Tuberculosis prophylaxis

Lou HX, Shullo MA, McKaveney TP. Limited tolerability of levofloxacin and pyrazinamide for multidrug-resistant tuberculosis prophylaxis in a solid organ transplant population. Pharmacotherapy 2002 22(6) 701-4. 

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. 

Active tuberculosis Rifabutin prophylaxis must not be administered to patients with active tuberculosis. HIV-positive patients are likely to have a nonreactive purified protein derivative (PPD) despite active disease. Chest X-ray, sputum culture, blood culture, urine culture, or biopsy of a suspicious lymph node may be useful in the diagnosis of tuberculosis in the HIV-positive patient. 

There is no evidence that rifabutin is effective prophylaxis against M. tuberculosis. Patients requiring prophylaxis against both M. tuberculosis and M. avium complex may be given isoniazid and rifabutin concurrently. 

Geriatric Considerations - Summary Age is not a contraindication to INH prophylaxis or treatment of tuberculosis. Follow adult guidelines for treatment. INH maybe used in patient wit h stable hepatic disease. The risk of clinical hepatitis increases with age and has been reported in 2% of adults aged greater than 50. INH interferes with the metabolism of pyridoxine therefore concomitant pyridoxine therapy at 25mg/day is recommended to prevent neurotoxicity. INH is metabolized via acetylation in the liver. Older adults who are slow acetylators of the drug may require lower doses to achieve effective serum concentrations and prevent adverse effects. Food, especially high-fat meals, delays and reduces absorption therefore administer INH on an empty stomach. 

Apart from its main use in tuberculosis, it is also used in leprosy and prophylaxis of meningitis due to H. influenzae and meningococci. It is also used with doxycycline in treatment of brucellosis. 

Ciprofloxacin and levofloxacin are no longer recommended for the treatment of gonococcal infection in the USA as resistance is now common. However, both drugs are effective in treating chlamydial urethritis or cervicitis. Ciprofloxacin, levofloxacin, or moxifloxacin is occasionally used for treatment of tuberculosis and atypical mycobacterial infections. These agents may be suitable for eradication of meningococci from carriers or for prophylaxis of infection in neutropenic patients. 

Rifampin, usually 600 mg/d (10 mg/kg/d) orally, must be administered with isoniazid or other antituberculous drugs to patients with active tuberculosis to prevent emergence of drug-resistant mycobacteria. In some short-course therapies, 600 mg of rifampin are given twice weekly. Rifampin 600 mg daily or twice weekly for 6 months also is effective in combination with other agents in some atypical mycobacterial infections and in leprosy. Rifampin, 600 mg daily for 4 months as a single drug, is an alternative to isoniazid prophylaxis for patients with latent tuberculosis only, who are unable to take isoniazid or who have had exposure to a case of active tuberculosis caused by an isoniazid-resistant, rifampin-susceptible strain. 

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). 

Impaired cell-mediated immunity leaves the host prey to many (opportunistic) infections including candidiasis, coccidioidomycosis, cryptosporidiosis, cytomegalovirus disease, herpes simplex, histoplasmosis, Pneumocystis carinii pneumonia, toxoplasmosis and tuberculosis (with multiply-resistant organisms). Treatment of these conditions is referred to elsewhere in this text for a comprehensive review of the antinticrobial prophylaxis of opportunistic infections in patients with HIV infection, readers are referred to Kovacs Masur 2000 New England Journal of Medicine 342 1416. 

Isoniazid is the hydrazide of isonicotinic acid. It is a first-line drug for therapy and prophylaxis of tuberculosis. It is bactericidal for rapidly dividing mycobacteria, but bacteriostatic for resting bacilli . Among non-tuberculous mycobacteria, only a few strains, such as Mycobacterium kansasii, are susceptible. As a rule, sensitivity should always be tested in vitro, since the minimum inhibitory concentration varies greatly. 

Rifabutin may be used in the prophylaxis of M. avium complex infections in immunocompromised patients and in the treatment, with other drugs, of pulmonary tuberculosis and non-tuberculous mycobacterial infections. 

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. ... 

Pape JW, Jean SS, Ho JL, et al. Effect of isoniazid prophylaxis on incidence of active tuberculosis and progression of HIV infection. Lancet 1993 342 268-272. 

The use of prophylactic isoniazid therapy for transplant patients with evidence of exposure to M. tuberculosis (those with a positive purified protein derivative skin test) remains controversial. Risk of reactivation and development of clinical tuberculosis is enhanced with posttransplant immunosuppression. Some clinicians believe, however, that the risk of isoniazid-induced hepatotoxicity, especially in liver transplant recipients, in whom the rate of hepatotoxicity has been reported as high as 40%, outweighs the benefits of treatment. High-risk patients who may be considered for isoniazid prophylaxis include those with a positive skin test, those with previously diagnosed tuberculosis who may not have been treated adequately, patients in close contact with individuals with active pulmonary disease, and patients with abnormal chest radiographs consistent with old tuberculosis who have not received prior prophylaxis. " ... 

MAC prophylaxis is now strongly recommended for all HIV-infected adults and adolescents with CD4 counts of fewer than 50 cells/mcL. The first-line choices are either azithromycin (1200 mg once weekly) or clarithromycin (500 mg twice daily) rifabutin is an alternative. Persons considered for prophylaxis should be evaluated to be sure that they do not have active disease owing to MAC or M. tuberculosis. 

Prophylactic therapy should be considered in patients exposed to tuberculosis who have evidence of infection, including immunosuppressed patients e.g., HIV-infected) with >5 mm induration on PPD testing immunocompetent patients with >10 mm induration on PPD testing and risk factors for TB but no apparent disease and those with a history of tuberculosis in whom the disease is currently inactive. The main risk of chemoprophylaxis is isoniazid-induced hepatitis. Monitored isoniazid prophylaxis minimizes this risk, even in patients over the age of 35. 

Patients with inactive tuberculosis who have not received adequate therapy should be considered for 1 year of isoniazid treatment. HIV-infected intravenous drug abusers with a positive PPD test have 8% chance per year of developing active tuberculosis. Isoniazid prophylaxis in HIV-infected persons appears to be as effective as in non-immunocompromised persons. The CDC recommends that isoniazid prophylaxis be continued for 12 months. Persons infected with HIV who are exposed to multidrug-resistant tuberculosis should receive prophylaxis with rifampin and pyrazinamide (with close monitoring for hepatic toxicity) or high-dose ethambutol and pyrazinamide, with or without a fluoroquinolone. 

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