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

INFECTION OR DISEASE CATEGORY	REGIMEN	REMARKS
LATENT TUBERCULOSIS INFECTION*
Isoniazid susceptible	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	6 mo of rifampin, once a day	If daily therapy is not possible, DOT twice a week can be used for 6 mo
Isoniazid-rifampin resistant‡	Consult a tuberculosis specialist
PULMONARY AND EXTRAPULMONARY INFECTION
Except meningitis	2 mo of isoniazid, rifampin, pyrazinamide, and ethambutol daily, followed by 4 mo of isoniazid and rifampin† by DOT§ for drug-susceptible Mycobacterium tuberculosis 9-12 mo of isoniazid and rifampin for drug-susceptible Mycobacterium bovis	If possible drug resistance is a concern (see text), another drug (ethambutol or an aminoglycoside) is added to the initial 3-drug therapy until drug susceptibilities are determined; DOT is highly desirable If hilar adenopathy only, a 6-mo course of isoniazid and rifampin is sufficient Drugs can be given 2 or 3 ×/wk under DOT in the initial phase if nonadherence is likely
Meningitis	2 mo of isoniazid, rifampin, pyrazinamide, and an aminoglycoside or ethambutol or ethionamide, once a day, followed by 7-10 mo of isoniazid and rifampin, once a day or twice a week (9-12 mo total) for drug-susceptible M. tuberculosis ≥12 mo of therapy without pyrazinamide for drug-susceptible M. bovis	A fourth drug, such as an aminoglycoside, is given with initial therapy until drug susceptibility is known For patients who might 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.

* 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

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. 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

Ethambutol is a synthetic form of ethylenedi-imino-di-1-butanol dihydrochloride that inhibits RNA synthesis needed for cell wall formation. At standard dosages it is bacteriostatic, but at dosages of >25 mg/kg ethambutol 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.

Aminoglycosides

The aminoglycosides used for mycobacterial infections include streptomycin, amikacin, kanamycin, and capreomycin. Streptomycin is isolated from Streptomyces griseus and was the 1st drug used to treat M. tuberculosis. Capreomycin, a cyclic polypeptide from Streptomyces capreolus, and amikacin, a semisynthetic derivative of kanamycin, are newer agents that are recommended when streptomycin is unavailable. Aminoglycosides act by binding irreversibly to the 30S subunit of ribosomes and inhibiting subsequent protein synthesis. Streptomycin exhibits concentration-dependent bactericidal activity, and capreomycin is bacteriostatic. Resistance results from mutation in the binding site of the 30S ribosome, by decreased transport into cells, or by inactivation by bacterial enzymes. Cross-resistance between aminoglycosides has been demonstrated.

The aminoglycosides are indicated for the treatment of M. tuberculosis and M. avium complex. All are considered 2nd-line drugs in the treatment of M. tuberculosis and should be used only when resistance patterns are known. Aminoglycosides are poorly absorbed orally and are administered by IM injection. Pediatric dosing ranges for streptomycin are 20 mg/kg/day if given daily and 20-40 mg/kg/day if given twice weekly; dosing is IM in a single daily dose. Capreomycin, amikacin, and kanamycin dosages are 15-30 mg/kg/day IM in a single dose not to exceed 1 g/day. Dosage adjustment is necessary in renal insufficiency.

Aminoglycosides have adverse effects on proximal renal tubules, the cochlea, and the vestibular apparatus of the ear. Nephrotoxicity and ototoxicity account for most of the significant adverse events. Rarely, patients exhibit fever or rash with the administration of aminoglycosides. Concomitant use of other nephrotoxic or ototoxic agents should be avoided, because adverse effects may be additive. An infrequent but serious, synergistic, dosage-dependent, aminoglycoside effect with nondepolarizing neuromuscular blockade agents can result in respiratory depression or paralysis.

Hearing and kidney function should be monitored at baseline and periodically. Early signs of ototoxicity include tinnitus, vertigo, and hearing loss. Ototoxicity appears to be irreversible, but early kidney damage may be reversible. As with other aminoglycosides, peak and trough drug levels are helpful in dosing and managing early toxicities.

Cycloserine

Cycloserine, derived from Streptomyces orchidaceus or Streptomyces garyphalus, is a synthetic analog of the amino acid D-alanine that interferes with bacterial cell wall synthesis via competitive inhibition of D-alanine components to be incorporated into the cell wall. It is bacteriostatic, and the mechanism of resistance is unknown.

Cycloserine is used to treat M. tuberculosis and M. bovis. The dosage is 10-20 mg/kg/day PO divided into 2 doses not to exceed 1g/day. It is available in a 250 mg capsule.

The major adverse event is neurotoxicity with significant psychologic disturbance, including seizures, acute psychosis, headache, confusion, depression, and personality changes. The neurotoxic effects are additive with ethionamide and isoniazid. It has also been associated with megaloblastic anemia. Cycloserine must be dosage adjusted with kidney impairment. It should be used with caution in patients with underlying psychiatric illness.

Routine laboratory monitoring includes kidney and hepatic function, CBC, and cycloserine levels. Psychiatric symptoms are less common at blood levels of <30 µg/mL.

Ethionamide

Ethionamide is structurally related to isoniazid and is an ethyl derivative of thioisonicotinamide that inhibits peptide synthesis by an unclear mechanism thought to involve NAD and NADP dehydrogenase disruptions. Ethionamide is bacteriostatic at most therapeutic levels. Resistance develops quickly if ethionamide used as a single-agent therapy, although the mechanism is unknown.

Ethionamide is used as an alternative to streptomycin or ethambutol in the treatment of M. tuberculosis and has some activity against M. kansasii and M. avium complex. A metabolite, ethionamide sulfoxide, is bactericidal against M. leprae. Ethionamide has been shown to have good central nervous system (CNS) penetration and has been used as a 4th drug in combination with rifampin, isoniazid, and pyrazinamide. The pediatric dosing is 15-20 mg/kg/day PO in 2 divided doses not to exceed 1 g/day. It is available as a 250 mg tablet.

GI upset is common, and other adverse effects include neurologic disturbances (anxiety, dizziness, peripheral neuropathy, seizures, acute psychosis), hepatic enzyme elevations, hypothyroidism, hypoglycemia, and hypersensitivity reaction with rash and fever. It should be used with caution in patients with underlying psychiatric or thyroid disease. The psychiatric adverse effects can be potentiated with concomitant use of cycloserine.

In addition to close assessment of mood, routine monitoring includes thyroid and liver function tests. In diabetic patients, blood glucose levels should be monitored.

Fluoroquinolones

The fluoroquinolones are fluorinated derivatives of the quinolone class of antibiotics. Ciprofloxacin is a 1st-generation fluoroquinolone, and levofloxacin is the more active L-isomer of ofloxacin. Moxifloxacin and gatifloxacin are agents with emerging use in pediatric mycobacterial disease. Fluoroquinolones are not indicated for use in children <18 yr of age, but studies of their use in pediatric patients continue to indicate that they may be used in special circumstances. Fluoroquinolones are bactericidal and exert their effect via inhibition of DNA gyrase. The alterations in DNA gyrase result in relaxation of super-coiled DNA and breaks in double-stranded DNA. The mechanism of resistance is not well defined but likely involves mutations in the DNA gyrase.

Levofloxacin is an important 2nd-line drug in the treatment of multidrug-resistant M. tuberculosis. Ciprofloxacin has activity against M. fortuitum complex and against M. tuberculosis. The pediatric dosage of ciprofloxacin is 20-30 mg/kg/day PO or IV not to exceed 1.5 mg/day PO or 800 mg/day IV. The adult dosage of ciprofloxacin is 500-750 mg/dose PO divided into 2 doses or 200-400 mg/dose IV every 12 hr. Ciprofloxacin is available in 100, 250, 500, and 750 mg tablets and can be made in 5% (50 mg/mL) or 10% (100 mg/mL) suspensions. The dosage of levofloxacin for children is 5-10 mg/kg/day given once daily either PO or IV not to exceed 1,000 mg/day, and for adults it is 500-1,000 mg/day PO or IV not to exceed 1,000 mg/day. Levofloxacin is available in 250, 500, and 750 mg tablets, and a 50 mg/mL suspension can be extemporaneously compounded. The suspension has a shelf life of only 8 wk.

The most common adverse effect of fluoroquinolones is GI upset, with nausea, vomiting, abdominal pain, and diarrhea, including pseudomembranous colitis. Other less common adverse effects include bone marrow depression, CNS effects (e.g., lowered seizure threshold, confusion, tremor, dizziness, headache), elevated liver transaminases, photosensitivity, and arthropathies. The potential for arthropathies (e.g., tendon ruptures, arthralgias, tendinitis) is the predominant reason that fluoroquinolones are not recommended for pediatric use. The mechanism of injury appears to involve the disruption of extracellular matrix of cartilage and depletion of collagen, a particular concern related to the bone and joint development of children.

Fluoroquinolones induce the cytochrome P450 isoenzymes that can increase the concentrations of dually administered theophylline and warfarin. Nonsteroidal anti-inflammatories can potentiate the CNS effects of fluoroquinolones and should be avoided while taking a fluoroquinolone. Both ciprofloxacin and levofloxacin should be dosage adjusted in patients with significant renal dysfunction.

While taking fluoroquinolones, patients should be monitored for hepatic and renal dysfunction, arthropathies, and hematologic abnormalities.

Linezolid

Linezolid is a synthetic oxazolidinone derivative. This drug is not currently approved for use against mycobacterial infection in pediatric or adult patients but has activity against some myobacterial species. Studies on efficacy of treatment of mycobacterial infections are under way. Linezolid inhibits translation by binding to the 23S ribosomal component of the 50S ribosome subunit, preventing coupling with the 70S subunit. Resistance is thought to be from a point mutation at the binding site but is poorly studied, because only a few cases of resistance have been reported.

The approved indications for linezolid are for bacterial infections other than myobacteria, but studies reveal in vitro activity against rapidly growing mycobacterium (M. fortuitum complex, M. chelonae, M. abscessus), M. tuberculosis, and M. avium complex. The dosage for 0-11 yr old children is 10 mg/kg/day PO or IV in divided doses every 8-12 hr. For persons >12 yr of age, the dosage is 600 mg PO or IV every 12 hr. Linezolid is available in 400 and 600 mg tablets and as a 20 mg/mL suspension.

Adverse effects of linezolid include GI upset (e.g., nausea, vomiting, diarrhea), CNS disturbances (e.g., dizziness, headache, insomnia, peripheral neuropathy), lactic acidosis, fever, myelosuppression, and pseudomembranous colitis. Linezolid is a weak inhibitor of monoamine oxidase A, and patients are advised to avoid foods with high tyramine content. Linezolid should be used cautiously in patients with pre-existing myelosuppression.

In addition to monitoring for GI upset and CNS perturbations, routine laboratory monitoring includes CBC at least weekly.

Para-Amino Salicylic Acid

para-Aminosalicylic acid (PAS) is a structural analog of para-aminobenzoic acid (PABA). It is bacteriostatic and acts by competitively inhibiting the synthesis of folic acid similar to the action of sulfonamides. Resistance mechanisms are poorly understood.

PAS acts against M. tuberculosis. The dosage is 150 mg/kg/day PO in 2 or 3 divided doses. PAS is dispensed in 4 g packets, and the granules should be mixed with liquid and swallowed whole.

Common adverse events include GI upset, and less common events include hypokalemia, hematuria, albuminuria, crystalluria, and elevations of hepatic transaminases. PAS can decrease the absorption of rifampin, and co-administration with ethionamide potentiates the adverse effects of PAS.

In addition to monitoring for weight loss, routine laboratory monitoring includes liver and kidney function tests.