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
- 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
- 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
- Ethambutol can be stopped if susceptibility of M.tuberculosis towards 3 core drugs (isoniazid, rifampicin & pyrazinamide).
- 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.
- use of fluoroquinolones as alternative therapy doesn’t do well probably because of the drugs’ poor penetrance into the granuloma.
- Isoniazid-resistant TB: rifampin + ethambutol + pyrazinamide + moxi/levofloxacin for 6-12 months.
- MDR TB: therapy needs to be tailored based on the susceptibility of the microorganism. Minimum of 20 months (2 years) according to WHO.
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