regimens between comparator groups.

  3. Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis. 2016;63(7):e147-e195.  [PMID:27516382]

    Comment: Current guidance for drug-susceptible and, therefore, more straightforward cases.

  4. Horsburgh CR, Barry CE, Lange C. Treatment of Tuberculosis. N Engl J Med. 2015;373(22):2149-60.  [PMID:26605929]

    Comment: Focus on regimens and some approaches with drug resistance.

  5. WHO consolidated guidelines on drug-resistant tuberculosis treatment. Geneva. World Health Organization. WHO/CDS/TB/2019.7 (accessed 1/8/2024).

    Comment: For MDR-TB (resistance to at least INH + RIF), two types of regimens are possible: 9-12 months (shorter) or 18-20 months (longer).

  6. U.S. Department of Health and Human Services. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. [online].; last updated 09/25/2023, accessed 1/8/2024.

    Comment: Recommendations for use of rifampin and rifabutin with antiretroviral therapy, including integrase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors.
    Updated regularly on-line: https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a...

References

  1. Furin J, Cox H, Pai M. Tuberculosis. Lancet. 2019;393(10181):1642-1656.  [PMID:30904262]

    Comment: Update on TB treatment, both drug-susceptible and drug-resistant disease.

  2. Lange C, Dheda K, Chesov D, et al. Management of drug-resistant tuberculosis. Lancet. 2019;394(10202):953-966.  [PMID:31526739]

    Comment: This review emphasizes the difficulties and recommendations for handling MDR and XDR TB.

  3. Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment–2017, Ahmad N, Ahuja SD, et al. Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis. Lancet. 2018;392(10150):821-834.  [PMID:30215381]

    Comment: Although much of the data is observational and heterogenous, this analysis suggests treatment outcomes were significantly better with the use of linezolid, later-generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for the treatment of multidrug-resistant tuberculosis.

  4. Hopewell PC, Fair EL, Uplekar M. Updating the International Standards for Tuberculosis Care. Entering the era of molecular diagnostics. Ann Am Thorac Soc. 2014;11(3):277-85.  [PMID:24673691]

    Comment: Molecular methods are revolutionizing diagnosis, although TB remains especially difficult in some settings, e.g., CSF.

  5. Blanc FX, Sok T, Laureillard D, et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med. 2011;365(16):1471-81.  [PMID:22010913]

    Comment: This study was open to patients with CD4 < 200, but the median CD4 count was only 25. Early ART initiation (within 2 weeks vs. 8 weeks after starting TB therapy) was associated with a decreased risk of death.

  6. Havlir DV, Kendall MA, Ive P, et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011;365(16):1482-91.  [PMID:22010914]

    Comment: Similar to the results of the study by Abdool Karim, early ART initiation (within 2 weeks vs. 8-12 weeks after starting TB therapy) was not associated with a decreased risk of the combined endpoint of AIDS or death among all study participants but was associated with a decreased risk among persons with CD4 < 50.

  7. Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med. 2011;365(16):1492-501.  [PMID:22010915]

    Comment: Early ART initiation (within 4 weeks vs. 8-12 weeks after starting TB therapy) was not associated with a decreased risk of the combined endpoint of AIDS or death among all study participants. Still, it was associated with a decreased risk among persons with CD4 < 50.

  8. Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med. 2010;363(11):1005-15.  [PMID:20825313]

    Comment: Xpert MTB/RIF test 98% sensitive in smear-positive patients and 90% sensitive in smear-negative patients if 3 tests are performed. 99% specific.

  9. Mazurek GH, Jereb J, Vernon A, et al. Updated guidelines for using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection - United States, 2010. MMWR Recomm Rep. 2010;59(RR-5):1-25.  [PMID:20577159]

    Comment: CDC guidelines for use of interferon gamma release assays.
    Rating: Important

  10. Centers for Disease Control and Prevention (CDC). Updated guidelines for the use of nucleic acid amplification tests in the diagnosis of tuberculosis. MMWR Morb Mortal Wkly Rep. 2009;58(1):7-10.  [PMID:19145221]

    Comment: The recommendation that nucleic acid amplification testing is performed on at least one respiratory specimen from patients with signs and symptoms of pulmonary TB for whom the test result would alter case management or TB control (e.g., contact investigations).

  11. Barnard M, Albert H, Coetzee G, et al. Rapid molecular screening for multidrug-resistant tuberculosis in a high-volume public health laboratory in South Africa. Am J Respir Crit Care Med. 2008;177(7):787-92.  [PMID:18202343]

    Comment: Genotype MTBDR (Hain Lifescience) test to detect TB and INH and RIF resistance.

Last updated: January 14, 2024