Drug Resistant TB

Introduction

Drug-resistant tuberculosis (DR-TB) presents a formidable challenge to global tuberculosis control, particularly in pediatric populations. In children, DR-TB is largely a result of primary transmission from an infectious adult contact with drug-resistant disease, rather than acquired resistance due to poor adherence, which is more common in adults. The prevalence of MDR-TB in children mirrors that of adults in the same population. The management of DR-TB has undergone a paradigm shift with the introduction of Universal Drug Susceptibility Testing (U-DST), shorter all-oral regimens, and the approval of newer potent drugs like Bedaquiline and Delamanid for pediatric use.

1. Classification and Definitions (NTEP 2022)

Understanding the precise definitions is crucial for designing appropriate treatment regimens.

• Rifampicin Resistant TB (RR-TB): Resistance to Rifampicin detected using phenotypic or genotypic methods, with or without resistance to other anti-TB drugs.
• Multidrug-Resistant TB (MDR-TB): Resistance to both Isoniazid (H) and Rifampicin (R).
• Isoniazid-Resistant TB (Hr-TB): Resistance to Isoniazid but susceptibility to Rifampicin confirmed.
• Pre-Extensively Drug-Resistant TB (Pre-XDR-TB): MDR/RR-TB plus resistance to any Fluoroquinolone (FQ).
• Extensively Drug-Resistant TB (XDR-TB): MDR/RR-TB plus resistance to any Fluoroquinolone (Levofloxacin or Moxifloxacin) AND at least one Group A drug (Bedaquiline or Linezolid).
• Severe Extrapulmonary TB: Presence of miliary TB, TB meningitis, or CNS TB. In children <15 years, extrapulmonary forms other than peripheral lymphadenopathy are considered severe.

2. Approach to Diagnosis

Diagnosis in children is complicated by the paucibacillary nature of the disease. The National Tuberculosis Elimination Program (NTEP) emphasizes Universal DST (U-DST), meaning every diagnosed TB patient should be tested for Rifampicin resistance upfront.

A. Microbiological Confirmation

• Upfront Molecular Testing (NAAT): Cartridge Based NAAT (CBNAAT/GeneXpert) or TrueNat are the preferred initial tests. They detect M. tuberculosis and Rifampicin resistance within 2 hours.
• Line Probe Assays (LPA):
  • First-Line LPA (FL-LPA): Used if Rifampicin resistance is detected (to check for Isoniazid resistance) or if Rifampicin is sensitive (to rule out Isoniazid mono-resistance).
  • Second-Line LPA (SL-LPA): Performed if Rifampicin resistance is detected to check for resistance to Fluoroquinolones (FQ).
• Liquid Culture (MGIT): The gold standard for drug susceptibility testing (DST) for newer drugs like Bedaquiline, Linezolid, Clofazimine, and Delamanid.

B. Diagnosis of "Probable MDR-TB"

In children where bacteriological confirmation is not possible (culture-negative) or specimens are inaccessible, a diagnosis of "Probable MDR-TB" can be made if the child has active TB symptoms AND meets one of the following criteria:

1. Close contact with a known MDR-TB case.
2. Close contact with a person who died while on TB treatment.
3. Close contact with a person who failed TB treatment.
4. Non-response or failure of a first-line regimen. Management: These children are treated according to the resistance pattern of the source case after approval by the Nodal DR-TB Committee.

3. Newer Drugs in DR-TB Management

The introduction of Bedaquiline and Delamanid has revolutionized pediatric DR-TB therapy, allowing for injectable-free regimens.

A. Bedaquiline (Bdq)

• Mechanism: It is a diarylquinoline that specifically inhibits mycobacterial ATP synthase, an enzyme essential for energy supply to M. tuberculosis. It is bactericidal and has sterilizing activity.
• Eligibility: Approved for children $\ge$ 5 years of age and weighing $\ge$ 15 kg.
• Dosage:
  • 15 to <30 kg: 200 mg daily for 2 weeks (loading), then 100 mg thrice weekly for 22 weeks.
  • >30 kg: 400 mg daily for 2 weeks, then 200 mg thrice weekly for 22 weeks.
• Administration: Should be taken with a light meal to increase absorption. Tablets can be suspended in water for children unable to swallow.
• Adverse Effects: QTc prolongation (requires ECG monitoring), hepatotoxicity.
• Duration: Usually given for 6 months. Can be extended in specific cases.

B. Delamanid (Dlm)

• Mechanism: A nitro-dihydro-imidazo-oxazole derivative. It inhibits mycolic acid synthesis (cell wall) and releases nitric oxide (poisoning the bacilli).
• Eligibility: Approved for children $\ge$ 6 years of age.
• Dosage:
  • 6-11 years: 50 mg twice daily for 24 weeks.
  • 12-17 years: 100 mg twice daily for 24 weeks.
• Adverse Effects: QTc prolongation (additive risk if used with Bdq, though concurrent use is permitted with monitoring), nausea, anxiety.

C. Pretomanid

Part of the BPaL regimen (Bedaquiline, Pretomanid, Linezolid). Currently considered under specific ethical conditions for XDR-TB but not yet routine in all pediatric guidelines.

D. Repurposed Drugs

• Linezolid (Lzd): An oxazolidinone inhibiting protein synthesis.
  • Role: Core Group A drug.
  • Toxicity: Bone marrow suppression (anemia, thrombocytopenia) and peripheral/optic neuropathy. Dose tapering is often required.
• Clofazimine (Cfz): An anti-leprosy drug causing skin discoloration.
• Fluoroquinolones (Lfx/Mfx): Levofloxacin and Moxifloxacin are the backbone of MDR-TB regimens (Group A).

4. Grouping of Anti-TB Drugs (WHO/NTEP 2022)

Regimens are constructed based on the following hierarchy:

• Group A (Include all three): Levofloxacin/Moxifloxacin, Bedaquiline, Linezolid.
• Group B (Add one or both): Clofazimine, Cycloserine/Terizidone.
• Group C (Add to complete regimen): Ethambutol, Delamanid, Pyrazinamide, Imipenem/Meropenem, Amikacin, Ethionamide, PAS.

5. Treatment Regimens

A. Isoniazid (H) Mono/Poly-Resistant TB

• Indication: Resistance to Isoniazid, sensitive to Rifampicin.
• Regimen: 6 Lfx R E Z (Levofloxacin, Rifampicin, Ethambutol, Pyrazinamide) daily for 6 months.
• Duration: No separate intensive/continuation phase. Extended to 9 months in extensive disease.

B. Shorter Oral Bedaquiline-Containing MDR/RR-TB Regimen

• Eligibility:
  • Children $\ge$ 5 years and weighing $\ge$ 15 kg.
  • Confirmed MDR/RR-TB.
  • Exclusion: Resistance to Fluoroquinolones (Pre-XDR), severe extrapulmonary TB (TBM, disseminated), or extensive pulmonary disease.
• Duration: 9–11 months.
• Regimen Structure:
  • Intensive Phase (4–6 months): Bedaquiline, Levofloxacin, Clofazimine, Z, E, High-dose Isoniazid (Hh), Ethionamide.
  • Continuation Phase (5 months): Levofloxacin, Clofazimine, Z, E.
  • Note: Bedaquiline is given for 6 months.

C. Longer Oral M/XDR-TB Regimen

• Eligibility:
  • Children < 5 years.
  • Children with Fluoroquinolone resistance (Pre-XDR/XDR).
  • Severe forms of EPTB (TBM, Miliary) or extensive pulmonary disease.
  • Those ineligible for the shorter regimen.
• Duration: 18–20 months (no separate IP/CP).
• Regimen Design:
  • Constructed using drugs from Group A, B, and C.
  • At least 4–5 effective drugs initially.
  • Pediatric Modification (<5 years): Since Bedaquiline is not approved, it is replaced by Group C drugs (e.g., Delamanid if >3y available, or Amikacin/PAS).
  • Standard composition: Lfx/Mfx, Lzd, Cfz, Cs, (+ Bdq if >5y).

6. Monitoring and Adverse Event Management

A. Monitoring Schedule

• Clinical: Monthly weight and symptom assessment.
• Microbiological:
  • Smear and Culture: Monthly/Quarterly. Culture conversion (two consecutive negative cultures) is the key prognostic indicator.
• Cardiotoxicity (QTc Prolongation):
  • ECG is mandatory for regimens containing Bedaquiline, Clofazimine, or Moxifloxacin.
  • Schedule: Baseline, at 2 weeks, then monthly.
  • Management: If QTc > 500 ms (or increase > 60 ms from baseline), withhold offending drugs, correct electrolytes (K+, Mg++, Ca++), and reintroduce cautiously.
• Hepatotoxicity:
  • Symptoms: Nausea, vomiting, jaundice.
  • Action: Stop hepatotoxic drugs (Z, H, Bdq, Eto, PAS) if ALT > 5x ULN (asymptomatic) or > 3x ULN (symptomatic).

B. Special Situations

• HIV Co-infection: All CLHIV with DR-TB should be started on ART. Efavirenz reduces Bedaquiline levels; Dolutegravir is the preferred agent as it can be used safely with Bdq and Dlm.
• Renal Failure: Dose adjustment required for Levo/Moxi, Aminoglycosides, and Ethambutol.

7. Prevention

• Contact Tracing: Mandatory for all household contacts of DR-TB patients.
• TB Preventive Treatment (TPT) for DR-TB Contacts:
  • Contacts of MDR-TB (FQ sensitive): Levofloxacin (daily) for 6 months is recommended for household contacts (including children) after ruling out active disease.
  • Contacts of H-resistant TB: Rifampicin (daily) for 4 months.