Therapies for Childhood Tuberculosis – Current and
Future Approaches
Cristina Pierry, M.D.
Division of Pediatric Pulmonology
Clinica Alemana de Santiago
Santiago, Chile
cpierry@alemana.cl
Tuberculosis (TB) in Children is an important cause of morbidity and mortality.
Multiple therapeutic regimens for different clinical manifestations are in use. The World
Health Organization (WHO) has suggested a category-based treatment that has its focus
on adult type of TB (1).
DOTS (directly observed therapy, short-course) has become the cornerstone for TB
control across the world. There are five key elements for treatment:
1) Government commitment to sustained TB control
2) Case detection by sputum smear microscopy
3) Standardized treatment regimens for all confirmed smear-positive cases
4) Regular uninterrupted supply of essential anti-TB drugs
5) A standardized recording and reporting system
DOTS has been adopted by 148 of 210 countries around the world (2).
The main objectives in TB treatment are:
1) To cure the patient of TB (by rapidly eliminating most of the bacilli)
2) To prevent death from active TB or its late effects
3) To prevent relapse of TB (by eliminating the dormant bacilli)
4) To prevent development of drug resistance (by using a combination of drugs)
5) To reduce transmission of TB (1).
Anti-tuberculosis drugs:
TB treatment is divided into two phases:
• An intensive initial multidrug phase that aims at killing of the majority of viable
bacilli and preventing the emergence of drug resistance.
• A continuation phase: aims at sterilization of TB lesions and prevention of
relapse by eradicating the dormant organisms. Fewer drugs are generally used.
The action of anti-TB drugs on these different populations may be bactericidal or
sterilizing (or both). Bactericidal activity refers to the agent’s ability to rapidly kill
the actively metabolizing organisms in the sputum of patients with pulmonary TB.
Agents can be compared by determining their “Early bactericidal activity” (EBA),
defined as the fall in viable colony-forming units (cfu) of Mycobacterium
tuberculosis per ml of sputum per day during the first 2 days of treatment (3).There
are five “first line” anti-TB agents that have been in use for over 30 years: Isoniazid
(INH, H); Rifampicin (RMP, R); Pyrazinamide (Z); Ethambutol (EMB, E) and
Streptomycin (S).
Regimens: Most children are not smear-positive and do not require four drugs in the
initial intensive phase; those who are smear-positive or have a visible cavity on chest
radiograph have a high bacillus count and should be treated with four drugs. Also those
with severe disease such as extensive lung disease, meningitis or disseminated and
Spinal TB with neurological signs, are managed with four drugs in the intensive phase.
There is a standard code for TB treatment regimens (4). (Table 1)
Table 1. - Recommended treatment regimens for each diagnostic category based
on WHO recommendations:
Daily
Three times a
Regimen
week regimen
TB diagnostic TB cases
Intensive
Continuation
category
phase
phase
III
New smear- negative PTB. Less
2HRZ
4HR or 6HE
severe forms of EPTB
I
New smear- positive PTB
2HRZS (or
4HR or 6HE
New smear-negative PTB with
E)
extensive parenchymal
involvement
Severe forms of EPTB
Severe concomitant HIV disease
I
TB meningitis
2RHZS
7RH
Disseminated TB
Spinal TB
II
Previously treated smear-positive 2RHZS
4RH
PTB
IV
Chronic and MDR-TB
Specially
Specially designed
designed
TB: tuberculosis; PTB: pulmonary tuberculosis; EPTB: extra-pulmonary tuberculosis;
H: isoniazid; R: rifampicin; Z: pyrazinamide; E: ethambutol; S: streptomycin; HIV: human
immunodeficiency virus; MDR-TB: multidrug resistant TB; The number in front of each phase
represents the duration of that phase in months.
Doses: The need for better data on anti-TB drug pharmacokinetics in children is
highlighted by the variations in national recommendations for drug doses, particularly
those related to INH. Based on several studies it appears that dosage calculations of
RPM and EMB are more valid based on body surface area rather than body weight, the
latter may be leading to higher doses. Most of the guidelines worldwide recommend the
same doses (5). (Table 2)
Table 2. - Doses of first line anti-TB drugs in children in mg/kg body weight
(range) and varying regimens (1).
Drug
Daily regimen
Three time/ week
regimen
Isoniazid
5 (4 – 6) max 300 mg
10 (8 – 12)
Rifampicin
10 (8 – 12) max 600 mg
10 (8 – 12)
Pyrazinamide 25 (20 – 30)
35 (30 – 40)
Ethambutol
20 (15 – 25)
30 (25 – 35)
Streptomycin 15 (12 – 18)
15 (12 – 18)
•
Isoniazid: remains the most important agent, because of its high EBA,
outstanding pharmacokinetics and relatively low toxicity. It is rapidly absorbed
and has excellent penetration into most body compartments. It is the first agent
against which resistance develops. Recent pediatric studies suggest higher doses
of INH per kilogram of body weight to achieve similar concentration to those in
adults (6).
•
Rifampicin: is a key drug in chemotherapy because it rapidly kills the majority
of bacilli in TB lesions and prevents relapse, it has moderate EBA. Absorption is
influenced by gastric pH. Pharmacokinetic studies of higher dosages in children
are urgently needed (7).
•
Pyrazinamide: has favorable pharmacokinetics and penetrates most tissues,
including cerebrospinal fluid; serum levels are related to body weight.
Resistance is uncommon but modern studies with molecular methodologies
suggest that the prevalence of resistance to PZA may be higher than previously
appreciated (3).
•
Ethambutol: Inhibits cell-wall biosynthesis and is effective against actively
growing M. Tuberculosis. A review of recent publication showed that children
have significantly lower peak serum concentrations than adults receiving the
same dose; additionally use of higher dose of EMB does not increase ocular
toxicity. The recommended dose in children is 20 mg/kg (8-9).
•
Streptomycin: An aminoglycoside, has the highest bactericidal activity in vitro
of any anti-TB agent, though it has low EBA. Its aim is to prevent resistance to
companion drugs. It can cause otovestibular damage and nephrotoxicity.
•
Corticosteroids: While not an anti-TB agent per se, is used in meningitis,
endobronchial TB, enlarged lymph nodes that compress the tracheobronchial
tree, localized emphysema, or severe pulmonary disease. It can also be used in
tamponade with TB-related pericardial effusion. The most frequently used drug
is prednisone, at a dose of 1 to 2 mg/kg/day for 4 to 6 weeks with gradual
tapering (dose should be reduced over 1 – 2 weeks before stopping) (1).
Adverse effects: Are less common than in adults. The most frequent is hepatotoxicity,
which can be caused by INH, RMP or Z. An asymptomatic mild elevation of serum
liver enzymes is not an indication for cessation of treatment, but hepatomegaly and
jaundice should lead to discontinuation of the potentially hepatotoxic drugs. If treatment
needs to be completed, non-hepatotoxic drugs should be utilized, such as: ethambutol,
an aminoglycoside and a fluoroquinolone.
INH may cause symptomatic pyridoxine deficiency, particularly in severely
malnourished children and HIV-infected children on highly active antiretroviral therapy.
Supplemental pyridoxine (5 – 10 mg/day) is recommended in such cases.
Latent infection:
Treatment of latent TB infection or chemoprophylaxis is important to prevent future
disease activation. WHO guidelines recommend that children under 5 years of age in
close contact with an infectious case receive 6 months of INH once active disease has
been excluded; recent studies suggest that 3 months of combined INH and RPM is
equally effective (10). Another trial recommends 4 months of RMP because of fewer
adverse events (11).
Second line drugs:
Treatment is further complicated by the emergence of multidrug resistant TB (MDRTB) and by the infection’s synergy with HIV/AIDS. Patients with MDR-TB must be
treated with a combination containing second-line drugs that are less effective, more
expensive, and more toxic:
•
Fluorquinolones: wide-spectrum antibiotics. The most used are ciprofloxacin
and ofloxacin, but new studies of levofloxacin, gatifloxacin and moxifloxacin
have shown high EBA similar to INH (12). Caution should be exercised with the
use of these medications since recent data suggest that they could lead to
emergence of invasive pneumococcal disease (13). Recommended dose of
ciprofloxacin is 30-50 mg/kg given twice a day. More studies about
pharmacokinetics of the rest of fluorquinolones in children are required in order
to recommend safe doses.
•
Thioamides: Ethionamide (ETH) and Prothionamide: two different
presentations of the same active substance. The mechanism of action is similar
to INH; they inhibit mycolic acid synthesis, with similar pharmacokinetics for
both preparations. Recommended dose: 15 – 20 mg/kg.
•
Aminoglycosides: Kanamycin or Amikacin (AM): both have similar structure
and low efficacy, AM is less ototoxic and preferred in children (15 – 20 mg/kg).
•
Terizidone/Cycloserine: Terizidone is a combination of two molecules of
cycloserine. Moderately active and bacteriostatic. Side effects are associated
with the central nervous system and include depression (15 – 20 mg/kg).
•
Capreomycin (CM) and Viomycin: macrocyclic peptide antibiotics with
similar structure, administered intramuscularly. Not recommended below 14
years of age (20 mg/kg).
•
Para-aminosalicylic acid: Is one of the oldest anti-TB drugs. It is a weak agent,
and produces severe gastrointestinal discomfort (150 mg/kg).
Multidrug-resistant TB:
Organisms that are resistant to both INH and RPM, with or without resistance to
other anti-TB drugs. Treatment is therefore difficult, some principles are as follows:
• Treat the child according to drug susceptibility testing (DST) of the source
case’s strain. Do not just add a new drug to a failing regimen
• Use at least four drugs that are certain to be effective
• Use daily treatment only, and DOTS is essential
• Follow up is important
• Treatment duration for most cases will be 12 months or more.
• Use second line drugs in correct dosing to avoid long-term adverse effects (1).
Future Developments:
For the first time in decades, there is now a promising pipeline of more than 20
compounds in various stages of development under the guidance of Global Alliance.
New anti-tuberculosis drugs are being developed and several have entered
preliminary clinical trials. Of these the following appear to be of particular value:
•
Rifapentine: recently approved and has not yet been widely used in clinical
settings, inhibits bacterial DNA-dependent RNA polymerase; this is unique
mechanism that is advantageous because it occurs even when enzyme exposure
to drug is very brief in otherwise metabolically dormant organisms. It should be
given with INH during continuation phase of treatment. Not recommended in
HIV patients and in children aged < 12 years; the half-life is long, which allows
once – weekly dosing. (600 mg) (14).
•
Diarylquinoline TMC207: Offers a new mechanism of anti-TB action by
inhibiting mycobacterial ATP synthase. In vitro, potently inhibits drug-sensitive
and drug-resistant M. tuberculosis isolates, it also has bactericidal effect against
dormant tubercular bacilli. Safety and efficacy findings in some studies validate
this treatment in patients with MDR –TB (15).
•
OPC-67683, A Nitro-Dihydro-Imidazooxazole derivative: Mycolic acid
biosynthesis inhibitor, free of mutagenicity and posseses high activity against
TB, including MDR-TB, as shown by its exceptionally low minimum inhibitory
concentration in vitro and highly effective therapeutic activity at low doses in
vivo (16).
References:
1) World Health Organization. Guidance for national tuberculosis
programmes on the management of tuberculosis in children.
WHO/HTM/TB/2006.371, 10-31. 2006
2) Shingadia D, Novelli V. Diagnosis and treatment of tuberculosis in
children. Lancet Infect Dis. 2003 Oct;3(10):624-32
3) Donald PR, Schaaf HS. Old and new drugs for the treatment of
tuberculosis in children. Paediatr Respir Rev. 2007 Jun;8(2):134-41
4) Stop TB Partnership Childhood TB Subgroup World Health
Organization. Guidance for National Tuberculosis Programmes on the
management of tuberculosis in children. Chapter 2: Anti – tuberculosis
treatment in children. Int J Tuberc Lung Dis. 2006 Oct;10(10):1091-7
5) Newton SM, Brent AJ, Anderson S, et al. Paediatric tuberculosis. Lancet
Infect Dis. 2008 Aug;8(8):498-510
6) McIlleron H, Willemse M, Werely CJ, et al. Isoniazid plasma
concentrations in a cohort of South African children with tuberculosis:
implications for international pediatric dosing guidelines.Clin Infect Dis.
2009 Jun 1;48(11):1547-53.
7) Schaaf HS, Willemse M, Cilliers K, et al. Rifampin pharmacokinetics in
children, with and without human immunodeficiency virus infection,
hospitalized for the management of severe forms of tuberculosis. BMC
Med. 2009 Apr 22; 7:19
8) Donald PR, Maher D, Maritz JS et al. Ethambutol dosage for the
treatment of children: literature review and recommendations. Int J
Tuberc Lung Dis. 2006 Dec;10(12):1318-30
9) Thee S, Detjen A, Quarcoo D et al. Ethambutol in paediatric
tuberculosis: aspects of ethambutol serum concentration, efficacy and
toxicity in children. Int J Tuberc Lung Dis. 2007 Sep;11 (9):965-71
10) Ena J, Valls V. Short-Course therapy with rifampin plus isoniazid,
compared with standard therapy with isoniazid, for latent tuberculosis
infection: a meta-analysis. Clin Infect Dis. 2005;40:670-6
11) Menzies D, Long R, Trajman A, et al. Adverse Events with 4 Months of
rifampin therapy or 9 months of isoniazid therapy for latent tuberculosis
infection: a randomized trial. Ann Intern Med. 2008 Nov
18;149(10):689-697
12) 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 Jun; 10(6):605-612
13) Von Gottberg A, Klugman KP, Cohen C et Al. Emergence of
levofloxacin-non-susceptible Streptococcus pneumoniae and treatment
for multidrug-resistant tuberculosis in children in South Africa: a cohort
observational surveillance study. Lancet. 2008 Mar 29;371(9618):110813
14) Munsiff SS, Kambili C, Ahuja SD. Rifapentine for the treatment of
pulmonary tuberculosis. Clin Infect Dis. 2006 Dec 1;43(11):1468-75
15) Diacon AH, Pym A, Grobusch M, et al. The Diarylquinoline TMC207
for Multidrug-Resistant Tuberculosis. The New England Journal of
Medicine. 2009 Jun;360(23):2397-2405
16) Matsumoto M, Hashizume H, Tomishige T, et al. OPC-67683, a nitrodihydro-imidazooxazole derivative with promising action against
tuberculosis in vitro and in mice. PloS Med 2006; 3:2131 – 2144