Antituberculosis Drugs
Alexander O. Tuazon
Cecilia C. Maramba-Lazarte
Tuberculosis remains a major global health problem, though the incidence per capita, prevalence, and death rates for tuberculosis are falling. Current challenges include the difficulty in correctly prescribing and adhering to complex and lengthy treatment protocols, emergence of Mycobacterium tuberculosis strains resistant to multiple drugs, and human immunodeficiency virus (HIV) infection (1). An estimated 1.7 million died due to tuberculosis in 2006. Of an estimated 14.4 million prevalent cases in the same year, 9.2 million or 64% were new cases of which 8% were HIV-positive (2). Of new cases, about 11% occur in children younger than 15 years, with countries reporting 3% to 25% of all cases (3).
Children are commonly infected through exposure to an infectious adult. The majority of infected children remain well and the only evidence of infection may be a positive tuberculin skin test, termed latent tuberculosis infection (LTBI). Progression to disease usually occurs within 2 years following exposure and infection. Infants and children younger than 5 years and the immunocompromised are at particular risk of developing disease. A small proportion of children, who are generally older, develop postprimary tuberculosis either due to reactivation or by reinfection (3,4).
Childhood tuberculosis is usually extrapulmonary in location. Severe and disseminated tuberculosis, such as tuberculous meningitis and miliary tuberculosis, may occasionally occur especially in children younger than 3 years (3). It is commonly primary, which has a much smaller bacterial load than adult-type tuberculosis with cavitation and sputum production. Bacterial confirmation of tuberculosis therefore will be difficult in children, and the choice of drugs will usually depend on results from the index case. On the other hand, failure, relapse, and development of resistance to antituberculosis drugs are of lesser concern (3,5,6).
Management guidelines are available (Table 34.1) for both resource-poor (3,5) and affluent areas (6). Central to these recommendations are short-course drug regimens administered by directly observed therapy (DOT), which involves providing the antituberculosis drugs directly to the patient and watching as he or she swallows the medications. While bacillary load and the type of disease may influence the effectiveness of treatment regimens, treatment outcomes in children are generally good, even in young and immunocompromised children, provided that treatment starts promptly. There is a low risk of adverse events associated with use of the recommended treatment regimens (3).
For LTBI in children, isoniazid administered for 6 to 12 months is the preferred treatment. It has also been shown to be effective as prophylaxis (7,8) but poor adherence is observed, especially with unsupervised treatment (9,10,11). An alternative treatment regimen of 3 to 4 months isoniazid plus rifampicin for the treatment of LTBI showed similar efficacy to 9 months isoniazid treatment with improved adherence (11,12). On the other hand, preventive therapy with rifampicin plus pyrazinamide causes severe hepatotoxicity and should generally not be offered to treat LTBI (13,14,15,16).
For an asymptomatic infant born into a household with an infectious tuberculosis patient, daily isoniazid is administered for 6 months or up to at least 3 months following cessation of relevant exposure, at which time a tuberculin test is done. If the tuberculin test is positive, treatment is continued as for LTBI, otherwise if the test is negative isoniazid is discontinued. Prophylactic treatment should be adjusted if the index case has a drug-resistant strain.
The principles of treatment of tuberculosis disease in infants and children are similar to that in adults, while keeping in mind pharmacokinetic differences and possibility of adverse effects (3,6,17,18). Published studies of treatment of children with tuberculosis (19,20,21,22,23,24,25,26,27,28,29,30,31) caused by organisms known or presumed to be susceptible to the first-line drugs have shown excellent results for pulmonary and lymph node tuberculosis, but less so for meningitis. For tuberculous meningitis, the higher end of the daily doses is recommended. Also, recent pharmacokinetic studies of isoniazid, pyrazinamide, and ethambutol have shown lower plasma drug levels in children than in adults suggesting that dosages per kilogram body weight need to be higher for children (32,33,34).
Short-course treatments are administered in two phases. An initial intensive phase, typically 2 months, employs a combination of drugs that is effective in rapidly eliminating the organism and in minimizing the chance for the development of resistance. Four drugs, usually isoniazid, rifampicin, pyrazinamide and ethambutol, are recommended when there is
risk of resistance, or when children and adolescents develop adult-type pulmonary tuberculosis. However, when the infecting strain is fully susceptible, or the likelihood of failure is low as in primary tuberculosis commonly seen in children, an initial phase combination of isoniazid, rifampicin, and pyrazinamide may be used (6). In the subsequent continuation phase, less number of drugs are administered but for at least 4 months to ensure that the patient is completely cured and does not relapse after completion of therapy (5,35,36).
risk of resistance, or when children and adolescents develop adult-type pulmonary tuberculosis. However, when the infecting strain is fully susceptible, or the likelihood of failure is low as in primary tuberculosis commonly seen in children, an initial phase combination of isoniazid, rifampicin, and pyrazinamide may be used (6). In the subsequent continuation phase, less number of drugs are administered but for at least 4 months to ensure that the patient is completely cured and does not relapse after completion of therapy (5,35,36).
Table 34.1 Recommended Treatment Regimens for Tuberculosis in Children | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Children with HIV infection and confirmed or presumptive tuberculosis disease are treated with the 6-month regimen with good response as in HIV-uninfected children. Cotrimoxazole as prophylaxis for other infections is administered and initiation of antiretroviral therapy should be carefully evaluated. Tuberculosis treatment failure can be due to noncompliance with therapy, poor drug absorption, drug resistance, and alternative diagnoses (3).
Resistance to isoniazid and/or rifampicin is the most important, as these two drugs form the mainstay of current chemotherapy. For cases with monoresistance to isoniazid, ethambutol is added to the intensive phase. For patients with more extensive disease, consideration should be given to the addition of a fluoroquinolone and to prolonging treatment to a minimum of 9 months. Monoresistance to rifampicin should be treated with isoniazid, ethambutol, and a fluoroquinolone for at least 12 to 18 months, with the addition of pyrazinamide for at least the first 2 months (3).
Multidrug resistant tuberculosis (MDR-TB) is resistant to at least both isoniazid and rifampicin and accounts for 4.3% of all tuberculosis cases (37). Mainly transmitted from an adult source case with MDR-TB, it is often not suspected unless a history of contact with an adult case is known. Children with MDR-TB should be treated with at least four drugs to which the bacterial strain, or that of its source case, is susceptible. Treatment should be given daily and preferably under DOT. Duration of treatment is usually 18 months or more. With correct dosing, few long-term
adverse events are seen with any of the more toxic second-line drugs in children. Treatment, however, is difficult and a referral to a specialist is advised (3).
adverse events are seen with any of the more toxic second-line drugs in children. Treatment, however, is difficult and a referral to a specialist is advised (3).
Isoniazid
Isoniazid, a hydrazide derivative of isonicotinic acid, is the most widely used first-line drug for tuberculosis. Isoniazid inhibits synthesis of long-chain mycolic acids, which are constituents of mycobacterial cell walls. It has the most potent early bactericidal activity against actively dividing M. tuberculosis (17) but is bacteriostatic against nondividing tubercle bacilli. Isoniazid-resistant strains demonstrate a reduced catalase-peroxidase activity, which has been associated with deletions or point mutations in the katG gene (38,39,40).
Isoniazid as single-drug therapy is indicated only for the prophylaxis of contacts of sputum smear-positive or culture-positive tuberculosis cases and for the treatment of LTBI. It is used in combination with other drugs for active disease (Table 34.1). In both, susceptibility of the bacilli to isoniazid should be established or confidently assumed. Isoniazid is administered orally at 5 mg per kg (range 4 to 15 mg per kg, maximum 300 mg) daily (3,5,6), or intermittently at 10 mg per kg (range 8 to 12 mg per kg) thrice weekly (3,5), or 20 to 30 mg per kg (maximum 900 mg) twice weekly (6). It may be administered intramuscularly.
Efficacy Data in Children
In children who received isoniazid prophylaxis for 6 months, only 1.9% developed active tuberculosis within a 10-year follow-up period (7). In another study, development of active disease was low among tuberculin-positive children who received isoniazid. A morbidity rate of 4.2 per 1,000 children was observed after a mean observation period of 6.1 years (41). Efficacy studies of isoniazid combined with other first-line drugs in short-course treatments in children with active tuberculosis showed excellent results approaching at least 95% efficacy in pulmonary and lymph node tuberculosis (19,20,21,22,23,24,25,26,27,28). The efficacy against tuberculous meningitis, however, is less, with increased mortality and sequelae for survivors (29,30,31).
The pharmacokinetic profile is dependent on N-acetylation capacity, which is trimodally distributed into slow, intermediate, or rapid phenotypes in accordance with the genotype of the polymorphic N-acetyltransferase (42,43). Peoples of European origin are predominantly slow acetylators, whereas Asian peoples are predominantly rapid acetylators (44,45). The lower plasma concentration seen in rapid acetylators becomes significant only in a once weekly dosing regimen, where a poorer response is observed (44).
Absorption of isoniazid is rapid and complete but is reduced by food. The effect of antacids on absorption is less clear (46,47,48). Peak plasma concentrations are reached in 1 to 2 hours (18,46,47,48). Isoniazid is distributed in all body fluids and tissues, (18,49,50), with excellent penetration into the cerebrospinal fluid (CSF) (51,52,53). The apparent volume of distribution is 0.62 to 0.83 L per kg with no significant difference between slow and rapid acetylators (54).
Isoniazid undergoes extensive presystemic metabolism. Isoniazid is acetylated by the liver to metabolites, which are excreted in the urine. Acetylisoniazid is further hydrolyzed to isonicotinic acid and monoacetylhydrazine. Isonicotinic acid is conjugated with glycine to form isonicotinylglycine, whereas monoacetylhydrazine is further acetylated to diacetylhydrazine. All metabolites are essentially devoid of antituberculosis activity. Hepatotoxicity is associated with an incompletely acetylated hydrazide group found in monoacetylhydrazine and isoniazid (44).
Pharmacokinetic Data in Children
Isoniazid levels expected in children is basically similar to adults. Excellent penetration into the CSF of children with tuberculous meningitis has been demonstrated (53). A trimodal pharmacokinetic profile is also evident in children. Clearance is 3.83 and 6.88 mL per minute per kg and half-life is 2.91 and 1.36 hours in slow and rapid acetylators, respectively. Apparent volume of distribution is 0.83 L per kg, and as in adults is not affected by acetylator phenotype (54). Younger children eliminate isoniazid faster than older children in all three genotypes. As a group, children eliminate isoniazid faster and achieve significantly less serum concentrations than adults who receive the same milligram per kilogram body weight dose. An isoniazid dose of at least 10 mg per kg might be more appropriate to rapid acetylators to achieve the recommended serum concentration of 1.5 mg per L (32).
Genetically slow acetylators are more at risk for various isoniazid-related toxicities. Acute poisoning is associated with significant toxicity and mortality, with slow acetylators at risk. Nausea, vomiting, hypotension, leukocytosis, hyperpyrexia, respiratory distress, seizures, and coma are seen in children. Metabolic acidosis, ketonuria, hyperglycemia, mild hyperkalemia, increased urinary excretion of pyridoxine, impaired liver function, and rhabdomyolysis have been observed (56,57,58,59,60).
The induction of seizures by isoniazid has been attributed to its lowering effect on pyridoxine levels, which may affect formation and catabolism of gamma-aminobutyric acid. Gram-for-gram treatment with vitamin B6 is recommended, and high-dose intravenous pyridoxine terminates seizures and may awake patients from coma (57,61). Niacinamide has also been shown to be effective in reversing isoniazid-induced hyperkinesis, suggesting interference by isoniazid of nicotinamide adenine dinucleotide–catalyzed reactions (56).
Dose-dependent peripheral neuropathies occur more in slow acetylators (62). It is uncommon and rare in children, except in malnourished patients whose vitamin B6 deficiency may result from or be aggravated by loss of pyridoxal hydrazone of isoniazid. Symptoms include tingling, numbness, tenderness, weakness, and stiffness in the extremities. It can be prevented by daily administration of supplementary vitamin B6 (18,63).
There is an appreciable but low risk of hepatotoxicity with isoniazid at current recommended dosing regimens. Elevations of liver enzymes are usually transient and normalize with continued therapy. Slow acetylators are possibly at increased risk (45).
Hepatotoxicity in Children
Asymptomatic liver dysfunction to frank liver disease can occur with isoniazid administration in children. Risk factors include severe tuberculous disease, higher isoniazid doses, and coadministration with rifampicin. With isoniazid alone, the occurrence is 0.18% to 0.5%, which is much less common than in adults (64,65,66,67).
Reported hematologic adverse effects include agranulocytosis, hemolytic anemia, sideroblastic anemia, aplastic anemia, thrombocytopenia, eosinophilia, red cell aplasia, and disseminated intravascular coagulation (68,69,70). Anorexia and nausea (69), gynecomastia (71), hyperthermia (72), pancreatitis (73,74), rheumatoid-like and lupus-like arthritis (69), and rhabdomyolysis (59,60) have been reported. Dermatologic side effects and hypersensitivity are uncommon (25,69).
Caution must be observed in the presence of liver disease and regular monitoring of liver enzymes is recommended. A full dose may still be given in impaired renal function (75). Isoniazid may increase pyridoxine requirements in children (63,76). Serum vitamin D concentrations are low when isoniazid is taken but rise to normal after discontinuance of isoniazid (77,78,79).
Isoniazid inhibits microsomal enzymes. Metabolism may thus be impaired leading to increased serum concentration and potentiation of the effects of warfarin, theophylline, triazolam (17), diazepam (80), and antiepileptics such as carbamazepine (81), phenytoin (82,83), and valproic acid (84). On the other hand, concomitant administration of isoniazid leads to decreased effectiveness of methoxyflurane, isoflurane, sevoflurane, and enflurane (85).
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