This article here will be focusing on the pharmacotherapy and aspects of community medicine in treating tuberculosis. 

In late 2019 RNTCP ( revised national tuberculosis control program) was renamed as National tuberculosis elimination program (NTEP). With the new name came subtle changes in the management guidelines of TB. Let’s first have a brief look about TB.

TUBERCULOSIS:

Tuberculosis is a disease caused by the bacteria Mycobacterium tuberculosis primarily affecting the respiratory system as well as other parts like lymph nodes, spine, meninges etc.
Tuberculosis can be divided into two types based on the organ that they affect:
  1. Pulmonary TB : involves the respiratory system.
  2. Extra - pulmonary TB: involves organs other than the respiratory system like lymph nodes, spine, meninges, liver etc.
We are now seeing emerging resistance by the mycobacterium tuberculosis to the first line drug therapy, this necessitates in defining the resistance pattern and their types:

  1. Mono - drug resistant TB : resistance is shown towards one of the first line drugs except Isoniazid and rifampicin.
  2. Poly - drug resistant TB: Resistance towards more than one 1st line drugs again with the exception of isoniazid and rifampicin.
  3. Multidrug resistant TB (MDR - TB): This variety shows resistance to both isoniazid and rifampicin with or without resistance to other 1st line drugs.
  4. Extensive drug resistant TB (XDR - TB): A case of MDR - TB who also shows resistance against 2nd line drugs - Flouroquinolones and injectable aminoglycoside (Amikacin, capreomycin and kanamycin).

NTEP (RNTCP) 2017 - 2025 Goals:
India is known to carry the highest burden in TB around the world, with more than a thousand lives lost each day to this easily preventable disease. With the advent of new drugs, diagnostic methods and effective strategy we are bringing TB under control. NTEP / RNTCP has come up with new targets and guidelines to eliminate TB.

Vision: TB-Free India with zero deaths, disease and poverty due to TB
GOAL: To achieve a rapid decline in burden of TB, morbidity and mortality while working towards elimination of TB in India by 2025.

Below is the targets that the NTEP has set to achieve by 2025 



Setting such ambitious goals comes with the huge responsibility to achieve them. Let’s now look at the strategy that we must adopt in order to achieve the targets set by NTEP 2017 - 2025.

To move towards elimination of TB we rely on the four pillars of DETECT - TREAT - PREVENT - BUILD.

DETECT:
Aim is to find all drug sensitivity and drug resistant TB cases with emphasis on reaching TB patients seeking care from private providers and under diagnosed TB in high risk population.

This can be done by:
  • Scaling up free, high sensitivity diagnostic tests and algorithms 
  • Scaling up effective private provider engagement approaches.
  • Universal testing for drug resistant TB.
  • Systematic screening of high risk population.
Treat:
This aims to initiate and sustain all patients on appropriate anti TB treatment whenever they seek care, with patient friendly ecosystem.
This can be achieved by:
  • Prevent the loss of cases in the TB care system
  • Free TB drugs for all TB cases
  • Universal daily regimen for TB cases and rapid scale up of short course regimens for drug resistant TB and drug sensitivity guided treatment approach.
  • Patient friendly adherence monitoring and social support in order to sustain TB treatment.
  • Elimination of high cost by linking eligible TB patients with social welfare schemes.

PREVENT:
Aims to prevent the emergence of TB in susceptible populations
How do we achieve it?
  • Scale up air borne infection control measures at health care setups.
  • Testing and treatment for latent TB infection in contacts of confirmed cases and in individuals who are at high risk.
  • Addressing social determinants of TB.

BUILD:
Build and strengthen policies, institutions, human resources and financial resources according to the plan.
This can be achieved by:
  • High level political commitment through supportive policy and institutions 
  • Restructuring RNTCP / NTEP management structure and implementation arrangements
  • Scaling up technical assistance at national and state levels.

Changes in the guidelines (2019) include treatment of TB in patients <18 years of age under the Pediatrics TB treatment protocol.

Follow up:
It is absolutely essential to have a strict adherence to treatment and follow up of the cases to completely eliminate TB.
In order to succeed in this area the following govt follow up programs are being implemented (new ones discussed here):
  • NIKSHAY - Online portal used for real time surveillance of TB cases and their outcomes
  • DOTS99 - Each blister pack of anti TB drug is wrapped in an envelope which contains a phone number, the patient is required to give a free missed call to the hidden number that he finds in the envelope when he opens it to consume the doses. This collects information on the adherence data of the patient. Missed doses trigger an SMS to the health care provider who is then required to follow up on the patient.
  • Real Time - Medication Event Reminder Monitoring Device (RT - MERM). This is an electronic device that monitors the exact date and time of consuming the given anti TB drug and uploads data of patient adherence to a central data pool enabling health care workers to monitor the patient remotely. This is still in experimental stages and is not available for wide spread public use.

Let’s now see the drugs that are available to treat a case of TB and later on learn the complete management protocol for TB.

DRUGS FOR TUBERCULOSIS:





FIRST LINE DRUGS:

First line drugs are the ones which are started to every patient that is diagnosed with TB (New or recurring). This is given as a daily dose regimen to the patients. Let’s see the drugs that are in this category.
  1. Isoniazid (H)
  2. Rifampicin (R)
  3. Pyrizinamide (Z)
  4. Ethambutol (E)
*Streptomycin (S) is only given in cases like TB of meninges or cases where a first line drug has to withdrawn due to adverse reaction.

SECOND LINE DRUGS FOR TB:

Second line drugs available for TB are used when a person acquires resistance to first line drugs, this also includes MDR TB. These are further divided into four groups :

GROUP A:
This group includes fluoroquinolones:
  1. Ofloxacin
  2. Levofloxacin
  3. Maxifloxacin
  4. Gatifloxacin
All these drugs are given orally

GROUP B:
Group B drugs are the injectable aminoglycosides:
  1. Amikacin
  2. Capreomycin
  3. Kanamycin
GROUP C:
This has other core drugs like: (Tip to remember them :  CyCLE ).
  1. Cy - Cycloserine
  2. C - Clofazimine
  3. L - Linezolid
  4. E - Ethionamide

GROUP D:
This is a group of addon drugs to the second line therapy. This is further divided into subgroups D1, D2 and D3.

D1:
Consists of first line drugs:
  1. Isoniazid (H)
  2. Pyrizinamide (Z)
  3. Ethambutol (E)
D2:
Consists of newly approved drugs as addon for the second line therapy:
  1. Bedaquiline
  2. Delamanid
  3. Pretomanid (awaiting approval in India, currently approved (Aug - 2019) in the USA for treatment of XDR TB)
D3:
Drugs of unproven efficacy:
  1. PAS
  2. Amoxicillin with clavilunate
  3. Imepenam 
  4. Meropenam
  5. Thioacetazone 
Now that we know the drugs that are available for the treatment of TB, lets dive in to learn the management protocol of TB as per latest guidelines according to NTEP.

Treatment protocol for TB:

Treatment of TB is achieved by administering drugs in two phases:
  • Intensive phase: the rapidly multiplying bacteria are eliminated in this phase. This is of shorter duration.
  • Continuation phase: In this phase the dormant and slow multiplying bacteria are killed in order to achieve complete remission of disease. This phase is usually longer than intensive phase.

New case of TB:
Standard first line drugs are instituted for the treatment of such cases.


Intensive phase (IP): (HRZE x 2 months)
  • Isoniazid
  • Rifampicin
  • Pyrizinamide 
  • Ethambutol 
*Streptomycin only if any first line drug is stopped due to adverse drug reaction. 

Continuation Phase: (HRE x 4 months)
  • Isoniazid
  • Rifampicin
  • Ethambutol 

Drug resistant TB:

Mono - drug resistant TB:

Intensive phase: ( 3 months)

  • Initiate first line drugs
  • Levofloxacin
  • Kanamycin (inj)
Continuation phase (5 months):
  • First line drugs
  • Levofloxacin
(Easy tip - drop the injectable drug in continuation phase)

Poly - drug resistant TB:
Intensive phase ( 3 months):
  • Start first line drugs
  • Levofloxacin 
  • Ethionamide
  • Kanamycin (inj)
Continuation phase (5 months):
  • First line drugs
  • Levofloxacin 
  • Ethionamide

MDR TB:


Intensive phase (6 months): ( Mnemonic - ZELECK )
  • Z - Pyrizinamide 
  • E - Ethambutol
  • L - Levofloxacin 
  • E - Ethionamide
  • C - Cycloserine
  • K - Kanamycin 
Continuation phase (18 months): (Drugs - ELEC)
  • E - Ethambutol 
  • L - Levofloxacin 
  • E - Ethionamide 
  • C - Cycloserine 
XDR - TB:
Intensive phase (6 months):
  • Clofazimine
  • Isoniazide ( High dose )
  • PAS
  • Linezolide
  • Amoxicillin - clavulunate
  • Capreomycin (inj)
  • Moxifloxacin
Continuation phase (18 months): (Stop capreomycin inj)
  • Clofazimine
  • Isoniazid
  • PAS
  • Linezolid
  • Amoxicillin - Clavulunate
  • Moxifloxacin

Addon drugs for MDR and XDR TB regimen:

1. Bedaquiline:
This is a newly approved drug for TB.
Mechanism of action: inhibits mycobacterial ATP synthase and causes energy depletion.

Contraindicated in pregnancy and lactational women.

Indicated only in pulmonary TB, given for 6 months only as addon therapy

DOSAGE:
0 - 2 weeks: 400mg daily
3 - 24 weeks: 200mg thrice daily

Side effects:
  • QT prolongation
  • Hepatotoxic 
Cross resistance with clofazimine noted.

2. Delamanid:
This is a nitroimidazole drug. Acts by inhibiting mycolic acid synthesis.
Addon drug for 6 months only.

Side effects:
  • QT prolongation 
  • Hepatotoxic
3. Pretonamid:
This is also a nitroimidazole derivative. With the same mechanism of inhibiting mycolic acid synthesis.
This drug was recently approved in the USA in August 2019, but is still awaiting approval in India.

Side effect:
  • Peripheral neuropathy

Let’s now see about important properties that we need to keep in mind about the first line drugs.

Isoniazid:

Mechanism of action:


Resistance to this drug is due to mutation in the KATg gene and INH-A or KAS-A gene.
Important point to remember is that isoniazid is metabolised by acetylation in our body, hence slow acetylators (people with low acetylation capability due to genetic variation in race) are prone to neurotoxicity (manifests as peripheral neuropathy and seizures).

Side effects: (mnemonic - NO HASH TAG)
  • Neurotoxic
  • Optic neuritis
  • Hepatotoxic 
  • Anemia
  • Drug induced Lupus
  • Hallucination
  • Transient memory loss
  • Arthralgia
  • Gynaecomastia
Rifampicin:

Mechanism of action : inhibits RNA polymerase 
Resistance is developed due to mutation in RPO - B (RNA polymerase B) gene.

Pharmacokinetics:
Rifampicin is a known inducer of CYP as well as P - glycoprotein, this causes failure of action of other drugs which are administered along with rifampicin. 
For example, contraceptive failure with OCP, Warfarin failure, anti HIV drug failure.

Rifampicin and Anti HIV Therapy:
Safe with :
  • Tenofavir
  • Lamivudine
  • Efavirenz
Causes failure of:
  • Nevirapine
  • Ritonavir
Hence change rifampicin to rifabutin in such cases.

Side effects:
  • Orange colour urine
  • Hepatotoxic ( pyrizinamide is most hepatotoxic )
  • Hypersensitivity 
Pyrizinamide:

Mechanism of action: this is a prodrug which is converted into active form by the protein coded by PNC - A gene, which finally inhibits mycolic acid synthesis.

Resistance is seen due to pnc - A gene mutation.

Side effects:
  • Hepatotoxic 
  • Hyperuricemia 

Ethambutol:

Mechanism of action: inhibits arabino acyl transferase

Side effects:
  • Retrobulbar optic neuritis - this causes painless loss of vision which children fail to notice, hence avoided in children.
  • Red green colour blindness
  • Hyperuricemia

Hope you guys enjoyed reading this article, an in depth article exclusively on the microbiological and pathological aspects of TB will be coming soon.