Antituberculosis Flashcards
TB Stats
Tuberculosis (TB) is second only to HIV/AIDS as the greatest killer worldwide due to a single infectious agent. In 2013, 9 million people fell ill with TB and 1.5 million died from TB.
Over 95% of TB deaths occur in low- and middle-income countries.
In 2009, there were about 10 million orphan children as a result of TB deaths among parents.
TB is a leading killer of people with HIV causing 25% of all deaths.
Multi-drug resistant TB (MDR-TB) is present in virtually all countries surveyed. MDR cases tripled between 2009-13 The estimated number of people falling ill with tuberculosis each year is declining. The TB death rate dropped 45% between 1990 and 2014.
Characteristics of the Disease
- Airborne pathogen
- Most infected individuals never develop symptoms
- Symptoms of active lung TB include cough with sputum and blood at times, chest pains, weakness, weight loss, fever and night sweats
- Disease can shift from inactive to active state without warning (~60% mortality rate for untreated active disease)
- Positive skin test demonstrates exposure; disease confirmed by chest X-ray
- Young adults are primarily targeted by TB
- It is estimated that one-third of the world population has latent (inactive) TB!
- Even if someone doesnt have symptoms but has the bug, you ideally want to teat before they have the chance to spread it. Initial symptoms can mimic those of normal respiratory infections but fail to subside.
Immune response to TB
The body is able to mount an immune response to the organism, but the mycobacteria species that
cause TB are able to fight back and will encase themselves into the lungs so that the antibodies and
immune cells cannot get in. Theyll basically sit there and grow very slowly. Mycobacteria generally grow
very slowly but constantly, and can eventually destroy the ability of the lungs to function. Young adults tend to be
targeted by TB for some reason.
Antimicrobials Used to Treat TB
- First line therapy: Isoniazid, Rifampacin, Pyrazinamide and Ehambutol. These are antimicrobials and generally you want to combine at least two of these for the treatment. A signle agent alone generally is not sufficientto completely cure the patient and eliminate the bacteria.
- Second line therapy (used for treating multi-drug resistant TB): An individual is resistant to multiple first line agents. In this case, a combination of at least two of these: Capreomycin, cycloserine, and
streptomycin.
Why is TB so prevalent in 3rd world countries
In third world countries, the screening and drugs may not be available to detect and effectively
treat tuberculosis. Individuals who have a good diet, general health care, and good hygiene, may not ever
develop symptoms even if they have the bug. Crowded regions often allow for quick spread.
TB cell wall
Tuberculosis bacteria have a very different type of cell wall (mycolic acid) compared to other
types of bacteria. Makes them acid fast. They are technically gram positive, but they dont have
the cell wall structure characteristic of a true gramp positive organism.
Isoniazid
Prodrug-activated by M. tuberculosis KatG (enzyme that has catalase
and peroxidase activity). Derivative of hydrazine (rocket fuel). Active drug
blocks enoyl-acyl carrier protein reductase which prevents mycolic acid
synthesis.
Acid fast carbol-fusion.
Bacteriocidal to rapiddly growing bacteria, bacteriostatic to slow/ non
growing bacteria.
Good oral bioavailability; penetrates caseous lesions in the lungs.
Slow acetylators show best response (part of a phase II reaction).
Inhibits P450 isozymes which is affected by oral contraceptives and
anti-epileptic drugs.
Use in prophylactic treatment of inactive TB.
Isoniazid is a weak inhibitor of MAO. MAO breaks down dopamine,
norepinephrine, and serotonin.
Adverse effects: hepatic toxicity, peripheral neuropathy, and drug allergy.
TB resistance
Some tuberculosis strains are completely resistant to all first line drugs. Since
tuberculosis organisms are very slow growing, the drugs need to be given
for a period of weeks to months, which gives plenty of opportunity to select
for resistant strains.
Rifampacin (Rifampin)
Inhibits bacterial RNA polymerase; bacteriocidal.
Semisynthetic derivative of compound isolated from streptomyces.
Orally administered.
Potent P450 inducer (increases metabolism of Warfarin, glucocorticoids,
estrogen-based control pills). Has to opposite effect of isoniazid.
Few side effects. Very rare but sometimes fatal liver damage.
Resistance develops readily. If youre experiencing a problem with drug-P450 interactions, its sometimes
possible to balance out the effects by giving a good mixture of isoniazid and
rifampacin. By inducing certain isozymes with rifampacin, you can compensate
for the fact that isoniazid will inhibit the P450 isozymes. Derived from biological organism (not chemically synthesized because
its too complicated. The original compound had a slightly different structure,
so it is semi-synthetic in that part of it is modified.
Ethambutol
Synthetic compound; activity discovered through large scale
screening.
Bacteriostatic. Shown in vitro to inhibit activity of arabinose transferase,
required for mycobacterial cell wall synthesis. Does not affect the cell wall
so seriously that it will be susceptible to environmental changes, so its
not bacteriocidal. Not a drug you want to give by itself, when treating
a patient, you usually will give multiple drugs. Not because they
are not effective, but mroeso to try to reduce the appearance of
multidrug resistance or drug resistance period.
Oral administration.
Unusual side effect: temporary red-green color blindness progressing
to loss of vision. If it shows up, switch to another drug before you go
blind!
What affects arabinoglycan synthesis?
arabinoglycan synthesis is affected by ethambutol.
Pyrazinamide
Nicotinamide analog.
Prodrug: converted to active form, pyrazoic acid by pyrazinamidase (found
only in mycobacteria which makes it selective).
MOA is unclear. In vitro studies show that it inhibits mycobacterial
fatty acid synthase I.
Bacteriostatic at acid pH; targets mycobacteria in phagosomes.
Oral administration.
Shortens tuberculosis treatment by several months.
Useful in treating tuberculosis meningitis.
Adverse effects: hepatotoxicity and gout. Not that effective on its own, but when combined with others
it can significantly shorten the duration of treatment.
How does pyrazinamide cross the membrane?
Mycobacteria often get engulfed by phagocytic cells. The initial endosome gets fused with a phagosome
with a low pH to degrade whatever gets engulfed. During this fusion, the drug goes into a noncharged state and
can cross the membrane, after which it can be charged again to be effective.
