The treatment of tuberculosis in childhood.
Article Type: Clinical report
Subject: Antitubercular agents (Dosage and administration)
Pharmacokinetics (Physiological aspects)
Pharmacokinetics (Research)
Tuberculosis (Diagnosis)
Tuberculosis (Care and treatment)
Tuberculosis (Research)
Author: Donald, Peter R.
Pub Date: 10/01/2007
Publication: Name: South African Medical Journal Publisher: South African Medical Association Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2007 South African Medical Association ISSN: 0256-9574
Issue: Date: Oct, 2007 Source Volume: 97 Source Issue: 10
Topic: Event Code: 310 Science & research
Product: Product Code: 2834850 Tuberculostatic Preparations NAICS Code: 325412 Pharmaceutical Preparation Manufacturing SIC Code: 2834 Pharmaceutical preparations
Geographic: Geographic Scope: South Africa Geographic Code: 6SOUT South Africa
Accession Number: 180219252
Full Text: The treatment of tuberculosis (TB) in children and adults has remained unchanged for more than 30 years, and although new drugs are at last entering clinical trials it will be 5-10 years before their precise place in therapy is established. It is therefore necessary to continue to use our current drugs with care and prudence and be particularly careful about preventing the further development of drug resistance. The principles of treatment in adults and children are the same, but there is an increasing appreciation that the spectrum of disease seen in childhood is different and that children also differ from adults with regard to the pharmacokinetics of drugs.

Drugs differ in their action on different populations of mycobacteria

Several populations of mycobacteria can be identified within TB lesions. (1) Within the walls of cavities there is a large population of actively multiplying organisms. A typical cavity might contain [10.sup.8] bacilli, and this large population increases the probability that mutations will occur that select for drug resistance. Smaller populations of progressively less active or dormant organisms will be found in caseation tissue and within macrophages. Killing the metabolically active organisms is a relatively easy task, and isoniazid (INH) is responsible for the death of 90% of these bacilli within 48 hours. The elimination of the intermittently active or dormant organisms is more difficult and it is failure to sterilise lesions by killing these persistent bacilli that leads to relapse. Drugs that rapidly eliminate the great bulk of metabolically active bacilli are termed bactericidal drugs, and the most active bactericidal agent is INH, with rifampicin (RMP) being about half as active in this respect. (2) Drugs that eliminate persisting intermittently active or dormant bacilli are termed sterilising agents, the most important being RMP and pyrazinamide (PZA); without them 6-month short-course treatment is not possible. INH will also ultimately sterilise lesions but this requires at least a year of treatment.

Essential anti-TB agents

Five drugs, INH, RMP, PZA, ethambutol (EMB) and streptomycin (SM), are regarded as essential agents by the World Health Organization (WHO). (3) RMP, INH and PZA are the most important elements in our current 'first-line' regimen. For most forms of uncomplicated childhood TB these three drugs are adequate. PZA completes most of its activity within the first 2 months of treatment; it is therefore customary to talk of an 'intensive' phase of treatment with INH, RMP and PZA, the main focus being to eliminate the bulk of the bacilli, and a 4-month 'sterilising' or 'continuation' phase with INH and RMP, when the main focus is the elimination of all remaining viable bacilli. When cavitation is present or in the case of more serious forms of disease a fourth drug is advisable, usually EMB or SM. The purpose of the fourth drug is to prevent the development of drug resistance in the face of a much larger bacterial load and prevent the further broadening of the resistance spectrum should initial INH resistance be present. Neither EMB nor SM has much sterilising activity and although EMB is moderately bactericidal at higher doses, SM has very low bactericidal activity, as do the other aminoglycosides, kanamycin (KM) and amikacin (AMK). The ability to prevent resistance in companion drugs is also important, and agents that are highly bactericidal will usually be best able to prevent resistance in other drugs.

Reserve anti-TB agents

In addition to the five 'first-line' drugs mentioned above there are a number of other less effective and often more toxic drugs classified by the WHO as reserve agents for use in drug resistance or in the event of toxicity or intolerance to the first-line agents. These agents include ethionamide (ETH) or prothionamide, KM or AMK, terizidone/cycloserine (CS), capreomycin (CP), viomycin (VM) and para-aminosalicylic acid (PAS). Although they have never been formally evaluated as anti-TB agents, the fluoroquinolones now have a well-established role in the management of drug-resistant TB. There is also considerable interest in the possibility that some of the more recently developed agents such as gatifloxacin or moxifloxacin may contribute to reducing duration of treatment; several studies are under way to evaluate this possibility. (4) Of the two fluoroquinolones available in South Africa at present, ofloxacin is to be preferred to ciprofloxacin.

Multidrug resistance (MDR) in children

MDR in children is fully dealt with in an accompanying paper by Schaaf. (5)

Response to TB treatment in children

One of the main differences between adult and childhood TB is the treatment response. In adult TB this can be measured microbiologically in nearly all cases and relatively little value is accorded to clinical or radiological changes. In much childhood TB we lack such a 'gold standard', but rely on clinical response, weight gain and improvement in radiological features. However radiology can be misleading and some changes, especially mediastinal lymph node enlargement, persist for more than a year after successful treatment completion. (6,7) Persistence of changes does not mean that treatment must be prolonged if there has been improvement in symptoms and weight gain.

Influence of HIV/AIDS on TB treatment in children

As with other aspects of TB, HIV has complicated childhood TB treatment considerably. There is some anecdotal evidence that HIV-infected TB patients may benefit from an extension of TB treatment from 6 to 9 months. (8, 9) Very few data are available with regard to this aspect of TB treatment in children, but in more serious forms of disease it would be prudent to continue INH and RMP until 9 months in HIV-infected children. It must also be kept in mind in planning antiretroviral treatment that RMP has important interactions with some antiretroviral agents. This is particularly true of the non-nucleoside reverse transcriptase inhibitors. If in doubt in this regard, seek advice from those who regularly manage TB in HIV-infected children.

Pharmacokinetics of anti-TB agents in children

In calculating the dosage of drugs for children it is recognised that body surface area provides a more accurate measure of appropriate dose than mg/kg body weight; nonetheless dosages currently recommended by the WHO for TB treatment are the same in adults and children. Several recent studies show that children receiving the same mg/kg body weight doses of anti-TB agents as adults have lower serum concentrations than adults. (10,11) Until this position is resolved it would be wise to calculate dosages for children making use of the upper limits of the suggested ranges.

The dosages recommended by the WHO for the treatment of TB in children and their commonest side-effects are summarised in Table I and the recommended regimens for the different categories of TB in Table II. (3,12) Whenever possible children should be included in one of these categories to ensure the full integration of childhood TB into national programmes. Most children will be sputum or gastric aspirate smear-negative and thus be included in category III. Children presenting in category III with limited lung opacification and non-cavitating disease, without any other complicating factor such as HIV infection, can be treated without EMB. In the case of TB meningitis it is recommended that SM replace EMB, but neither drug has very good entry into the cerebrospinal fluid. In South Africa a regimen of INH, RMP, PZA and ETH, all given for 6 months, has been used with success and a low relapse rate in the management of TB meningitis in children. (13)

INH may cause symptomatic pyridoxine deficiency, so it is recommended that children who are malnourished, HIV-infected children, breastfeeding infants or pregnant adolescents should receive supplemental pyridoxine 5-10 mg/kg/d. (12)

Directly observed therapy, short course (DOTS)

It is the bitter experience of TB services worldwide that a significant proportion of patients fail to comply with treatment recommendations. In the case of children a further element is introduced as young children are dependent on their parents or caregivers for their treatment. As support for patients to encourage completion of treatment as prescribed, the WHO now advocates DOTS. This approach emphasises standardised short-course chemotherapy under proper case management conditions, including direct observation of treatment. This implies technically sound and socially supportive treatment services. While the principles underlying DOTS are clear, their application to children is uncertain, and it has not been established how far a family-orientated approach to TB treatment of children can be adopted, and whether parents or other family members can be reliable treatment supervisors. The application of DOTS to childhood TB requires further study.

Future developments

The HIV/AIDS pandemic has focused attention on the serious nature of the ongoing TB epidemic in developing countries, and the devastating interaction of HIV and TB has dispelled any illusions that TB is under control. Explosive epidemics of drug resistance have exposed the limits of the anti-TB drug armamentarium. There is now an awareness of the urgent need for new anti-TB agents. In 2000 the Global Alliance for TB Drug Development was established to accelerate the development of new anti-TB agents. (14) For the first time in decades there is a promising pipeline of more than 20 compounds in development under the guidance of the Global Alliance or pharmaceutical companies. Several drugs with very promising characteristics during in vitro and in vivo animal studies (15,16) have already completed preliminary studies. However, before they can be used in routine regimens, a considerable amount of work must still be done; at any stage problems may be encountered precluding further development. Therefore, despite a more optimistic outlook than has been justified for several decades, it behoves all concerned about TB control and treatment to use existing regimens and drugs with due care and to do everything possible to prevent the development of drug resistance.

References

(1.) Mitchison DA. Basic mechanisms of chemotherapy. Chest 1979; 76: suppl 6, 771-781.

(2.) Donald PR, Sirgel FA, Venter A, et al. Early bactericidal activity of antituberculosis agents. Expert Rev Anti-infect Ther 2003; 1: 141-155.

(3.) World Health Organization. Treatment of Tuberculosis. Guidelines for National Programmes. Geneva: WHO, 2003. WHO/CDS/2003.313.

(4.) Johnson JL, Hadad DJ, Boom WH, et al. Early and extended bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis 2006; 10: 605-612.

(5.) Schaaf HS. Drug-resistant tuberculosis in children. S Afr Med J 2007; 97: 995-997 (this issue).

(6.) Reis FJC, Bedran MBM, Moura JAR, Assis I, Rodrigues MESM. Six-month isoniazid-rifampin treatment for pulmonary tuberculosis in children. Am Rev Respir Dis 1990; 142: 996-999.

(7.) Al-Dossary FS, Ong LT, Pa-C, Correa AG, Starke JR. Treatment of childhood tuberculosis with a six month directly observed regimen of only two weeks of daily therapy. Pediatr Infect Dis J 2002; 21: 91-97.

(8.) El-Sadr WM, Perlman DC, Denning E, Matts JP, Cohn DL. A review of efficacy studies of 6-month short-course therapy for tuberculosis among patients infected with human immunodeficiency virus: differences in study outcomes. Clin Infect Dis 2001; 32: 623-632.

(9.) Driver CR, Munsiff SS, Li J, Kundamal N, Osahan SS. Relapse in persons treated for drug-susceptible tuberculosis in a population with high coinfection with human immunodeficiency virus in New York City. Clin Infect Dis 2001; 33: 1762-1769.

(10.) Schaaf HS, Parkin DP, Seifart HI, et al. Isoniazid pharmacokinetics in children treated for respiratory tuberculosis. Arch Dis Child 2005; 90: 614-618.

(11.) Donald PR, Maher D, Maritz JS, Qazi S. Ethambutol dosage for the treatment of children: literature review and recommendatiions. Int J Tuberc Lung Dis 2006; 10: 1318-1330.

(12.) World Health Organization. Guidance for National Programmes on the Management of Tuberculosis in Children. Geneva: WHO, 2006 (WHO/HTM/TB/2006.371).

(13.) Donald PR, Schoeman JF, Van Zyl LE, De Villiers JN, Pretorius M, Springer P. Intensive short course chemotherapy in the management of tuberculous meningitis. Int J Tuberc Lung Dis 1998; 2: 704-711.

(14.) O'Brien RJ. Scientific blueprint for tuberculosis drug development. Tuberculosis 2001; 81: suppl 1, 1-51.

(15.) Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005; 307: 23-227.

(16.) Matsumoto M, Hashizume T, Tomishige T, et al. OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLos Med 2006; 3: 2131-2144.

Department of Paediatrics and Child Health, Faculty of Health Sciences, Stellenbosch University and Tygerberg

Children's Hospital, Tygerberg, W Cape

Peter R Donald, MB ChB, DCH (Glasg), DTM&H, FCP (SA), FRCP (Edin), MD

Corresponding author: P R Donald (prd@sun.ac.za)
Table I. World Health Organization recommended dosages and
side-effects of essential antituberculosis agents (3,12)

                  Dose in mg/kg (range)

Drug           Daily          Thrice
                              weekly

Isoniazid      5 (4 - 6)      10 (8 - 12)
               Maximum
               300 mg

Rifampicin     10 (8 - 12)    10 (8 - 12)
               Maximum
               600 mg

Pyrazinamide   25 (20 - 30)   35 (30 - 40)

Ethambutol     20 (15 - 25)   30 (25 - 35)

Streptomycin   15 (12 - 18)   15 (12 - 18)

Drug           Commonest side-effects

Isoniazid      Hepatotoxicity, peripheral neuropathy, less commonly
               optic neuritis or psychosis, concentrations of
               carbamazepine and phenytoin may increase

Rifampicin     Hepatotoxicity, exfoliative dermatitis in HIV-infected
               patients. With intermittent use flu syndrome and
               thrombocytopenia may occur. Induction of enzymes
               increases dosage requirements for corticosteroids, oral
               hypoglycaemic agents, digitalis and other agents

Pyrazinamide   Hepatotoxicity, hyperuricaemia with arthralgia and
               arthritis, particularly of shoulders, hypersensitivity
               reactions, especially flushing of the skin

Ethambutol     Dose-dependent optic neuritis with impairment of visual
               acuity and colour vision. Rare in children at
               recommended doses

Streptomycin   Irreversible auditory nerve damage, hypersensitivity
               reactions

Table II. Regimens recommended by the World Health Organization
for management of tuberculosis (3,12)

                                             TB treatment regimens

                                        Intensive
                                        initial        Continuation
                                        phase (daily   phase (daily
Diagnostic                              or thrice      or thrice
category     TB patient                 weekly)        weekly)

I            New smear-positive         2HRZE          4HR or 6HE daily
             patients; new smear-
             negative PTB with
             extensive lung
             involvement; severe
             concomitant HIV disease
             or severe extrapulmonary
             TB

II           Previously treated         2HRZES/1HRZE   5HRE
             smear-positive PTB
             following relapse,
             treatment after
             interruption or
             treatment failure

III          New smear-negative PTB     2HRZE          4HR or 6HE daily
             (other than category I);
             less severe forms of
             extrapulmonary TB

IV           Chronic and MDR TB         Specialised treatment needed
                                        under the guidance of a
                                        specialist

H = isoniazid; R = rifampicin; Z = pyrazinamide; E = ethambutol;
S = streptomycin. The numerical prefix refers to the length of time
in months. TB = tuberculosis; PTB = pulmonary tuberculosis;
MDR = multidrug-resistant.
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