Anti-TB drugs have been classified into five different groups. this classification aims to facilitate the physicians to make an effective treatment regimen for patients with Drug-Resistant Tuberculosis.

Prescribing anti-TB drugs for Drug-Resistant Tuberculosis is a complex task

The treatment regimen for Drug-Resistant Tuberculosis is a complex task and many physicians are inconvenient to write an effective prescription. An effective treatment regimen for Drug-Resistant Tuberculosis must include the following key components:

  1. The treatment regimen should be complete in terms of the number of drugs to be used in the intensive and continuation phase
  2. The drugs should be prescribed for the required duration as recommended by the World Health Organization.
  3. The treatment regimen should also include regular follow-ups as recommended. At each follow-up, patients should be inquired about drug compliance, adverse effects and resolution of symptoms like fever, cough, sputum production and weight gain.
  4. The physician should also advise sputum and other complementary investigations as recommended by the WHO at recommended intervals.

Classification of anti-Tuberculous medications:

tb treatment drugs

Traditionally, anti-Tuberculous medications were classified as either first line or second line. First line anti-tuberculous drugs included

  1. Isoniazid
  2. Rifampicin
  3. Ethambutol
  4. Pyrazinamide
  5. Streptomycin

All anti-TB drugs other than those used as the first-line were classified as second-line anti-TB drugs.

The latest anti-TB drugs classification is divided into five drug groups.

Drugs in the same group do not necessarily belong to the same class or have the same efficacy.

Anti-Tuberculous medicines from group 1 are the most potent and time-tested drugs.

These drugs should be used whenever Mycobacterium Tuberculosis organisms are susceptible. If Mycobacterium Tuberculosis strains are resistant to low concentration but susceptible to high concentration, its use in high doses is justified.

Group Name Anti-TB Drugs Abbreviations
Group 1.

First line oral agents

Isoniazid H
Rifampicin R
Ethambutol E
Pyrazinamide Z
Rifabutin Rfb
Rifapentine Rpt
Rifabutin and rifapentine have similar microbiological activity as rifampicin.

Rifabutin is not on the WHO list of essential medicines, however, it has been added here as it is used routinely in patients on protease inhibitors in many settings.

Group 2.

Injectable anti-TB Drugs

Streptomycin S
Kanamycin  Km
Amikacin Am
Capreomycin Cm
There are high rates of streptomycin resistance in strains of MDR-TB; therefore, streptomycin is not considered a second-line anti-TB injectable agent.
Group 3.

Fluoroquinolones

Levofloxacin Lfx
Moxifloxacin Mfx
Gatifloxacin Gfx
Gatifloxacin can have severe side-effects including serious diabetes (dysglycaemia). The drug has been removed from the market of a number of countries.
Group 4.

Oral bacteriostatic Drugs

Ethionamide Eto
Prothionamide Pto
Cycloserine Cs
Terizidone Trd
Para-aminosalicylic acid PAS
Para-aminosalicylate sodium PAS-Na
Terizidone has limited programme data and effectiveness data as compared to cycloserine.
Group 5.

Anti- TB Drugs with limited data

Bedaquiline Bdq
Delamanid Dlm
Linezolid Lzd
Clofazimine Cfz
Amoxicillin/ clavulanate Amx/Clv
Imipenem/cilastatin Ipm/Cln
Meropenem Mpm
High-dose isoniazid High dose H
Thioacetazone* T
Clarithromycin* Clr
Clavulanate (Clv) is recommended as an adjunctive agent to imipenem/cilastatin and meropenem.

*Limited data on the role of thioacetazone and clarithromycin in MDR-TB treatment has resulted in many experts not including these drugs as options for Group 5.

Table: WHO classification of anti-Tuberculous medications

 


Group 1 – First Line Oral Agents:

First line Tb drugs

Pyrazinamide resistance cannot be reliably tested in the laboratories.

Therefore, pyrazinamide should be part of every MDR treatment regimen unless there is a reasonable clinical contraindication to its use like hepatotoxicity.

Contrary to Pyrazinamide, Ethambutol is never considered a key drug in MDR treatment regimen and should be avoided.


Group 2 – Injectable anti TB drugs:

Injectable medicines

Injectable anti-TB drugs include Amikacin, Kanamycin, and capreomycin. Because of the high prevalence of resistance to Streptomycin and its used as a first-line treatment in many countries, it is not usually included in the MDR treatment regimen.

Streptomycin is not usually included in the MDR treatment regimen

If the Mycobacterium Tuberculosis is resistant to all the injectables and shows susceptibility to streptomycin, it can, however, be used then.

Injectable antibiotics make an essential component of the MDR TB treatment regimen

Injectable antibiotics make an essential part of the MDR treatment regimen. These drugs should be used for a minimum of eight months (i.e. the intensive phase).

Amikacin is the preferred drug because of the low cost. Amikacin and kanamycin have a high frequency of cross-resistance and resistance to either of the drugs should not be replaced with one another. In such cases, Capreomycin is the drug of choice.

All these injectable antibiotics are nephrotoxic and ototoxic. Furthermore, these drugs are not available in oral forms and should be given as a daily intramuscular injection or as an intravenous slow infusion given over one hour.


Group 3 – Fluoroquinolones:

fluroquinolones

For an effective MDR TB treatment regimen, Fluoroquinolones must be a part and parcel. Later generation fluoroquinolones should be used instead of the older fluoroquinolones. Approved drugs in this group include levofloxacin, moxifloxacin, and gatifloxacin.

Levofloxacin and Moxifloxacin are the preferred Drugs

Among these drugs, levofloxacin and moxifloxacin are the preferred drugs. Gatifloxacin is associated with severe hyperglycemia, hypoglycemia and the occurrence of new onset diabetes mellitus. Furthermore, gatifloxacin use has been disapproved in many countries because of the serious adverse events associated with these drugs.

All quinolones cause prolongation of the QT interval and in rare cases life-threatening arrhythmias like torsade de pointes. Moxifloxacin and gatifloxacin are mostly associated with prolongation of the QT interval and cardiac dysrhythmias. Cardiac monitoring may be advisable in patients at risk of cardiac arrhythmias.


Group 4 – Bacteriostatic second-line drugs:

Among group 4 drugs, Cycloserine and or para-aminosalicylic acid should be added to the MDR treatment regimen. Both these drugs share no cross-resistance to other anti TB drugs.

When three or more group 4 drugs are required to complete the treatment regimen, the rates of adverse effects increase. This is specifically true with a combination of ethionamide/ prothionamide, PAS and cycloserine.

There is a high incidence of gastrointestinal adverse events and incidence of hypothyroidism. Group 4 drugs should be started in a low dose and the dose is escalated to the maximum in ten days.


Group 5 – Anti-TB drugs with limited data available:

sirturo

Anti-TB drugs with limited data i.e. group 5 drugs should not be used routinely as a part of the MDR treatment regimen. With the exception of bedaquiline and delamanid, all other

Group 5 drugs are not approved for the treatment of MDR treatment but used as off-label. Furthermore, combining delamanid and bedaquiline has not been studied and there aren’t any recommendations made by WHO regarding the combination of delaminid and bedaquiline.

Linezolid – a very potent group 5 drug

Among the group 5 drugs, apart from bedaquiline and delaminid, linezolid is a very potent drug and make an essential component of the XDR TB treatment regimen.

Side effects of linezolid include myelosuppression (anemia, leucopenia, thrombocytopenia, and pancytopenia), peripheral neuropathy and lactic acidosis. In case adverse events happen, the dose of linezolid should be reduced to 300 mg daily.

Clofazamine has been studied extensively in the treatment of MDR and XDR treatment regimens. This drug should be included in the 9 to 12 months treatment regimen.

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