Tuberculosis, isoniazid for

Frequency 45-65% of Caucasians and African Americans 10-15% of Asians Slow inactivation of drugs such as isoniazid (for tuberculosis), dapsone (for leprosy), and hydralazine (for high blood pressure), leading to toxicity from the drug at doses well tolerated in people with rapid acetylator phenotype Clinical consequences depend on the specific side effects of the drugs... 

P. Gurumurthy, M. S. Krishnamurthy, O. Nazereth, R. Parthasarathy, G. R. Sarma, P. R. Somasundaram, S. P. Tripathy, G. A. Ellard, Lack of Relationship between Hepatotoxicity and Acetylator Phenotype in Three Thousand South Indian Patients during Treatment with Isoniazid for Tuberculosis , Am. Rev. Respir. Dis. 1984, 129, 58-61. 

Gurumurthy P, Krishnamurthy MS, Nazareth O, Parthasarathy R, Sarma GR, Somasundaram PR, Tripathy SP, Ellard GA. Lack of relationship between hepatic toxicity and acetylator phenotype in three thousand South Indian patients during treatment with isoniazid for tuberculosis. Am Rev RespirDis 1984 129(1) 58-61. 

A distal sensory neuropathy is the commonest neurological complication in HIV-infected individuals, and has been documented in up to 30% of patients with AIDS. There is evidence from a retrospective case-note review in 30 individuals that co-administration of stavudine and isoniazid increases the incidence of distal sensory neuropathy. Of 22 patients taking stavudine in combination with other drugs, all took isoniazid for tuberculosis and 12 developed a distal sensory neuropathy, with a median time to onset of 5 months (7). Those taking stavudine alone had an incidence of 11%. 

Migita K, Umeno T, Miyagawa K, Izumi Y, Sasaki E, Kakugawa T, et al. Development of interstitial pneumonia in a patient with rheumatoid arthritis induced by isoniazid for tuberculosis chemoprophylaxis. Rheumatol Int 2012 32(5) 1375-7. 

Aiititubercular drug s are used in combination with other aiititubercular dm to treat active tuberculosis. Isoniazid (INH) is the only aiititubercular drug used alone While isoniazid is used in combination with other drains for the treatment of primary tuberculosis, a primary use is in preventive therapy (prophylaxis) against tuberculosis. For example, when a diagnosis of tuberculosis is present, family members of the infected individual must be given prophylactic treatment with isoniazid for 6 months to 1 year. Display 12-1 identifies prophylactic uses for isoniazid. 

The initial phase must contain three or more of the following drugp isoniazid, rifampin, and pyrazin-amide, along with either ethambutol or streptomycin. The CDC recommends treatment to begin as soon as possible after the diagnosis of tuberculosis. The treatment recommendation regimen is for the administration of rifampin, isoniazid, and pyrazinamide for a minimum of 2 months (8 weeks), followed by rifampin and isoniazid for 4 months (16 weeks) in areas with a low incidence of tuberculosis. In areas of high incidence of tuberculosis, the CDC recommends the addition of streptomycin or ethambutol for the first 2 months. 

ALA synthase, the rate-limiting enzyme, requires pyridoxine (vitamin B ). Deficiency of pyri-doxine is associated with isoniazid therapy for tuberculosis and may cause sideroblastic anemia with ringed sideroblasts. 

Rifampin and pyrazinamide daily for 2 months is appropriate for isoniazid-resistant tuberculosis. 

Isoniazid Inhibits synthesis of mycolic acids, an essential component of mycobacterial cell walls Bactericidal activity against susceptible strains of M tuberculosis First-line agent for tuberculosis treatment of latent infection less active against other mycobacteria Oral, IV hepatic clearance (half-life 1 h) reduces levels of phenytoin Toxicity Flepatotoxic, peripheral neuropathy (give pyridoxine to prevent)... 

The widespread use of isoniazid prophylaxis for tuberculosis has focused attention on the liver injury caused by this drug. About 20% of patients treated with isoniazid will show elevated blood concentrations of liver enzymes and bilirubin that subside as treatment is continued (25). However/ clinical hepatitis develops in some patientS/ and these reactions can prove fatal. Current understanding of the mechanism of isoniazid-induced hepatotoxicity is based on the metabolic pathways shown in Figure 16.6 (26/ 27). It has been demonstrated in an animal model that hepatotoxicity is correlated with plasma concentrations of hydrazine but not of acetylhydrazine or isoniazid (28)/ and that pretreatment with an amidase inhibitor can prevent toxicity (27). However/ it is postulated that hydrazine is further metabolized to a chemically reactive he pa to toxin by the cytochrome P450 system/ and in vitro studies with hepatocytes have implicated CYP2E1 as the cytochrome P450 isoform responsible for cytotoxic metabolite formation (29). 

Despite these advances in our understanding of the risk factors that predispose to isoniazid-induced hepatotoxicity/ it remains unclear whether age/ the predominant risk factor (Table 16.3)/ exerts its effects either on isoniazid metabolism or on protective mechanisms that as yet remain undefined. Clearly/ more work is needed in this area/ especially because understanding the biochemical basis of these risk factors plays a central role in developing guidelines for using isoniazid for chemoprophylaxis of tuberculosis (35). 

This effect, attributed here to bucillamine, is a rare but well-established adverse effect of penicillamine. Although the patient had also taken isoniazid for pulmonary tuberculosis, that was unlikely to have played a part, since the breast enlargement started earlier and progressed after the isoniazid had been withdrawn. 

Reactivation of latent tuberculosis is a major concern with infliximab (SEDA-26, 402), and accounts for about one-third of infections in these patients. According to data from the manufacturers, 130 cases of active tuberculosis were notified up to October 2001. Many of the cases were disseminated or extrapulmonary tuberculosis, and several patients died. Several case reports have provided detailed information in at least seven other patients, including three who developed miliary tuberculosis and one who developed Mycobacterium tuberculosis enteritis (44-48). A detailed analysis of 70 cases of tuberculosis reported to the FDA has been published (49). Two-thirds of the cases were noted after three or fewer infusions and 57% of the patients had extrapulmonary disease. There were 64 cases from countries with a low incidence of tuberculosis. From these reports and the number of patients treated with infliximab, the estimated rate of tuberculosis in patients with rheumatoid arthritis treated with infliximab was four times higher than the background rate. Patients with evidence of active infection should not receive infliximab until the infection is under control all should be screened for tuberculosis before starting infliximab (50). From these and other data it has been estimated that the risk of tuberculosis in the first year of infliximab treatment is 0.035 in US citizens and 0.2% in non-US citizens. Further investigations, such as a chest X-ray and a Mantoux test, and prophylactic treatment with isoniazid, will show whether the incidence can be reduced in patients taking anti-TNF treatment (51). 

The authors noted that isoniazid-induced pellagra was first described in 1956, shortly after the introduction of isoniazid for the treatment of tuberculosis, but that subsequent reports have been very uncommon. 

Dutt AK, Moers D, Stead WW. Undesirable side effects of isoniazid and rifampin in largely twice-weekly short-course chemotherapy for tuberculosis. Am Rev Respir Dis 1983 128(3) 419-24. 

Singapore Tuberculosis Service and British Medical Research Council. Controlled trial of intermittent regimens of rifampicin plus isoniazid for pulmonary tuberculosis in Singapore. Lancet 1975 2(7945) 1105-9. 

Linna O, Uhari M. Hepatotoxicity of rifampicin and isoniazid in children treated for tuberculosis. Eur J Pediatr 1980 134(3) 227-9. 

B6 (pyridoxine) Treats symptoms of neuritis causes by isoniazid (INH) therapy for tuberculosis... 

Isoniazid is widely prescribed for tuberculosis. It can chemically react with pyridoxal and pyridoxal phosphate, thus significantly reducing the availability of this coenzyme (Fig. 8.37) (61). Pyridoxinesupplements commonly are recommended to prevent isoniazid-caused... 

Aside from consideration of drug toxicity, some antimicrobial use requires more in tensive risk-benefit analysis. An example of this is the decision to use isoniazid prophylactically to prevent tuberculosis. Because the hepatotoxicity of isoniazid increases in frequency with age, older persons (>45 years) who are candidates for isoniazid prophylaxis (positive skin test) must have additional risk factors for tuberculosis to balance the potential toxic effects. These include evidence of recent skin-test conversion, immunosuppression, or previous gastrectomy. Older patients without additional risk factors are more likely to suffer toxicity from isoniazid than derive benefit from its use. ... 

Isoniazid-resistant Same as isoniazid-sensitive high probability of exposure to isoniazid-resistant tuberculosis Rifampin 600 mg orally once daily plus pyrazinamide 200 mg/kg orally once daily for 2 mo... 

Unfortunately, MAC is resistant to the standard drugs used for tuberculosis, such as isoniazid and pyrazinamide. Multiple agents such as rifampin, rifabutin (ansamycin), clofazimine, imipenem, amikacin, ethambutol, ciprofloxacin, clarithromycin, and azithromycin have varying degrees of in vitro anti-MAC activity. Controversy formerly existed as to whether treatment for MAC is beneficial, but data indicate that an aggressive therapeutic approach decreases symptoms... 

Still other important and innovative new drugs were introduced during the same period, including the antihypertensive hydralazine, the anti-inflammatory drug phenylbutazone, the carbonic anhydrase inhibi-tor/diuretic acetazolamide, and isoniazid for the treatment of tuberculosis. 

Isoniazid (nydrazid, others) remains the primary drug for tuberculosis. All patients with disease caused by sensitive strains should receive the drug if they can tolerate it. 

Household contacts and other close associates of patients with tuberculosis who have negative tuberculin tests should receive isoniazid for at least 6 months after the contact has been broken, regardless of age. This is especially important for children. If the PPD test becomes positive, therapy should be continued for 12 months. 

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