b) Treatment regimen

List the drug regimen(s) used as first-line therapies in this patient after initial diagnosis with their mechanisms of action. (12 marks)


12 marks


Mycobacterium tuberculosis (MTB)


For new cases and assuming it is drug susceptible

  • First two months 'Intensive phase': isoniazid (INH), rifampicin (US rifampin) (RIF), pyrazinamide (PZA), and ethambutol (EMB)
  • After the first two months of the intensive phase, drug regimen is cut back down to INH and RIF for four months - 'continuation phase'.

Can use the mnemonic RIPE to help remember the first line TB drugs


Isoniazid

MOA: interferes with MTB cell wall synthesis

  • It passes into the bacteria via passive diffusion
  • activated by the katG enzyme. This enzyme is specific to MTB. This converts isoniazid into oxidative radicals which interfere with synthesis of mycolic acids which are required for cell wall synthesis


Isoniazid is the most active drug against TB. it exhibits the greatest early bactericidal activity, with rapid mycobacterial suppression and 95 per cent kill within five days.

It is small simple molecule related to vitamin B pyridoxine, which is able to penetrate into macrophages.

It is cheap and highly effective.

It is also used in patients with dormant TB, and for prophylaxis of TB patient family members.

Isoniazid can be used on its own but would take 12 months to eradicate MTB, plus there is a high risk of drug resistance development.

It is more effective on actively growing bacteria

It interferes with pyridoxine (vit B6) activation which causes peripheral neuropathy. For this reason it is given with pyridoxine tablets.

It may cause liver function test disturbances


Rifampicin - (US: rifampin) 

MOA: Rifampicin inhibits bacterial RNA polymerase. RNA polymerase transcribes DNA.


Rifampicin is is a powerful antibiotic which has activity against a lot of bacteria, not just MTB.

But because it is one of only a few antibiotics which have anti-TB activity, it is reserved for TB and other hard to treat organisms including leprosy, to prevent resistance developing.

Adding rifampicin to isoniazid shortens the course to 9 months.

It is more effective on slow growing bacteria, particularly those that remain after the first five days.

It is highly pigmented and will stain body fluids orange/red. This may cause staining of contact lenses and white clothes.

It is a very powerful CYP inducer causing many drug interactions.

Rifabutin has less CYP450 effect, thus favoured for HIV patients

´╗┐May cause LFT disturbances



Pyrazinamide

MOA of pyrazinamide is not clear, but the following statements could be made:

  • It is activated by an enzyme within MTB (active form pyrazinoic acid)
  • It inhibits multiple targets including energy production and translation.
  • It may inhibit bacterial synthesis of Coenzyme A
  • It is only active in non-replicating MTB (non-replicating persisters)


The mode of action of PZA is unusual and is still puzzling investigators even though it has been in use since the 1950s.

Unlike most antibiotics, it kills non-replicating bacteria, but has no activity against active bacteria

It is the most effective anti-TB agent against non replicating persisters.

It plays a key role in shortening the TB therapy, added to INH + RIF reduces course length from 9 months to 6 months.

It is a vital inclusion in any drug combinations including those for multi drug-resistant TB

It is stopped after 2 months because does not add any further benefit after 2 months

It is a niacin (vit B3) analogue.

May cause LFT disturbances


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268777/

https://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(19)30231-7



Ethambutol

MOA: Interferes with mycobacterial cell wall synthesis.

It inhibits the enzyme arabinosyl transferase 3 which is required for the synthesis of arabinogalactan which is an important part of the cell wall.

It is not bactericidal but it is bacteriostatic, and increases permeability of the bacterial cell wall.


It does not have strong bactericidal activity, but its ability to increase permeability of the cell wall helps improve the activity of the other antibacterials.

It is included in regimen for the first two months as a back up in case the MTB is resistant to isoniazid, after that it is stopped.

It can affect eye sight - optic neuropathy. Eye tests are required before and during treatment.



Refs

Medbullets

Pharmaceutical Journal

CDC https://www.cdc.gov/tb/topic/treatment/guidelinehighlights.htm

HK 2001 https://www.info.gov.hk/tb_chest/doc/chemotherapy.pdf

HK 2015 HIV plus TB coinfection https://www.chp.gov.hk/files/pdf/recommendations_on_the_management_of_human_immunodeficiency_virus_and_tuberculosis_coinfection_march_2015.pdf

https://www.currytbcenter.ucsf.edu/sites/default/files/course-material/%5Bnid%5D/1a_printable_pharmacokinetics_pharmacology_of_tb_drugs_final_narsai.pdf


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