HWN Suggests

Using Isoniazid More Safely and More Effectively: The Time Is Now

INH has been part of the treatment for TB for 70 years. It is a potent and useful drug and it is unlikely to disappear soon from the armamentarium. New drug development for TB remains painfully slow. TB is largely a disease of poor people living in poor countries, so the market has not been an attractive one for pharmaceutical companies. The global health community has struggled to address this injustice. When bedaquiline was approved for the treatment of TB, some 40 years after rifampin, there was optimism that the TB drug pipeline would start to flow rapidly, but in reality it is more like a very slow trickle. Using INH in as safe and effective a manner as is possible is a medical and ethical…

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Featured

 Isoniazid-resistant tuberculosis: A problem we can no longer ignore

For decades, people working in tuberculosis (TB) knew that monoresistance to isoniazid (INH) was common. INH has been in clinical use since the 1950s, and drug resistance was expected because its use became widespread. But this knowledge did not necessarily lead to testing for INH-resistant, rifampicin-susceptible TB (Hr-TB) or to the use of special drug regimens for this form of TB. Indeed, for decades, no drug-susceptibility testing (DST) for any drug was done unless patients failed first-line therapy or had risk factors for drug-resistant TB (DR-TB). Simply put, we chose to ignore the problem.

Articles of Interest

A Simple Regimen Can Prevent TB. Why Aren’t More People on It?

Two antibiotics, taken for a month, can stop a leading killer. But “when it’s for TB, people just sort of shrug.” For decades, the standard course has been an antibiotic called isoniazid that kills the bacteria causing TB only when they are replicating. The drug must be taken daily for nine months, in the hope of catching the bacteria as they multiply, and it can cause numbness, nausea and fever. Isoniazid also can cause liver toxicity, so people taking it are advised not to drink alcohol for the entire nine months.

Focus on Pharm: Isoniazid

Isoniazid is very selective for mycobacteria and works by inhibiting the synthesis of mycolic acid, which disrupts the cell wall. It also disrupts the synthesis of DNA and other key components in the mycobacterium.

Isoniazid overdose

The antidote for isoniazid is pyridoxine. If there is a suspicion that status epilepticus could be the result of isoniazid toxicity, pyridoxine should be given as soon as possible. However, pyridoxine, especially in the doses required, will take time to get and give. I want it on board as soon as possible, but terminating the seizure and managing the ABCs is still my priority. Pyridoxine is necessary cofactor in the production of GABA, the major inhibitory neurotransmitter in the CNS. (GABA’s effects are evident if you remember that benzodiazepines, barbituates, propofol, and inhaled anesthetics all act as GABA agonists). Isoniazid combines with pyridoxine, making pyridoxine inactive, lowering brain levels of GABA and increasing susceptibility to seizures.

Isoniazid toxicity

isoniazid toxicity, like other hydrazines, primarily cause life-threatening seizures and lactic acidosis through depletion of vitamin B6 the antidote is pyridoxine

The Isoniazid Paradigm of Killing, Resistance, and Persistence in Mycobacterium tuberculosis

Isoniazid (INH) was the first synthesized drug that mediated bactericidal killing of the bacterium Mycobacterium tuberculosis, a major clinical breakthrough. To this day, INH remains a cornerstone of modern tuberculosis (TB) chemotherapy.

ToxCard: Pyridoxine for INH Toxicity

INH toxicity causes a pyridoxine deficient state in the brain, which decreases the concentration of the inhibitory neurotransmitter, GABA, and causes seizures. In seizures that are refractory to our usual treatment with benzodiazepines and first line anti-epileptics like levetiracetam and fosphenytoin, consider pyridoxine (B6) deficiency and treat with 5 g of IV pyridoxine (or 70 mg/kg in pediatrics).

Resources

Treatment Action Group

Treatment Action Group (TAG) envisions the end of the HIV, tuberculosis (TB), and hepatitis C (HCV) pandemics with the discovery, development, and worldwide dissemination of safe and effective diagnostics, preventives, and cures through public health structures that end systemic harms and promote human rights, and that are developed by the diverse communities most affected by these conditions.

StatPearls

Isoniazid has been the most important drug used in TB treatment regimens since 1952. It is a prodrug activated by the catalase-peroxidase KatG, creating a variety of radicals and adducts that inhibit the mycobacterium's production of the mycolic acids that make up its cell wall. This activity lends INH to being a potent bactericidal agent.