Antituberculosis drugs. Antileprosy drugs

01Drug classification

These drugs are grouped by the disease they treat rather than by what they do: drugs for tuberculosis, first-line and for resistant strains; drugs for Mycobacterium avium complex; and drugs for leprosy. Several drugs appear on more than one card, because the same drug treats more than one mycobacterium.

Treatment lasts months, needs several drugs at once, and uses drugs that are mostly their own, kept for mycobacterial disease, so that resistance to them stays rare.

02Pharmacokinetics

Doses are by weight and taken once a day, mostly as fixed-dose combination tablets so that no drug can be left out by accident.

Rifampicin switches on the liver's drug-clearing enzymes, CYP3A4 above all, and the transporters that go with them. That takes about a week to build up and two to four weeks to wear off, and it is the single most important thing about the drug after its power against tuberculosis: it lowers the level of hormonal contraceptives, warfarin, corticosteroids, ciclosporin and tacrolimus, methadone, azole antifungals, many drugs for HIV and hepatitis C, and more. Of the contraceptives, the combined pill, patch and ring, the progestogen-only pill and the implant cannot be relied on, during treatment and for 28 days after it; the copper coil, the levonorgestrel coil and the depot injection are not weakened. It also speeds its own clearance, which is why its half-life falls over the first days. It reaches the cerebrospinal fluid well enough to treat meningitis when the meninges are inflamed.

Isoniazid is acetylated by an enzyme whose activity is inherited. Slow acetylators, who carry two copies of the slow variant, reach higher levels and are more prone to neuropathy, and slow acetylation is counted among the risk factors for liver injury. The proportion differs by population, high in the Middle East, low in Japan, about half in the United States. It made no difference to cure on daily treatment, so the dose is not adjusted for it.

Pyrazinamide works best in acid, inflamed tissue, which is why it is given for the first two months only. Ethambutol is the one first-line drug cleared almost entirely by the kidneys, so its dose is the one most often wrong when they fail, and aluminium hydroxide antacids lower its absorption.

Bedaquiline and clofazimine both linger for months after the last dose, bedaquiline because it leaves the tissues slowly, clofazimine because it is stored in fat and in macrophages. That long tail matters twice over: the effect continues after treatment ends, and so does the risk, bedaquiline's on the heart's rhythm and clofazimine's on the skin.

03Pharmacodynamics

What each drug does

Resistance, as it matters to the patient

Resistance to rifampicin is the one that changes treatment: with it, the standard six-month regimen no longer works, and a regimen for rifampicin-resistant tuberculosis is needed. A rapid test for rifampicin resistance is done on the first sample, above all where there are risk factors for resistance, and the drugs are chosen by the result. Resistance to both rifampicin and isoniazid is multidrug-resistant tuberculosis. Tuberculosis that also resists a fluoroquinolone is pre-extensively drug-resistant, and extensively drug-resistant when it resists bedaquiline or linezolid too; the older definition named an injectable drug instead.

Resistance follows from treatment that was incomplete, poorly taken or built on too few drugs, so the main defences are a full regimen, a fixed-dose combination tablet, and support to finish it. Cross-resistance between drugs matters when choosing a regimen. A strain resistant to rifampicin is resistant to the other rifamycins, though some strains stay susceptible to rifabutin. Isoniazid-resistant strains can also resist ethionamide. Bedaquiline and clofazimine share resistance, so clofazimine in a regimen adds less when bedaquiline has been used before. Pretomanid and delamanid share it. Mycobacteria of the tuberculosis complex resist macrolides by nature, which is why azithromycin and clarithromycin treat Mycobacterium avium complex, not tuberculosis.

04Clinical indications

carry the infection

1 in 4people in the worldcarry the infection

and 1.23 million died of it

10.7 millionpeople ill with tuberculosis in 2024and 1.23 million died of it

with the standard six-month regimen in drug-susceptible disease

85%successful outcomewith the standard six-month regimen in drug-susceptible disease

against 52% on the older regimens for rifampicin-resistant disease

89%success with BPaLMagainst 52% on the older regimens for rifampicin-resistant disease

05Adverse drug reactions

• Serious
  Hepatitis with isoniazid, rifampicin and pyrazinamide. It shows as nausea, vomiting, dark urine and jaundice, and the liver tests rise. Isoniazid is stopped when the AST is over three times normal, or when the bilirubin rises, in the UK; elsewhere up to five times normal is allowed when there are no symptoms. The risk grows with age, alcohol, liver disease, HIV and malnutrition. Pyrazinamide that caused hepatitis is not given again.
• Life-threatening
  Liver failure and liver necrosis with isoniazid, rifampicin or pyrazinamide, rarely, with deaths and liver transplants reported when the drugs were continued after symptoms began.
• Life-threatening
  Severe skin reactions: Stevens–Johnson syndrome, toxic epidermal necrolysis and DRESS with rifampicin, isoniazid, ethambutol, rifabutin and dapsone. The drug is stopped and never given again.
• Serious
  Liver injury with bedaquiline, pretomanid and linezolid together (BPaL, BPaLM), the reason for liver tests every week in the first month; the whole regimen is interrupted when the transaminases are very high, or raised together with the bilirubin.
• Life-threatening
  Agranulocytosis and haemolytic or aplastic anaemia with isoniazid, rarely.
• Serious
  Peripheral neuropathy, seizures and psychosis with isoniazid. Neuropathy is dose-related and prevented by pyridoxine; seizures and psychosis are rarer and need the drug stopped.
• Serious
  Optic neuritis with ethambutol: blurred vision, a dim central patch and loss of red and green. It is dose-related, in under 1% at 25 mg/kg, and usually clears over weeks to months after the drug is stopped, but rarely takes more than a year or does not clear. Ethambutol is not normally restarted.
• Life-threatening
  Blood and kidney reactions with rifampicin: thrombotic microangiopathy, thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome; purpura that can end in cerebral haemorrhage if the drug is continued; disseminated intravascular coagulation; and, with intermittent dosing, anaphylaxis and other immune reactions. Rifampicin is stopped, and is not restarted without specialist advice.
• Serious
  Acute kidney injury with rifampicin, mostly from interstitial nephritis or tubular damage after an interruption in treatment.
• Life-threatening
  Interstitial lung disease and pneumonitis with rifampicin, potentially fatal.
• Life-threatening
  Severe bleeding from a deficiency of vitamin K-dependent clotting factors with rifampicin, mostly in people with liver disease or poor nutrition.
• Serious
  Gout from raised uric acid with pyrazinamide.
• Life-threatening
  QT prolongation and torsades de pointes with bedaquiline, delamanid, clofazimine and moxifloxacin, the risk greatest when two are combined, with other QT-prolonging drugs, with low potassium, magnesium or calcium, or in heart disease. Bedaquiline is stopped when the QTcF is over 500 ms.
• Serious
  Marrow suppression, neuropathy and optic neuritis with linezolid in BPaLM, which is why the dose is lowered to 300 mg when they appear (see Linezolid and other protein synthesis inhibitors).
• Serious
  Haemolysis and methaemoglobinaemia with dapsone, which is dose-related and worse in G6PD deficiency: breathlessness, a blue tinge and dark urine.
• Life-threatening
  Agranulocytosis and the dapsone syndrome. Dapsone can cause agranulocytosis, and a hypersensitivity syndrome with fever, rash, hepatitis and eosinophilia that has been fatal.
• Life-threatening
  Bowel obstruction, bleeding and splenic infarction from crystals of clofazimine, rarely, with deaths reported. Abdominal pain, nausea, vomiting or diarrhoea means the dose is lowered, the interval lengthened or the drug stopped, and doses above 100 mg a day are kept to under 3 months.
• Serious
  Depression and suicide with clofazimine, secondary to the skin discolouration; the patient and the family are asked to watch for it.
• Serious
  Uveitis and a fall in white cells with rifabutin, the reason for blood counts and for stopping it if the eye becomes painful or red.
• Serious
  Hallucinations and psychotic disorder with delamanid, hallucinations in 5.4% of children.
• Serious
  Hearing loss that cannot be undone, and kidney damage, with amikacin and streptomycin (see Aminoglycosides).
• Serious
  Clostridioides difficile colitis, with the rifamycins and the fluoroquinolones.
• Serious
  Neuropathy and blood clots with thalidomide, the reason for low-dose aspirin or an anticoagulant in those at risk.

06Side effects

• Mild
  Orange-red urine, tears, sweat and sputum with rifampicin and rifabutin, which stain soft contact lenses and can discolour teeth; the colour fades when the drug is stopped. Patients are told before it happens.
• Mild
  Nausea, vomiting and loss of appetite, above all in the first weeks and with rifampicin and pyrazinamide. Taking the tablets at night or with a light meal helps; rifampicin is taken on an empty stomach where it can be borne.
• Mild
  Joint pain with pyrazinamide, and with bedaquiline in 45% against 33% on the background regimen alone.
• Mild
  Headache, dizziness and tiredness, common in the first weeks.
• Mild
  A flu-like illness with intermittent rifampicin: fever, chills and bone pain, common with intermittent dosing, which is one reason daily dosing is used.
• Mild
  Rash and itching with most of the drugs, and photosensitivity with pyrazinamide, dapsone and clofazimine.
• Mild
  Dry, darkened skin with clofazimine, a pink to brownish-black tint in 75 to 100%, which takes months to years to fade after it is stopped.
• Mild
  Reactions to foods rich in tyramine or histamine with isoniazid: flushing, palpitations and headache after cheese, red wine or some fish.
• Mild
  Sleep disturbance with delamanid.

07Contraindications

• Contraindicated
  An allergy to the drug or its family: to any rifamycin with rifampicin, rifabutin and rifapentine; to a nitroimidazole with pretomanid; and to dapsone, sulfonamides or other sulfones with dapsone. Isoniazid is not given again after a severe reaction, including drug-induced liver disease.
• Contraindicated
  Rifampicin in jaundice, and with the combination of saquinavir and ritonavir, with lurasidone, sofosbuvir, daclatasvir, telaprevir, cabotegravir, fostemsavir and lenacapavir, whose levels it lowers too far or whose own effects it increases.
• Contraindicated
  Pyrazinamide in liver disease, in hyperuricaemia or gout, and in acute porphyria.
• Contraindicated
  Ethambutol in optic neuritis or retrobulbar neuritis, unless the benefit clearly outweighs the risk.
• Contraindicated
  Rifabutin with rilpivirine as a long-acting injection.
• Contraindicated
  Delamanid with an albumin under 2.8 g/dL, or with strong inducers of CYP3A4 such as carbamazepine.
• Contraindicated
  Dapsone in severe anaemia, in porphyria and in severe G6PD deficiency.
• Contraindicated
  Thalidomide in pregnancy, in women who could become pregnant unless every condition of the pregnancy prevention programme is met, and in men who won't use a condom.
• Avoid
  Rifampicin with halothane, with cephalosporins that carry an N-methylthiotetrazole group such as cefazolin, and with clopidogrel, and the combined pill, patch and ring, the progestogen-only pill and the implant during rifampicin, which it makes unreliable, for the treatment and 28 days after it.
• Avoid
  Isoniazid with carbamazepine unless both are monitored, and with itraconazole.
• Avoid
  Bedaquiline with the rifamycins, efavirenz and other moderate or strong inducers of CYP3A4, which lower its level; and starting it in heart failure, a QTcF over 450 ms, congenital long QT, hypothyroidism, a slow heart rhythm, previous torsades or a low potassium.
• Avoid
  Moxifloxacin with delamanid, and any two QT-prolonging drugs where an alternative exists.
• Avoid
  Pretomanid outside BPaL or BPaLM, and alcohol or other drugs that harm the liver with bedaquiline or pretomanid.
• Avoid
  Aluminium hydroxide with ethambutol, which lowers its absorption.
• Avoid
  Delamanid in moderate to severe liver impairment or severe kidney impairment.
• Caution
  Rifampicin with warfarin, phenytoin, corticosteroids, ciclosporin and tacrolimus, methadone, antiretrovirals, azole antifungals, theophylline, sulfonylureas, levothyroxine and digoxin, all of which it makes less effective. Doses and levels are adjusted, and a patient on a corticosteroid for adrenal insufficiency needs more.
• Caution
  Isoniazid with phenytoin, benzodiazepines and theophylline, whose levels it raises.
• Caution
  Liver disease, alcohol, age, malnutrition and HIV in anyone taking isoniazid or rifampicin: the liver tests are watched, and the dose or the regimen may change.
• Caution
  Kidney impairment, with ethambutol, rifabutin and the aminoglycosides in particular, for which the dose is lowered or the interval lengthened.
• Caution
  Isoniazid in diabetes, alcohol dependence, malnutrition, HIV, kidney failure and pregnancy, where neuropathy is likelier and pyridoxine is given.
• Caution
  Pyrazinamide in diabetes and gout. Glycaemic control is harder, and uric acid is watched.
• Caution
  Ethambutol in young children, who cannot report a change in their sight.
• Caution
  Dapsone in mild G6PD deficiency, and with rifampicin or trimethoprim, which change its levels.
• Caution
  Delamanid with an albumin under 3.4 g/dL, or with strong inhibitors of CYP3A4.
• Caution
  Foods rich in tyramine or histamine with isoniazid, such as cheese and red wine.
• Caution
  Antacids with rifampicin, which are taken at least an hour afterwards; paracetamol with rifampicin, which raises the risk of liver injury; and rifabutin with clarithromycin, fluconazole or boosted protease inhibitors, which raise its level.

08Pregnancy and lactation

• Compatible
  The first-line drugs in pregnancy. Untreated tuberculosis is the greater hazard for mother and baby, and the first-line drugs are regarded as safe in pregnancy, except streptomycin. Pyridoxine is given with isoniazid, and the newborn may be given vitamin K when the mother took rifampicin. Their licences are more guarded, and weigh the benefit against the risk.
• Compatible
  Breastfeeding with rifampicin, isoniazid, pyrazinamide and ethambutol. They pass into milk in amounts too small to matter, and breastfeeding goes on. Isoniazid is given with pyridoxine to the mother, and pyridoxine for the baby may be considered. Their licences are stricter: the UK licence of pyrazinamide contraindicates breastfeeding, ethambutol's does not recommend it, and rifampicin's advises against it unless the benefit justifies it.
• Avoid
  Streptomycin and amikacin in pregnancy, as they can deafen the baby; they are usually contraindicated, as are ethionamide and prothionamide.
• Avoid
  Rifabutin in pregnancy, as its licence says it should not be used, for want of data; in breastfeeding it is likely to be compatible, though its licence is stricter.
• Caution
  BDLLfxC in pregnancy and breastfeeding. It is recommended, as untreated rifampicin-resistant tuberculosis is a greater risk. Bedaquiline was linked to low birth weight in 45% of babies against 26%, and its licence advises avoiding it unless the benefit justifies it; in one report it reached milk at 14 times the mother's blood level, and its licence advises against breastfeeding, though it is likely to be compatible with the baby watched. Delamanid's licence doesn't recommend it in pregnancy and advises against breastfeeding.
• Avoid
  BPaLM and pretomanid in pregnancy and breastfeeding. They are not used, for want of data, though the licence leaves the choice to benefit and risk.
• Caution
  Dapsone in pregnancy and breastfeeding. In pregnancy the benefit outweighs the risk, and folic acid 5 mg may be given. In breastfeeding it is likely to be compatible, but it is avoided in the first two weeks and with a baby who has G6PD deficiency.
• Caution
  Clofazimine in pregnancy and breastfeeding. The baby may be born pigmented, which fades over the first year, and in the milk it can turn the baby's skin pink or red, which is reversible. The benefit justifies it.
• Contraindicated
  Thalidomide in pregnancy, because it causes severe birth defects, and while breastfeeding, which is stopped during treatment.