Principles of Antimycobacterial Therapy


The treatment of mycobacterial infection and disease can be challenging. Patients require therapy with multiple agents, the offending pathogens commonly exhibit complex drug resistance patterns, and patients often have underlying conditions that affect drug choice and monitoring. Several of the drugs have not been well studied in children, and current recommendations are extrapolated from the experience in adults.

Single-drug therapy of Mycobacterium tuberculosis and nontuberculous mycobacteria is not recommended because of the high likelihood of developing antimicrobial resistance. Susceptibility testing of mycobacterial isolates often can aid in therapeutic decision-making.

Agents Used Against Mycobacterium Tuberculosis

Commonly Used Agents

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 INHA 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 INHA gene or in other genes encoding enzymes that activate INH, such as katG .

INH is indicated for the treatment of M. tuberculosis, M. kansasii, and M. bovis. The pediatric dosage is 10-15 mg/kg/day orally (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 (DOT) , 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 241.1 ). INH needs to be taken 1 hr before or 2 hr after meals because food decreases absorption. It is available in liquid, tablet, intravenous (IV; not approved by the FDA), and intramuscular (IM) preparations.

Table 241.1
Recommended Usual Treatment Regimens for Drug-Susceptible Tuberculosis in Infants, Children, and Adolescents
Adapted from American Academy of Pediatrics: Red book: 2018–2021 report of the Committee on Infectious Diseases, ed 31, Elk Grove Village, IL, 2018, AAP (Table 3.85).
INFECTION/DISEASE CATEGORY REGIMEN COMMENTS
LATENT MYCOBACTERIUM TUBERCULOSIS INFECTION a
Isoniazid susceptible 12 weeks of isoniazid plus rifapentine, once a week
or
4 mo of rifampin, once a day
or
Continuous daily therapy is required. Intermittent therapy even by DOT is not recommended.
9 mo of isoniazid, once a day If daily therapy is not possible, DOT twice a week can be used for 9 mo.
Isoniazid resistant 4 mo of rifampin, once a day Continuous daily therapy is required. Intermittent therapy even by DOT is not recommended.
Isoniazid-rifampin resistant Consult a tuberculosis specialist. Moxifloxacin or levofloxacin with or without ethambutol or pyrazinamide.
PULMONARY AND EXTRAPULMONARY INFECTION
Except meningitis b 2 mo of isoniazid, rifampin, pyrazinamide, and ethambutol daily or twice weekly, followed by 4 mo of isoniazid and rifampin c by DOT d for drug-susceptible M. tuberculosis Some experts recommend a 3-drug initial regimen (isoniazid, rifampin, and pyrazinamide) if the risk of drug resistance is low. DOT is highly desirable.
If hilar adenopathy only and the risk of drug resistance is low, 6 mo course of isoniazid and rifampin is sufficient.
Drugs can be given 2 or 3 times/wk under DOT.
9-12 mo of isoniazid and rifampin for drug-susceptible Mycobacterium bovis
Meningitis 2 mo of isoniazid, rifampin, pyrazinamide, and an aminoglycoside e or ethionamide, once daily, followed by 7-10 mo of isoniazid and rifampin, once daily or twice weekly (9-12 mo total) for drug-susceptible M. tuberculosis
At least 12 mo of therapy without pyrazinamide for drug-susceptible M. bovis
For patients who may have acquired tuberculosis in geographic areas where resistance to streptomycin is common, kanamycin, amikacin, or capreomycin can be used instead of streptomycin.

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

a Positive TST or IGRA result, no disease. See text for comments and additional acceptable/alternative regimens.

b Duration of therapy may be longer for human immunodeficiency virus (HIV)-infected people, and additional drugs and dosing intervals may be indicated

c Medications should be administered daily for the 1st 2 wk to 2 mo of treatment and then can be administered 2-3 times/wk by DOT. (Twice-weekly therapy is not recommended for HIV-infected people.)

d If initial chest radiograph shows pulmonary cavities, and sputum culture after 2 mo of therapy remains positive, the continuation phase is extended to 7 mo, for a total treatment duration of 9 mo.

e Streptomycin, kanamycin, amikacin, or capreomycin.

Major adverse effects include hepatotoxicity in 1% of children and approximately 3% of adults (increasing with age) and dose-related peripheral neuropathy. Pyridoxine can prevent the peripheral neuropathy and is indicated for breastfeeding 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 241.2 ). The metabolism of INH is by acetylation. Acetylation rates have minimal 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 receiving concomitant hepatotoxic drugs, including other antimycobacterial agents, acetaminophen, or alcohol. Monthly clinic visits while taking INH alone are encouraged to monitor adherence, adverse effects, and worsening of infection.

Table 241.2
Isoniazid Drug-Drug Interactions
DRUG USED WITH ISONIAZID EFFECTS
Acetaminophen, alcohol, rifampin Increased hepatotoxicity of isoniazid or listed drugs
Aluminum salts (antacids) Decreased absorption of isoniazid
Carbamazepine, phenytoin, theophylline, diazepam, warfarin Increased level, effect, or toxicity of listed drugs due to decreased metabolism
Itraconazole, ketoconazole, oral hypoglycemic agents Decreased level or effect of listed drugs due to increased metabolism
Cycloserine, ethionamide Increased central nervous system adverse effects of cycloserine and ethionamide
Prednisolone Increased isoniazid metabolism

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. These agents 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 the activity of rifampin. 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 (approximately 4 wk), so it should not be compounded with other antimycobacterial agents. An IV 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 pediatric use.

Rifampin can be associated with adverse effects 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 (CYP) 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 nonnucleoside 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 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 effects include GI upset (e.g., nausea, vomiting, poor appetite) in approximately 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 PZA in combination with rifampin for short-course treatment of latent tuberculosis is associated with serious liver dysfunction and death, and this combination should be avoided.

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

Ethambutol

Ethambutol is a synthetic form of ethylenedi-imino-di-1-butanol dihydrochloride that inhibits RNA synthesis needed for cell wall formation. At standard dosages ethambutol is bacteriostatic, but at dosages >25 mg/kg it has bactericidal activity. The mechanism of resistance to ethambutol is unknown, but resistance develops rapidly when ethambutol is used as a single agent against M. tuberculosis.

Ethambutol is indicated for the treatment of infections caused by M. tuberculosis, M. kansasii, M. bovis, and M. avium complex. Ethambutol should only be used as part of a combination treatment regimen for M. tuberculosis. Daily dosing is 15-20 mg/kg PO in a single dose, not to exceed 2,500 mg/day. Twice-weekly dosing is with 50 mg/kg PO in a single dose, not to exceed 2,500 mg/day. Dosage adjustment is needed in renal insufficiency. Ethambutol is available in 100 and 400 mg tablets.

The major adverse effect with ethambutol is optic neuritis , and thus ethambutol should generally be reserved for children old enough to have visual acuity and color discrimination reliably monitored. Visual changes are usually dosage dependent and reversible. Other adverse events include headache, dizziness, confusion, hyperuricemia, GI upset, peripheral neuropathy, hepatotoxicity, and cytopenias, especially neutropenia and thrombocytopenia.

Routine laboratory monitoring includes baseline and periodic visual acuity and color discrimination testing, CBC, serum uric acid levels, and kidney and liver function tests.

Less Commonly Used Agents

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