Anti-tubercular Drugs Tuberculosis
Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis (MTB). Tuberculosis generally affects the lungs, but can also affect other parts of the body. It is spread through the air when people who have an active TB infection cough, sneeze, or otherwise transmit respiratory fluids through the air.
Symptoms
Most infections do not have symptoms, known as latent tuberculosis. About 10% of latent infections progress to active disease which, if left untreated, kills about 50% of those infected.
The classic symptoms of active TB are a chronic cough with blood-containing sputum, fever, night sweats, and weight loss (the latter giving rise to the formerly common term consumption). Infection of other organs causes a wide range of symptoms.
Diagnosis
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) [putting a small amount of TB protein (antigens) under the top layer of skin on your inner forearm] and / or blood tests.
Transmission
When people with active pulmonary TB cough, sneeze, speak, sing, or spit, they expel infectious aerosol droplets 0.5 to 5.0 µm in diameter. A single sneeze can release up to 40,000 droplets. Each one of these droplets may transmit the disease, since the infectious dose of tuberculosis is very small (the inhalation of fewer than 10 bacteria may cause an infection).
Transmission should only occur from people with active TB. Those with latent infection are not thought to be contagious.
The probability of transmission from one person to another depends upon several factors-
Number of infectious droplets expelled by the carrier
Effectiveness of ventilation
Duration of exposure
Virulence of the M. tuberculosis strain
Level of immunity in the uninfected person
Antituberculosis drugs:
Antituberculosis drugs are medicines used to treat tuberculosis. The disease can be cured with proper drug therapy, but because the bacteria may become resistant to any single drug, combinations of antituberculosis drugs are used to treat tuberculosis (TB) are normally required for effective treatment.
Antituberculosis drugs are available only with a physician's prescription. Some commonly used antituberculosis drugs are-
First line drugs
1. Isoniazid (INH) 2. Ethambutol (EMB) 3. Pyrazinamide (PZA)
4. Rifampin (RMP) or other rifamycin 5. Streptomycin (SM)
Tuberculosis is treatable with a six-month course of antibiotics. A combination of antibiotics containing isoniazid, rifampicin, pyrazinamide, and either ethambutol or streptomycin should be used for the first two months, and only isoniazid and rifampicin for the last four months. Where resistance to isoniazid is high, ethambutol may be added for the last four months as an alternative.
1. Isoniazid
Isoniazid is the first-line medication in prevention and treatment of tuberculosis.
Mechanism of action:
Isoniazide inhibits the synthesis of mycolic acids, which are essential component of the mycobacterial cell walls.Isoniazid is a prodrug and must be activated by a bacterial (M. tuberculosis) catalase- peroxidase enzyme (KatG).
The activated form of isoniazid forms a covalent complex with an acyl carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein synthetase, which blocks mycolic acid synthesis and kill the cell.
Isoniazid is bactericidal to rapidly dividing mycobacteria, but is bacteriostatic if the mycobacteria are slow growing.
Adverse reactions:
The incidence and severity of untoward reactions to isoniazid are related to dosage and duration of administration.
2. Rifampicin
Rifampicin was introduced in 1967, as a major addition to the cocktail-drug treatment of tuberculosis, along with pyrazinamide, isoniazid, ethambutol, and streptomycin. It must be administered regularly daily for several months without break; otherwise, the risk of drug-resistant tuberculosis is greatly increased.
Mechanism of action
Rifampicin binds to the β subunit of bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis.
3. Ethambutol
Ethambutol (commonly abbreviated EMB or simply E) is a bacteriostatic antimycobacterial drug prescribed to treat tuberculosis. It is usually given in combination with other tuberculosis drugs.
4. Pyrazinamide
Pyrazinamide is used in the first two months of treatment to reduce the duration of treatment required. Regimens not containing pyrazinamide must be taken for nine months or more.
Pyrazinamide in conjunction with rifampin is a preferred treatment for latent tuberculosis.
5. Streptomycin
Streptomycin is a bactericidal antibiotic. Adverse effects of this medicine are ototoxicity, nephrotoxicity, fetal auditory toxicity, and neuromuscular paralysis.
Second line drugs
The second line drugs are only used to treat disease that is resistant to first line therapy (i.e., for extensively drug-resistant tuberculosis (XDR-TB) or multidrug-resistant tuberculosis (MDR-TB)).
A drug may be classed as second-line instead of first-line for one of three possible reasons:
Less effective than the first-line drugs (e.g., p-aminosalicylic acid); or,
Toxic side-effects (e.g., cycloserine); or
Effective, but unavailable in many developing countries (e.g., fluoroquinolones)
Aminoglycosides: e.g., amikacin, kanamycin
Polypeptides: e.g., capreomycin, viomycin, enviomycin;
Fluoroquinolones: e.g., ciprofloxacin, levofloxacin, moxifloxacin
Thioamides: e.g. ethionamide, prothionamide
Cycloserine Third line drugs
Third-line drugs include drugs that may be useful, but have doubtful or unproven efficacy:
Rifabutin
Macrolides: e.g., clarithromycin
Linezolid
Thioacetazone
Thioridazine
These drugs are listed here either because they are not very effective (e.g., clarithromycin) or because their efficacy has not been proven (e.g., linezolid). Rifabutin is effective, but is not included on the WHO list because for most developing countries, it is impractically expensive.
Why Tuberculosis Is So Hard to Cure
When microbes divide a cell splits up and creates two identical copies of itself. Mycobacteria divide asymmetrically, generating a population of cells that grow at different rates, have different sizes, and differ in how susceptible they are to antibiotics, increasing the chances that at least some will
survive.
TB gets swallowed up but then interferes with the killing process of the macrophage and escapes .In a normal macrophage, the bacteria are swallowed up into a vesicle called a phagosome. The pH of the phagosome drops and the interior gets more acidic and secondly the phagosome fuses with another vesicle called a lysosome. The lysosome contains lots of enzymes that help to destroy and degrade pathogens. The bacterium prevents the phagosome from being converted to a lysosome.
After M. avium is engulfed by the macrophage, it avoids getting degraded and hides in a separate compartment inside the macrophage, a vesicle, where it is no longer recognized and thrive.
The TB bacterium actively slows, and maybe stops, the acidification of the phagosome and it also blocks the fusion of the phagosome and the lysosome. It then escapes the relatively comfortable phagosome into the main body of the macrophage
Eventually, the immune system walls off this site with fibrous tissue and a granuloma forms. It is these which you see as spots on a lung X-ray.
It’s pretty difficult to target drugs into these granulomata. They're walled off pretty tightly from the rest of the lung and, if you can get drugs into them the bugs are often inside the macrophages inside the granuloma.
Another factor is the very slow growth rate of TB. Most bacteria will grow and show visible colonies overnight in a lab. TB can take weeks and weeks to grow to visible colonies.
Mycobacterium tuberculosis is an obligate aerobe mycobacterium, which is neither gram positive or negative. It is an acid fast bacillus meaning that it is resistant to decolorization by acid during staining processes. This characteristic makes it difficult to characterize using standard gram staining.
It is a slow dividing bacterium, usually dividing every 16 to 20 hours.
Mycobacterium leprae is a bacterium that causes leprosy, also known as "Hansen’s
disease", which is a chronic infectious disease that damages the peripheral nerves and targets the skin, eyes, nose, and muscles.
It was discovered in 1873 by the Norwegian physician Gerhard Armauer Hansen. It was the first bacterium to be identified as causing disease in humans.
Symptoms of leprosy:
• the appearance of skin lesions that are lighter than normal skin and remain for weeks or months
• patches of skin with decreased sensation, such as touch, pain, and heat
• muscle weakness
• numbness in the hands, feet, legs, and arms, known as "glove and stocking anesthesia"
• enlarged nerves, especially in the elbows or knees
• stuffy nose and nosebleeds
• curling of the fingers and thumb, caused by paralysis of small muscles in the hand ulcers on the soles of the feet.
Drugs for leprosy:
