tuberculosis%20-%20pulmonary%20(pediatric)
TUBERCULOSIS - PULMONARY (PEDIATRIC)
Tuberculosis (TB) is caused by Mycobacterium tuberculosis, a gram-positive bacteria with slow growth rate that is enhanced by 6-8% carbon dioxide and temperature of 35-40ºC.
It is primarily transmitted through airborne route.
The number of tubercle bacilli expelled in the air by a TB infected person is directly related to their infectiousness.
TB transmission is rare in children <10 years old due to their inability to expectorate sputum and low TB bacilli load in their sputum.
TB infection in children is usually obtained from an infectious adolescent or adult depending on the closeness and length of contact and the index case's severity of lung involvement and infectiousness.

Tuberculosis%20-%20pulmonary%20(pediatric) Treatment

Principles of Therapy

  • Choice of treatment regimen depends on the extent of  tuberculosis (TB) disease, the host, possibility of drug resistance
  • Treatment consists of the intensive phase where actively dividing organisms are efficiently killed and bacillary populations are greatly reduced, and the continuation phase which kills organisms irregularly and slowly, and sterilizes lesions and prevents relapse
    • Intensive phase provides symptom relief, termination of transmission, and prevention of emergence of drug resistance

 PHARMACOLOGICAL THERAPY REGIMEN FOR PATIENTS WITH ACTIVE TUBERCULOSIS
TB Treatment Category Intensive Phase Follow Intensive Phase with Continuation Phase

Category I

  • New smear-positive PTB
  • New smear negative with or without extensive parenchymal involvement
  • Concomitant HIV disease
H + R + Z + E daily x 2 months or
H + R + Z daily x 2 months
H + R daily x 4 months* or
H + E daily x 6 months*

Category II

  • Previously treated sputum smear positive: Relapse, treatment failure or treatment after interruption
Treatment regimen based on drug susceptibility testing (DST) result Treatment regimen based on DST result

Category III

  • New smear-negative PTB other than in category I
H + R + Z daily x 2 months** H + R daily x 4 months or
H + E daily x 6 months

Category IV

  • Chronic case (still sputum positive after supervised re-treatment)
  • Suspected/proven multiple drug-resistant TB
Individualized regimens or specialty designed standard regimens
  • There are several different possible treatment regimens
  • The above shown are the drug regimens recommended by the World Health Organization (WHO)
  • Directly-observed treatment (DOT) is recommended especially during intensive phase and whenever continuation phase contains Rifampicin
  • E = Ethambutol; H = Isoniazid; R = Rifampicin; Z = Pyrazinamide

*May be associated with increased rate of treatment failure and relapse compared with Rifampicin given for 6 months during continuation phase
**In patients with noncavitary, smear-negative pulmonary TB who are known to be HIV negative, Ethambutol may be omitted from the initial phase



Treatment Regimen for New TB Patients

  • Therapy consists of 1st-line anti-TB agents
  • The 6-month Rifampicin-based therapy (2HRZE/4HR) is the recommended approach for drug-susceptible tuberculosis
    • The 4-month fluoroquinolone-based therapy is not recommended

Dosing Formulation and Frequency

  • In the management of drug-susceptible TB, fixed-dose combination tablets are preferred over separate drug formulations
    • In patients with concomitant medical conditions (eg renal dysfunction, liver disease), separate drug formulations are favored in order to adjust the dose for each drug if needed 
  • An everyday type of dosing is preferred for the treatment of drug-susceptible TB
  • The 3x/week dosing, whether in the intensive phase or in the continuation phase, is no longer recommended due to disease recurrence, drug resistance and treatment failure in comparison to everyday dosing
    • DOT should be implemented if 3x/week dosing is to be used
  • Twice-weekly dosing is no longer recommended because of an increase in the noncompliance rate of PTB patients, applicable in both phases of TB treatment
  • Effectiveness of the treatment depends on patient’s adherence to the regimen
  • Adjustment of dosages should be done depending on the patient’s weight, which should be monitored at least once a month

Special Subgroups

  • Infants or children living in places where HIV prevalence or Isoniazid resistance is high, with suspected or confirmed PTB or tuberculous peripheral lymphadenitis, or children with extensive pulmonary disease that live in places with low prevalence of HIV or resistance to Isoniazid should be treated with 2 months of Isoniazid, Rifampin, Pyrazinamide and Ethambutol followed by 4 months of Isoniazid and Rifampin
    • Yields 100% success rate and <2% clinically significant adverse reaction
  • Infants or children with suspected or confirmed PTB or tuberculous peripheral lymphadenitis living in settings with low HIV prevalence or resistance to Isoniazid, and HIV-negative children can be managed with 3-drug regimen consisting of 2 months of Isoniazid, Rifampin and Pyrazinamide followed by 4 months of Isoniazid and Rifampin
  • Intermittent treatment regimen is not recommended in patients with suspected or confirmed PTB or tuberculous peripheral lymphadenitis who live in high HIV prevalence settings

Treatment Supervision

  • Treatment adherence interventions include tracers (home visitation) and/or digital medication monitor (phone calls, messaging), material support (food, transportation fees, monetary allowance, etc), education of staff members and psychological support
  • Treatment administration strategies include Directly Observed Therapy (DOT), non-everyday DOT, video observed treatment (VOT), unsupervised therapy
    • DOT given at home or in the local municipal area is preferred rather than in a health care institution
    • DOT facilitated by health care practitioners or lay people who underwent training are preferred than those provided by relatives and those that are self-administered
    • VOT is an alternative to DOT if video communication technology is available and with proper coordination with healthcare provider

TB Retreatment

  • Patients who need to undergo repeat TB treatment, either due to treatment interruption or disease recurrence, should undergo DST
    • If the test reveals absence of resistance to the 1st-line therapy, the same treatment can be prescribed again
    • If the test reveals resistance to Rifampicin, an MDR-TB treatment regimen should be carried out based on the current recommendations of WHO

Multidrug Resistant Tuberculosis (MDR-TB)

  • Treatment for MDR-TB depends on DST results
    • Perform repeat DSTs prior to administration of fluoroquinolones, 2nd-line injectable agents and other regimen components
  • For patients with Isoniazid-resistant, Rifampicin-susceptible TB, 6-month treatment with Rifampicin, Ethambutol, Pyrazinamide and Levofloxacin is recommended
    • Studies showed that addition of Streptomycin or other injectable agents to an HREZ regimen with <4 months Pyrazinamide reduced likelihood of treatment success and thus is not recommended
  • All patients with confirmed RR-TB should be placed on a MDR-TB treatment regimen
  • For longer MDR-TB regimen, intensive phase should include at least 5 effective drugs and 4 drugs in the continuation phase, with treatment duration of 18-20 months
    • All 3 group A agents and at least 1 group B agent should be included during treatment initiation composed of at least 4 TB agents, and at least 3 agents throughout treatment duration after Bedaquiline (for patients ≥6 years old) is stopped
    • Both group B agents should be included if only 1-2 group A agents are used
    • May consider using an agent belonging to group C if agents from group A and B are unavailable
    • Treatment duration of 15-17 months may be considered after culture conversion
    • An intensive phase with treatment duration of 6-7 months may be considered for patients under regimen containing Amikacin or Streptomycin
  • A shorter MDR-TB treatment regimen (9-12 months) is recommended for RR-TB or MDR TB-resistant patients who have not received treatment for >1 month with any 2nd-line anti-TB agents, and without resistance to fluoroquinolones and/or 2nd-line injectable agents
    • May also add Isoniazid to a conventional MDR-TB regimen for patients proven to be without Isoniazid resistance
    • Patients with disseminated, meningeal or CNS TB or HIV patients with any extrapulmonary disease are disqualified for shorter MDR-TB regimen

Pharmacotherapy

1st-Line Anti-TB Agents
Isoniazid (H)
  • Indicated for all forms of tuberculosis (TB) caused by organisms that are known or presumed to be susceptible
  • Highly bactericidal against replicating tubercle bacilli
  • Baseline or monthly liver function test is recommended in patients with underlying hepatic disease or on concomitant hepatotoxic drugs (eg other antimycobacterial agents, Paracetamol, alcohol)
Rifampicin (R)
  • Indicated for all forms of TB caused by organisms that are known or presumed to be susceptible and also considered to be an essential component of all short-course regimens
  • Has bactericidal action and a potent sterilizing effect against tubercle bacilli in both cellular and extracellular locations
  • Not to be given with Pyrazinamide for short-course latent TB therapy because of risk for serious liver dysfunction
Pyrazinamide (Z)
  • Indicated for all forms of TB caused by organisms that are known or presumed to be susceptible
  • Weakly bactericidal, but has potent sterilizing activity, particularly in macrophages and in areas of acute inflammation
  • Should not be given with Rifampicin for short-course latent TB therapy because of risk for serious liver dysfunction
Ethambutol (E)
  • Generally used in combination with other anti-TB drugs to prevent or delay the emergence of resistant strains
  • May be omitted from the treatment regimen if patient is clear of drug resistance
  • Bacteriostatic at standard dosages but bactericidal at doses >25 mg/kg
  • Not recommended in patients whose visual acuity and color discrimination cannot be monitored reliably
Streptomycin (S)
  • Used in combination with other antituberculous agents for patients with sputum smear-positive patients in relapse, treatment failure or treatment after interruption
Multi-Drug Resistant Tuberculosis (MDR-TB)
Group Classification of Agents Used in the Treatment of MDR-TB
  • Group A: Fluoroquinolones (in order of preference) - Levofloxacin, Moxifloxacin, Gatifloxacin
    • For longer treatment regimens, Bedaquiline and Linezolid are included in this group
    • Gatifloxacin is not included in this group for longer treatment regimens
  • Group B: 2nd-line injectable agents - Amikacin, Capreomycin, Kanamycin, Streptomycin
    • Not recommended for children with mild TB
  • Group C: Other core 2nd-line agents (in order of preference) - Ethionamide/Prothionamide, Cycloserine/Terizidone, Linezolid, Clofazimine
  • Group D: Add-on agents (agents not included in the MDR-TB core regimen):
    • D1: Pyrazinamide, Ethambutol, high-dose Isoniazid
      • May be added if deemed beneficial to patient
    • D2: Bedaquiline, Delamanid
    • D3: Para-aminosalicylic acid, Imipenem-cilastatin, Meropenem, Amoxicillin-clavulanate, Thioacetazone
      • Carbapenems and Clavulanate should be used concomitantly
      • Clavulanate is available only in combination with Amoxicillin
      • Thioacetazone is contraindicated in HIV patients
    • Agents belonging to D2 or D3 may be added if the 4-agent core 2nd-line regimen (composed of drugs from groups A to C) is unattainable
Aminoglycosides
  • Eg Kanamycin, Amikacin, Capreomycin
  • Amikacin is preferred over Kanamycin for intravenous administration
  • Kanamycin and Capreomycin are not recommended in longer MDR-TB treatment regimens
Bedaquiline
  • May only be considered to be included in longer MDR-TB regimens for children >6 years of age with extrapulmonary TB or comorbidities if other therapies are unavailable or ineffective
Cycloserine
  • Belongs to 2nd-line oral treatment option for patients with MDR-TB
Delamanid
  • A dihydro-nitroimidazooxazole that inhibits mycolic acid synthesis and has been approved for the treatment of MDR-TB
  • May now be used in patients ≥3 years of age on longer regimens of MDR-TB and RR-TB therapy
Ethambutol
  • Recommended 1st-line oral treatment for MDR-TB patients
  • Added to H+R+Z therapy in the presence of monoresistance
Ethionamide
  • Belongs to 2nd-line oral treatment option for patients with MDR-TB
Fluoroquinolones
  • Eg Gatifloxacin, Levofloxacin, Moxifloxacin, Ofloxacin
  • May be given to patients with proven or suspected PTB caused by MDR bacilli in the context of a well-functioning MDR-TB control programme and within an appropriate MDR-TB regimen
  • Belongs to group 3 treatment option for patients with MDR-TB
  • Levofloxacin and Moxifloxacin should be included in longer MDR-TB treatment regimens
  • Added to H+R+Z therapy in patients with more extensive and monoresistant TB
Linezolid
  • Should be included in longer MDR-TB treatment regimens
Para-aminosalicylic acid
  • Recommended 2nd-line oral treatment for MDR-TB patients
Other Rifamycins
  • Eg Rifabutin, Rifapentine
  • Rifabutin is a treatment option for patients with intolerance to Rifampicin
    • Also used for patients who are undergoing other treatments that have unacceptable interactions with Rifampicin
  • Rifapentine may be used for patients with latent TB infection
    • May be used as a treatment option for patients with drug-resistant TB but further studies are needed to prove its safety and efficacy
Streptomycin (S)
  • Should be used for the treatment of MDR-TB in children with known drug susceptibility
  • Low to moderate evidence of efficacy in children and injection-based treatment regimen limits its use
Extensively Drug-Resistant Tuberculosis (XDR TB)
  • Treatment for XDR TB should be individualized depending on the patient’s drug susceptibility
  • Therapeutic options are the same as with MDR TB patients
Comorbidities
  • All TB patients with HIV should receive antiretroviral treatment (ART) regardless of their CD4 cell count
    • ART should be introduced within the first 8 weeks of TB therapy and within the first 2 weeks of TB therapy if there is significant immunosuppression (eg CD4 cell count <50 cells/mm3)
    • Patients with HIV and TB meningitis should receive vigilant attention since immediate administration of ART is related to more severe adverse reactions
  • All drug-susceptible TB patients with HIV should take ART preferably for 6 months, instead of ≥8 months, during the period of TB treatment
  • The treatment approach for TB meningitis includes the addition of corticosteroid, (eg Prednisolone, Dexamethasone) in a tapering manner for a period of 6-8 weeks
  • Corticosteroid may also be added in the treatment regimen of tuberculous pericarditis

Surgical Intervention

  • May be considered for patients with Rifampicin-resistant and MDR-TB/XDR TB, in conjunction with pharmacological therapy
  • Elective partial lung resection (lobectomy, wedge resection, pneumonectomy) is preferred
  • Not applicable for patients with HIV, extrapulmonary disease, or for those with XDR TB strains during primary transmission
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