CONTENTS




KINDLY
SUPPORTED BY










Treatment
The treatment of children with active TB and latent TB infection includes both medical treatment of the individual patient and the activities of the health department. Because of the high risk of disseminated tuberculosis in infants and children younger than 5 years of age, treatment should be started as soon as the diagnosis of tuberculosis is suspected. Unfortunately, although there is a lower bacillary burden in childhood-type tuberculosis, the regimens recommended for adults are also the regimens of choice for infants, children and adolescents with tuberculosis with the exception that ethambutol is not used routinely in children.

In vitro and probably in vivo, the likelihood of a population of M.tuberculosis organisms developing resistance to any single antituberculosis drug depends primary upon the size of the bacillary population. With larger populations, as found in most forms of tuberculosis disease, treatment with a single drug leads to growth of organisms genetically resistant to the drug that occur at a predictable frequency, resulting in relapse of drug-resistant tuberculosis. With smaller populations, as in tuberculosis infection, genetically resistant organisms are statistically unlikely to be present and treatment with a single drug is effective. A simple adage for tuberculosis is “More bugs, more drugs”. Because antituberculosis drugs are so well-tolerated by children and inadequate treatment of tuberculosis can have devastating effects, it is usually safer to overestimate rather than underestimate the extent of disease, particularly in the young child known to be at high risk for recent infection by M.tuberculosis. Regimens using twice weekly treatment after 4-8 weeks daily therapy, under the direct observation of a health care worker are as safe and effective as those using daily therapy.


Antituberculosis drugs
Treatment is aimed at the eradication of bacilli, prevention of complications and avoidance of drug resistance. A key point in the treatment of M.tuberculosis infections is to supply the proper medications in proper doses for an appropriate amount of time. In vitro observations and results of clinical therapy trials have lead to a hypothesis concerning the behavior of the organism within the host and the actions of various antimycobacterial drugs and drug combinations. Within the host, tubercle bacilli can survive in several environments, open cavities, closed caseous lesions and inside macrophages. Today, the goal of therapy is to attack the bacillus with a combination of bactericidal medications that exert their effect in all of the organism’s potential environments.

Isoniazid, Rifampin and Pyrazinamide have become the backbone of antituberculosis therapy. Ethambutol and Streptomycin complete the arsenal of the most common antituberculosis medications used in children.


Isoniazid (INH)
Isoniazid is the most widely used of the antituberculosis agents. It is bactericidal, relatively non-toxic, easily administrated and inexpensive. It is highly active against M.T. Most strains of M.tuberculosis are inhibited in vitro by a concentration of 0.05 to 0.20 μg/ml and a usual dose of 3 to 5 mg/kg body weight in adults produces a peak concentration of approximately 5 μg/ml. Absorption from the gastrointestinal tract is nearly complete. The drug penetrates well into all body fluids and cavities, producing concentrations similar to those found in serum.

For children, it is preferable to use the tablets instead of the suspension because the latter may cause diarrhea. The tablets may be crashed and given with food.

Pyridoxine replacement is not routinely indicated for children, except malnourished infants and adolescents. The major toxicity related to INH is hepatic toxicity. As many as 10% of children will experience elevated serum aminotransferase levels while taking the medication. These liver enzyme abnormalities are rarely severe and most children can be followed with clinical signs and symptoms instead of routine biochemical monitoring.


Rifampin (RIF)
Rifampin is bactericidal for M.tuberculosis. It is quickly absorbed from the gastrointensinal tract, with peak serum concentrations (of 6-7 μg/ml) occuring 1.5 to 2 hours after ingestion. If the suspension is used, it should only be taken without food due to its erratic absorption. Most strains of M.T. are inhibited in vitro by concentrations of 0.5 μg/ml. Although approximately 75% of the drug is protein-bound, it penetrates well into tissues and cells. Penetration through noninflamed meninges is poor, but therapeutic concentrations are achieved in cerebrospinal fluid when the meninges are inflamed.

The most common side effect from RIF is gastrointestinal upset. Other reactions include skin eruptions, hepatitis and occasionally thrombocytopenia or cholestatic jauntice. Rifampin is excreted in urine, tears, sweat and other body fluids. These body fluids will become orange and contact lenses will become discolored while on medication.

Because RIF induces hepatic microsomal enzymes it may accelerate clearance of drugs metabolized by the liver. These include methadone, glycocorticoids, estrogens, oral hypoglycemic agents, digitoxin, antiarrythmic agents, ketoconazole and cyclosporin.


Pyrazinamide (PZM)
Pyrazinamide is bactericidal for M. Tuberculosis in an acid environment. This antituberculosis agent exerts its maximal effect during the early phase of therapy (2 months) rather than throughout the treatment course. It is absorbed very well from the gastrointestinal tract, with peak serum concentrations occurring approximately 2 hours after ingestion. Serum concentrations range from 30-50 μg/ml with doses of 20-25 mg/kg and penetrates well into most tissues, including the CSF. At a pH of 5,5 the minimal inhibitory concentration of PZM for M.T. is 20 μg/ml. Pyrazinamide is active against intracellular M.tuberculosis, because of the acid environment within the cell. Liver dysfunction, gastrointestinal upset and skin rashes can be seen with PZM administration. Hyperuricemia occurs frequently, occasionally accompanied by arthralgia but acute gout is uncommon in children.


Ethambutol (EMB)
Ethambutol in usual doses of 15 to 20 mg/kg is generally considered to have a bacteriostatic effect on M.tuberculosis. It may have a bactericidal effect when given in the higher dosage used for intermittent therapy. It is easily administered and well absorbed, but penetrates poorly into the CSF, even in inflamed meninges.

Ethambutol is used primarily when there is a high likelihood of primary resistance.

Retrobulbar neuritis is the most frequent and serious adverse effect of EMB. Symptoms include blurred vision, central scotomata and red-green color blindness. This complication is dose-related, occuring in less than 1% of persons given a daily dose of 15 mg/kg and increasing with a daily dose of 25 mg/kg. Patients should be informed to report any change in vision. In children who are too young for assessment of visual aquity and red-green color discrimination, EMB should be used with particular caution.


Streptomycin (STM)
Is bactericidal in an alkaline environment. The drug must be given parenterally. With a dose of 15 mg/kg the peak concentration is in the range of 40 μg/ml. Most strains of M.tuberculosis are inhibited in vitro at a concentration of 8 μg/ml. Excretion is almost entirely renal and for this reason should be used in reduced dosage and with extreme caution in patients with renal insufficiency.

The drug has good tissue penetration; however, it enters the CSF only in the presence of meningeal inflammation.

The most common side effect of STM is ototoxicity. This usually results in vertigo, but hearing loss may also occur. The drug has less adverse effects on the kidneys than the capreomycin, but nephrotoxicity occasionally occurs.


Corticosteroids
Because of enzyme induction the maintainance dose of corticosteroid taken for other conditions should be increased if RIF is used.

There are several indications for the use of corticosteroids as an adjuvant in the treatment of tuberculosis. Corticosteroids are beneficial in the management of tuberculosis in children when the host inflammatory reaction is contributing significantly to tissue damage or impairment of function. There is convincing evidence that corticosteroids decrease mortality rates and long-term neurologic sequelae in patients with TB meningitis by reducing vasculitis, inflammation and intracranial pressure. Children with enlarged hilar lymph nodes that compromise the tracheobronchial tree, causing respiratory distress, localised emphysema or collapse-consolidation lesions, frequently benefit from corticosteroid therapy. Other forms of tuberculosis that may improve with corticosteroids include miliary disease with alveolar-capillary block, pleural and pericardial effusion, “toxic” symptoms of tuberculosis, (high fever, anorexia, failure to thrive) and in tuberculosis affecting the ureter. Initial dose of prednisolone or prednisone is 1-2 mg/kg per day for 4-6 weeks, with gradual tapering over 2-4 weeks depending on the degree of local regression. In meningitis, some experts prefer Dexamethasone (0.2 mg/kg for the same time period).


Treatment regimens
The list of drugs with activity against tuberculosis includes INH, RIF, PZM as first line drugs and capreomycin, ciprofloxacin, clarithromycin, cycloserine, ethionamide and STM as second line. (tables 1 and 2).

Table 1: Commonly used drugs for the treatment of tuberculosis in infants, children and adolescents.
DrugDosageDaily dose2-3 times weekly dose*Major Adverse Reactions
Isoniazid*Scored tablets 100 or 300 mg
Syrup 10mg/ml
10-20 mg/kg ** PO/IV, maximum 300 mg 20-40 mg/kg, maximum 900 mg Elevated liver transaminases, hepatitis, peripherial neuropathy
RifampinCapsules 150 or 300mg
Syrup 10 mg/ml
10-20 mg/kg PO/IV, maximum 600 mg10-20 mg/kg, maximum 600 mg Orange coloration of body fluids, vomiting, hepatitis, thrombocytopenia, influenza-like illness
PyrazinamideScored tablets 500 mg 20-30 mg/kg PO, maximum 2 gr40-50 mg/kg PO, maximum 3 grHyperuricemia, skin rash, joint involvement, hepatotoxity
EthambutolTablets 100 or 400 mg15-25 mg/kg PO, maximum 2,5 g25-50 mg/kg PO, maximum 2,5 gRash, vision loss, color blindness
* The rate of hepatitis increases in proportion to increasing age and dose of INH.
** 5-10 mg/kg according to the British Thoracic Society, WHO and IUATLD

Table 2: Recommended Second-line Drugs for Pediatric tuberculosis
DrugDosageDaily doseMaximum Dose (g)Major Adverse Reactions
CapreomycinVial (1 g) 15-30 mg/kg IM 1 Ototoxity, nephrotoxity
CiprofloxacinTablets 100, 250, 500 or 750 mg20-30 mg/kg PO in 2 divided doses1.5 Gastrointestinal disturbances, headache, psychosis, photosensitivity rash
CycloserineCapsules 250 mg 15-20 mg/kg PO in 2 divided doses1Psychosis, personality changes, seizures, rash
EthionamideTablets 250 mg15-20 mg/kg in 2 divided doses1Gastrointestinal disturbances, hepatoxicity, hypersensitivity reaction
KanamycinVial 75 mg, 500mg, 1g15-30 mg/kg IM1Ototoxity, nephrotoxicity
Para-aminosalicylic acidTablets 500mg, 1g
Bulk powder
Delayed-release granules
150-200 mg/kg PO10Gastrointestinal disturbances, hepatoxicity, hypersensitivity reaction

Table 3: Recommended treatment for pulmonary and extrapulmonary tuberculosis in children
DiseaseDuration (months)Initial DrugsContinuation
Pulmonary6INH+RIF+PZA 2 months, dailyINH+RIF 4months, daily or 2 x weekly
 6INH+RIF+PZA 2 months, 2 x weeklyINH+RIF 4months, 2 x weekly
 6INH+RIF+PZA 3 x weekly 
 9INH+RIF daily  
 9INH+RIF 1 month, dailyINH+RIF 8 months, 2 x weekly
Cervical adenopathy6As for pulmonaryAs for pulmonary
Extra-pulmonary12INH+RIF+PZA+EMB or STM 2 months, daily INH+RIF 10 months, daily or 2 x weekly
MDR-TB18-243-6 drugs daily 
HIV infection6-12INH+RIF+PZA (+EMB for 2 months) 

A.Management of children who are in close contact with smear positive adults (Primary chemoprophylaxis)

Young children who are exposed to a household contact with smear-positive pulmonary tuberculosis are at high risk for developing both infection and disease. Young children (less than 2 years for BTS, less than 4 years for ATS/CDC and less than 5 years for WHO), who are thus exposed should begin INH chemoprophylaxis irrespective of the TST at baseline. Tuberculin Skin Test is repeated at 12 weeks. If the TST is positive in baseline or becomes positive on re-testing, then the duration of therapy should be that for tuberculosis infection. Although the WHO has made the recommendation of providing chemoprophylaxis to children younger than 5 years old, it remains unclear to what extent this recommendation is being followed in areas of high tuberculosis incidence. In industrialized countries with low tuberculosis incidence we believe that, children and adolescents who are TST-negative, but who have been in close contact with infected persons, should be considered for preventive therapy. Disease could be prevented in 60% of the infected children in this group if we administer INH for just 3 months, and we believe that this policy is justified considering that INH is cost-effective and safe.

Β. Treatment of tuberculosis infection (secondary chemoprophylaxis or treatment of latent tuberculosis infection or treatment of subclinical tuberculosis)

Tuberculosis infection occurs when the individual inhales airborne droplet nuclei carrying M.tuberculosis and the organism becomes intracellular within the lung, associated lymphoid tissue and other sites such as CNS, bones, joints, kidneys etc. Preventive therapy is indicated in all children and adolescents with tuberculous infection without disease.

The purpose of treating asymptomatic tuberculosis infection is to prevent the development of tuberculosis in the forthcoming or distant future. At the present the ultimate goal of tuberculosis services should be the eradication of M.tuberculosis, and to date, only diseases for wich effective vaccines are available have been eradicated. As tuberculosis in children is rarely sputum smear-positive, this has lead many to believe that children are not important in tuberculosis control. This is a misconseption, because mainly in industrialized countries with low incidence of tuberculosis, infected untreated children constitute the pool of tuberculosis of the future.

Τreatment of tuberculosis infection, involves the use of one or two antituberculosis agents. Many studies have shown that INH for 12 months is highly effective, as well as shorter courses of 6-9 months duration. A 6-month regimen of INH is generally recommended in the U.K, although ATS/CDC recommends a 9-month course. Regimens of INH plus RIF lasting for 3 months have been used in the U.K. with good effect and no increased adverse reactions. This form of chemoprophylaxis is applied since 1995 in our clinic with good compliance and excellent results in 530 patients.

Two months of RIF+PZM has been shown to be as efficacious as 12 months of INH in HIV-infected individuals. However, reports of fatal and severe liver injuries with this combination means that it should be used with caution in adults and not used in children.


Images from Greece...