Antituberculosis agents

TUBERCULOSIS (TB)

The classic symptoms of active TB infection are:

a chronic cough with blood-tinged sputum,

fever, chills,

night sweats,

loss of appetite, weight loss, fatigue.

Diagnosis of active TB relies on radiology (commonly chest X-rays), as well as microscopic examination and microbiological culture of body fluids.

Diagnosis of latent TB relies on the tuberculin skin test (TST) and/or blood tests.

Mycobacterial cell wall

Baron S (ed.) Medical Microbiology. 4th edition. Chapter 33

Chemotherapy in tuberculosis

• Goals of anti-tubercular chemotherapy

• Kill dividing bacilli: Patient is non-contagious : transmission of TB is interrupted.

• Kill persisting bacilli: To effect cure and prevent relapse.

• Prevent emergence of resistance: so that the bacilli remain susceptible to the drugs.

Antitubercular Agents

First line drugs:

Isoniazid

Rifampicin

Ethambutol

Pyrazinamide

Antitubercular Agents

Second line drugs:

Para aminosalicylic acid (PASA)

Ethionamide

Kanamycin and other amynoglycosides

Cycloserine

Capreomycin

Antitubercular Agents

Newer Second Line drugs:

Fluoroquinolones

Microlides

Isoniazid

◼ Isoniazid is the hydralazide of isonicotinic acid.

◼ It inhibits synthesis of mycolic acids, which are essential components of mycobacterial cell wall.

◼ Effect tuberculocidal.

◼ It acts on extracellular as well as on the intracelular mycobacteria.

Clinical use◼ Used in combination with other antituberculosis

agents in the treatment of pulmonary and extrapulmonary tuberculosis.

◼ Used as a single monotherapy in case of prophylaxis of tuberculosis.

Side effects of Isoniazid

◼ Peripheral neuropathy (occurs frequently )

◼ Hepatitis has been reported in less than 5% of patients.Jaundice have rarely been reported.

◼ Hypersensitivity

◼ Isoniazid-induced lupus-like reactions

◼ Psychosis, depression, and aggression have been rarely reported with isoniazid therapy.

◼ Exacerbations of preexisting schizophrenia.

◼ G.I.T. side effects include nausea, vomiting, and epigastric distress. A few cases of pancreatitis have been reported.

Rifampicin.

Mechanism of action: incorporation into DNA spiral, inhibition of DNA-dependent RNA-polymerase → inhibition of replication and transcription in microorganisms.Spectrum of action: wide, Mycobacterium tuberculosis, leprosy.Bactericidal.Indications: tuberculosis, leprosy, infections caused by multidrug-resistant pathogens.

Rifampicin (side effects)◼ Hepatotoxic - hepatitis, liver failure in severe cases.

◼ Respiratory – breathlessness.

◼ Cutaneous - flushing, pruritus, rash, redness and watering of eyes.

◼ Abdominal - nausea, vomiting, abdominal cramps with or without diarrhea.

◼ Flu-like symptoms - chills, fever, headache.

◼ Arthralgia, and malaise.

◼ Rifampin has good penetration into the brain, this may directly explain some malaise and dysphoria in a minority of users.

◼ Red staining of urine and other body fluids.

Pyrazinamide

◼ Pyrazinamide is derivative of INH like isoniazid. It is more active in acidic medium.

◼ More tuberculocidal to intracellularly located mycobacteria.

◼ Pyrazinamide may be bacteriostatic or bactericidal against Mycobacterium tuberculosis depending on the concentration of the drug attained at the site of infection.

Indications: Pyrazinamide is indicated for the initial treatment of active tuberculosis in adults and children.

It should only be used in conjunction with other effective antituberculous agents.

Pyrazinamide

◼ Side effects:

◼ Hyperuricemia,

◼ acute gouty arthritis,

◼ fever,

◼ loss of appetite, nausea and vomiting,

◼ yellowish discoloration of the skin and eyes.

Ethambutol

◼ An antitubercular agent that inhibits the transfer of mycolic acids into the cell wall of the tubercle bacillus.

◼ It may also inhibit the synthesis of spermidine in mycobacteria.

◼ The action is usually bactericidal, and the drug can penetrate human cell membranes to exert its lethal

effect.

◼ The most commonly recognized toxic effect of ethambutol is optic neuropathy, which generally is considered uncommon and reversible in medical literature.

◼ Other side effects: are pruritus, joint pain, gastrointestinal upset, abdominal pain, malaise, headache, dizziness, mental confusion, disorientation, and possible hallucinations.

Ethambutol

Ethionamide◼ Ethionamide may be bacteriostatic or bactericidal in action,

depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism.

◼ The exact MECHANISM OF ACTION of ETHIONAMIDE has not been fully elucidated, but the drug appears to inhibit peptide synthesis in susceptible organisms.

◼ Antimicrobial spectrum of Ethionamide comprises M.tuberculosis, M. bovis and M. Segmatis.

◼ Ethionamide is structurally similar to methimazole,,has been shown to inhibit thyroid hormone synthesis, and was reported to cause hypothyroidism in several TB patients.

Para-Aminosalicylic Acid

◼ Aminosalicylic acid is an anti-mycobacterial agent used with other anti-tuberculosis drugs (most often isoniazid) for the treatment of all forms of active tuberculosis due to susceptible strains of tubercle bacilli.

◼ There are two mechanisms responsible for aminosalicylic acid's bacteriostatic action against Mycobacterium tuberculosis.

◼ Firstly, aminosalicylic acid inhibits folic acid synthesis. The binding of para-aminobenzoic acid to pteridine synthetase acts as the first step in folic acid synthesis.

◼ As bacteria are unable to use external sources of folic acid, cellgrowth and multiplication slows.

◼ Secondly, aminosalicylic acid may inhibit the synthesis of the cell wall component, mycobactin, thus reducing iron uptake by M. tuberculosis.

Para-Aminosalicylic Acid

◼ The most common side effects: GIT intolerance nausea, vomiting, diarrhea, and abdominal pain.

◼ Hypersensitivity reactions: fever, skin eruptions of various types, exfoliative dermatitis, lymphoma-like syndrome, leucopenia, agranulocytosis, thrombocytopenia, Coombs' positive hemolytic anemia, jaudice, hepatitis, pericarditis, hypoglycemia, optic neuritis, encephalopathy, and vasculitis and a reduction in protrombin.

◼ Crystalluria may be prevented by the maintenance of urine at a neutral or an alkaline pH!!!

Para-Aminosalicylic Acid

CHEMOPROPHYLAXIS

Prevention of active disease from latent inf.

Standard drug is isoniazid daily for 6-12 months.

OR: isoniazid + Rifampin daily for 6 months.

If Isoniazide can not be used: Rifampin (4 months)+

Pyrazinamide (2 months).

OR: Ethambutol + Pyrazinamide +

Fluoroquinolones.