Treatment of Tuberculosis

Principles of tuberculosis treatment

  • 2-month induction phase with at least isoniazid, rifampin, and pyrazinamide, followed by a 4-month consolidation phase with at least isoniazid and rifampin.
    – Ethambutol is added as protection in case the M.tb is resistant to three other core drugs.
    – Once the susceptibility has been confirmed, ethambutol can be discontinued.
  • Biphasic killing curve of anti-TB drugs
    – Rapidly killed
    – Slowly killed
  • 2 theories for slowly killed M.tuberculosis
    – Some bacteria are in non-replicating state which is more resistant (“persistent bacteria theory”).
    – Some bacteria are sequestered in thick walled granuloma (“persistent disease theory”).
  • Therefore, using combinational therapy (bactericidal + sterilizing) makes sense in TB treatment.
  • Important to complete 6 months (although after 2 months sputum does not have bacilli anymore) to avoid relapse.
    – Some patients may not need full 6 months but difficult to identify these patients. Therefore, overtreatment to ensure cure.
  • Drugs efficacy differ because of
    i) Drug’s property
    ii) Serum level of drugs
  • Fluoroquinolones have poor penetration into the granuloma, isoniazid and rifampin have good penetration. Perhaps explain why FQs use as an alternative does not work very well.
  • Food intake can reduce serum level of anti-TB drugs. Also the rate of metabolism eg in fast acetylators (affects isoniazid)

Challenges in TB treatment regimen

  • Drug toxicity esp hepatotoxicity
  • Compliance
  • Drug resistance

Monodrug resistant TB

  • INH resistance:
    – Most guidelines: rifamycin + ethambutol + pyrazinamide, with or without a fluoroquinolone, for 6 to 12 months
  • Rifampicin resistance is rare without INH resistance.
    – 9 months regimen of INH + pyrazinamide + ethambutol + streptomycin

Multidrug resistant TB

  • Individually tailored according to the results of drug-susceptibility
    testing.
  • WHO: minimum of 20 months regimen using 4 susceptible drugs determined by culture or by DNA-based methods.

HIV and TB

  • CD4 <50: start ART within 2 weeks of anti-TB therapy
  • CD4 >50: start ART within 2 months of anti-TB therapy
  • High risk of IRIS when initiating ART in active TB

 

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  1. Ethambutol can be stopped if susceptibility of M.tuberculosis towards 3 core drugs (isoniazid, rifampicin & pyrazinamide).
  2. Important to complete 6 months of therapy to prevent relapse. However, some may need lesser than 6 months but it’s difficult to identify those patients.
  3. use of fluoroquinolones as alternative therapy doesn’t do well probably because of the drugs’ poor penetrance into the granuloma.
  4. Isoniazid-resistant TB: rifampin + ethambutol + pyrazinamide + moxi/levofloxacin for 6-12 months.
  5. MDR TB: therapy needs to be tailored based on the susceptibility of the microorganism. Minimum of 20 months (2 years) according to WHO.

Reference:

C. Robert Horsburgh, Jr., M.D., Clifton E. Barry III, Ph.D., and Christoph Lange, M.D. Treatment of Tuberculosis. N Engl J Med 2015;373:2149-60

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