Drug combinations are necessary for the treatment of tuberculosis. To help doctors create a successful treatment plan, the WHO has classified anti-TB medications. This will help reduce the burden of multidrug-resistant tuberculosis and reduce the overall prevalence of Tuberculosis indirectly. Previously, medications used to treat TB were either first-line or second-line treatments. However, with the addition of novel agents and with the emergence of drug-resistant tuberculosis, the WHO has reclassified the drugs into five classes.

Tuberculosis treatment - Drugs classification by WHO

Group 1 - The first-line anti-TB drugs:

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   Rifampicin - Bactericidal - dose is 10 mg/kg daily
2. Pyrazinamide - Weakly bactericidal - dose is 25 mg/kg daily (maximum: 2 gm/day)
3. Rifapentine: 600 mg once weekly (a total of 12 doses of 900 mg once weekly is recommended for latent TB
4. Ethambutol - Bacteriostatic - dose is 15 mg/kg daily
5. Isoniazid - highly bactericidal - dose is 5 mg/kg daily
6. Rifabutin: 5 mg/kg/day (maximum: 300 mg/day)

Group 2 - The injectable anti-TB drugs:

1. Kanamycin: 15 mg/kg daily (10 mg/kg in patients older than 59 years). The maximum dose is 1 gm daily.
2. Streptomycin: 15 mg/kg daily (10 mg/kg in patients older than 59 years). The maximum dose is 1 gm daily.
3. Capreomycin: 15 mg/kg daily (10 mg/kg in patients older than 59 years)
4. Amikacin: 15 mg/kg daily (10 mg/kg in patients older than 59 years)

Group 3 - The quinolones:

1. Gatifloxacin: 400 mg/day
2. Moxifloxacin: 400 mg once daily
3. Levofloxacin: It is bactericidal. 10-15 mg/kg/day.

Group 4 - Oral bacteriostatic drugs:

1. Cycloserine: The daily dose is 10-15 mg/kg in two or three divided doses to a maximum dose of 1 gm daily. Pyridoxine in a dose of 50 mg per 250 mg of cycloserine should be added.
2. Ethionamide/ prothionamide: 15-20 mg/kg/day in two divided doses (maximum 1 gm daily). 50-100 mg of pyridoxine should be added to the regimen.
3. Para-aminosalicylic acid: 8-12 gm/day (200 - 300 mg//kg/day) in two to three divided doses
4. Terizidone: 15- 20 mg/kg daily (maximum: 1 gm daily)

Group 5 - Anti-TB drugs with limited Data:

1. Bedaquiline: 400 mg once every day for two weeks, then 200 mg three times per week for 22 weeks.

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   Delamanid: For 24 weeks, take 100 mg twice daily (not recommended in children)

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   Linezolid: One dosage of 600 mg per day (10 mg per kg, with a maximum of 600 mg twice daily)

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   Clofazimine: 200 mg each day for two months, then 100 mg per day. Children's dosage: 1 mg per kg per day

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   Amoxicillin-clavulanic acid: Amoxicillin 80 mg per kg each day, split into two doses (maximum dose is 3 gm daily)

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   Imipenem-cilastatin: 1000 mg of imipenem twice daily. It should be given with clavulanate 125 mg every 8 to 12 hours.

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   Meropenem: 1 gm thrice daily (must be co-administered with clavulanic acid 125 mg thrice daily, available as amoxicillin-clavulanic acid)

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   High-dose Isoniazid

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   Thioacetazone: 150 mg daily (generally used as a replacement for ethambutol)

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    Clarithromycin: either a 1 gm extended-release pill or 500 mg twice day. (7.5 mg/kg twice every day, up to 500 mg per day in youngsters)

Briefly, Important side-effects of the drugs used in the therapy of Tuberculosis:

Group 1 - The first-line anti-TB drugs:

1. Isoniazid - Patients with unstable liver conditions and those who are allergic to isoniazid should not use it. Hepatotoxicity, peripheral neuropathy, and drug-induced SLE are some of the side effects of isoniazid.

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   Rifampicin - Patients with unstable liver condition and those who are allergic to rifampicin should not use it. 
   • Hepatotoxicity, nausea/vomiting, vomiting, rash, thrombocytopenia, influenza-like illness, and exfoliative dermatitis are significant adverse effects.

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   Ethambutol - It is contraindicated in patients who are allergic to ethambutol and those with optic neuritis of any cause.
   • Patients may notice a reduction in vision, have peripheral neuropathy and occasionally become totally blind. Rare side-effects include hepatotoxicity, rash, and joint pains.

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   Pyrazinamide - It is contraindicated in patients with liver disease, patients allergic to pyrazinamide and in porphyria.
   • It may cause gastrointestinal disturbances, hepatotoxicity, sideroblastic anemia, and dermatitis.
   • One of the very important side-effects is hyperuricemia and flare-up of a gouty attack. Patients may require allopurinol or totally withdraw pyrazinamide.

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   Rifabutin: Hypersensitivity to rifamycins.
   • MDR-TB should not be treated with it.
   • Side effects include thrombocytopenia, leukopenia, rash, anterior uveitis, hepatotoxicity, and arthralgias.

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   Rifapentine: Contraindicated in patients allergic to rifamycins.
   • Side effects include yellow-orange discolouration of body secretions, rash, pruritis, hepatotoxicity, and hematologic toxicity.

Group 2 - The injectable anti-TB drugs:

1. Streptomycin: Contraindications include pregnancy and hypersensitivity to aminoglycosides.
   • Side effects include nephrotoxicity, ototoxicity, vestibular toxicity, injection site pain, and electrolyte abnormalities.

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   Kanamycin - Contraindications include hypersensitivity, deafness, pregnancy, and ototoxicity with the use of previous aminoglycoside use.
   • It should be used with caution in patients with intestinal obstruction.
   • Kanamycin is more nephrotoxic than streptomycin but less vestibular and ototoxic.

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   Amikacin - Contraindicated in patients who are allergic, are deaf and in pregnancy.
   • Common side effects include local injection site pain and proteinuria.
   • Other less common but significant side effects include nephrotoxicity, ototoxicity, vestibular toxicity, hypokalemia, hypomagnesemia, hypocalcemia, and rash.

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   Capreomycin: Contraindications include hypersensitivity, deafness, pregnancy, and ototoxicity with the use of previous aminoglycoside use.
   • Other less common but significant side effects include nephrotoxicity, ototoxicity, vestibular toxicity, hypokalemia, hypomagnesemia, hypocalcemia, and rash.

Group 3 - The quinolones:

tendon rupture caused by quinolones used in the treatment of tuberculosis[/caption]

1. Levofloxacin - It is contraindicated in patients with allergies, prolonged QT intervals, and pregnancy.
   • Side effects include gastrointestinal intolerance, QT prolongation, tendon rupture, neurotoxicity and disturbed glycemic control.

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   Moxifloxacin: QT-prolongation and quinolone intolerance.
   • Side effects include nausea, diarrhea, headache, dizziness, tendon rupture, arthralgias, hepatotoxicity, impaired glycemic control, and neurotoxicity.

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   Gatifloxacin - It is contraindicated in pregnancy, and allergy and may be used in diabetic patients with caution.
   • Side effects include gastrointestinal intolerance, neurotoxicities like insomnia, restlessness, irritability, and dizziness.
   • It may also cause hepatotoxicity, diarrhea, tendon rupture and disturb glycemic control in diabetic patients

Group 4 - Oral bacteriostatic drugs:

seizures caused by ATT

1. Ethionamide/ prothionamide - In those who are allergic to it, it is not recommended. 
   • gastrointestinal issues, a metallic taste, hepatotoxicity, gynecomastia, hair loss, acne, irregular menstrual periods, neurotoxicity, and reversible hypothyroidism are some of the side effects.

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   Cycloserine: Patients with psychotic disorders, seizure disorders, and alcohol addicts should generally avoid it.
   • Side effects include CNS toxicity like impaired concentration, seizures, depression, psychosis and suicidal ideation, peripheral neuropathy, steven-johnsons syndrome and lichenification of the skin.

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   Terizidone: It is contraindicated in epileptic patients and those with an allergy to terizidone, psychosis, and severe depression.
   • Side effects include nausea, vomiting, depression, psychosis, suicidal ideation, and seizures.

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   Para-aminosalicylic acid: Pregnancy is a relative contraindication.
   • Side effects include hepatotoxicity, coagulopathy, gastrointestinal disturbance, and reversible hypothyroidism.

Group 5 - Anti-TB medications with little data:

1. Bedaquiline - It is contraindicated in patients with a prolonged QT interval, ventricular arrhythmias, liver disease, and deranged electrolytes.
   • Common side effects include gastrointestinal disturbances, skeletal pains, hyperuricemia, deranged liver enzymes, and sudden cardiac death.

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   Delamanid - It is contraindicated in patients with a prolonged QT interval, ventricular arrhythmias, liver diseases, hypoalbuminemia, and electrolyte imbalance.
   • Common side effects include nausea, vomiting, dizziness, and prolonged QT interval.

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   Linezolid - It is contraindicated in patients with allergy and neuropathy as manifested by numbness, paraesthesias and limb weakness.
   • Myelosuppression (anaemia, thrombocytopenia, and leukopenia), diarrhoea, nausea, peripheral and optic neuropathy, and lactic acidosis are a few of the side effects.

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   Clofazimine - It is contraindicated in patients with an allergy to clofazimine.
   • The orange or red colouring of the skin, conjunctiva, cornea and bodily fluids are side effects.
   • Dry skin, pruritis, rash, ichthyosis, xerosis, gastrointestinal issues, retinopathy, bowel obstruction, and QT prolongation are some more adverse effects.

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   Amoxicillin-clavulanic acid: It is contraindicated in penicillin and cephalosporin allergy.
   • Abdominal discomfort, diarrhoea, nausea, vomiting, and rash are examples of side effects.

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   Imipenem-cilastatin - It is contraindicated in allergic patients and should not be used in meningitis.
   • Side effects include diarrhea, nausea, vomiting, seizures, palpitations, and pseudomembranous colitis.

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   Meropenem: It is contraindicated in patients allergic to meropenem.
   • Seizures, hematologic and hepatotoxicity, diarrhoea, nausea, and vomiting are examples of side effects.

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   Thioacetazone: Patients with HIV infection and allergies to the drug should avoid thioacetazone.
   • Side effects include neurotoxicity (neuropathy, clumsiness, mood changes), cytopenias including aplastic anemia, hepatotoxicity and skin rash including the severe form - steven johnson syndrome.

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   Clarithromycin - It should not be used concurrently with bedaquiline, cisapride, pimozide, astemizole, terfenadine, ergotamine, or dihydroergotamine in individuals who are allergic to macrolides.