Drug Treatment of Tuberculosis

Tuberculosis is a chronic disease caused by mycobacteria, which are acid fast bacilli, once stained by basic dyes, cannot be decolourized by alcohol. Acid fast character is due to the presence of mycolic acids in cell wall. It gives integrity to cell wall and makes it resistant against antibiotics. Mycobacteria are of two types:
a.      Typical Mycobacteria

1. M tuberculosis
2. M bovis
3. M leprae

b.      Atypical  Mycobacteria

These bacteria are less pathogenic but more resistant to common anti-tuberculosis drugs.

1. M kansasii
2. M marinum
3. M scrofulaceum
4. M avium complex
5. M chelonae
6. M fortuitum
7. M ulcerans

Treatment of Tuberculosis

There are three main principles of treatment of tuberculosis:

1. Rest
2. Prolonged chemotherapy
3. Follow up

In treatment of tuberculosis, we give a combination of drugs. Treatment is started with two or more drugs. The reason for combination is that if bacteria become resistant against one drug, others can still act. Treatment is started with three or four drugs and continued with two drugs.

There are two main difficulties:

1. Patient compliance –as drugs have to be taken for prolonged duration
2. Chances of toxicity

The main drugs are:

First line drugs (mainly used, treatment is started with these)

• Isoniazid
• Rifampicin
• Pyrazinamide
• Ethambutol
• Streptomycin

Second line drugs (only in cases resistant to 1^st line)

• Amikacin, thiacetazone
• Para amino salicylate
• Ethionamide
• Ciprofloxacin/ofloxacin
• Rifabutin
• Clarithromycin
• Cycloserine
• Capreomycin

Drugs for atypical mycobacteria

• Erythromycin
• Clarithromycin
• Azithromycin
• Rifampicin
• Quinolones
• Rifabutin

Isoniazid

Chemically drug is hydrazide of isonicotinic acid.

Anti-bacterial Spectrum:

Has a narrow spectrum. Effective only against mycobacterium tuberculosis. Also  has some effects against atypical mycobacteria.

Mechanism of action of isoniazid

Drug enters the bacterial cells by active transport mechanism and is bactericidal for rapidly dividing cells and bacteriostatic for resting or dormant bacterial cells.

Drug is a prodrug and in bacterial cells is converted to active compound by enzyme catalase peroxidase. This active form acts by:

1. Inhibition of mycolic acid synthetase responsible for synthesis of mycolic acid in cell wall, resulting in damage to cell wall and increase in permeability, leading to entry of water and death of bacterial cell.
2. Inhibition of nucleic acid synthesis in bacteria
3. Inhibition of lipid synthesis
4. Inhibition of glycolysis

Mechanism of resistance

Develops by various mechanisms:

1. Mutation/deletion of catalase peroxidase (katg) responsible for converting the drug to active form
2. Mutations in various transporters in bacterial cell
3. Mutation of acyl carrier proteins
4. Over expression of NADH dependent acyl carrier protein reductase (INHA) enzyme

Pharmacokinetics

Well absorbed after oral administration. Peak plasma concentration occurs after 2-4 hours. After absorption drug is easily distributed to all body compartments.

It can penetrate macrophages, caseous material, can easily penetrate into CNS. It distributes well in all body compartments including CNS and caseous material in lungs.

Metabolized by acetylation. There are genetically two kinds of people:

1. Slow acetylators –half life in these is 4 hours
2. Fast/rapid acetylators –half life in these is 1 hour

Most of the drug and metabolites are excreted in urine.

Uses of isoniazid

Reserved for the treatment of tuberculosis, used in various forms of tuberculosis.

1. Active tuberculosis
2. Tuberculin positive converters of close contact with active cases (prophylactically)
3. Tuberculin positive cases on immuno suppressive or antineoplastic chemotherapy (prophylactically)

Dose: 300mg/day

Advantages of isoniazid

1. Highly selective against mycobacteria
2. Bactericidal action
3. Cost- effective/easily available
4. Orally administered
5. Well absorbed
6. Widely distributed in body tissues/ fluids
7. Enters macrophages
8. Penetrates caseous material
9. Crosses blood brain barrier
10.  Once daily administration
11.  Well tolerated

Adverse effects – isoniazid

1. Peripheral neuropathy

Most important adverse effect. Manifested in the form of:

1. Numbness
2. Change in sensations of touch, temperature, pain
3. May affect motor functions
4. Weakness of muscles
5. Mainly affects sensations

Occurs mainly due to decreased/deficiency of vitamin B6 or pyridoxine.

The main thing is that it interferes with the metabolism of pyridoxine. It also causes increased excretion of this vitamin.

Person routinely taking isoniazid is given tablets of pyridoxine in dose of 10 mg daily to avoid peripheral neuropathy.

2. Hepatotoxicity

Occurs especially in elderly and patients who are alcoholic.

3. Hypersensitivity reactions

• Skin rashes
• Articaria
• Maculopapular rash
• Leukopoenia
• Thrombocytopenia
• Hemolytic anemia esp. in patients with G6PD deficiency

4. Hematological reactions

5. Vasculitis

Rare but may occur especially when given parentally.

6. Arthralagia

In joints pain especially in knee, elbow, wrist and joint of fingers.

7. Mental disturbances (CNS toxicity)

• Headache
• drowsiness

8. GIT upsets
9. Methaemoglobinaemia
10. Incordination
11. SLE like syndrome –although rare but may occur

Drug Interactions

1. May cause inhibition of microsomal enzymes especially those of hydroxylation so increased levels are observed of:
   1. Phenytoin
   2. Carbamazepines (anti-epileptics)
   3. Also cause CNS stimulation when given in combination with monoamine inhibitors.

Rifampicin

Very important drug in the treatment of tuberculosis, belonging to the rifamycin group of antibiotics. It is obtained from Streptomyces species. Mainly rifamycin B is modified to obtain rifampicin.

Mechanism of action

Drug mainly acts by inhibiting DNA dependent RNA polymerase enzyme in bacteria. This enzyme is mainly responsible for formation of mRNA. When inhibited  no or less formation of mRNA occurs, resulting in decreased formation of proteins. The important fact is that this bactericidal action differs from other drugs which inhibit protein synthesis, as most of them are bacteriostatic drugs. Here it is bactericidal, as it acts on transcription level.

Resistance

Mainly occurs:

1. Due to mutation in DNA dependent RNA polymerase  enzyme, which has less affinity for drug
2. There is decreased entry of drug into bacteria.

Spectrum Of Activity – Rifampicin

Has wide antibacterial spectrum. In addition to mycobacteria affects various gram positive and negative bacteria:

1. M. tuberculosis
2. M. leprae
3. Atypical mycobacteria
4. Gram negative microorganism e.g. E.coli, pseudomonas, Proteus, Klebsiella, Brucella, H.Influenzae, N.meningitidis
5. Staphylocci
6. Meningococci
7. Legionella
8. Chlamydia
9. Anti viral activity (pox virus)

Pharmacokinetics

Well absorbed after oral administration. Peak plasma concentration occurs after 2 hours. Drug is easily distributed to all body compartments including CNS.

It is mainly metabolized in liver by deacetylation, drug also undergoes enterohepatic circulation.

Most of the drug is excreted in feces through bile.

Half life is about 3 to 5 hours. On prolonged use it is decreased even up to 2 hours as is enzyme inducer.

Therapeutic uses of Rifampicin

1. Tuberculosis (in combination with other tuberculosis drugs)
2. Leprosy
3. Atypical mycobacterial infections
4. Chemoprophylaxis for meningococcal disease and meningitis due to H. influenzae
5. Staph. endocarditis or osteomyelitis
6. Eradication of staph. nasal carrier state in chronic furunculosis
7. Brucellosis –in combination with doxycycline
8. Legionnaire’s disease –in combination with ciprofloxacin and quinolones

Dose: 450 – 600mg/d or 10-20mg/kg

Adverse effects – rifampicin

1. Hepatotoxicity –as metabolized in liver and excreted in bile
2. Thrombocytopenia
3. Cutaneous reactions -articaria
4. Discoloration of secretions especially orange colour of urine, sputum, various body secretions. It is harmless, actually indicates that patient is taking the medicine.

On intermittent dosing –immediately after administration of drug due to immunity and immunological basis:

1. Flu – like syndrome –chills, fever, malaise, myalgia, joint pain
2. Acute hemolytic anemia
3. Acute renal failure

Drug Interactions

Drug is enzyme inducer and can increase the metabolism of various drugs.

Rifabutin

Differs from rifampicin in that although mechanism of action and chemistry is same as rifampicin, but differs in:

1. Longer half life of 36 hrs.
2. Less drug interactions
3. In adverse effects differs in that when given in high doses, in combination with other drugs, enzyme inhibition may cause toxicity especially reversible uveitis.

Mainly used in resistant cases of tuberculosis in combination with other drugs, can also be used in prophylaxis of tuberculosis in close contacts.

Dose: 300mg OD

When given with enzyme inhibitors like HIV Protease Inhibitors including Indinavir & Ritonavir, and non nucleoside reverse transcriptase inhibitors, dose is reduced to half (150 mg).

Rifapentin

• Half life 13 hrs.
• Potent enzyme inducer
• Active metabolite is desacetyl rifapentin

Dose: 600 mg once or twice weekly

Pyrazinamide

Derivative of nicotinamide.

Mechanism of action

Drug is very effective against mycobacteria, residing in cells and dormant. It is more active in acidic medium of cells.

More effective inside cell (acidic medium), it is a pro drug converted into cell to active metabolite pyrazinoic acid by enzyme pyrazinamidase.

Bactericidal –Kill persisters

Pharmacokinetics

Well absorbed after oral administration. Distributes to all body compartments well. It crosses blood brain barrier and attains a high concentration in CSF.

Drug is always used in combination with other drugs for tuberculosis and meningitis.

It is metabolized in liver and half life is 9 hours.

Uses

1. Treatment of tuberculosis in combination with other drugs specifically mycobacterium tuberculosis.
2. Has little activity against mycobacterium bovis.

Dose:20-30mg/kg or 1.5 -2.5g/day upto 3gm

Adverse effects

1. Arthralgia –active metabolite pyrazinoic acid is responsible for hyperuricemia as decreases the secretion of uric acid.
2. Hepatitis –in high doses
3. GIT upsets
4. Hemolytic anemia
5. Allergy
6. Dysuria
7. Sideroplastic anaemia

Ethambutol

• L isomer – toxic
• D isomer – active (mainly used in therapeutics)
• b isomer – no antibacterial activity

Mechanism of Action

Drug is rapidly uptaken by cells. Resistance develops when decreased uptake of drug occurs by bacterial cells. It:

1. Inhibits incorporation of mycolic acid in bacterial cell wall
2. Inhibits RNA synthesis
3. Inhibits mycobacterial arabinoglycan synthesis in cell wall

Pharmacokinetics

• Well absorbed after oral administration. Peak plasma concentration occurs after 2-4 hours.
• Drug attains high concentration in lungs.
• It also enters CSF when meninges are inflamed, thus can be used for tuberculosis meningitis.
• Two thirds of the drug are excreted unchanged in urine, rest is metabolized in the liver.
• Half life is about 4 hours.

Uses

Mainly used for treatment of tuberculosis in combination with other drugs.

Adverse Effects

Mainly when given in high doses:

1. Ocular effects

• Retrobulbar neuritis
• Red green colour blindness

Although incidence is rare (2%) but can lead to blindness if continued.

2. Increase plasma uric acid
3. GIT effects
4. CNS –drowsiness, confusion

Dose: 15mg/kg to 25mg/kg

Streptomycin

Aminoglycoside used in combination with other anti-tuberculosis drugs.

Second line drugs

In second line drugs, Amikacin belongs to aminoglycosides. Thiacetazone is a toxic drug having low therapeutic index, which is very cost-effective. It is used as a second line drug in treatment of tuberculosis. Half life is 13 hours. Main adverse effects are:

1. GIT upsets
2. CNS problems
3. Arthritis
4. Blood dyscrasias –leukopoenia, hemolytic anemia

Para amino Salicylate (PAS)

Chemically it resembles PABA (sulfonamides).

Mechanism of action is same as sulfonamides.

Acts by inhibiting synthesis of folic acid, folic acid synthetase in inhibited. Drug is bacteriostatic.

Pharmacokinetics

Well absorbed after oral administration. Always given with food. Drug distributes in all body compartments except CSF. It cannot cross BBB.

Metabolized by acetylation. Half life is one hour.

Drug is mainly used as a second line drug in treatment of tuberculosis.

Dose: High 10-20 grams

Adverse effects

1. Drug mainly causes GIT upsets
2. Allergic reactions –articaria

3. Blood dyscrasias

• Leukopoenia
• Thrombocytopenia
• Hemolytic anemia in G6PD deficiency

4. Hypothyroidism when used for prolonged period.

Ethionamide

Chemically resembles isoniazid.

Mechanism of action

Mechanism of action is same, it interferes with synthesis of cell wall.

Half life is about 2-4 hours. It is a very toxic drug and is mainly reserved for resistant cases of tuberculosis.

Adverse effects

1. GIT problems
2. Allergic reactions
3. Blood dyscrasias

Dose is 250 mg twice daily, which may be increased to 1 g daily.

Ciprofloxacin

Quinolones

Clarithromycin

Macrolides. 2^nd line drug

Cycloserine

Obtained from Streptomyces. Chemically drug resembles d-alanine (cell wall synthesis, peptidoglycan synthesis)

Mechanism of action

Same as that of penicillins. Interferes with synthesis of peptidoglycan.

When given orally, well absorbed. About 35% of drug is metabolized, rest is excreted unchanged in urine.

Adverse effects

Main are on:

1. CNS –neurotoxic effect, as drug crosses BBB.
2. Headache
3. Drowsiness
4. Dizziness
5. Convulsions

Dose 15-20 mg/kg body weight.

Capreomycin

Resembles aminoglycosides.

Mechanism of action –same as that of aminoglycosides

Adverse effects –same. May cause:

1. Ototoxicity
2. Nephrotoxicity –main effect

Steroids in Tuberculosis

• Massive pleural effusion
• Pericardial effusion
• Tuberculous meningitis
• Miliary tuberculosis with involvement of adrenal cortex

Regimens Of Antituberculosis Drugs

There are two main phases:

1. Start with 3 or 4 drugs, called induction phase
2. Continued with 2 or more drugs known as continuation phase.

New Cases

Patients who have not received treatment for T.B previously

Patients who have taken the treatment for less than 4 weeks

Initial Intensive Phase -For 02 months

• Isoniazid
• Rifampicin
• Pyrazinamide
• Ethambutol

Continuation Phase -For 06 months

• Isoniazid
• Ethambutol

In continuation phase, rifampicin is not used with isoniazid, because patient may develop resistance to isoniazid, making the therapy monotherapy. Thus resistance against rifampicin may also develop.

In Western countries, Rifampicin is preferred in continuation phase, with which duration of treatment is reduced to 7 months.

Re- Treatment Cases

In cases of relapse, after 1 to 2 months if symptoms  disappear and patient stops taking drugs, there is re-emergence of tuberculosis, which is difficult to treat, resulting in treatment failure.

Now the treatment is started with five drugs.

Intensive Phase -For three months

• Rifampicin
• Isoniazid
• Pyrazinamide
• Ethambutol
• Streptomycin -For first two months

Continuation Phase -For five months

• Rifampicin
• Isoniazid
• Ethambutol

Intermittent Regimens –given twice weekly

• Streptomycin 1g
• Isoniazid 15 mg/kg
• Ethambutol 50 mg/kg

Multiple Drug Resistant Tuberculosis (MDR-T.B)

If patient is resistant to INH and rifampicin after about 5 months treatment, still acute tuberculosis bacilli is present in sputum, the patient is labeled multiple drug resistant.

Treatment is the use of second line drugs.

DOT (Directly observed therapy)

Patient takes medicine in clinic or undergoes supervised treatment in hospital. Patient may be called twice or thrice weekly and given anti–tuberculosis drug in front of the doctor or medical personelles. This is because the main problem is compliance of the patient.