Introduction and Causes of tuberculosis
Tuberculosis otherwise known as TB is an airborne disease caused by the bacteria Mycobacterium tuberculosis and Mycobacterium bovis. It can be transmitted through microscopic droplets released into the air when an infected person coughs, speaks, sneezes, spits, laughs or sings.
Treatment of Tuberculosis
Streptomycin (SM) was the first drug used in the effective treatment of tuberculosis. There was frequent emergence of SM resistance which was greatly reduced by combined treatment with SM and para-aminosalicylic acid (PAS). A highly efficacious isoniazid (INH, H) was later introduced. The properties of INH that confirmed its efficacy included its low minimum inhibitory concentration (MIC) against Mycobacterium tuberculosis and its low toxicity. INH was used alone, or in combination with SM or PAS.
Due to resistant to only one of the three available drugs, a regimen starting with the three drugs, SM, PAS and INH (SPH) was introduced so that two would be available for almost any resistant strain in the community; followed by a continuation phase of the two oral drugs, PAS and INH (PH). After clinical trials, a year’s treatment with PAS and INH supplemented initially with SM (3SPH/9PH) was adopted. However, the limitations of this regimen was that it required at least 1 year of treatment and it is very expensive due to the large amounts of PAS that needed to be administered. Solutions for the major limitations of the 3SPH/9PH regimen were provided by substituting the far cheaper thioacetazone for PAS and shortening the treatment period to ensure compliance.
The ability of pyrazinamide (PZA, Z) to kill bacilli that persisted in organs after treatment with INH and SM was established. Later experiments also established that rifampicin (RMP, R) could accelerate the killing of tubercle bacilli in mouse organs. Consequently RMP or PZA was added to a basic 6-month regimen of SM+INH to radically reduce the relapse rate. This finding was the basis for the development of modern short-course treatment of tuberclosis. Due to increased toxicity of thioacetazone, ethambutol (EMB, E) was later given in its place. The 6-month regimen of 2HRZE/4RH was shown to be much more effective in patients whose organisms were initially resistant to INH. The WHO now recommends only the 6-month regimen.
The main problems with current chemotherapy are:
- The 6-month treatment regimen is too long and cumbersome. This causes poor compliance and emergence of drug resistance.
- There is increasing prevalence of multidrug-resistant (MDR) strains of M. tuberculosis resistant to RMP and INH, and sometimes to injectables and fluoroquinolones as well (extensively drug-resistant [XDR]).
Any solution to these problems depends on an understanding of the two theoretical issues underlying the success of chemotherapy.
i. Prevention of the emergence of drug resistance
ii. And the reasons for the very slow killing of all M. tuberculosis in lesions.
Prevention of drug resistance
Resistance arises against each of the anti-tuberculosis drugs by bacterial chromosomal mutations. The origins of drug resistance appear to be due to 1) irregularity in drug taking. 2) Inadequate dosage, particularly of RMP. 3) Prescription of single-drug treatment for financial reasons by private practitioners.
Slow killing during treatment
A rapidly growing culture of M. tuberculosis is killed within days by the antibacterial drugs, but it takes 6 months to complete the sterilisation of tuberculous lesions in the lungs of patients. This phenomenon was attributed to the presence of slowly growing or non-multiplying populations of bacilli, in particular those in the stationary phase of growth or existing under anaerobic conditions.
Isoniazid
Isoniazid is also known as isonicotinylhydrazide (INH). For active tuberculosis it is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol. For latent tuberculosis it is often used alone. It is usually taken by mouth but may be used by injection into muscle. Isoniazid is bactericidal to rapidly dividing mycobacteria, but is bacteriostatic if the mycobacteria are slow-growing.
Mechanism of action of Isoniazid
Isoniazid is a prodrug that inhibits the synthesis of mycolic acids thus inhibiting the formation of the mycobacterial cell wall.
Dosages of Isoniazid
Adult doses for pulmonary tuberculosis: initial regimen is 5 mg/kg orally once a day; (maximum of 300 mg/day). Plus rifampicin, pyrazinamide, ethambutol/streptomycin. Duration of therapy is 8 weeks. Continuation regimen: 5 mg/kg orally once a day (maximum of 300 mg/day); Plus rifampicin. Duration of therapy is 16 weeks.
Children: initial regimen is 10 – 15 mg/kg orally once a day; (maximum of 300 mg/day). Plus rifampicin, pyrazinamide, ethambutol/streptomycin. Duration of therapy is 8 weeks. Continuation regimen: 10 – 15 mg/kg orally once a day (maximum of 3oo mg/day); Plus rifampicin. Duration of therapy is 16 weeks.
Absorption
INH is a small water soluble molecule and easily absorbed from the GIT.
Distribution of Isoniazid
It is distributed widely into body tissues and fluids. It crosses the placental barrier and enters breast milk.
Special populations
Vitamin B6 is used to prevent isoniazid-induced B6 deficiency and neuropathy in people with a risk factor, such as pregnancy, lactation, HIV infection, alcoholism, diabetes, kidney failure, or malnutrition. People with liver dysfunction are at a higher risk for hepatitis caused by INH, and may need a lower dose.
Side Effects of Isoniazid
Common side effects include increased blood levels of liver enzymes and numbness in the hands and feet. Serious side effects may include liver inflammation. Other side effects include: peripheral neuropathy, nausea and vomiting, aplastic anemia, thrombocytopenia, and agranulocytosis. Hypersensitivity reactions (rash and fever), headache, poor concentration, weight gain, poor memory, insomnia, and depression have all been associated with isoniazid use.
Isoniazid is associated with pyridoxine (vitamin B6) deficiency because of its similar structure. This causes insufficient heme formation in early red blood cells leading to sideroblastic anemia.
Drug interactions with Isoniazid
People taking isoniazid and acetaminophen are at risk of acetaminophen toxicity. Isoniazid decreases the metabolism of carbamazepine. It is possible that isoniazid may decrease the serum levels of ketoconazole after long term treatment. Isoniazid may increase the amount of phenytoin in the body. Isoniazid may increase the plasma levels of theophylline. There are some cases of theophylline slowing down isoniazid elimination. Valproate levels may increase when taken with isoniazid.
Metabolism of Isoniazid
INH is metabolized in the liver via acetylation into acetylhydrazine. Two forms of the enzyme are responsible for acetylation, so some patients metabolize the drug more quickly (fast acetylators) than others who are slow acetylators.
Excretion of Isoniazid
the metabolites are excreted in the urine. Doses do not usually have to be adjusted in case of renal failure.
Streptomycin
Streptomycin is an antibiotic used to treat a number of bacterial infections including tuberculosis. For active tuberculosis it is often given together with isoniazid, rifampicin, and pyrazinamide. It is given by injection into a vein or muscle.
Dosages of Streptomycin
It is not necessary to give large toxic doses of streptomycin in the treatment of pulmonary tuberculosis and its complications. Doses of 0.33 gram of streptomycin daily, 1.0 gram administered every three days, or 2.0 grams once a week are usually safe and effective.
Mechanism of action of Streptomycin
Streptomycin binds to the 30S subunit of the bacterial ribosome. This leads to inhibition of protein synthesis and ultimately death of microbial cells.
Distribution of Streptomycin
Appreciable concentrations are found in all organs and tissues except the brain. Significant amounts have been found in pleural fluid and tuberculous cavities. Streptomycin passes through the placenta with serum levels in the cord blood similar to maternal levels.
Metabolism of Streptomycin
Aminoglycosides are not metabolized by the body.
Excretion of Streptomycin
Streptomycin is excreted by glomerular filtration. Small amounts are excreted in milk, saliva, and sweat.
Side Effects of Streptomycin
The most concerning side effects, as with other aminoglycosides, are kidney toxicity and ear toxicity (Ototoxicity). Transient or permanent deafness may result. Common side effects include tinnitus, vertigo, ataxia, vomiting, numbness of the face, fever, and rash.
Contraindications of Streptomycin
Use is not recommended during pregnancy. Congenital deafness has been reported in children whose mothers received streptomycin during pregnancy. It is not recommended in people with myasthenia gravis.
Drug Interactions with Streptomycin
The ototoxic effects of the aminoglycosides, including streptomycin, are potentiated by the co-administration of ethacrynic acid, furosemide, mannitol and possibly other diuretics.
Rifampicin
Rifampicin, also known as rifampin, is an antibiotic used to treat several types of bacterial infections, including tuberculosis and leprosy. It is almost always used together with other antibiotics. Rifampicin may be given either by mouth or intravenously.
Mechanism of action
Rifampicin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase.
Dosages of Rifampicin
For tuberculosis, refampicin is given 10 mg/kg/day orally; or 10 mg/kg orally twice weekly; not to exceed 600 mg/day.
Absorption of Rifampicin
Rifampicin is easily absorbed from the gastrointestinal (GI) tract. Food consumption inhibits its absorption from the GI tract.
Distribution of Rifampicin
When administered orally, rifampicin results in peak plasma concentration in about 2 – 4 hours. Distribution of the drug is high throughout the body, and reaches effective concentrations in many organs and body fluids, including the cerebrospinal fluid. About 60% to 90% of the drug is bound to plasma proteins.
Metabolism of Rifampicin
Its ester functional group is quickly hydrolyzed in bile, and it is catalyzed by a high pH and substrate-specific esterases.
Excretion of Rifampicin
Only about 7% of the administered drug is excreted unchanged in urine, though urinary elimination accounts for only about 30% of the drug excretion. About 60% to 65% is excreted through feces. The half-life of rifampicin ranges from 1.5 to 5.0 hours, though hepatic impairment significantly increases it.
Adverse effects of Rifampicin
The most serious adverse effect is hepatotoxicity. The more common side effects include fever, gastrointestinal disturbances (such as nausea, vomiting, diarrhea, and loss of appetite), rashes, and immunological reactions. Allergic reactions include: Rashes, itching, swelling of the tongue or throat, severe dizziness, and trouble breathing.
Contraindication of Rifampicin
Since rifampicin may be excreted in breast milk, breast feeding should be avoided while it is being taken.
Drug Interactions with Rifampicin
Rifampicin is the most powerful known inducer of the hepatic cytochrome P450 enzyme system. It increases metabolism of many drugs and as a consequence, can make them less effective, or even ineffective, by decreasing their plasma concentration. Examples of drugs affected include warfarin, contraceptives, antiretrovirals, atorvastatin, clarithromycin, voriconazole, lorazepam, gentamicin.
Pyrazinamide
Pyrazinamide is a medication used to treat tuberculosis. For active tuberculosis, it is often used with rifampicin, isoniazid, and either streptomycin or ethambutol. It is not generally recommended for the treatment of latent tuberculosis. It is taken by mouth.
Dosages of Pyrazinamide
The recommended dose has been reduced from 50 – 70 mg/kg to 12–30 mg/kg daily to reduce the incident of drug induced hepatitis.
Absorption of Pyrazinamide
Pyrazinamide is well absorbed orally.
Distribution of Pyrazinamide
It crosses inflamed meninges and is an essential part of the treatment of tuberculous meningitis.
Mechanism of action of Pyrazinamide
Pyrazinamide is a prodrug of pyrazinoic acid that stops the growth of M. tuberculosis by unclarified mechanism.
Metabolism of Pyrazinamide
It is metabolised by the liver
Excretion of Pyrazinamide
The metabolic products are excreted by the kidneys.
Side Effects of Pyrazinamide
Common side effects include nausea, loss of appetite, muscle pains, joint pains (arthralgia) and rash. Other side effects include nausea and vomiting, anorexia, sideroblastic anemia, urticaria, dysuria, interstitial nephritis, malaise, rarely porphyria, and fever.
Contraindications of Pyrazinamide
It is not recommended in those with significant liver disease or porphyria.
Adverse effects of Pyrazinamide
The most dangerous effect of pyrazinamide is hepatotoxicity, which is dose-related. In the standard four-drug regimen (isoniazid, rifampicin, pyrazinamide, and ethambutol), pyrazinamide is the most common cause of drug-induced hepatitis.
Ethambutol
Ethambutol (EMB, E) is a medication primarily used to treat tuberculosis. It is usually given in combination with other tuberculosis medications, such as isoniazid, rifampicin and pyrazinamide. It is taken by mouth.
Dosages of Ethambutol
The currently recommended daily dose of ethambutol (EMB) for the treatment of tuberculosis (TB) in children varies from a maximum daily dose of 15 mg/kg body weight daily (without a range) to 15-20 mg/kg and 20 mg/ kg (range 15-25 mg/kg). After 60 days, decrease to 15 mg/kg PO qDay
Adult daily administration
- 40-55 kg: 800 mg PO
- 56-75 kg: 1.2 g PO
- >75 kg: 1.6 g PO
Adult Twice weekly administration
- 40-55 kg: 2 g PO
- 56-75 kg: 2.8 g PO
- >75 kg: 4 g PO
Absorption of Ethambutol
It is well absorbed from the gastrointestinal tract.
Distribution of Ethambutol
Distributed widely into body tissues and fluids, especially into lungs, erythrocytes, saliva, and kidneys; lesser amounts distribute into brain, ascitic, pleural, and cerebrospinal fluids. Ethambutol is 8% to 22% protein-bound.
Mechanism of Action of Ethambutol
Ethambutol is bacteriostatic against actively growing TB bacilli. It works by obstructing the formation of cell wall. Ethambutol is also believed to work by interfering with the bacteria’s metabolism.
Metabolism of Ethambutol
Undergoes partial hepatic metabolism.
Excretion of Ethambutol
After 24 hours, about 50% of unchanged ethambutol and 8% to 15% of its metabolites are excreted in urine; 20% to 25% is excreted in feces. Small amounts of drug may be excreted in breast milk. Plasma half-life in adults is about 31/4 hours; half-life is prolonged in decreased renal or hepatic function.
Side Effects of Ethambutol
Common side effects include problems with vision, joint pain, nausea, headaches, and feeling tired. Other side effects include liver problems and allergic reactions.
Contraindications of Ethambutol
It is not recommended in people with optic neuritis, significant kidney problems, or under the age of five.
Adverse Effects
Optic neuritis, red-green color blindness and peripheral neuropathy.
Summary of first and second line drugs for TB Treatment
First Line Drugs
- Isoniazid (H)
- Rifampin (R)
- Ethambutol (E)
- Pyrazinamide(Z) and
- Streptomycin (S)
Second Line Drugs
- Aminoglycosides (kanamycin, amikacin)
- Quinolones (ciprofloxacin, ofloxacin, levofloxacin)
- Ethionamide or prothionamide, cycloserine, para-aminosalicylic acid (PAS) and
- Polypeptide (capreomycin)
References
- Jyotsna M. Joshi. Tuberculosis chemotherapy in the 21st century: Back to the basics. NCBI. Accessed August 9, 2021
- Dobbs TE, Webb RM. Chemotherapy of Tuberculosis. Microbiol Spectr. 2017;5(2):10.1128/microbiolspec.TNMI7-0040-2017. doi:10.1128/microbiolspec.TNMI7-0040-2017. Accessed August 9, 2021
- Marcos A. Espinal, MD, DrPH et al. Standard short course treatment for drug-resistant tuberculosis. JAMA. Accessed August 9, 2021