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A 20-year-old man is brought to the emergency department by his fiance with a high-grade fever, headache, confusion, and a diffuse rash that started the night before. His temperature is 40°C (104°F), pulse is 120/min, respirations are 26/min, blood pressure is 100/60 mm Hg, and oxygen saturation is 94% in room air. He is in acute distress, oriented only to himself with a positive Brudzinski's sign and a petechial rash on the trunk and upper extremities. The results of a lumbar puncture show a gram-negative diplococcus. The patient is immediately administered intravenous antibiotics while his fiance was given an oral prophylactic antibiotic. Which of the following is the most likely mechanism of action of the oral prophylaxis?
Content Reviewers:Yifan Xiao, MD
Mycobacteria are an interesting bunch, they’re slender, rod-shaped, and need oxygen to survive, in other words, they’re “strict aerobes.”
They’ve got an unusually waxy cell wall, which is mainly a result of the production of mycolic acid.
This waxy cell wall makes them incredibly hardy, and allows them to resist weak disinfectants and survive on dry surfaces for months at a time.
Antituberculosis medications act mainly by preventing the production of mycolic acid and the synthesis of this cell wall.
Although about two billion people worldwide are infected with tuberculosis, or simply ‘TB, the vast majority, about 90-95%, don’t develop symptoms. And this is because usually the immune system can contain it.
So Mycobacterium tuberculosis is usually transmitted via inhalation, which is how they gain entry into the lungs.
With TB, they recognize foreign proteins on their cell surface, and phagocytize them, or essentially package them into a space called a phagosome.
With most cases, the macrophage then fuses the phagosome with a lysosome, which has hydrolytic enzymes that can pretty much break down any biochemical molecule.
TB’s tricky though, and once inside the macrophage, they produce a protein that inhibits this fusion, which allows the mycobacterium to survive.
It doesn’t just survive, though, it proliferates, and creates a localized infection.
The tissue inside the middle dies as a result, a process referred to as caseous necrosis. This area is known as a “Ghon focus”.
In some cases, the mycobacteria is killed off by the immune system, and that’s the end of that.
In other cases, even though they were walled off, they remain viable, and are therefore still alive, but they’re just dormant. This stage of the disease is called latent TB.
When a person’s immune system becomes compromised, like with AIDS or with aging, the Ghon focus can be reactivated.
This time though, it tends to cavitate, or form cavities, which can allow the bacteria to disseminate.
Fortunately, there are many medications that can treat tuberculosis and they are often used together, in case the bacteria is resistant to one or more of the drugs.
Let’s start with isoniazid. It can be used on its own to treat latent infections and as prophylaxis for people traveling to regions where tuberculosis is common.
Isoniazid can be administered orally or parenterally.
In order to work, it’s first converted by a mycobacterial enzyme called peroxidase, into its active metabolite, iproniazid.
A mutation in the gene that codes for this enzyme helps the bacteria develop resistance, because the mutated enzyme won’t activate the medication.
Iproniazid inactivates enzymes associated with mycolic acid synthesis, and mycolic acid is needed to build bacterial cell walls.
It also inhibits mycobacterial peroxidase, preventing the bacteria from metabolizing hydrogen peroxide, which accumulates inside the cell causing serious damage.
Side effects include rash, fever, and systemic lupus erythematosus, called drug-induced SLE.
Fortunately, these side effects can be prevented with the administration of pyridoxine, or vitamin B6.
If liver damage is present, the medication should be discontinued right away.
Rifampin is the next medication. It can be administered orally or parenterally and acts by inhibiting mycobacterial RNA polymerase, and therefore, the synthesis of RNA.
A mutation in the gene that codes for this enzyme helps the bacteria develop resistance.
Since rifampin gets widely distributed throughout the body, it can get into urine, saliva, tears, feces and sweat, which turns them orange!
But, the most important side effect is hepatitis, which is more severe at high doses.
Luckily, it’s pretty uncommon, but elderly or alcoholic patients, or those who already have liver disease, are at higher risk.
This can be problematic since these people with HIV are at a higher risk of developing active tuberculosis.
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