Tuberculosis (TB)

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What is TB?

Tuberculosis (TB) is an infectious disease caused by bacteria (Mycobacterium tuberculosis). While TB usually affects the lungs, it can also involve the kidneys, brain, spine and skin. TB spreads through airborne droplets when people with TB cough, sneeze or spit. About 25% of the global population is estimated to have been infected with TB bacteria. Those who are infected but free of disease cannot spread it. About 7.5% of people infected with TB will eventually get symptoms and develop TB disease. If left untreated, active TB disease kills around 50% of those affected.

TB and HIV

People living with HIV are ~16 times more likely to fall ill with TB disease than people without HIV. TB is the leading cause of death among people with HIV. HIV and TB form a lethal combination, each speeding the other’s progress.

Mycobacterium tuberculosis has been suggested to exist in three states, showcased in (Clewe et al. 2016).

Figure 1: Pharmacodynamic model for different states of Mycobacterium tuberculosis. NB unidirectional from fast to non-multiplying (“dormant”). Clewe et al. (2016).

Drug resistant TB

Myobacterium tuberculosis divides more slowly (~q18h) than most bacteria, making development of antibiotic resistance more likely. In addition, the mycolic acids in its cell wall limit the effectiveness of some antibiotics.

MDR-TB has been defined as resistance to rifampicin plus isoniazid.

Extensively drug-resistant TB (XDR-TB) describes resistance to at least one fluoroquinolone as well as bedaquiline and/or linezolid and/or a second-line injectable in addition to rifampicin and isoniazid.

What are the symptoms?

The symptoms people get depend on which part of the body is affected by TB.

  • Prolonged cough (sometimes with blood) 😮‍💨
  • Chest pain 🫁💥
  • Weakness 😩
  • Fatigue 😩
  • Weight loss 📉
  • Fever 🤒
  • Loss of apetite 🍽️

Typical patient population

Low- and middle-income countries. About half of all people with TB can be found in 8 countries:

  • Bangladesh
  • China
  • India
  • Indonesia
  • Nigeria
  • Pakistan
  • Philippines
  • South Africa

Risk factors

  • Diabetes (high blood sugar)
  • Weakened immune system (e.g. HIV/AIDS)
  • Malnourishment
  • Tobacco use
  • Harmful use of alcohol

Diagnosis

A sputum sample is collected and tested using the Xpert MTB/RIF Ultra assay (Cepheid, Sunnyvale, USA). This diagnoses TB and the detects rifampicin resistance.

TB is particularly difficult to diagnose in children.

How can TB be treated?

Tuberculosis is preventable and curable. Treatment is recommended for both TB infection and disease. Active pulmonary TB is treated with several antibiotics for a minimum of 6 months.

The most common antibiotics used are:

  • isoniazid (H)
  • rifampicin (R)
  • pyrazinamide (Z)
  • ethambutol (E)

Drug-susceptible TB (DS-TB) (6 months of treatment)

  1. 2 months: isoniazid, rifampicin, pyrazinamide, ethambutol (2HRZE)
  2. 4 months: isoniazid, rifampicin (4HR)

Such a regimen is also spelled as 2HRZE/4HR, meaning 2 months of HRZE treatment followed by 4 months of HR treatment.

12% of cases are resistant to at least rifampicin

For children (3 mo – 16 y), 2HRZ(E)/2HR should be used.

Multi-drug/rifampicin resistant TB (MDR/RR-TB) (6–18 months of treatment)

  • 6 months: bedaquiline, pretomanid, linezolid, moxifloxacin (BPaLM)

The second-line treatment contains bedaquiline, levofloxacin/moxifloxacin, ethionamide, ethambutol, isoniazid, pyrazinamide and clofazimine (all-oral regimen) administered for up to 9 months.

Drug characteristics

Bedaquiline

  • fb ≈ 99%
  • Food effect
  • CYP3A4 metabolism
  • Most common adverse events: QTc-prolongation, and hepatotoxicity

Linezolid

  • Highly variable PK
  • Inhibits its own CL
  • F ≈ 100%
  • No food effect
  • “non-enzymatic metabolism”
  • Known toxicity at higher doses and/or longer durations

Rifampicin

Old drug.

  • Strong enzyme inducer of enzymes and pumps, it thus induces its own CL
  • Also saturable biliary excretion -> higher than dose-prop exposures -> F is dose dependent.

References

  • WHO consolidated guidelines on TB. 2022. https://iris.who.int/bitstream/handle/10665/353829/9789240048126-eng.pdf

  • Clewe O, Aulin L, Hu Y, Coates ARM, Simonsson USH. A multistate tuber- culosis pharmacometric model: a framework for studying anti-tubercular drug effects in vitro. J Antimicrob Chemother. 2016 Apr;71(4):964–74