Tuberculosis

Tuberculosis

TB is a disease caused by bacteria called Mycobacterium tuberculosis M.bovis. The bacteria usually attack the lungs, but they can also damage other parts of the body.

Usually TB results from inhaling airborne particles that contain M. tuberculosis. These particles, called droplet nuclei, contain one to here bacilli and are small enough (1 to 5 mm) to reach the alveolar surface. Inoculation (puncture wound) and Ingestion (swallowing) are other rare pathways to acquire M. tuberculosis infection.

Mode of transmission: TB spreads through the air when a person with TB of the lungs or throat coughs, sneezes, or talks.

Symptoms: Coughing up blood or mucus, Fever, Loss of appetite, Night sweats, Weight loss, Weakness or fatigue.

Pathophysiology: M. tuberculosis can inhibit the fusion of lysosomes to phagosomes inside the macrophages. This prevents the destructive enzymes found in the lysosomes from getting to the bacilli captured in the phagosomes. This stay of execution allows time for M. tuberculosis to escape into the cytoplasm. M. tuberculosis has several ways of evading or resisting the host immune response.

Diagnosis: Skin tests, blood tests, x-rays.

Vaccination:

Bacilli Calmette-Guerin Vaccine: The BCG vaccine is an attenuated, hybridized strain of M. bovis and is used as a prophylactic vaccine against TB. Vaccination with BCG produces a subclinical infection resulting in sensitization of T lymphocytes and cross-immunity to M. tuberculosis, as well as cutaneous hypersensitivity and in many cases, a positive tuberculin skin test.

Adverse effects: Severe or prolonged ulceration at the vaccination site, lymphadenitis, and lupus vulgaris.

Treatment:

First line therapy for Tuberculosis:

Isoniazid: It is one of the two most important TB drugs. The most common mechanisms of resistance result from mutations in the katG or inhA genes. It is highly specific for mycobacterium, with a MIC against M. tuberculosis of 0.01 to 0.25 mcg/mL. Most non-tuberculous mycobacterium such as M. avium is resistant to Isoniazid.

Isoniazid is readily absorbed from the GI tract and from intramuscular injection sites. Isoniazid should be given on an empty stomach whenever possible.

Adverse effects: Hepatotoxicity, Neurotoxicity.

Rifampin: Rifampin shows bactericidal activity against M. tuberculosis and several other mycobacterial species, including M. bovis and M. kansasii. The drug resistance to rifampin is a prognostic factor because it is frequently associated with Isoniazid resistance and leaves the patient with few good therapeutic options. Rifampin also is active against a broad array of other bacteria. Alteration of the target site on RNA polymerase, primarily through changes in the rpoB gene, leads to most forms of rifampin resistance. It is usually given orally, on an empty stomach, but it also can be given as an intravenous infusion (30- minute).

Adverse effects: rash, fever, and gastrointestinal distress.

Rifabutin: Most rifampin-resistant organisms are resistant to rifabutin. Because rifabutin is a less-potent enzyme inducer than rifampin, it may be used in patients who are receiving protease inhibitors. This drug is used for the disseminated M. avium infection in AIDS patients and is quite active against M. tuberculosis.

Rifapentine: Rifapentine is approximately 85% as potent an enzyme inducer as rifampin, It is a long-acting rifamycin that can be used once weekly in the continuation phase of treatment (after the first 2 months) in carefully selected HIV-negative patients.

Pyrazinamide: Adding the pyrazinamide to the first 2 months of treatment with Isoniazid and rifampin shortens the duration to 6 months for most patients. It is usually well absorbed and displays a fairly long half-life.

Toxicities: Arthralgias, gastrointestinal distress, hepatotoxicity, gout and elevations in the serum uric acid concentrations.

Ethambutol: Ethambutol is used as a fourth drug for TB while awaiting susceptibility data. If the organism is susceptible to Isoniazid, rifampin, and pyrazinamide, Ethambutol can be stopped. Ethambutol is active against most mycobacteria, including M. tuberculosis and M. avium, but it is generally bacteriostatic.

Contraindication: Ethambutol should not be given with antacids.

Adverse effect:  Retro bulbar neuritis

Second-Line therapy for tuberculosis:

Cycloserine: It is only used to treat MDR-TB. It is well absorbed orally taken on an empty stomach.

Adverse effects: CNS toxicity including lethargy, confusion, seizures.

Streptomycin: Streptomycin is one of three amino glycoside antibiotics (along with amikacin-kanamycin) that are active against mycobacteria. Streptomycin is quite active against MAC and several other mycobacteria, enterococci, Brucella, Yersinia, and various other bacteria.

Adverse effects:  Occasionally causes nephrotoxicity, ototoxicity.

Para-Amino salicylic Acid: It is a synthetic compound which is less potent than INH or streptomycin.

 Adverse effects: Gastrointestinal disturbances

Ethionamide: Ethionamide is active only against organisms of the genus Mycobacterium, and it should be considered primarily bacteriostatic because it is difficult to achieve serum concentrations that would be bactericidal.

Adverse effect: Gastrointestinal toxicity, menorrhagia, gynecomastia, alopecia, photo dermatitis and acne.

Clofazimine: Clofazimine is a drug with good activity against Mycobacterium leprae and weak activity against M. tuberculosis and M. avium.

Adverse reactions:  Gastrointestinal distress and skin discoloration.

Thiacetazone: It is a weak agent used rarely in parts of the developing world because of its low cost. Thiacetazone must be discontinued permanently as soon as a rash appears.

Adverse effects: Rash and Stevens-Johnson’s syndrome.

Quinolones: Quinolones are useful because most are available in oral and intravenous dosage forms, so they can be used in critically ill patients. Levofloxacin, moxifloxacin and ciprofloxacin are used sometimes to treat MDR-TB.

β-Lactam and β-Lactamase Inhibitor Combinations: Combinations of β-Lactam with β-lactamase inhibitors have been used in salvage regimens for TB patients with no other options, but are not used routinely to treat TB. The β-lactams have limited activity against mycobacteria because of β-lactamases and because β-lactams fail to enter macrophages. Cefoxitin, a β-lactamase–stable cephalosporin, has useful activity against rapidly growing mycobacteria, such as M. fortuitum and Mycobacterium chelonae.

Macrolides/Azalides: The macrolide, clarithromycin and azalide, azithromycin represent substantial advances in the treatment of MAC but demonstrate limited activity against M. tuberculosis and are not used frequently for TB.

Tb, bcg, isoniazid, ethambutol