Disclaimer:- All the points described here are based on current training modules for Medical officers given by the National TB Elimination Programme Central TB Division Ministry of Health & Family Welfare, Government of India, New Delhi

Key Facts:–

• The most common cause of acquiring Drug resistance to TB is inadequate or poorly administered treatment regimens
• Rifampicin Resistant (RR) patients are managed as per the MDR treatment regimens.
• All DR-TB patients are given the tablet Pyridoxine.
• In a shorter MDR regimen, if IP is prolonged, the injectable is given only Thrice a week in an extended Intensive phase.
• Newer Drugs like Bedaquiline and Delmanid Shall be given for initial 6 months (24 weeks) only in MDR/ RR patients.
• Treatment of H mono/poly DR-TB patients can be started even at PHI (peripheral health institution) level.
• The patient should be advised not to take heavy fatty meals or milk or milk products with anti-tb drugs at the same time
• Clofazamine (Cfz) causes dark brown discoloration of the skin. Accordingly, the patient should be counseled prior to the initiation of this drug

Drug-Resistant Tuberculosis (DR-TB)

When the bacilli causing TB (Mycobacterium tuberculosis) are resistant to one or more anti-TB drugs, it is called Drug-resistant Tuberculosis (DR-TB)

the most common cause of acquiring DR-TB is associated with inadequate or poorly administered treatment regimens (monotherapy, irregular consumption, frequent interruption etc.)

Classification of DR-TB Based on Drug Resistance

All samples which came out positive During the diagnosis of Tuberculosis are tested for the sensitivity of anti-TB drugs. If resistance is found, tuberculosis is classified as below:

*Rifampicin Resistant (RR) cases are managed as if they are MDR cases.

**Kanamycin and capreomycin are no longer recommended for MDR patients in treatment regimens.

Drug Regimens for DR-TB Patients

Programmatic management of DR-TB started in 2007 and gained Nationwide coverage by March 2013.

As per the recent guidelines for programmatic management of DR-TB Under NTEP, there are 3 standard DR-TB regimens for treatment as given below:

Lfx= Levofloxacin, R=Rifampicin, Z= Pyrazinamide, Mfx= Moxifloxacin, Km= Kanamycin, A= Amikacin Eto= Ethionamide, Cfz=clofazamine Cs= cycloserine Z H^h= Isoniazide (high dose) E= Ethambutol Bdq= Bedaquiline Lzd

@ tab pyridoxine is given to all DR-TB patients

# dose of Lzd is reduced to 300 mg/day after 6 to 8 months.

* In case of drug intolerance to Eto, Cs and Na-PAS, these drugs can be given in divided doses (Twice a day)

DR-TB Treatment Regimen: Important Points

• If LPA reveals H mono/poly DR-TB, the patient is started on All orla H mono/poly regimen even at PHI (peripheral health institution) level in India. for any additional resistance, the patient is sent to a Nodal or District DR-TB centre for modification in the regimen.

• In shorter MDR regimens IP is 4 months but if IP is prolonged (up to a maximum of 2 months in case of sputum smear microscopy positive at the end of 4th month), IP is prolonged (provided no additional resistance is found) but injectable is given only thrice a week in an extended Intensive phase.
  • if the patient remains positive even at the end of the first 6 months of IP, the patient is declared Treatment Failure.
  • The duration of CP remains fixed (5 months) and is not extended.
• In All oral longer MDR / RR TB regimens:
  • All patients, eligible for Bedaquiline and Delamanid shall be given these medicine for 24 weeks as given in the dose table provide:-
    • For Delamanid (Dlm): patient aged >6 yrs, Dlm can be given. for use in 3-6 yrs approval of DCGI is required.
    • For Bedaquiline (Bdq): Patients aged >18 yrs can be given Bdq. for use in 6-17 yrs approval of DCGI is required.
    • For Both Bdq /Dlm:
      • Non-pregnant females or females not on hormonal birth control methods are eligible
      • Even patients with controlled stable arrhythmia can be considered after obtaining a cardiologist’s opinion.
  • Linezolid shall be tapered to 300mg after initial 6-8 months depending upon the culture report of the patient.
  • If a patient remains culture positive after 8 months of treatment, the patient is declared a treatment failure.
  • Alloral Longer MDR TB regimen can be initiated on an OPD basis if:
    1. QTcF <450ms in males and <470ms in females ( QT_cF -the corrected QT interval by Fridericia)
       • For QT_cF above acceptable up to 500ms, the patient requires daily ECG monitoring for 3 days along with electrolytes. duration of indoor management shall be decided by the Nodal or District DR-TB centre committee.
    2. Normal serum Electrolytes (Potassium, Magnesium and Calcium) levels.
    3. No ECG abnormality or Structural cardiac abnormality
• All treatment failure cases are put on appropriately modified regimens based on extended DST (drug sensitivity testing)
• For XDR TB patients same treatment (All Oral longer MDR TB regimens depending upon the extended DST shall be followed for 20 months.
• Patients initiated on a regimen can be subjected to changes in drugs depending on the DST (drug sensitivity testing- First line DST, second-line DST or Liquid culture DST) reports.
• If taking a light meal with anti-TB drugs, Milk or milk products should not be taken at the same time (calcium in milk inhibit the absorption of Fluoroquinolones) and large fatty meal should also be avoided (impair absorption of drugs like- Isoniazid, and cycloserine, etc.)

Dose of Various Drugs Used in Treatment of DR-TB

You can also download the pdf file of the dosing chart given below:

1 For H mono/poly resistant TB;

2 For adults more than 60 yrs of age, the dose of SLI should be reduced to 10mg/kg (max up to 750 mg)

3 In patients of PAS with 80% weight/volume the dose will be changed to 7.5gm (16-29Kg); 10 gm (30-45 Kg); 12

gm (46-70 Kg) and 16 gm (>70 Kg)

4. Drugs can be given in divided doses in a day in the event of intolerance

Pre-Treatment Evaluation in DR-TB

Some investigations are required to be done prior to the initiation of treatment in DR-TB patients. For a patient to be put on H mono/poly DR-TB treatment only basic investigations are sufficient (similar to DS-TB patients):

• history and physical examination,

• height/weight,

• random blood sugar (RBS),

• urine pregnancy test (in women of reproductive age group),

• chest X-ray and

• HIV testing

for other patients of DR-TB, more baseline investigations are required to be done. the complete list is given in the pdf below.

ADRs Associated with Anti-TB Drugs

• The median absolute risk of Serious adverse effects is maximum with Linezolid (17.2%) and least with Bedaquiline (2.4%)

• Cycloserine should be used carefully in pre-existing seizure disorders (neurologist opinion recommended). it should also be used with caution in patients with severe depression as it can aggravate depression and suicidal tendencies.

• Clofazamine (Cfz) causes dark brown discolouration of the skin. Accordingly, the patient should be counselled prior to the initiation of this drug.

• There is a grading of ADRs given by DAIDS for both clinical conditions and lab values which can help assess the patient for the severity of ADRs and early intervention.

Severe Signs and Symptoms Requiring Urgent Care or Referral

• Severe GI Symptoms like:
  • S. vomiting or diarrhoea leading to dehydration,
  • Severe diarrhoea with fever
  • Severe abdominal pain
  • Blood in vomit
• Hearing loss
• EYE:
  • Blurred & diminished vision,
  • pain in the eye with eye movement,
  • loss of colour vision,
  • flashing lights
• Hepatic toxicity
  • ALT (Alanine Aminotransferase) or AST ( Aspartate Aminotransferase) is >5 times the upper limit of normal (ULN) or
  • ALT or AST > 3 times ULN with hepatitis symptoms/jaundice
  • Jaundice
• Renal toxicity:- oliguria, anuria, puffiness of eyes, pedal oedema
  • Skin:
    • symptoms suggesting of Stevens-Johnson Syndrome or
    • symptoms (fever, bullous & erosive lesions involving mucosa and epidermal detachment) suggesting Toxic Epidermal Necrolysis (Lyell’s syndrome).
• Severe depression, suicidal tendency
• Convulsions
• Severe hypokalaemia
• QT prolongation & Unstable dysrhythmia on ECG
• Lactic acidosis
• Severe medullar aplasia (grade 3) of the WBC or RBC or platelets

Safe and Unsafe Drugs in DR-TB

Follow-up Schedule of DR-TB Patients During Treatment

follow up of the patients is a very important aspect as it tells about their response to the treatment and also suggests any modification in the regimen.