AMERICAN ACADEMY OF PEDIATRICS

PEDIATRICS Vol. 89 No. 1 January 1992 161

Chemotherapy for Tuberculosis in Infants and Children

Committee on Infectious Diseases

Active tuberculosis is diagnosed in more than 1100children annually in the United States. The therapyfor patients with tuberculosis has undergone majorchanges during the past decade, including demon-stration of the efficacy of multidrug, short-coursechemotherapy for pulmonary tuberculosis in adults.’At least nine studies of 6-month antituberculosischemotherapy have demonstrated comparable resultsin children.2’#{176} The purpose of this statement is togive revised recommendations for treatment of tuber-culosis in infants and children. These recommenda-tions have been formulated in collaboration with theDivision of Tuberculosis Elimination of the Centersfor Disease Control and the American Thoracic Society.

MICROBIOLOGIC RATIONALE FOR TREATMENT

Laboratory observations of Mycobacterium tubercu-

losis and clinical therapy trials have led to a hypoth-esis concerning the populations of tubercie bacilli andthe actions of various antimycobacterial drugs anddrug combinations.11’12 Mycobacteria replicate slowly,can remain dormant for prolonged periods, and canbe killed by drugs only during replication. In the host,bacilli live in several sites: open cavities, closed ca-seous lesions, and within macrophages. Each sitecontains bacilli with a different population size, met-abolic activity, and rate of replication. Open cavities,which are rare in infants and children, have thelargest number of mycobacteria. Naturally occurringdrug-resistant mutants of M tuberculosis occur withinlarge bacterial populations even before chemotherapyis started. The number of drug-resistant mutants isproportional to the size of the mycobacterial popula-tion; thus, they are common in open cavities, but lesscommon in caseous lesions and within macrophages.Mutants naturally resistant to two drugs are virtuallynonexistent.

The various antituberculosis drugs differ in theiractions and primary sites of activity. Isoniazid andrifampin are bactericidal against all populations ofmycobacteria. Streptomycin is most active against Mtuberculosis in open cavities, while pyrazinamide maycontribute to killing organisms within macrophages.Other drugs, including ethambutol, ethionamide, andp-aminosalicylic acid, prevent replication of mycobac-teria but do not readily kill the organisms. The earliesttreatment regimens for tuberculosis combined the

The recommendations in this publication do not indicate an exclusive course

of treatment or serve as a standard of medical care. Variations, taking into

account individual circumstances, may be appropriate.

PEDIATRICS (ISSN 0031 4005). Copyright C 1992 by the American Acad-

emy of Pediatrics.

actions of a bactericidal drug such as isoniazid and!or streptomycin with a bacteriostatic drug that sup-pressed emergence of drug-resistant mutants. Micro-biologic cure required 18 to 24 months of treatment.Current chemotherapy using at least two bactericidaldrugs to which the isolate is susceptible usually caneffect a cure in 6 to 9 months.

RECENT CLINICAL TRIALS

Nine months of therapy with isoniazid and rifam-pin will cure virtually 100% of adults’3 and children’4with drug-susceptible pulmonary tuberculosis. Thedrugs are given daily for the first 1 to 2 months, andfor the remaining time can be given daily or twiceweekly with equivalent results and rates of adversereactions. The success of twice weekly therapy allowsdirect observation of drug administration by a healthcare professional in cases of suspected or provennoncompliance. While trials for most forms of tuber-culosis in adults and children using only isoniazidand rifampin have evaluated therapy of 9 monthsduration, hilar adenopathy in children has beentreated successfully with only 6 months of this com-bination.’5

Adults with pulmonary tuberculosis are treatedsuccessfully with a 6-month regimen of isoniazid,rifampin, and pyrazinamide daily for the first 1 to 2months, followed by isoniazid and rifampin daily ortwice weekly for 4 to 5 months.16 The nine publishedpediatric studies of 6-month therapy for pulmonarytuberculosis have included more than 1500 childrenand used slightly different regimens, all containing atleast three drugs in the initial phase of treatment,usually isoniazid, rifampin, and pyrazinamide.2�#{176}Giving directly observed medications twice weeklyduring the continuation phase was as effective andsafe as daily self-administration. Two studies usingintermittent therapy for the entire 6 months yieldedsuccess rates equivalent to the studies in which ther-apy was initially given daily.7”#{176}In several studies,success was <95%, but for all studies combined itwas >95%.

The three major antituberculosis drugs, isoniazid,rifampin, and pyrazinamide, achieve tissue and bodyfluid concentrations adequate to kill M tuberculosis inall body sites. Although fewer studies of treatment ofdrug-susceptible extrapulmonary tuberculosis havebeen reported, infection in most sites is treated ade-quately by 9 months of isoniazid and rifampin’5”7 or6-month regimens using isoniazid, rifampin, and pyr-azinamide for 2 months, followed by isoniazid andrifampin for 4 months.2’9’#{176} Bone or joint tuberculosis

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162 CHEMOTHERAPY FOR TUBERCULOSIS

occasionally requires longer durations of therapy.Treatment of tuberculous meningitis with isoniazidand rifampin for 12 months is well established,’8 butdurations of 6 to 9 months using four drugs (usuallyisoniazid, rifampin, pyrazinamide, and streptomycin)in the initial phase also appear to be effective.’8

Adjunct treatment of certain forms of tuberculosiswith corticosteroids has been considered controver-sial. Corticosteroids have been used for therapy oftuberculous meningitis to reduce vasculitis, inflam-mation, and ultimately, intracranial pressure.’9 A re-cent study demonstrated lower rates of mortality andlong-term neurologic sequelae among patients withtuberculous meningitis treated with corticosteroidscompared with nonsteroid-treated controls.2#{176} Con-trolled trials have demonstrated beneficial effects ofcorticosteroids for patients with endobronchial pri-mary tuberculosis,2’ pleural effusion with mediastinalshift,22 and pericardial effusion.23

DRUG RESISTANCE

The incidence of drug-resistant tuberculosis is in-creasing in many parts of the United States andthroughout the world. The three major factors thatcontribute to the emergence of drug resistance are asfollows: 1) the use of antituberculosis medications inuncontrolled over-the-counter preparations availablein many foreign countries; 2) poor compliance bypatients; and 3) improper treatment by physicians,most commonly the failure to employ an adequateantituberculosis regimen at the beginning of therapy.Regimens for drug-resistant tuberculosis must includeat least two bactericidal drugs to which the isolate issusceptible. Primary resistance to streptomycin or iso-niazid is most common. Primary resistance to rifam-pin or pyrazinamide remains rare, but pyrazinamidemay not effectively prevent the emergence of rifam-pin resistance during therapy when primary isoniazidresistance is also present. A fourth drug, usuallyethambutol, should be added to the initial regimenwhen the patient is at increased risk for primaryisomazid resistance.

COMPLIANCE

Noncompliance is a major problem in tuberculosiscontrol due to the long-term nature of treatment.24As treatment regimens become shorter in duration,compliance assumes an even greater importance. Sus-pected cases of tuberculosis must be reported to thelocal health department so it can compile accuratestatistics, perform necessary contact investigations,and assist both patients and health care providers inovercoming barriers to compliance. To comply, thepatient and family must know what is expected ofthem through verbal and written instructions in thepatient’s main language. Appointment reminders,both by postcard and telephone, are helpful. Anassessment of potential noncompliance should bemade at the initiation of therapy. Missed appoint-ments should be brought quickly to the attention ofthe responsible public health officials who may beable to use incentives/enablers, behavior modifica-tion, or even confinement to ensure compliance. Ifthe physician suspects any chance of noncompliance

with daily self-administered medications, directly ob-served therapy should be instituted.

RECOMMENDATIONS

See Tables 1, 2, and 3 for Summary and Drug Doses

1 . For drug-susceptible pulmonary tuberculosis,the Academy recommends as standard therapy a 6-month regimen using isoniazid, rifampin, and pyra-zinamide daily for 2 months, followed by isoniazidand rifampin given daily or twice weekly for 4months. Twice-weekly drug administration should bedirectly observed by a health care professional, i.e.,the professional is present when the medication isadministered.

An alternative in areas where the incidence of drugresistance is low is a 9-month regimen of isoniazidand rifampin given daily for 1 month, then daily ortwice weekly for 8 months.

2. If any doubt exists about the reliability of self-administered daily medication, directly observedtwice-weekly therapy administered by an employeeof the local health department or other health careprofessional should be given. When social or otherconstraints prevent reliable daily self-administrationof drugs in the initial phase, drugs can be given twoor three times per week from the beginning underdirect observation. The optimal duration of therapygiven in this manner is not firmly established, butdurations of 6 to 9 months are generally successfulfor pulmonary tuberculosis and hilar adenopathy.

3. In general, the treatment of hilar adenopathyshould be the same as that for pulmonary tuberculo-sis. However, when drug resistance is unlikely, a 6-month regimen of isoniazid and rifampin is usuallysufficient. Because hilar adenopathy frequently re-quires 2 to 3 years for complete radiographic resolu-tion, a normal chest radiograph is not a necessarycriterion for discontinuation of antituberculosis med-ications in children.

4. In most cases, extrapulmonary tuberculosis, in-cluding cervical adenopathy, can be treated with thesame regimens as pulmonary tuberculosis. Exceptionsmay be bone and joint disease, disseminated (miliary)disease, and meningitis; data are inadequate at pres-ent to support 6-month therapy for these conditions.

For tuberculous meningitis, the Academy recom-mends a 12-month regimen using initial daily treat-ment with isoniazid, rifampin, pyrazinamide, andstreptomycin for 2 months, followed by isoniazid andrifampin administered daily or twice weekly underdirect observation for 10 months. Based on personalexperience and as yet unpublished data, some expertsrecommend a treatment duration of 6 to 9 months.Four drugs are used initially to ensure adequate ther-apy even if unsuspected drug resistance is present.For non-central nervous system extrapulmonary tu-berculosis, ethambutol can be used instead of strep-tomycin if the risk of drug resistance is significant.

5. For all cases of childhood tuberculosis, drugsusceptibility information should be sought from theadult source case and/or the child and should be usedto determine appropriate therapy. Drug-resistant tu-berculosis is an increasing problem and is more likely

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TABLE 1. Recommended Treatment Regimens for Tuberculosis in Infants, Children, and Adolescents

AMERICAN ACADEMY OF PEDIATRICS 163

Tuberculous Infection/Disease Regimens’ Remarks

Asymptomatic infection #{149}At least 6 consecutive mo of therapy with

(positive skin test, no good compliance should be given.disease) #{149}If daily therapy is not possible, twice-

Isoniazid susceptible 9 mo of I weekly therapy may be used for 9 mo.Isoniazid resistant 9 mo of R

Pulmonary 1. 6-mo (standard). 2 mo of I, R, & Z daily, #{149}If drug resistance is possible, especially

followed by 4 mo of I & R daily for the 9-mo regimen, an additional drugor (ethambutol or streptomycin) should be

2 mo of I, R, & Z daily, followed by 4 mo of added to the initial therapy until drug

I & R twice weekly, directly observed susceptibility is determined.

2. 9-mo (alternative). 9 mo of I & R daily #{149}Drugs can be given two or three times

or per week under direct observation in the1 mo of I & R daily followed by 8 mo of I & initial phase if noncompliance is likely.

R twice weekly, directly observedHilar adenopathy Same as Pulmonary #{149}See Pulmonary.

#{149}6-months of I & R has been successful inareas where drug resistance is rare.

Meningitis, disseminated 2 mo of I, R, Z & S daily, followed by 10 mo #{149}Streptomycin used in initial therapy until

(miliary) and bone/joint of I & R daily drug susceptibility is known.

or #{149}For patients who may have acquired hi-2 mo of I, R, Z & S daily, followed by 10 mo berculosis in geographic locales where re-

of I & R twice weekly, directly observed sistance to streptomycin is common, ca-preomycin (15-30 mg/kg/d) or kanamy-

an (15-30 mg/kg/d) may be used instead

of streptomycin.Extrapulmonary other than Same as Pulmonary #{149}See Pulmonary.

meningitis, disseminated

(miliary) or bone/joint

a i = isoniazid; R = rifampin; Z = pyrazinamide; S = streptomycin.

TABLE 2. Commonly Used Drugs for the Treatment of Tuberculosis in Infants, Children, and Adolescents

Drugs Dosage Forms Daily Dose, Twice-Weekly Dose, Maximum Dose Adverse Reactions

mg/kg/d mg/kg/dose

Isoniazid’ Scored tablets: 10-15t 20-40 Daily: 300 mg Mild hepatic enzyme elevation,

100 mg Twice weekly: 900 mg hepatitis, peripheral neuritis,300 mg hypersensitivity

Syrup:

lOmg/mI4Rifampin’ Capsules: 10-20 10-20 600 mg Orange discoloration of secre-

150 mg tions/urine, staining contact

300 mg lenses, vomiting, hepatitis,

Syrup: flu-like reaction, thrombocy-

formulated in syrup topenia, may render birth-

from capsules� control pills ineffectivePyrazinamide Scored tablets: 20-40 50-70 2 g Hepatotoxicity, hyperuricemia

500 mg

Streptomycin Vials: 20-40 (IM)fl 20-40 (IM) 1 g Ototoxicity, nephrotoxicity,

lg,4g skinrashEthambutolil Tablets: 15-25 50 2.5 g Optic neuritis (reversible), de-

100 mg creased visual acuity, de-400 mg creased red-green color dis-

crimination, gastrointestinal

disturbance, hypersensitivity

#{149}Rifamate is a capsule containing 150 mg of isoniazid and 300 mg of rifampin. Two capsules provide the usual adult (>50 kg) daily dosesof each drug.

t When isoniazid is used in combination with rifampin, the incidence of hepatotoxicity increases if the isoniazid dose exceeds 10 mg/kg/d.

I Many experts recommend not using isoniazid syrup, because it is unstable and is associated with frequent gastrointestinal complaints,especially diarrhea.§ Some experts recommend not using rifampin syrup because of instability.I Ethambutol is probably safe in young children, but should be used with caution when monitoring visual acuity or color discriminationis difficult.I, IM = intramuscular.

to occur in certain regions of the United States andamong the following groups: foreign-born individualsfrom high-risk areas of Asia, Africa, and Latin Amer-ica; the homeless; persons previously treated for tu-

berculosis; and children with tuberculosis whoseadult source case is in one of the aforementionedgroups. If the child is at risk for drug resistance,

streptomycin or ethambutol should be added to theinitial phase of all regimens until drug susceptibilitiesare known. In cases of tuberculosis with isoniazid orrifampin resistance, standard short-course chemo-therapy is not recommended.

6. Optimal therapy of tuberculosis in children withhuman immunodeficiency virus (HIV) infection is not

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TABLE 3. Summary of Drug Doses

164 CHEMOTHERAPY FOR TUBERCULOSIS

Child’s

lb

Weight

kg

Isoniazid Rifampin Pyrazinamide

Dose Resulting

Ethambutol

Dose Resulting Dose Resulting Dose Resulting

offered, dose, offered, dose, offered, dose, offered, dose,mg mg/kg/d mg mg/kg/d mg mg/kg/d mg mg/kg/d

15-21 6-9.5 100 11-17 150 16-25 250 26-42 150 16-25

22-29 10-13 150 12-15 150 12-15 250 19-25 250 19-25

30-40 14-18 200 11-14 300 17-21 500 28-36 350 19-25

41-51 19-23 250 11-13 300 13-16 750 33-39 500 22-26

52-62 23.5-28 300 11-13 300 11-13 1000 36-43 600 22-26

63-78 28.5-35 300 9-11 450 13-16 1000 29-35 750 21-2679-89 35.5-40 300 <10 450 11-13 1250 31-35 1000 25-28

90-100 40.5-45 300 <10 600 13-15 1500 33-37 1000 22-25

100+ 46+ 300 <10 600 13- 2000 43- 1000 22-

Adapted from Smith MHS. What about short course and intermittent chemotherapy for tuberculosis in children? Pediatr Infect Dis J.1982;1:298-303.

yet established. Most HIV-infected adults with tuber-culosis respond well to antituberculosis drugs but mayrequire longer duration of treatment.25’26 Therapy al-ways should include at least three drugs initially andshould be continued for at least 9 months. HIV testing(with informed consent) is recommended for infantsand children with tuberculous disease, especiallythose with risk factors for HIV infection. Cultureconfirmation and drug susceptibility patterns fromthe child should be sought vigorously.

7. Because rates of adverse reactions to antituber-culosis medications are low in infants and children,routine laboratory monitoring of blood counts, liverfunction tests, and serum uric acid is usually notnecessary. Physician-patient contact at monthly in-tervals is important to assess toxicity, compliance, andeffectiveness. In cases of severe tuberculosis, espe-cially meningitis and disseminated disease, the mci-dence of hepatotoxic reactions to antituberculosisdrugs is higher, and results of liver function testsshould be monitored during the first several monthsof treatment.27’28

8. The Academy recommends a 9-month regimenof isoniazid for children with asymptomatic tubercu-bus infection (i.e., those with a positive tuberculinskin test and no evidence of disease). For adults withasymptomatic infection, isoniazid alone for 6 to 12months has been demonstrated to be highly effectivein preventing the development of tuberculous disease.Rifampin given for 9 months is recommended forchildren with isoniazid-resistant infection, such asthose whose source has been proven microbiologi-cally to be excreting isoniazid-resistant organisms.Although controlled trials have not been reported,either drug can be given twice weekly under directobservation when compliance with daily self-admin-istered therapy cannot be ensured.

9. Administration of pyridoxine is not generallynecessary for children taking isoniazid, because pe-ripheral neuritis or convulsions caused by inhibitionof pyridoxine metabolism are extremely rare. How-ever, pyridoxine supplements are recommended forchildren or adolescents on meat- or milk-deficientdiets, malnourished children, breast-feeding infants,and pregnant women.

10. The administration of corticosteroids should beconsidered in cases of tuberculous meningitis. Most

commonly, corticosteroids are given daily for 4 to 6weeks, then tapered during the next 2 to 3 weeks.Corticosteroids also may be considered in cases ofpleural and pericardial effusions to hasten reabsorp-tion of fluid, in severe miliary disease to mitigatealveolocapillary block, and in endobronchial diseaseto relieve obstruction and atelectasis. Corticosteroidsshould be given only when accompanied by adequateantituberculosis therapy.

1 1 . Consultation with an expert in tuberculosis isrecommended in the following situations: 1) cases ofdrug-resistant tuberculosis; 2) children with severeforms of tuberculosis in which therapy with cortico-steroids may be indicated; and 3) the treatment oftuberculosis in pregnant women and HIV-infectedchildren.

Co�n-rni� ON INFECTIOUS DISEASES, 1990 to 1991

Georges Peter, MD, Interim ChairmanStanley Plotkin, MD, Past ChairmanJames G. Easton, MDNeal A. Halsey, MDMartha L. Lepow, MDEdgar K. Marcuse, MDMelvin I. Marks, MDGeorge A. Nankervis, MDCarol F. Phillips, MDLarry K. Pickering� MDGwendolyn B. Scott, MD

Russell W. Steele, MD

Uaison RepresentativesKenneth J. Bart, MD, MPH, National Vaccine

ProgramAlan R. Hinman, MD, Centers for Disease

ControlJohn R. La Montague, PhD, National Institute

of Allergy & Infectious DiseasesN. Noni E. MacDonald, MD, Canadian

Paediatric SocietyWalter A. Orenstein, MD, Centers for Disease

ControlM. Carolyn Hardegree, MD, Food and Drug

Administration

ConsultantsJeffrey R. Starke, MDRichard F. Jacobs, MDRichard J. O’Brien, MD

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AMERICAN ACADEMY OF PEDIATRICS 165

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