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 classic (may be cavitary); atypical presentations especially in children or if HIV+; hilar adenopathy.
  • Diagnostics:
    • Sputum AFB smear: ~50% sensitive
    • AFB culture: ~80% sensitive
    • PCR: best for sputum with positive AFB smear, expensive (e.g., GeneXpert).
    • Tuberculin skin test (Mantoux, PPD) and IFN-gamma release assays: cannot distinguish 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: provides indication of infectiousness in respiratory specimens, i.e., AFB smear-positive more infectious than smear-negative.
  • Amplification methods:
    • GeneXpert MTB/RIF: highly sensitive and specific for detecting TB and RIF resistance directly in sputum.
      • Sometimes used on other samples.
    • 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 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 specimen rather than waiting for culture.
  • IFN-gamma release assays (QuantiFERON-Gold, T.SPOT.TB) have been approved by the FDA for diagnosis of TB infection and disease, but they cannot distinguish between infection and disease.

TREATMENT

Adults

  • Typically four drugs used for 8 wks, then using susceptibilities reduce to 2 or 3 drugs (usually INH + RIF) used for 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, methadone. Rifampin can be given with raltegravir but must increase raltegravir dose to 800 mg twice daily.
  • Check drug susceptibilities when available. Treat with at least 2 drugs to which M. tb is susceptible.
  • Duration: determined by site of disease, response to therapy.
    • Usual duration 6 mos, 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
  • Refer to health department so pt 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.

Children

  • Similar to adults, four-drug regimen used initially, then trim to 2-drug minimum when susceptibilities 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 first two months of treatment 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 if can monitor visual acuity (e.g., usually age > 8 yrs).
  • Can use rifabutin in place of rifampin in persons on HIV protease inhibitors, integrase inhibitors, NNRTI. Dose adjustments necessary.
  • Check drug susceptibilities; treat with at least 2 drugs to which M. tb is susceptible.
  • Rx duration determined by site of disease, response to therapy (see adult section above).
  • Refer to health department so pt. 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.
    • 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 patient will be transferred to 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

Can be used in place of rifampin; drug interactions to 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 known. Visual/color acuity testing needed if continued long term.

Pyrazinamide

Hepatotoxicity, hyperuricemia possible.

Rifampin

Important for 6-month "short-course" therapy. Many drug interactions. May cause LFT abnormalities, especially cholestatic picture.

Isoniazid

Hepatotoxicity, peripheral neuropathy possible; risk of latter decreased with use of pyridoxine (vitamin B6).

FOLLOW UP

  • Refer all cases to local health department for treatment and contact investigation.
  • DOT 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 expert in resistant TB infections. 
  • HIV-infected patients w/ TB:
    • Concerns for drug interactions, immune reconstitution inflammatory syndrome (IRIS), drug toxicity. Manage in consultation with knowledgeable expert.
    • 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 only clear with negative cultures after response to therapy (may occur 10-20%+ of TB patients depending on presentation).
    • May need to treat empirically, especially in severely ill (e.g., TB meningitis) prior to obtaining definite diagnosis.

Basis for recommendation

  1. Nahid P 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 63:e147, 2016  [PMID:27516382]

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

  2. Horsburgh CR, Barry CE, Lange C: Treatment of Tuberculosis. N Engl J Med 373:2149, 2015  [PMID:26605929]

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

References

  1. Dheda K, Barry CE, Maartens G: Tuberculosis. Lancet 387:1211, 2016  [PMID:26377143]

    Comment: Discussion includes diagnostic methods and treatments.
    Rating: Important

  2. Masur H et al: Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Updated Guidelines From the Centers for Disease Control and Prevention, National Institutes of Health, and HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 58:1308, 2014  [PMID:24585567]
  3. Hopewell PC, Fair EL, Uplekar M: Updating the International Standards for Tuberculosis Care. Entering the era of molecular diagnostics. Ann Am Thorac Soc 11:277, 2014  [PMID:24673691]

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

  4. Abdool Karim SS et al: Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med 365:1492, 2011  [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, but was associated with a decreased risk among persons with CD4 < 50.

  5. Blanc FX et al: Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med 365:1471, 2011  [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 et al: Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med 365:1482, 2011  [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. Boehme CC et al: Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med 363:1005, 2010  [PMID:20825313]

    Comment: Xpert MTB/RIF test 98% sensitive in smear-positive patients and 90% sensitive in smear-negative patients if 3 tests performed. 99% specific. Not FDA-approved.

  8. Sterling TR, Pham PA, Chaisson RE: HIV infection-related tuberculosis: clinical manifestations and treatment. Clin Infect Dis 50 Suppl 3:S223, 2010  [PMID:20397952]

    Comment: Recent TB/HIV review of clinical manifestations and treatment.

  9. Mazurek M et al: Updated guidelines for using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection - United States, 2010. MMWR Recomm Rep 59:1, 2010  [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 58:7, 2009  [PMID:19145221]

    Comment: Recommendation that nucleic acid amplification testing be 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. Pai M, Zwerling A, Menzies D: Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update. Ann Intern Med 149:177, 2008  [PMID:18593687]

    Comment: Update on IGRAs.
    Rating: Important

  12. Barnard M 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 177:787, 2008  [PMID:18202343]

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

  13. 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 08/17/2016.

    Comment: Recommendations for use of rifampin and rifabutin with HAART. Updated regularly.
    Updated regularly on-line:https://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-oi-prevention-and-treatment-guidelines/0

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Last updated: January 3, 2017