High Dose Isoniazid

Clinical studies have suggested that high-dose isoniazid may be active against drug-resistant TB. The WHO recommends high-dose isoniazid as a medication with “unclear efficacy” against MDR / XDR TB. High doses are perhaps effective for treating patients infected with strains of bacteria that are resistant to low doses of isoniazid. High dose isoniazid also may make patients with bacterial resistance to other first-line medications susceptible to these drugs. More clinical studies are needed to establish the effectiveness of this medication. Dosage ------ _Adults:_ 1000 to 1500 mg per day _Children:_ Pediatric dosage has not been determined How it works ------------ Isoniazid inhibits the synthesis of a compound that is required for the cell wall in TB-causing bacteria. By doing so, it disrupts the cell wall, killing bacteria and preventing them from growing. Bacteria can mutate and develop resistance to low doses of isoniazid. This is called low-level isoniazid resistance, and is defined as an infection that is resistant to the critical concentration of 0.1µg/ml but susceptible to the higher concentration of 0.4µg/ml. However, in a bacterial population classified as low-level resistant, sometimes not all of the bacteria have this resistance. This means that there could be both resistant and non-resistant bacteria infecting a single patient. Using high dose isoniazid may be effective against TB in two different ways. Firstly, it may kill the bacteria in a population that are not resistant to isoniazid. Secondly, it may also kill the bacteria that have low-level isoniazid resistance, because these bacteria might not have developed resistance to high doses of the drug. Side effects ------------ Isoniazid may cause fevers, rashes, and, in rare cases, conditions such as peripheral neuropathy, neurotoxicity, hepatoxocity (damage to the liver), psychosis, and convulsions. These side effects may be more pronounced with high dose isoniazid. In those taking the medication, there is a slightly higher risk of liver damage and peripheral neuropathy. Pyridoxine (vitamin B6) deficiency is also sometimes observed. Clinical trials and approval ---------------------------- High dose isoniazid is classified by the WHO as a Group 5 medication with unclear efficacy, only to be used when regimens involving drugs from Groups 1-4 are not possible. There is currently debate over whether high dose isoniazid should be used for the treatment of drug-resistant TB. Many experts believe that high-dose isoniazid can be used to treat a TB infection that is resistant to low doses of isoniazid. This may be because all or part of the bacterial population has resistance to only low doses of the drug. In addition, it has been shown that bacteria that are resistant to low doses of isoniazid are sometimes resistant to two other first-line drugs, ethionamide and pyrazinamide. However, bacteria that are resistant to higher doses of isoniazid are often NOT resistant to these drugs. Therefore, giving high dose isoniazid to patients who are resistant to ethionamide and pyrazinamide may make these patients responsive to these drugs; this is because the high dose isoniazid, by killing bacteria that are resistant to low dose isoniazid, may also be eliminating resistance to ethionamide and pyrazinamide.[^Moulding] Clinical studies of the use of high dose isoniazid in the treatment of MDR / XDR TB have produced mixed results. One study in 1999 that tested high dose isoniazid in mice suggested that high doses of the drug might not be useful as a treament. When both low and high doses of isoniazid were given to different groups of mice, researchers found that raising the dose of isoniazid was not more active in fighting drug-resistant TB than low dose isoniazid.[^Cynamon] However, a more recent study done in 2008 in India produced more encouraging results. This study examined high dose isoniazid in HIV negative patients infected with MDR TB. The study was controlled, meaning that patients were randomly assigned to different groups. Group 1 received high dose isoniazid (16‐18mg/kg), Group 2 received normal dose isoniazid (5mg/kg), and Group 3 received a placebo. Patients of every group also received a combination of other TB drugs: anamycin, levofloxacin,prothionamide, cycloserine, p‐aminosalicylic acid. Researchers found that patients who received high dose isoniazid became sputum-negative (meaning that there were no detectable TB bacilli in their sputum) 2.38 times more quickly than patients who did not receive the medication. On average, patients in Group 1 became sputum-negative after 3.4 months. This period for Group 2 was 6.4 months, and for Group 3 was 6.6 months. When tested after six months of receiving treatment, Group 1 patients were 2.37 times more likely to be sputum-negative than those not receiving the high dose drug. The study concluded that the treatment programme for drug-resistant TB can be improved by using high dose isoniazid.[^Katiyar] Pricing ------- There is no formulation for high dose isoniazid. Please refer to prices for [low dose isoniazid](http://www.tbonline.info/posts/2011/8/22/isoniazid/ "Isoniazid"). Advocacy issues --------------- - Information on the use of high dose isoniazid as a treatment for drug-resistant TB is mostly based on experience and opinion rather than clinical trials. The clinical studies done thus far have produced mixed results. More studies are needed to determine the effectiveness of high dose isoniazid therapy, particularly in patients co-infected with HIV and TB. - No information is available on the use of high dose isoniazid in children and elderly patients. [^Moulding]: TS Moulding. Should Isoniazid be used in Retreatment of Tuberculosis Despite Acquired Isoniazid Resistance? AM Rev Respir Dis. Mar 1981; 123(3):262-4 [^Cynamon]: M.H. Cynamon et al. High-Dose Isoniazid Therapy for Isoniazid-Resistant Murine Mycobacterium tuberculosis Infection? Antimicrob Agents Chemother. Dec 1999; 43(12): 2922-2924. [^Katiyar]: SK Katiyar et al. A Randomised Controlled Trial of High-Dose Isoniazid Adjuvant Therapy for Multidrug-Resistant Tuberculosis. Int J Tuberc Lung Dis. Feb 2008; 12(2): 139-45.