Anti-Tubercular Drugs Used in Pediatric Patients

Topic Introduction First-Line Drugs Second-Line Drugs Drug Administration Side Effects and Monitoring Special Considerations First-Line Drugs Isoniazid (INH) Rifampicin (RIF) Pyrazinamide (PZA) Ethambutol (EMB) Second-Line Drugs Fluoroquinolones Injectable Agents Ethionamide/Prothionamide Cycloserine Linezolid

Introduction to Anti-Tubercular Drugs in Pediatrics

Tuberculosis (TB) remains a significant global health concern, particularly in children. The treatment of pediatric TB requires a careful approach due to the unique physiological characteristics of children and the potential long-term effects of medications. Anti-tubercular drugs used in children are generally similar to those used in adults, but dosing, formulations, and monitoring may differ.

The primary goals of anti-tubercular therapy in children are:

• To cure the disease and prevent relapse
• To prevent the development of drug resistance
• To minimize toxicity and side effects
• To ensure adherence to the treatment regimen

Treatment typically involves a combination of drugs administered over several months, with the exact regimen depending on factors such as the type of TB (pulmonary or extrapulmonary), drug susceptibility, and the child's overall health status.

First-Line Anti-Tubercular Drugs for Children

The first-line drugs form the cornerstone of TB treatment in children. They are highly effective against drug-susceptible TB and are generally well-tolerated. The main first-line drugs include:

1. Isoniazid (INH):
   • Mechanism: Inhibits mycolic acid synthesis
   • Dosage: 10-15 mg/kg/day (max 300 mg)
   • Key considerations: Hepatotoxicity, peripheral neuropathy (preventable with pyridoxine supplementation)
2. Rifampicin (RIF):
   • Mechanism: Inhibits bacterial RNA synthesis
   • Dosage: 10-20 mg/kg/day (max 600 mg)
   • Key considerations: Potent enzyme inducer, orange discoloration of body fluids
3. Pyrazinamide (PZA):
   • Mechanism: Disrupts membrane energetics and inhibits trans-translation
   • Dosage: 30-40 mg/kg/day (max 2000 mg)
   • Key considerations: Hepatotoxicity, hyperuricemia
4. Ethambutol (EMB):
   • Mechanism: Inhibits arabinosyl transferase
   • Dosage: 15-25 mg/kg/day (max 1000 mg)
   • Key considerations: Optic neuritis (rare in children at recommended doses)

These drugs are typically used in combination, with the standard regimen for drug-susceptible TB consisting of 2 months of HRZE (Isoniazid, Rifampicin, Pyrazinamide, Ethambutol) followed by 4 months of HR (Isoniazid, Rifampicin).

Second-Line Anti-Tubercular Drugs for Children

Second-line drugs are used in cases of drug-resistant TB or when first-line drugs cannot be used due to toxicity or other contraindications. These drugs are generally less effective, more toxic, and require longer treatment durations. Key second-line drugs include:

1. Fluoroquinolones:
   • Examples: Levofloxacin, Moxifloxacin
   • Mechanism: Inhibit DNA gyrase and topoisomerase IV
   • Key considerations: Arthropathy (though less concern in recent studies), QT prolongation
2. Injectable Agents:
   • Examples: Amikacin, Kanamycin, Capreomycin
   • Mechanism: Inhibit protein synthesis
   • Key considerations: Ototoxicity, nephrotoxicity
3. Ethionamide/Prothionamide:
   • Mechanism: Inhibit mycolic acid synthesis
   • Key considerations: Gastrointestinal intolerance, hepatotoxicity
4. Cycloserine:
   • Mechanism: Inhibits cell wall synthesis
   • Key considerations: Neuropsychiatric effects
5. Linezolid:
   • Mechanism: Inhibits protein synthesis
   • Key considerations: Myelosuppression, peripheral neuropathy

The choice and combination of second-line drugs depend on the resistance pattern of the TB strain and should be guided by expert consultation.

Drug Administration in Pediatric TB

Administering anti-tubercular drugs to children requires special considerations:

• Dosing: Based on weight, with regular adjustments as the child grows
• Formulations: Child-friendly formulations (e.g., dispersible tablets, syrups) are preferred when available
• Fixed-Dose Combinations (FDCs): Can improve adherence but may limit dosing flexibility
• Directly Observed Therapy (DOT): Recommended to ensure adherence, especially in longer regimens
• Administration with food: Most drugs can be given with or without food, except for Rifampicin which should be given on an empty stomach when possible

It's crucial to educate caregivers about proper administration techniques and the importance of completing the full course of treatment.

Side Effects and Monitoring

Children generally tolerate anti-tubercular drugs better than adults, but monitoring for adverse effects is essential:

• Hepatotoxicity: Monitor liver function tests, especially with INH, RIF, and PZA
• Visual disturbances: Regular vision checks for children on Ethambutol
• Peripheral neuropathy: Watch for symptoms, especially with INH (preventable with pyridoxine)
• Ototoxicity and nephrotoxicity: Regular audiometry and renal function tests for injectable agents
• Growth and development: Regular monitoring of weight, height, and developmental milestones

Baseline tests and regular follow-ups should be conducted. The frequency of monitoring may vary based on the drugs used and the child's risk factors.

Special Considerations in Pediatric TB Treatment

Several factors require special attention when treating TB in children:

• HIV co-infection: Requires careful management of drug interactions and overlapping toxicities
• Malnutrition: May affect drug metabolism and increase the risk of adverse effects
• Extrapulmonary TB: May require longer treatment duration or adjunctive therapies
• Neonatal TB: Requires specialized management and close monitoring
• Adolescents: May require adult dosing and have unique adherence challenges
• Drug-resistant TB: Requires expert consultation and individualized treatment plans

A multidisciplinary approach involving pediatricians, infectious disease specialists, and public health professionals is often necessary for optimal management of pediatric TB cases.

Isoniazid (INH)

Isoniazid is a cornerstone of first-line anti-tubercular therapy in children.

Mechanism of Action

INH is a prodrug activated by the bacterial enzyme KatG. It inhibits the synthesis of mycolic acids, essential components of the mycobacterial cell wall, leading to bacterial death.

Dosage in Children

• Daily dosing: 10-15 mg/kg/day (maximum 300 mg)
• Intermittent dosing (if necessary): 20-30 mg/kg 3 times per week

Pharmacokinetics

• Absorption: Rapid and complete absorption from the gastrointestinal tract
• Distribution: Widely distributed in tissues and body fluids
• Metabolism: Primarily acetylated in the liver; acetylation rate is genetically determined
• Elimination: Mainly through urine; half-life varies based on acetylator status

Side Effects

• Hepatotoxicity: More common in children over 5 years old
• Peripheral neuropathy: Preventable with pyridoxine (Vitamin B6) supplementation
• Rash: Typically mild and self-limiting
• CNS effects: Rare occurrences of seizures or psychosis

Monitoring

• Baseline and periodic liver function tests
• Clinical monitoring for signs of peripheral neuropathy
• Regular assessment of adherence and potential side effects

Special Considerations

• Pyridoxine supplementation: Recommended for malnourished children, HIV-infected children, and breastfeeding infants
• Drug interactions: May interact with anticonvulsants, particularly phenytoin
• Formulations: Available as tablets, syrup, and in fixed-dose combinations

Rifampicin (RIF)

Rifampicin is a potent bactericidal agent and a crucial component of first-line anti-tubercular therapy.

Mechanism of Action

RIF inhibits bacterial DNA-dependent RNA polymerase, preventing RNA synthesis and subsequently protein synthesis in mycobacteria.

Dosage in Children

• Daily dosing: 10-20 mg/kg/day (maximum 600 mg)
• Intermittent dosing (if necessary): 10-20 mg/kg 3 times per week

Pharmacokinetics

• Absorption: Well absorbed orally, but absorption is reduced by food
• Distribution: Widely distributed in tissues and body fluids, including cerebrospinal fluid
• Metabolism: Hepatic metabolism with enterohepatic circulation
• Elimination: Primarily through bile and feces; some urinary excretion

Side Effects

• Hepatotoxicity: Less common than with INH, but can occur
• Gastrointestinal upset: Nausea, vomiting, abdominal pain
• Orange discoloration of body fluids: Harmless but should be explained to patients/caregivers
• Flu-like syndrome: Rare, usually with intermittent dosing
• Thrombocytopenia: Rare but can be severe

Monitoring

• Baseline and periodic liver function tests
• Complete blood count if symptoms suggest hematologic effects
• Regular assessment of adherence and potential side effects

Special Considerations

• Drug interactions: Potent inducer of cytochrome P450 enzymes, affecting many other medications
• Administration: Ideally given on an empty stomach, but can be given with food if necessary to improve tolerability
• Formulations: Available as capsules, tablets, and in fixed-dose combinations
• Contact lenses: May permanently discolor soft contact lenses

Pyrazinamide (PZA)

Pyrazinamide is a key sterilizing drug in the intensive phase of TB treatment, particularly effective against intracellular bacilli.

Mechanism of Action

PZA is a prodrug converted to pyrazinoic acid, which disrupts membrane energetics and inhibits trans-translation in mycobacteria, particularly in acidic environments.

Dosage in Children

• Daily dosing: 30-40 mg/kg/day (maximum 2000 mg)
• Intermittent dosing (if necessary): 50 mg/kg 3 times per week

Pharmacokinetics

• Absorption: Well absorbed orally
• Distribution: Widely distributed in tissues and body fluids, including cerebrospinal fluid
• Metabolism: Hepatic metabolism to pyrazinoic acid
• Elimination: Primarily through renal excretion

Side Effects

• Hepatotoxicity: Can cause transient elevation of liver enzymes
• Hyperuricemia: Common but usually asymptomatic in children
• Arthralgia: Typically mild and self-limiting
• Gastrointestinal upset: Nausea, vomiting, anorexia
• Photosensitivity: Rare but possible

Monitoring

• Baseline and periodic liver function tests
• Uric acid levels if symptoms of gout appear (rare in children)
• Regular assessment of adherence and potential side effects

Special Considerations

• Duration of use: Typically used only in the intensive phase of treatment (first 2 months)
• Gout: Use with caution in children with a history of gout (though rare in pediatrics)
• Formulations: Available as tablets and in fixed-dose combinations
• Effectiveness: Particularly useful in treating intracellular bacilli and in acidic environments (e.g., within macrophages)

Ethambutol (EMB)

Ethambutol is a bacteriostatic agent used in combination with other first-line drugs, particularly to prevent the development of drug resistance.

Mechanism of Action

EMB inhibits arabinosyl transferase, an enzyme involved in cell wall biosynthesis, specifically interfering with the synthesis of arabinogalactan, an essential component of the mycobacterial cell wall.

Dosage in Children

• Daily dosing: 15-25 mg/kg/day (maximum 1000 mg)
• Intermittent dosing (if necessary): 50 mg/kg 3 times per week

Pharmacokinetics

• Absorption: Well absorbed orally
• Distribution: Widely distributed in body tissues and fluids, but poor penetration into cerebrospinal fluid
• Metabolism: Partially metabolized in the liver
• Elimination: Primarily through renal excretion; dose adjustment needed in renal impairment

Side Effects

• Optic neuritis: Rare in children at recommended doses, but can cause reversible visual impairment
• Color vision changes: May be an early sign of optic neuritis
• Gastrointestinal upset: Nausea, vomiting, abdominal discomfort
• Skin rash: Uncommon
• Peripheral neuropathy: Rare, especially in children

Monitoring

• Baseline and monthly visual acuity and color vision tests in children old enough to cooperate
• Regular questioning about visual changes for all children
• Renal function tests in children with known renal impairment
• Regular assessment of adherence and potential side effects

Special Considerations

• Visual testing: Challenging in young children; careful clinical monitoring is essential
• Renal impairment: Dose adjustment required; consider therapeutic drug monitoring
• Formulations: Available as tablets and in fixed-dose combinations
• Use in young children: Some guidelines recommend avoiding EMB in children too young for reliable visual testing, but WHO supports its use at recommended doses

Fluoroquinolones

Fluoroquinolones are a key component of multidrug-resistant TB (MDR-TB) treatment in children.

Examples

• Levofloxacin
• Moxifloxacin

Mechanism of Action

Fluoroquinolones inhibit bacterial DNA gyrase and topoisomerase IV, enzymes essential for DNA replication, transcription, and repair in mycobacteria.

Dosage in Children

• Levofloxacin: 15-20 mg/kg/day (divided into 1-2 doses)
• Moxifloxacin: 10-15 mg/kg/day (once daily)

Pharmacokinetics

• Absorption: Well absorbed orally
• Distribution: Excellent tissue penetration, including cerebrospinal fluid
• Metabolism: Varies by specific drug; levofloxacin is largely excreted unchanged, while moxifloxacin undergoes some hepatic metabolism
• Elimination: Primarily renal for levofloxacin; mixed renal and hepatic for moxifloxacin

Side Effects

• Gastrointestinal disturbances: Nausea, vomiting, diarrhea
• Central nervous system effects: Headache, dizziness, sleep disturbances
• QT interval prolongation: Particularly with moxifloxacin
• Arthropathy: Historical concern, but recent studies suggest minimal risk in children
• Tendinopathy: Rare but possible, especially in adolescents

Monitoring

• Baseline and follow-up ECG, especially if combined with other QT-prolonging drugs
• Clinical monitoring for musculoskeletal complaints
• Regular assessment of adherence and potential side effects

Special Considerations

• Use in children: Once controversial, now recommended by WHO for MDR-TB in children of all ages
• Drug interactions: May interact with antacids, iron, and dairy products (affecting absorption)
• Formulations: Available as tablets; some have dispersible formulations
• Resistance: Cross-resistance can occur between different fluoroquinolones

Injectable Agents

Injectable agents, also known as aminoglycosides or polypeptides, are used in the intensive phase of MDR-TB treatment.

Examples

• Amikacin
• Kanamycin
• Capreomycin (polypeptide)

Mechanism of Action

These drugs inhibit protein synthesis by binding to the 30S ribosomal subunit in mycobacteria.

Dosage in Children

• Amikacin: 15-20 mg/kg/day (max 1000 mg)
• Kanamycin: 15-20 mg/kg/day (max 1000 mg)
• Capreomycin: 15-20 mg/kg/day (max 1000 mg)

Pharmacokinetics

• Absorption: Poor oral absorption, must be given parenterally
• Distribution: Limited penetration into cerebrospinal fluid
• Metabolism: Minimal metabolism
• Elimination: Primarily through renal excretion

Side Effects

• Ototoxicity: Can cause irreversible hearing loss
• Nephrotoxicity: Renal function impairment, usually reversible
• Electrolyte disturbances: Particularly hypokalemia and hypomagnesemia
• Vestibular toxicity: Vertigo, ataxia
• Pain at injection site

Monitoring

• Baseline and monthly audiometry
• Regular renal function tests and electrolyte monitoring
• Therapeutic drug monitoring when possible
• Clinical monitoring for vestibular symptoms

Special Considerations

• Duration: Generally limited to the intensive phase of treatment (usually first 6-8 months)
• Administration: Can be given intramuscularly or intravenously
• Renal impairment: Dose adjustment required; consider therapeutic drug monitoring
• Newer guidelines: Trend towards avoiding injectable agents in children when possible, due to toxicity concerns

Ethionamide/Prothionamide

Ethionamide and its propyl analog, prothionamide, are oral bacteriostatic agents used in MDR-TB treatment.

Mechanism of Action

These drugs inhibit mycolic acid synthesis, similar to isoniazid, but through a different mechanism.

Dosage in Children

• 15-20 mg/kg/day (max 1000 mg), usually divided into 2-3 doses

Pharmacokinetics

• Absorption: Well absorbed orally
• Distribution: Good penetration into cerebrospinal fluid
• Metabolism: Hepatic metabolism
• Elimination: Primarily renal excretion of metabolites

Side Effects

• Gastrointestinal disturbances: Nausea, vomiting, abdominal pain (very common)
• Hepatotoxicity: Can cause elevated liver enzymes
• Hypothyroidism: Especially when used with para-aminosalicylic acid (PAS)
• Neurological effects: Peripheral neuropathy, optic neuritis (rare)
• Psychiatric disturbances: Depression, anxiety

Monitoring

• Baseline and periodic liver function tests
• Thyroid function tests, especially if used with PAS
• Clinical monitoring for neurological and psychiatric symptoms
• Regular assessment of adherence and gastrointestinal tolerability

Special Considerations

• Gastrointestinal intolerance: Often improves with time; can be mitigated by gradual dose escalation
• Pyridoxine supplementation: Recommended to reduce risk of neurological side effects
• Formulations: Available as tablets; no pediatric formulations widely available
• Cross-resistance: Complete cross-resistance between ethionamide and prothionamide

Cycloserine

Cycloserine is an oral bacteriostatic agent used as part of MDR-TB regimens.

Mechanism of Action

Cycloserine inhibits cell wall synthesis by interfering with the enzymes D-alanine racemase and D-alanine:D-alanine ligase.

Dosage in Children

• 10-20 mg/kg/day (max 1000 mg), usually divided into 2 doses

Pharmacokinetics

• Absorption: Well absorbed orally
• Distribution: Good penetration into cerebrospinal fluid
• Metabolism: Minimal metabolism
• Elimination: Primarily renal excretion

Side Effects

• Neuropsychiatric effects: Headache, irritability, depression, psychosis
• Seizures: Can lower seizure threshold
• Peripheral neuropathy
• Skin reactions: Rash, allergic dermatitis

Monitoring

• Close clinical monitoring for neuropsychiatric symptoms
• Consider therapeutic drug monitoring if available
• Regular assessment of adherence and side effects

Special Considerations

• Pyridoxine supplementation: Recommended to reduce risk of neurological side effects
• Use with caution: In patients with a history of seizures, psychiatric illness, or substance abuse
• Renal impairment: Dose adjustment required
• Drug interactions: Can interact with alcohol, increasing risk of seizures

Linezolid

Linezolid is an oxazolidinone antibiotic increasingly used in MDR-TB and extensively drug-resistant TB (XDR-TB) treatment in children.

Mechanism of Action

Linezolid inhibits protein synthesis by binding to the 50S ribosomal subunit, preventing the formation of the 70S initiation complex.

Dosage in Children

• 10-12 mg/kg/day for children <12 years (max 600 mg)
• 10 mg/kg/day for children ≥12 years (usually 600 mg once daily)

Pharmacokinetics

• Absorption: Well absorbed orally
• Distribution: Good tissue penetration, including cerebrospinal fluid
• Metabolism: Hepatic metabolism, primarily through oxidation
• Elimination: Primarily renal excretion of metabolites

Side Effects

• Myelosuppression: Particularly anemia and thrombocytopenia
• Peripheral neuropathy: Can be irreversible
• Optic neuropathy: Can lead to vision loss if not recognized early
• Lactic acidosis: Rare but serious
• Gastrointestinal disturbances: Nausea, vomiting, diarrhea

Monitoring

• Regular complete blood counts
• Clinical monitoring for symptoms of peripheral neuropathy
• Regular vision checks
• Consider therapeutic drug monitoring if available

Special Considerations

• Duration of treatment: Risk of toxicity increases with prolonged use
• Dosing strategies: Some regimens use lower doses or intermittent dosing to reduce toxicity
• Drug interactions: Potential serotonergic interactions with certain antidepressants
• Formulations: Available as tablets and oral suspension

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