Drugs For Tuberculosis

First Line Drugs For Tuberculosis

There are five drugs in first line attack against tuberculosis. The durgs differ in their mechanism of action; whether they are bactericidal i.e. kill bacteria rapidly or bacteriostatic i.e. inhibits the multiplication and growth of bacteria but do not kill them. They also differ in their action against intracellular bacilli (those mycobacteria that are in the cell), extracellular bacilli (those mycobacteria that are outside the cell) and the bacilli in the lesion itself.

No single drug is effective in treating the disease but when used in combination, they can cure the disease. Here are the first line drugs used in treatment of tuberculosis.

All except streptomycin are given orally.

Isoniazid

It is bacteriostatic for resting bacilli but kills those which divide actively.   It is active against intracellular bacilli, extracellular bacilli and bacilli at lesion. It has good penetration in cerebrospinal fluid and possesses good overall activity. Along with rifampicin, it is the main drug in treatment of tuberculosis.

It inhibits cell wall mycotic acid synthesis.

Side Effects

• Gastrointenstinal disturbances
• Hepatotoxicity- elevation of liver enzymes, hepatic failure
• Hypersenstivity reactions-  fever,  rashes, purpura, vasculitis, drug induced lupus
• Agranulocytosis
• Pellagra
• Neurotoxicity,
• Peripheral neuropathy, optic neuritis
• Convulsions
• Psychoses
• Gynecomastia

It should be used along with pyridoxine 10 mg daily to prevent neurotoxicity. Liver function should be monitored regularly. The resistance against drug may develop due to failure of penetration into bacillus.

Rifampicin

Rifampicin is a bactericidal drug and active against all kind of bacteria. It inhibits DNA dependent RNA polymerase. It has following side effects-

• Gastrointenstinal disturbances
• Pseudomembranous colitis
• Hepatotoxicity (transient elevation enzymes)
• Shortness of breath
• Collapse and shock
• Thrombocytopenic purpura
• Hemolytic anemia
• Renal failure
• Hhypersensitivity reactions

The drug should be used on empty stomach and causes orange discoloration of the urine. This feature is used to evaluate compliance of the patient with the treatment. Liver function and blood counts should be monitored. The drug has wide range of activity and is used in leprosy, resistant staphylococcal infections, Legionnaire’s disease and prophylaxis of meningococcal meningitis.

Pyrazinamide

It is a  and active against intracellular bacilli only. Exact mechanism of action is unknown. Side effects include

• Gastrointenstinal disturbances
• Hepatotoxicity- elevation of liver enzymes, hepatic failure
• Hypersenstivity reactions-  fever,  rashes
• Sideroblastic anaemia
• Hyperuricemia – increase in serum uric acid levels

It requires regular monitoring of serum uric acid and liver function test.

Ethambutol

Ethambutol is bacteriostatic and active against intra as well extracellular bacteria and also shows activity against bacilli in caseous lesion. It is more active against dividing bacilli. It is supposed to act by inhibiting bacterial cell wall synthesis.

It has follwing side effects

• Optic neuritis – reduced visual acuity
• Loss of red-green discrimination
• Peripheral neuropathy
• Hyperuricemia

It is not recommended in children below six years as they cannot report visual symptoms.

Streptomycin

It is a bactericidal drug and is mostly active against extracellular bacteria. It is given by intra muscular route.

As side effect it can cause

• Ototoxicity (vestibular more than cochlear)
• Nephrotoxicity
• Rash and fever

It is not prescribed in fresh cases as per new regime of WHO. It has traditionally be used locally in cold abcesses formed in tuberculosis.

Second Line Antitubercular Drugs

A second line drug for tuberculosis is either less effective than the first line drug or has an associated toxicity that makes second choice for use in tuberculosis patients.
Second class drugs are used when the patient either does not respond to first line or does not tolerate them and substantiating the treatment is necessary.

Following are  second-line drugs used for the treatment of tuberculosis.

• Thioacetazone (T)
• P-aminosalicylic acid (PAS or P).
• Thioamides – Ethionamide, prothionamide
• Cycloserine
• Polypeptides- capreomycin, viomycin, enviomycin
• Aminoglycosides: e.g., amikacin (AMK), kanamycin (KM)
• Fluoroquinolones-Ciprofloxacin (CIP), levofloxacin, moxifloxacin (MXF), Ofloxacilin

Commonly used drugs are discussed below-

Thiacetazone

Thioacetazone is a bacteriostatic drug [Inhibits the growth of bacteria but does not kill existing]. 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 gastrointenstinal  disturbances, skin reactions including exfoliative dermatitis,hepatotoxicity, myelosuppression [suppression of bone marrow].

It is not used in AIDS patients. Due to its toxic profile the use of Thioacetazone is reducing and it is used in cases where other choices have exhausted.

PAS

P-aminosalicylic acid is again a bacteriostatic drug with poor CSF penetration. It acts by inhibiting folate synthesis and interferes with incorporation of p-amino benzoic acid. The dose is 150 mg/kg per oral in divided doses with meals. Maximum allowed dose is 12 gm.

Side effects like gastrointenstinal disturbances, hypersensitivity like rash, feve malaise, arthralgia,  and  changes in blood count like leucopenia, agranulocytosis, eosinophilia, lymphocytosis, atypical mononucleosis, thrombocytopenia, hemolytic anemia. This drug is active against mycobacterium tuberculosis only.

Ethionamide

It is a bacteriostatic drug  and has a good CSF penetration.  It acts as nicotinamide analog and possibly inhibits incorporation of cysteine and methionine proteins. 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 gastrointenstinal  disturbances, neurotoxicity, visual disturbances, olfactiry distubances, peripheral neuropathy, convulsions, hepatotoxicity, hypersensitivity reactions, alopecia and gynecomastia.

Pyridoxine supplements can reduce the toxicity. Liver functions must be monitored during therapy.

If used alone, resistance develops very soon. It also shows cross resistance with thioacetazone

Cycloserine

A bacteriostatic drug with very good CSF penetration. It inhibits cell wall synthesis. Dose is 10-20 mg/kg per oral in 2 divided doses. Maximum dose is 500 mg twice daily. Headcahe, dizziness, vertigo, drowsiness, tremors, convulsions, depresion, psychosis, abnormal liver function, megaloblastic anemia, rashes are known side effects.

Hematological, renal and hepatic functions should be monitored.

Capreomycin

The drug is given in intramuscular injection form. It is a bacteriocidal drug with poor CSF penetration. The dose is 15-30mg/kg . Maximum dose is 1 gram. Induration at the site of injection, Ear and kidney toxicity, fever, rashes, 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.

Amikacin, Kanamicin

These are bacteriocidal drugs that belong to aminoglycocide class and have poor CSF penetration. Dose is 15mg/kg intramuscular injection form.

Ootoxicity, nephrotoxicity, pesudomembranous colitis and neuromucular blockade are common side effects.

Fluoroquinolones should not be used in children.

Newer drugs like macrolides (e.g. Azithromycin; Clarithromycin), rifamycins, (e.g. Rifabutin and the long-acting Rifapentine) and nitroimidazoles (e.g. PA-824) are being evaluated fro their efficacy.

A number of adverse drug reactions are possible from the use of antitubercular drugs. If  cause is identifiable then it becomes easy to tackle the issue. Then the offending drug is withdrawn.   However,  if a reaction occurs but its nature does not single out a particular drug, the situation is little more difficult.

Then only the offending drug or drugs is cautious rechallenge.

In rechallenge, all the drugs are withdrawn and one by one they are reintroduced starting with the one least likely to be responsible for the symptoms.

Rechallenge is started with one drug in a small challenge dose, which is increased stepwise to full therapeutic dose over a few days.

This procedure is repeated, with one drug added at a time.

If the reaction recurs, the offending drug has been identified, it must be withdrawn.

Combination tablets are not suitable for this purpose and rechallenge should not be attempted.

Any reaction to thioacetazone, even if it is simple itching, should prompt immediate withdrawal of the drug and rechallenge should not be attempted with this drug.

Treatment may be continued by replacing the offending drug with a suitable alternative, or with a reduced number of drugs if none is suitable.

Specialist advice may be sought. It is also noteworthy that the resumed regimen is considered to be a new start to the treatment. This prolongs the duration of therapy but, on the other hand, reduces the chance of recurrence.

For example

Antitubercular drugs are mainstay of treatment of tuberculosis. The major drugs used and effective are called first line drugs. Following are the first line drugs in tuberculosis

• Isoniazid
• Rifampin
• Pyrazinamide
• Ethambutol
• Streptomycin

These five drugs are responsible for control and containment of tubercular disease, among other factors.

The drugs are given on basis of patient weight and dosage may vary in different individuals. The dosage also differ depending on the regimen given. There are three regimen that traditionally have been used for treatment

• 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

Note

• Doses based on weight must be adjusted as the patient’s weight changes
• Pyrazinamide and streptomycin should not be used to treat pregnant women.
• Ethambutol is not recommended for children who are too young to be monitored for changes in their vision.
• Daily dose of streptomycin should not exceed 0.75 g for patients over 50 years of age.

The World Health Organization does not recommend twice weekly regimens because of the greater risk of treatment failure from missed doses.

Toxicity of Antitubercular Drugs

Most antitubercular drugs, particularly pyrazinamide, rifampicin, and isoniazid, can cause hepatotoxicity, while ethambutol isseldom responsible. If a patient  develops hepatitis, and no other cause is likely, drug-induced hepatitis must be presumed and the drugs stopped.

Once the hepatitis has resolved, the same regimen may be cautiously reintroduced. If the hepatitis has been severe, then it is probably safer to avoid pyrazinamide, and possibly also rifampicin, altogether.

An alternative regimen in such patients can be a 2-month initial phase of daily isoniazid, ethambutol and streptomycin followed by a 10-month continuation phase of isoniazid plus ethambutol.

A severely ill tuberculosis patient with drug-induced hepatitis may die without antiTB treatment. In this case the patient may be treated with the two least hepatotoxic drugs, namely streptomycin and ethambutol instead of interrupting TB treatment. Isoniazid may be cautiously reintroduced after the hepatitis has resolved.

Duration of chemotherapy In Osteoarticular Tuberculosis

Duration of chemotherapy in tuberculosis is a controversial issue.  This is an area where there is no consensus. According to World Health Organization, the spinal tuberculosis is a severe form of extrapulmonary tuberculosis and is  assigned to CategoryI. All other cases are placed in category II.

Therefore, by WHO criteria, all caries spine cases should be treated for a minimum of 6 months and others for 5 months. However, many surgeons in India [where the disease in endemic] prefer to continue treatment till there is adequate radiological evidence of healing, which can take much longer than 6 months. The practiced range of duration is 1-1.5 years.

However  in a systematic review of chemotherapeutic treatment for spinal TB, it was concluded that 6 months of therapy is probably sufficient for the majority of patients.

The United States Centers for Disease Control recommends that for infants and children with miliary tuberculosis or bone and joint TB treatment should last at least 12 months. For adults with these forms of extrapulmonary TB, the patient’s response to therapy should be monitored closely. If response is slow or inadequate, treatment may be prolonged on a case-by-case basis.  Treatment would probably be needed to be prolonged in immunocompromised subject and in the absence of surgical debridement.