Antitubercular drugs or anti-TB drugs are the drugs that are used for the treatment of tuberculosis. Drugs for tuberculosis are the same for any kind of tuberculosis, be it lung tuberculosis or musculoskeletal tuberculosis.
To effectively kill the bacteria and cure the disease, a combination of antitubercular drugs needs to be used. A single drug is ineffective and causes the development of resistance in the pathogen.
However, there may be variations in duration and combination options of different drugs for tuberculosis in various regions. The regimes may also vary with age.
Types of Antitubercular Drugs
Conventional Classification
Conventionally, the drugs for tuberculosis are broadly classified into first-line and second-line drugs. Most of the regimens chose first-line drugs first. Only when there are issues or complications with the use of some drugs, the choice of second-line antitubercular drugs is made.
First Line Drugs For Tuberculosis
- Isoniazid
- Rifampin
- Pyrazinamide
- Ethambutol
- Streptomycin
Second Line Drugs for Tuberculosis
The second line has groups of drugs. These are
Fluoroquinolones
- Ofloxacin
- Levofloxacin
- Moxifloxacin
- Ciprofloxacin
Other Oral Drugs
- Ethionamide
- Prothionamide
- Cycloserine
- Terzidonw
- Paraamino salicylic acid
- Rifabutin
- Rifapentine
Injectable Drugs
- Kanamycin
- Amikacin
- Capreomycin
Alternative Five Group Classification of Drugs for Tuberculosis
Recently, a new classification of drugs for tuberculosis has been suggested. This is based on the grouping of antitubercular drugs in order of efficacy or priority of use
First Line Oral Drugs for tuberculosis
These are the most potent drugs that are routinely used for treating tuberculosis. Plus these are quite well tolerated as compared to other drugs.
These drugs are
- Isoniazid
- Rifampin
- Pyrazinamide
- Ethambutol
Injectable Drugs
These are potent and bactericidal drugs but their limiting factor is that they cannot be given orally but rather need to be injected.
- Streptomycin
- Kanamycin
- Amikacin
- Capreomycin
Fluoroquinolones
These are bactericidal oral drugs belonging to the group fluoroquinolones. These are often used in drug-resistant tuberculosis.
- Ofloxacin
- Levofloxacin
- Moxifloxacin
- Ciprofloxacin
Second Line Other Oral Drugs
The drugs are less effective than previous drugs and have a more toxic profile. These are considered for use in multidrug-resistant tuberculosis.
- Ethionamide
- Prothionamide
- Cycloserine
- Terizidone
- Para amino-salicylic acid
- Rifabutin
- Rifapentine
Unclear Efficacy Drugs
- Bedaquiline
- Clarithromycin
- Clofazimine
- Linezolid
- Co-amoxiclav
- Imipenem/Cilastatin
Bactericidal and Bacteriostatic Drugs
The drugs for tuberculosis may differ in their mechanism of action
- Bactericidal- kills bacteria rapidly
- Bacteriostatic- inhibits the multiplication and growth of bacteria but does not kill them.
The drugs also differ in their action against
- intracellular bacilli (those mycobacteria that are in the cell)
- extracellular bacilli (those mycobacteria that are outside the cell)
- bacilli in the lesion itself
First Line Drugs for Tuberculosis
Isoniazid
Isoniazid is bacteriostatic for resting bacilli but kills those which divide actively. It is active against intracellular bacilli [those bacteria that are present in macrophages], extracellular bacilli, and bacilli at the lesion. Along with rifampicin, it is the main drug in the treatment of tuberculosis.
It has good penetration in cerebrospinal fluid and possesses good overall activity.
Other Names of Isoniazid
- Isonicotinic acid hydrazide
- Isonicotinyl hydrazine
- INH
- INHA
Mechanism of Action
It inhibits mycolic acid synthesis of the bacterial cell wall. Mycolic acids are unique fatty acid components of the mycobacterial cell walls.
Side Effects
INH is quite well tolerated by most individuals.
- Gastrointestinal disturbances
- Hepatotoxicity- elevation of liver enzymes, hepatic failure [rare in children, more common in adults]
- Hypersensitivity reactions- fever, rashes, purpura, vasculitis, drug-induced lupus
- Agranulocytosis
- Pellagra [A condition caused by Niacin deficiency]
- Neural Issues
- Neurotoxicity
- Peripheral neuropathy
- Optic neuritis
- Convulsions
- Psychoses
- Gynecomastia
- Rashes
Dosage and Administration
The drug is given orally in tablet form or syrup form. The doses are as follows
- Adults and teenagers
- 300 mg once a day
- 15 mg per kg of body weight, up to 900 mg, two times a week or three times a week
- Children
- 10 to 20 mg per kg of body weight, up to 300 mg, once a day
- 20 to 40 mg per kg up to 900 mg, two times a week or three times a week
Addition of pyridoxine 10 mg daily to prevent neurotoxicity.
Liver function should be monitored regularly.
The resistance against the drug may develop due to the failure of penetration into bacillus.
Rifampicin or Rifampin [R]
Rifampicin is a bactericidal drug and is active against all kinds of bacteria. Apart from mycobacterium tuberculosis, rifampin is effective against many other gram-positive and negative bacteriae.
Mechanism of Action
It inhibits DNA-dependent RNA polymerase and results in the RNA synthesis of bacteria. The selective effect occurs because it has no affinity to human RNA polymerase.
It is well absorbed orally but the food decreases absorption and therefore it should be taken empty stomach in the morning.
Side Effects
It has a side-effects profile similar to INH. The main adverse effects are
- GI disturbances
- Pseudomembranous colitis
- Raised liver enzymes
- Shortness of breath
- Collapse and shock
- Thrombocytopenic purpura
- Hemolytic anemia
- Renal failure
- Hypersensitivity reactions
- Rash, flu-like symptoms
Dosage
The drug is to be used on empty stomach.
The dosage is
- Adults- 10 mg per kg of body weight once a day. The maximum dosage is 600 mg per day.
- 10- 20 mg per kg of body weight once a day.
Rifampicin causes orange discoloration of the urine. This feature is used to evaluate the compliance of the patient with the treatment. Liver function and blood counts should be monitored.
Other than tuberculosis, the drug is used in
- Leprosy
- Resistant staphylococcal infections
- Legionnaire’s disease
- Prophylaxis of meningococcal meningitis.
Pyrazinamide
pyrazinamide is chemically similar to INH. The exact mechanism of action is unknown. Probably, it is converted into a metabolite that disrupts bacterial cell membrane.
is more active in an acidic medium. Pyrazinamide is especially lethal to intracellular and those bacilli which are present at inflammatory response [acidic pH is the probable reason].
Pyrazinamide can be either bacteriostatic or bactericidal depending on the concentration of drug attained at the site of infection.
Dosage and Administration
The drug is given orally. The daily dose is limited to 25-30 mg/kg [due to hepatotoxicity higher doses are not given. The risk of hepatotoxicity is reduced at these doses.
Side effects
- Gastrointestinal disturbances
- Hepatotoxicity- elevation of liver enzymes, hepatic failure
- Hypersensitivity reactions- fever, rashes
- Sideroblastic anemia
- Hyperuricemia – increase in serum uric acid levels
It requires regular monitoring of serum uric acid and liver function tests.
Ethambutol
Ethambutol is bacteriostatic and active against intra and extracellular bacteria and shows activity against bacilli in the caseous lesion. It is more active against dividing bacilli. When added to RHZ, it increases the rate of sputum sterilization in pulmonary tuberculosis and also prevents the development of resistance.
This feature of preventing the development of resistance is the main purpose of its use as the fourth drug along with rifampin, INH, and pyrazinamide.
Mechanism of Action
The mechanism of action is not completely understood but is supposed to act by inhibiting bacterial cell wall synthesis.
Dosage and Administration
The drug is given orally in doses of 15-20 mg/kg per day
Adverse Effects
It has the following side effects
- Optic neuritis – reduced visual acuity
- Loss of red-green discrimination
- Peripheral neuropathy
- Hyperuricemia
It is not recommended for children below six years as they cannot report visual symptoms.
Streptomycin
It is a bactericidal drug and is most active against extracellular bacteria. It does not cross cerebrospinal fluid and has poor action in
Dosage and Administration
It can’t be given orally. It is given as an injection by intramuscular route at a dose of 1–15 mg/kg per day. Because of the need for injections and its renal toxicity, streptomycin is used only in conjunction with other drugs.
Adverse Effects
As a side effect, it can cause
- Ototoxicity resulting in hearing loss (vestibular more than cochlear)
- Nephrotoxicity
- Rash and fever
It is not prescribed in fresh cases as per the new regime of WHO. It has traditionally been used locally in cold abscesses formed in tuberculosis.
Second Line Drugs for Tuberculosis
A second-line drug for tuberculosis is either less effective than the first-line drug or has associated toxicity that makes it the second choice for use in tuberculosis patients.
Aminoglycosides [Kanamycin (Km), Amikacin(Am)]
Streptomycin is already discussed with first-line drugs
Kanamycin and Amikacin are similar to streptomycin in their antitubercular action, toxicity profile, dosage, and administration. These drugs are effective on multidrug-resistant strains of tuberculosis.
Both drugs show cross-resistance.
Capreomycin (Cm)
Capreomycin is a cyclic peptide antibiotic having a different structure but a similar antitubercular profile as that of aminoglycosides. This also needs to be given as an injection. The dose is 0.75-1.0 g/day. Capreomycin is an alternative to aminoglycosides. Many bacteria that are resistant to streptomycin and amikacin remain susceptible to capreomycin.
Induration at the site of injection, Ear and kidney toxicity, fever, rashes, and eosinophilia are known side effects. High doses may cause neuromuscular blockade. Resistance to this drug develops after short use. It also shows cross-resistance with aminoglycosides.
Fluoroquinolones
Oflaxacin (ofx), Levoflxacin (Lfx), ciprofloxacin (Cfx) and Moxiflxacin (Mfx) are oral bactericidal drugs for tuberculosis. These drugs have recently gained attention as potent second-line drugs for tuberculosis due to their profile, oral use, and being well tolerated.
Moxifloxacin is the most active drug of them followed by levofloxacin, ofloxacin, and ciprofloxacin.
Some studies have successfully replaced ethambutol with fluoroquinolones as 1st line drug. However, these are indicated in drug-resistant cases mainly where they have an important role.
Ethionamide (Eto), Prothionamide (Pro)
It is a bacteriostatic drug and has a good CSF penetration. Its structure is similar to INH. The mechanism of action also appears to be similar.
It is recommended in doses of 15-20 mg/kg orally in divided doses with meals. The maximum dose should not increase more than one gram.
The known side effects are gastrointestinal disturbances, neurotoxicity, visual disturbances, olfactory disturbances, peripheral neuropathy, convulsions, hepatotoxicity, hypersensitivity reactions, alopecia, and gynecomastia.
Pyridoxine supplements can reduce toxicity. Liver functions must be monitored during therapy.
If used alone, resistance develops very soon. It also shows cross-resistance with thioacetazone
Cycloserine/Terizidone
A bacteriostatic drug with very good CSF penetration. It inhibits cell wall synthesis of the bacteria. The dose is 10-20 mg/kg per oral in 2 divided doses. The maximum dose is 500 mg twice daily. Headache, dizziness, vertigo, drowsiness, tremors, convulsions, depression, psychosis, abnormal liver function, megaloblastic anemia, and rashes are known side effects.
Hematological, renal, and hepatic functions should be monitored. It is contraindicated in patients with a history of mental illness or seizures.
ITerizidone contains two molecules of cycloserine and has lower adverse effects. The rest of the profile is similar.
Thiacetazone
Thioacetazone is a bacteriostatic drug [Inhibits the growth of bacteria but does not kill existing ones]. It has poor cerebrospinal fluid penetration. Its mechanism of action is not clear. The dose of the drug is 150 mg per oral. It may cause gastrointestinal disturbances, and skin reactions including exfoliative dermatitis, hepatotoxicity, and myelosuppression [suppression of bone marrow].
It is not used in patients with AIDS.
Due to its toxic profile, the use of Thioacetazone is reduced and it is used in cases where other choices have been exhausted.
P-aminosalicylic acid (PAS)
P-aminosalicylic acid is a bacteriostatic drug with poor CSF penetration. It acts by inhibiting folate synthesis and interferes with incorporating p-aminobenzoic acid.
The dose is 150 mg/kg per oral in divided doses with meals. The maximum allowed dose is 12 gm.
Side effects are
- Gastrointestinal disturbances
- Hypersensitivities
- Fever
- Malaise
- Arthralgia
- Changes in blood count
- Leucopenia
- Agranulocytosis
- Eosinophilia
- Lymphocytosis
- Thrombocytopenia
- Hemolytic anemia
This drug is active against Mycobacterium tuberculosis only.
Rifabutin
Rifabutin is related to rifampin in terms of structure and mechanism of action. Its role in tuberculosis treatment is limited to replacing rifampin to minimize strong drug interactions of rifampin due to its enzyme-inducing properties.
It is more effective against the mycobacterium avium complex. The dose is 5 mg/kg or 300 mg given orally.
Rashes, GI intolerance, myalgia, and uveitis are the reported side effects.
Rifapentine
It is a congener of rifampin and very similar activity and mechanism of action. Its half-life is more and therefore can be given twice weekly.
It has a role only in the continuation phase of TB where can be used to substitute daily rifampin. But there is no use in the intensive phase.
Bedaquiline (BDQ)
Bedaquiline is an antitubercular drug that belongs to the diarylquinoline group.
It inhibits mycobacterial ATP synthase.
It is given orally and is well absorbed after intake. The absorption is improved by fat in the meal.
Bedaquiline is used only in multi-drug resistant tuberculosis.
It is contraindicated in pregnant females and if one is to be put on bedaquiline, she should be willing to remain non-pregnant during bedaquiline use.
It has to be used only in the combination of at least three other drugs.
The dosage is 400mg per day for a maximum of 24 weeks followed by 200 mg thrice a week for the next 22 weeks.
Nausea, headache, joint pains, and prolongation of QTc interval are known adverse effects.
How to Give the Drugs for Tuberculosis?
The drugs are given on basis of patient weight and dosage may vary in different individuals. The dosage also differs depending on the regimen given. There are three regimens that traditionally have been used for treatment.
[Read more: Antitubercular chemotherapy for musculoskeletal tuberculosis]
- Daily
- Twice Weekly
- Thrice Weekly
Dosage in Children
Daily Regimen
- Isoniazid 10-20 mg/kg
- Rifampin 10-20 mg/kg
- Pyrazinamide 15-30 mg/kg
- Ethambutol 15-25 mg/kg
- Streptomycin 20-40 mg/kg
Twice Weekly Regimen
- Isoniazid 20-40 mg/kg
- Rifampin 10-20 mg/kg
- Pyrazinamide 50-70 mg/kg
- Ethambutol 50 mg/kg
- Streptomycin 25-30 mg/kg
Thrice Weekly Regimen
- Isoniazid 20-40 mg/kg
- Rifampin 10-20 mg/kg
- Pyrazinamide 50-70 mg/kg
- Ethambutol 25-30 mg/kg
- Streptomycin 25-30 mg/kg
Dosage In Adults
Daily Regimen
Isoniazid 5 mg/kg
Rifampin 10 mg/kg
Pyrazinamide 15-30 mg/kg
Ethambutol 15-25 mg/kg
Streptomycin 12-18 mg/kg
Twice Weekly Regimen
Isoniazid 5 mg/kg
Rifampin 10 mg/kg
Pyrazinamide 50-70 mg/kg
Ethambutol 50 mg/kg
Streptomycin 25-30 mg/kg
Daily Regimen
Isoniazid 15 mg/kg
Rifampin 10 mg/kg
Pyrazinamide 50-70 mg/kg
Ethambutol 25-30 mg/kg
Streptomycin 25-30 mg/kg
The World Health Organization does not recommend twice-weekly regimens because of the greater risk of treatment failure from missed doses.
Contraindications to Antitubercular Drugs
Aminoglycosides like streptomycin, amikacin, and kanamycin are not given in pregnancy. These could have ototoxic effects on the fetal ear.
Pyrazinamide is considered teratogenic [the drug that causes malformation of the embryo] and prohibited for use in pregnancy in some countries.
References
- Ben Amar J, Dhahri B, Aouina H, Azzabi S, Baccar MA, El Gharbi L, Bouacha H. [Treatment of tuberculosis]. Rev Pneumol Clin. 2015 Apr-Jun;71(2-3):122-9. [Link]
- World Health Organization. WHO treatment guidelines for drug-resistant tuberculosis 2016 update. WHO/HTM/TB 2016.04. Geneva: WHO; 2016.
- J.A. Caminero, A. Scardigli. Classification of antituberculosis drugs: a new proposal based on the most recent evidence. Eur Respir J, 46 (2015), pp. 887-893
- World Health Organization. Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis. WHO/HTM/TB/2014.11. Geneva: WHO; 2014.
- Guglielmetti et al. Is bedaquiline as effective as fluoroquinolones in the treatment of multidrug-resistant tuberculosis? Eur Respir J, 48 (2016), pp. 582-585.
