Isoniazid

Isoniazid (INH) is a hydrazide form of isonicotinic acid and is bactericidal for rapidly growing M. tuberculosis. The primary target of INH involves the INH A gene, which encodes the enoyl ACP (acyl carrier protein) reductase needed for the last step of the mycolic acid biosynthesis pathway of cell wall production. Resistance to INH occurs following mutations in the INH A gene or in other genes encoding enzymes that activate INH, such as kat G.

INH is indicated for the treatment of M. tuberculosis, M. kansasii, and M. bovis. The pediatric dosage is 10-15 mg/kg/day PO in a single dose not to exceed 300 mg/day. The adult dosage is 5 mg/kg/day PO in a single dose not to exceed 300 mg/day. Alternative pediatric dosing is 20-30 mg/kg PO in a single dose not to exceed 900 mg/dose given twice weekly under directly observed therapy, in which patients are observed to ingest each dose of antituberculosis medication to maximize the likelihood of completing therapy. The duration of treatment depends on the disease being treated (Table 206-1). INH needs to be taken 1 hr before or 2 hr after meals because food decreases absorption. It is available in liquid, tablet, IV (not approved by the Food and Drug Administration [FDA]), and IM preparations.

Table 206-1 RECOMMENDED TREATMENT REGIMENS FOR DRUG-SUSCEPTIBLE TUBERCULOSIS IN INFANTS, CHILDREN, AND ADOLESCENTS

DOT, directly observed therapy; IGRA, interferon-γ release assay; TST, tuberculin skin test.

* Positive TST or IGRA result, no disease.

^† Duration of therapy is longer for human immunodeficiency virus (HIV)-infected people, and additional drugs may be indicated.

^‡ Medications should be administered daily for the first 2 weeks to 2 months of treatment and then can be administered 2 to 3 × per week by DOT.

^§ If initial chest radiograph shows cavitary lesions and sputum after 2 months of therapy remains positive, duration of therapy is extended to 9 months.

From American Academy of Pediatrics: Tuberculosis. In Pickering LK, Baker CJ, Kimberlin DW, Long SS, editors: Red Book 2009 Report of the Committee on Infectious Diseases, ed 28, Elk Grove Village, IL, 2009, American Academy of Pediatrics.

Major adverse events include hepatotoxicity in 1% of children and ∼3% of adults (increasing with age) and dose-related peripheral neuropathy. Pyridoxine can prevent the peripheral neuropathy and is indicated for breast-feeding infants and their mothers, children and youth on milk- or meat-deficient diets, pregnant adolescents, and symptomatic HIV-infected children. Minor adverse events include rash, worsening of acne, epigastric pain with occasional nausea and vomiting, decreased vitamin D levels, and dizziness. The liquid formulation of INH contains sorbitol, which often causes diarrhea and stomach upset.

INH is accompanied by significant drug-drug interactions (Table 206-2). The metabolism of INH is by acetylation. Acetylation rates have little effect on efficacy, but slow acetylators have an increased risk for hepatotoxicity, especially when used in combination with rifampin. Routine baseline liver function testing or monthly monitoring is only indicated for persons with underlying hepatic disease or on concomitant hepatotoxic drugs, including other antimycobacterial agents, acetaminophen, and alcohol. Monthly clinic visits while on INH alone are encouraged to monitor adherence, adverse effects, and worsening of infection.

Table 206-2 ISONIAZID DRUG-DRUG INTERACTIONS

Rifamycins

The rifamycins (rifampin, rifabutin, rifapentine) are a class of macrolide antibiotics developed from Streptomyces mediterranei. Rifampin is a synthetic derivative of rifamycin B, and rifabutin is a derivative of rifamycin S. Rifapentine is a cyclopentyl derivative. The rifamycins inhibit the DNA-dependent RNA polymerase of mycobacteria, resulting in decreased RNA synthesis. They are generally bactericidal at treatment doses, but they may be bacteriostatic at lower doses. Resistance is from a mutation in the DNA-dependent RNA polymerase gene (RpoB) that is often induced by previous incomplete therapy. Cross resistance between rifampin and rifabutin has been demonstrated.

Rifampin is active against M. tuberculosis, M. leprae, M. kansasii, and M. avium complex. Rifampin is an integral drug in standard combination treatment of active M. tuberculosis disease and can be used as an alternative to INH in the treatment of latent tuberculosis infection in children who cannot tolerate INH. Rifabutin has a similar spectrum, with increased activity against M. avium complex. Rifapentine is undergoing pediatric clinical trials and appears to have activity similar to rifampin’s. The pediatric dosage of rifampin is 10-15 mg/kg/day PO in a single dose not to exceed 600 mg/day. The adult dosage of rifampin is 5-10 mg/kg/day PO in a single dose not to exceed 600 mg/day. Commonly used rifampin preparations include 150 and 300 mg capsules and a suspension that is usually formulated at a concentration of 10 mg/mL. The shelf life of rifampin suspension is short (∼4 wk), so it should not be compounded with other antimycobacterial agents. An intravenous form of rifampin is also available for initial treatment of patients who cannot take oral preparations. Dosage adjustment is needed for patients with liver failure. Other rifamycins (rifabutin and rifapentine) have been poorly studied in children and are not recommended for use in children.

Rifampin can be associated with adverse events such as transient elevations of liver enzymes; gastrointestinal (GI) upset with cramps, nausea, vomiting, and anorexia; headache; dizziness; and immunologically mediated fever and flulike symptoms. Thrombocytopenia and hemolytic anemias can also occur. Rifabutin has a similar spectrum of toxicities, except for an increased incidence of rash (4%) and neutropenia (2%). Rifapentine has fewer adverse effects but is associated with hyperuricemia and cytopenias, especially lymphopenia and neutropenia. All rifamycins can turn urine and other secretions (tears, saliva, stool, sputum) orange, which can stain contact lenses. Patients and families should be warned about this common but otherwise innocuous adverse effect.

Rifamycins induce the hepatic cytochrome P450 isoenzyme system and are associated with the increased metabolism and decreased level of several drugs when administered concomitantly. These drugs include digoxin, corticosteroids such as prednisone and dexamethasone, dapsone, fluconazole, phenytoin, oral contraceptives, warfarin, and many antiretroviral agents, especially protease inhibitors and non-nucleoside reverse transcriptase inhibitors. Rifabutin has less of an effect on lowering protease inhibitor levels.

The use of pyrazinamide in combination with rifampin for short-course latent tuberculosis therapy has been associated with serious liver dysfunction and death. This combination has never been well studied or recommended for pediatric patients and should not be used.

No routine laboratory monitoring for rifamycins is indicated unless the patient is symptomatic. In patients with signs of toxicity, complete blood count (CBC) and kidney and liver function tests are indicated.

Pyrazinamide

Pyrazinamide (PZA) is a synthetic pyrazide analog of nicotinamide that is bactericidal against intracellular M. tuberculosis organisms in acidic environments, such as within macrophages or inflammatory lesions. A bacteria-specific enzyme (pyrazinamidase) converts PZA to pyrazinoic acid, which leads to low pH levels not tolerated by M. tuberculosis. Resistance is poorly understood but can arise from bacterial pyrazinamidase alterations.

PZA is indicated for the initial treatment phase of active tuberculosis disease in combination with other antimycobacterial agents. The pediatric dosage is 15-30 mg/kg/day PO in a single dose not to exceed 2,000 mg/day. Twice weekly dosing with directly observed therapy only is with 50 mg/kg/day PO in a single dose not to exceed 4,000 mg/day. It is available in a 500 mg tablet and can be made into a suspension of 100 mg/mL.

Adverse events include GI upset (e.g., nausea, vomiting, poor appetite) in ∼4% of children, dosage-dependent hepatotoxicity, and elevated serum uric acid levels that can precipitate gout in susceptible adults. Approximately 10% of pediatric patients have elevated uric acid levels but with no associated clinical sequelae. Minor reactions include arthralgias, fatigue, and, rarely, fever.

Use of pyrazinamide in combination with rifampin for short-course treatment of latent tuberculosis has been associated with serious liver dysfunction and death, and this combination should be avoided.

No routine laboratory monitoring for pyrazinamide is required, but monthly visits to reinforce the importance of therapy are desirable.

Ethambutol