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In this essay we will discuss about the first line and second line drugs used for the treatment of tuberculosis.
Essay # 1. First Line Drugs:
These include isoniazid, rifampicin, pyrazinamide, streptomycin and ethambutol. They have high anti-tubercular efficacy and low toxicity and are used routinely.
i. Isoniazid (INH):
INH is highly effective, and is always included in any anti-tubercular regimen; unless there is a specific contraindication (e.g. drug induced liver disease). INH is bactericidal to tubercle bacilli. The exact mode of action is not known. It probably interferes with cellular metabolism, especially the synthesis of mycolic acid, an important constituent of the myobacterial cell wall.
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INH is rapidly absorbed from the intestine and is largely excreted by the kidneys. It diffuses widely throughout the body, it enters into the cells, crosses the meningeal barrier with therapeutic effective concentrations in the CSF.
Isoniazid is metabolized in the liver and the plasma concentration depends on whether the patient is a fast or slow acetylator of the drug (a genetically determined characteristic). However, the acetylator status does not matter, because the drug is given daily.
The only common side effect of INH is peripheral neuropathy, which is more likely to occur where there are pre-existing risk factors such as diabetes, alcoholism, chronic renal failure, malnutrition and HIV infection. This can be prevented by giving pyridoxine 10 mg daily. Other side effects such as hepatitis, psychosis and hypersensitivity reactions are rare.
ii. Rifampicin:
Rifampicin is a key antibiotic of any anti-tubercular regimen and like isoniazid should always be included, unless there is a specific contraindication (e.g. jaundice). Rifampicin inhibits RNA synthesis in bacteria and Chlamydiae by binding to DNA dependent RNA polymerase. Rifampicin is effective against several Gram-positive and Gram- negative organisms and in particular against the tubercle bacillus. As an anti-tubercular drug, it is as effective bacteriocidal as INH. The use of the drug as a single therapeutic agent always promotes the emergence of resistant organism.
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Apart from tuberculosis, it is also used in brucellosis, Legionnaires disease, serious Staphylococcal infections, leprosy in combination with other appropriate drugs, and for prophylaxis of close contacts of patients with infection caused by N. meningitides, and as adjunctive treatment of osteomyelitis associated with prosthetic material or devices. Rifampicin is well absorbed orally and is widely distributed in the body tissues and is mainly excreted in the bile.
Side effects are uncommon, but it should be used with caution in hepatic impairment (requires reduction of doses). Liver function tests and blood counts should be monitored in hepatic disorders. Persistent nausea, vomiting or jaundice requires discontinuation of the drug. It may cause red colouration of urine and sputum. Rifampicin induces hepatic enzymes, which accelerate the metabolism of several drugs including estrogens, glucocorticoids, phenytoin, sulphonylureas and warfarin.
iii. Rifabutin:
Rifabutin is similar to rifampicin. It is principally used to treat Mycobacterial (tuberculsis and M. avium complex) infections in HIV-positive patients who are receiving highly active antiretroviral therapy, as it has less deleterious effects on protease inhibitor metabolism than does rifampicin. Uveitis has been associated with its use.
iv. Pyrazinamide:
Pyrazinamide is a powerful bactericidal drug only active against intracellular dividing forms of tubercle bacillus. It is absorbed orally, and has good penetration into tubercular lesions. It is particularly useful in tubercular meningitis, because of good meningeal penetration. It exerts its effects only in the first two or three months and is an important component for the initial anti-tubercular regimen. Pyrazinamide may cause liver damage with jaundice, light sensitisation and attacks of gout. It is contraindicated in liver disease.
v. Ethambutol:
Ethambutol is also commonly used in the treatment regime, when resistance to isoniazid is suspected. It can be omitted, if the risk of resistance to INH is low. Mode of action of ethambutol is not known. It is bacteriostatic and resistance occurs rapidly, when used alone. Ethambutol is well absorbed orally and is widely distributed in the body, including the CSF. It is partly metabolized and partly excreted by kidney. The most important side effect of ethambutol is damage to optic nerve leading to deterioration of visual acuity and colour vision. Other side effects include peripheral neuritis and rarely rashes.
vi. Streptomycin:
Streptomycin is an aminoglycoside that can be used as a substitute for ethambutol and for drug-resistant MTB It does not adequately penetrate the CNS and should not be used for TB meningitis. It is bactericidal against actively multiplying tubercle bacilli. The main disadvantage of streptomycin lies in its administration by intramuscular injection and its toxicity (especially ototoxicity and sensitisation phenomena, which may even occur to the person handling the drug). Streptomycin should not be used in pregnancy because of auditory or vascular damage to the fetus.
Treatment Regimens for Tuberculosis:
Treatment of choice is short course treatment, which consists of an initial (intensive) phase and a continuation phase. Initial phase consists of two months therapy with at least three or four drugs and aims at the reduction of the bacterial population as rapidly as possible and prevention of the emergence of drug resistant bacteria. Continuation phase of treatment is of four months.
Initial phase:
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Isoniazid 300 mg, rifampicin 450-600 mg, pyrazinamide 1.5-2.0 g and ethambutol 600-800 mg are given once daily before breakfast for 2 months. Ethambutol may be omitted from the regimen, if the risk of isoniazid resistance is low.
Continuation phase:
Rifampicin and isoniazid should be continued for a further period of 4 months. Since isoniazid, rifampicin and pyrazinamide are associated with liver toxicity; hepatic functions should be checked before starting the treatment.
vii. Directly Observed Treatment Short Course (DOTS):
The totally unsupervised domiciliary ‘short course treatment (SCC)’ of 6 months cannot be relied upon in patients, who fail to comply with the treatment regimen. The outcome of the standard SCC regimen, thus, remains uncertain with a high failure rate and emergence of resistant strains. As a consequence, the treatment needs to be fully supervised under DOTS programme which can only ensure the control of tuberculosis.
viii. Multidrug Resistance (MDR) Tuberculosis:
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MDR tubercle bacilli are resistant to at least isoniazid and rifampicin. The drug regimen for MDR-TB depends on microbiological properties of anti-tubercular drugs. In absence of susceptibility test or resistant to isoniazid, rifampicin, streptomycin and ethambutol, the treatment of MDR-TB is carried out by an initial phase consisting of capreomycin, ethionamide, pyrazinamide, ofloxacin and cycloserine for a period of 3 months followed by a continuation phase with ethionamide, ofloxacin and cycloserine for a further period of 18 months.
Essay # 2. Second Line Drugs:
These are ethionamide, cycloserine, capreomycin, para-amino salicylic acid and ofloxacin. They have either low anti-tubercular efficacy or high toxicity and are used for MDR-TB.
i. Ethionamide:
Ethionamide is a tuberculocidal drug. It acts on both extra- and intracellular organisms. It is absorbed orally, widely distributed including CSF and is completely metabolized. Side effects include gastrointestinal disorders and hepatitis.
ii. Capreomycin:
Capreomycin, like other aminoglycoside antibiotics, is bactericidal. It is given by deep intramuscular injection daily for 2-4 months and then 2-3 times each week. Side effects include deafness, loss of vestibular and renal functions, hypersensitivity reactions and changes in liver function tests.
iii. Cycloserine:
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Cycloserine, an antibiotic, acts as bacteriostatic against tubercle bacilli, some Gram positive bacteria, E. coli and Chlamydial infections. It is absorbed orally, widely distributed including CSF, partly metabolised and rest excreted unchanged by kidney.
It is a toxic drug and gives rise to high incidence of neurological disorders including depression, personality changes, psychosis and convulsions. Cycloserine is contraindicated in severe renal impairment, epilepsy, psychotic states and alcohol dependence.
iv. Para-Amino Salicylic Acid (PAS):
PAS is only active against tubercle bacilli. It is one of the least active tuberculostatic drug and only delays development of resistance to other anti-tubercular drugs. It is only used as an alternative to cycloserine in patients, when cycloserine is contraindicated. PAS is completely absorbed by oral route and distributed all over except CSF. It competes with the acetylation of isoniazid. It is partly acetylated and rest excreted by kidney. Side effects include diarrhea, hepatitis and hypersensitivity reactions.
