Overview of

National
Guidelines on
Management of
Drug-Resistant TB
Global and National Magnitude of TB and DR-TB

2
 Method of DRT & DST

Xpert Xpert Line Probe Solid Liquid

Truenat
MTB/RIF MTB/XDR Assay culture culture

Chip based,
Follow on micro real Discontinued DST for first
Cartridge time PCR- PCR &
test to due to & second-
based NAAT based NAAT reverse
molecular longer turn line anti-TB
(CBNAAT) hybridization
test around time drugs
comes in
Uno-, Duo-,
and Quattro Interpreted LJ slope is
Simultaneou Detect based on inoculated Monitoring
s detection resistance development as a backup of treatment
of TB & RR- towards H, Point of Care / absence of for every response
TB FQ, SLI & Eto (POC) test WT & MUT MGIT culture
bands
3
 Operational aspects- specimen collection and
transport

• Enrol the patient in Ni-kshay and raise a test request using diagnostic
module
• Collect 2 specimens – adequate volume and good quality
• Fill the “Request form examination of biological specimen” (erstwhile-
Annexure 15A) with all relevant details
• Pack the collected specimen following the SOP for triple layer packaging
• Transport the specimens in cool chain to the linked NAAT site for TB
diagnosis and DRTB detection
• NAAT site to update the test results (MTB/RIF) in request form as well as
Ni-kshay portal and escalate to facilities for further DRTB testing
 Specimen collection and transport

Monitoring the Specimen

Demonstrate patients on Ensure collection of good
transportation to linked
collecting good quality quality specimen at all levels
diagnostic facility following
sample for testing
triple layer packaging and
cool chain transport
Integrated Diagnostic and Treatment Algorithm for Drug Susceptible and
Resistant Tuberculosis
All presumptive TB / persons with abnormal Chest X-Ray with or without
All notified TB patients not offered RR-TB test 1 Non-responders to any regimen
symptoms2

Collect 2 specimen and test for resistance to R, H, FQ or other drugs as needed 3

MTB +ve, R resistance detected MTB +ve, R resistance not detected

<14 yrs 2HRZE/4HRE

>14 yrs

Test for H resistance

Eligible for B Pa L M 4
No Yes
H resistance detected H resistance not detected/ Awaited
Eligible for shorter oral
regimen 6 B Pa L M 5
6-9 Lfx R E Z
No Yes
Additional resistance7 or intolerance or
non-availability of any drug in use

(4-6) Bdq(6) Lfx Lzd(2) Cfz Z E Hh H mono/poly DR-TB regimen,

(5) Lfx Cfz Z E modify as per replacement table

Still clinical deterioration, test for

Longer oral M/XDR-TB
resistance amplification+ SSLPA/ follow
regimen, modify with Additional resistance7 or intolerance or non- up-
replacement table as availability of any drug in use or emergence a) RR detected- MDR TB or Person Improving, Complete
applicable of exclusion criteria b) RR not detected- Probable MDR TB complete treatment 2HRZE/4HRE
Treatment regimen options for DR-TB includes

1. 6-9 months BPaLM shorter oral regimen.

2. 9-11 months shorter oral MDR/RR-TB regimen

3. 18-20 months longer oral M/XDR –TB regimen

4. 6-9 months H mono/ poly DR-TB regimen.

 BPaLM regimen

Inclusion Criteria:

1)Persons with age 14 years and above, New microbiologically confirmed RR-TB.

2)H/o exposure-

• less than one month intake of Bdq, Lzd and/ or Pa in the past

• more than one month intake of Bdq, Lzd and/ or Pa and documented sensitivity to the drugs.

• Persons who had not failed treatment with Bdq or Lzd containing shorter or longer regimen, and

sensitivity to the drugs are documented

• QTcF in ECG is  450 ms in males and  470 ms in females,

 Inclusion and exclusion criteria for the BPaLM
BPaLM regimen (
Exclusion Criteria
 Persons with age below 14 years

 Person with documented resistance to Bdq, Lzd and/ or Pa.

 Persons with significant liver dysfunction [LFT (Liver enzymes and/ or total bilirubin) >3xUpper Limit of
Normal

 People with severe forms of extrapulmonary-MDR-TB like CNS TB, spinal/ skeletal TB or disseminated
TB

 Pregnant and lactating/breastfeeding women

 Persons with significant Cardiac conduction abnormalities in the heart- including structural heart
disease, syncope, long QT syndrome, AV blocks, Reentry arrhythmias etc apart from asymptomatic
QTcF>500ms, uncontrolled cardiac arrhythmia that requires medication, history of additional risk factors
for Torsade de Pointes, e.g. heart failure, hypokalemia, family history of long QT syndrome
 Pre-treatment evaluation
All MDR/RR-TB patients would be subjected to a thorough pre-treatment evaluation (PTE)
at the N/DDR-TB centres as per table below.
Clinical evaluation Laboratory- based evaluation
• History and physical examination (including • Random blood sugar (RBS)
previous drug use, alcohol/substance abuse, family • HIV testing following counselling
planning methods etc.) • Complete blood count (Hb, TLC, DLC, platelet
• Previous history of ATT taken, especially Bdq, Pa, count)
Dlm and • Liver function tests#
• Lzd (defined as more than one month exposure) • Serum electrolytes (Na, K, Mg, Ca)
• A thorough clinical examination • Urine pregnancy test (in women of reproductive
• Assess nutritional status [Height (m), Weight (kg), age group)
BMI] • Chest X-ray
• Neurological evaluation, if required • ECG.
• Ophthalmic evaluation, visual acuity, and color
vision test

# HBsAG and other viral markers (Hepatitis A, C and E) to be done in case of jaundice
 6-9m BPaLM
regimen
• Administered orally with food and adequate water intake. All patients above 14 years of age
receive these doses. There are no weight bands.
• BPaLM =/> 85% supervised dose is of critical importance by Program staff, or at least
by Treatment supporter
• Dosage are given below in table-

(4 × Bdq 100 mg
First Two Weeks 400 mg once daily tablets)
Bedaquilin
e
(2 × Bdq 100 mg
200 mg three times
Weeks 3rd-26/39* tablets)
a week

(1 × Pa 200 mg
Pretomani
Weeks one to 26-39* 200 mg daily tablet)
d

600 mg once daily (1 x 600 mg tablet)

Linezolid Weeks one to 26-39*

Moxifloxac (1 x 400 mg tablet)

Weeks one to 26-39* 400 mg once daily
 Pyridoxine - Regimen, dosage and administration

 Pyridoxine (Pdx) will be administered as per weight band given below: (Reference: for the
entire duration of treatment as per weight band in line with the Guidelines for PMDT in India -–
2021).

Drugs 16-29 kg 30-45 kg 46-70 kg >70 kg

Pyridoxine (Pdx) 50 mg 100 mg 100 mg 100 mg

 Pyridoxine supplementation has been shown to reduce the incidence of neuropathy in patients,
supporting its inclusion in treatment protocols to mitigate drug-induced neuropathy.
 Pyridoxine to be used in the BPaLM regimen to provide added protection against neuropathy.
 Dose Reduction of Lzd

 All the efforts are to be made to continue the regimen with Lzd 600 mg throughout the course.

a. If Lzd 600 mg can’t be continued, because of severe/ grade 03 toxicity, up to 09 weeks, the

regimen is to be declared as failed.

b. The dose reduction of Lzd to 300 mg, because of severe/ grade 03 toxicity, can be considered

after 09 weeks.

c. If dose of Lzd is reduced to 300 mg the period of the regimen will be extended upto 39 weeks.

• If anytime during the course of treatment,Lzd is to be discontinued permanantely, the regimen is

declared as failed and new treatment regimen has to be initiated as applicable.

 Regimen Change as per DST

 NTEG recommended that BPaLM regimen can be initiated in all the eligible MDR-TB patients irrespective

of availability of baseline DST to these drugs. The change of the regimen may be considered whenever

the DST results are available.

 Mfx is a part of BPaLM regimen for full course, irrespective of resistance pattern to FQ at baseline or

during the treatment.

 Follow-up monitoring
Once the BPaLM/BPaL regimen is started, the patient will be monitored with regular clinical, radiological,
ECG, biochemical investigations and specialist consultation, if needed, as shown in table below
Follow-up assessments Timeline

Duration 26 weeks (extended up to 39 weeks)

Clinical review, including weight and BMI, Monthly

concomitant medication, adherence,
signs/symptoms suggesting adverse events

CBC (with Hb, platelets)^, and ECG$ Day 15, 30, then monthly till month 6, and more frequently if clinically indicated

Visual acuity, and color vision test Week 9, 13, 26 and more frequently if clinically indicated
Smear microscopy@ With culture at the C&DST lab
Culture@ Monthly from month 2 onwards. If the culture results of month 4 or later are
positive, collect one repeat specimen immediately and send it for culture to
rapidly ascertain bacteriological conversion or reversion and if the repeat
specimen is culture negative, then collect and send the subsequent monthly or
end-of- treatment specimen.
 Follow-up monitoring
Follow-up assessments Timeline

DST@ NAAT MTB/XDR or FL and SL LPA (Lfx, Mfx, Am, Eto) and LC DST (Mfx
1.0, Lzd, Z, Bdq, Pa*, Dlm*) if culture +ve at the end of month 4, end of Rx
and as and when clinically indicated during treatment
Urine pregnancy test As and when clinically indicated
Chest X-ray and LFT# At the end of month 3, the end of treatment, as and when clinically
indicated
S. Electrolytes (Na, K, Mg, Ca) As and when clinically indicated in case of any QTcF prolongation
Specialist (Ophthalmic, As and when clinically indicated
Neurological) consultation
Surgical evaluation After culture conversion
Long term follow-up At 6, 12, 18, and 24 months after completion of treatment (Clinical, CXR,
Smear and C&DST if symptomatic) and whenever the patient returns to the
health system
^ Lzd containing regimen to rule out bone marrow suppression and optic neuritis
$ In case of baseline ECG abnormality or QTcF between > 450 to 500 ms in males and > 470 to 500 ms in females, ECG must be done on a daily basis for initial three days or as suggested by a
cardiologist. Repeat ECG with long II lead after an hour to reconfirm abnormal ECG
@ During clinical follow-up if the patient deteriorates or shows no improvement at month two, send an additional specimen to the C&DST lab for a smear, set up a culture if smear is positive and
test on NAAT [Link]/XDR or SL-LPA to assess amplification to FQ. All positive cultures of this time point should be preserved for such patients. Update the test results in Ni-Kshay on the same day
* DST whenever available
# HBsAG and other viral markers (Hepatitis A, C and E) to be done in case of jaundice
 9-11Month Shorter Oral
MDR/RR-TB Regimen
• Preferred over the longer (≥ 18 months) regimen <14 yrs children with MDR/RR-TB.
A (2) Lzd (4-6) Lfx Cfz Z E Hh (6-9) Bdq (5) Lfx Cfz Z E
• Eligibility Criteria – B (4-6) Lfx Cfz Eto Z E Hh (6-9) Bdq (5) Lfx Cfz Z E
*
i. RR detected/inferred
B in case of Lzd intolerance/ resistance
ii. MDR / RR-TB with H resistance detected or inferred based on InhA mutation only or based on KatG
mutation only (not both)
iii. MDR/RR-TB with FQ resistance not detected
iv. No history of exposure to previous treatment with second-line medicines in the regimen (Bdq, Lfx, Cfz
or Lzd as applicable) for more than one month (unless susceptibility to these medicines is confirmed)
v. No extensive TB disease (Extensive disease -presence of bilateral cavitary disease or extensive
parenchymal damage on chest radiography-lobe collapse, fibrotic tracks or atelectasis, more than three
zones with cavities or six radiological zones)
vi. No severe forms of extra-pulmonary TB or disseminated TB (Miliary TB, CNSTB, Skeletal, Spinal TB)
vii. Non-pregnant or pregnant women with < 24 weeks gestation (willing for MTP)- for Eto containing
regimen
 18-20m Longer Oral M/XDR-TB
Regimen

(6-9m)Bdq (18-20) Lfx Lzd# Cfz

Cs
• Longer oral M/XDR-TB regimen is individualized/modified in duration and in
composition in accordance with the replacement sequence.

• Start with all 5 drugs of Group A and B and continue with 4 drugs in the latter
part of the treatment (beyond 6-9 months) if the patient can tolerate the drugs
and for operational ease.

• As per WHO recommendations, to constitute the regimen- (i) all three Group A
agents & (ii) at least one Group B agent should be included to ensure that
treatment starts with at least four TB drugs likely to be effective and at least
three agents are included for rest of the treatment if Bdq is stopped.

• If only one or two Group A agents are used, both Group B agents are to be
included.

• If the regimen cannot be composed with agents from Groups A and B alone,
 Pregnancy and
Lactation
• DR-TB poses a great risk to both the mother and foetus. BPaLM cant be given

• SLIs are contraindicated in pregnancy due to their effect on the 8th cranial nerve (auditory) of the foetus. Eto is
contraindicated during the first 32 weeks of pregnancy due to teratogenic effects.

• For pregnant and lactating women, it is recommended to use the 9-month shorter oral MDR/RR-TB regimen with Lzd.

• Bdq in pregnancy has been shown to be associated with infants born with a lower mean birth weight when
compared with infants whose mothers did not take Bdq; however, when infants were followed up over time, no
other significant differences in infant outcomes, pregnancy outcomes or maternal treatment outcomes, including
weight gain in infants until one year of age were observed.

• Pa is not recommended during the lactating period unless the mother is willing to replace breastfeeding with
formula feed. Thus, the recommendation of the BPaLM regimen doesn’t apply to pregnant and breastfeeding
women. It is prudent to solicit the opinion of an experienced gynaecologist or obstetrician while treating such
patients.
 Pregnancy and
Lactation.
Duration of pregnancy

<20 or <24 weeks >20 or> 24 weeks

Advise MTP Pt unwilling for MTP

MTP done
Start/continue
• BPaLM OR & Start/continue –
• 9-month shorter oral MDR/RR-TB regimen (with Lzd)# OR
• 9-month shorter oral MDR/RR-TB regimen (with Lzd) # OR
• longer oral M/XDR-TB regimen@
• longer oral M/XDR-TB regimen@

& Regimen: 6/9 Bdq, Pa, Lzd, Mfx

# Regimen: 4-6 Bdq (6m or longer) Lfx/Mfx, Cfz, Lzd (2m), Hh, Z, E / 5 Lfx/Mfx, Cfz, Z, E. Lzd can be replaced with Eto if required post MTP or only after 32 weeks’ gestation
@ Regimen:18-20 Lfx, Bdq (6m or longer) Lzd, Cfz, Cs. Modify regimen if one or more drug cannot be used due to reasons of resistance, tolerability, contraindication, availabilit
etc
• in the order of Z E PAS
• Eto may be considered after 32 weeks’ gestation, if required
• Am may be considered in post-partum period only. Am will not be started in the final 12 months of treatment
20
 Children

• Safety and effectiveness of BPaLM regimen with Pa in children < 14 years have not

been established.

• Children below 14 years can be treated with 9-11 month shorter or 18-20 month

longer oral regimens as per eligibility in consultation with the pediatrician available

or linked to the N/DDR-TBC.

• <5yr: Bdq is not available for this grp.

• In Shorter Oral 09-11 mth regimen -Bdq is replaced by Am/Km;

• in Longer oral regimen -Bdq is replaced by dlm

 BPaLM-PLHIV

• BPaLM regimen can be given to eligible MDR/RR-TB and Pre-XDR-TB regardless of their HIV status
and CD4 count provided they fulfil all other eligibility criteria.
• However, care should be taken when CD4 counts are below 100 cells/mm3. It is important to
consider drug–drug interactions when administering TB and HIV medications in combination with
respect to the following points:
o Efavirenz induces metabolism ,reduces exposure to Bdq and Pa -co -administration is to be
avoided. Dolutegravir (DTG)-should be used if the BPaLM regimen is considered.
o Ritonavir may increase Bdq exposure, which could potentially increase the risk of Bdq-related
adverse reactions
o Zidovudine should be avoided, if possible, because both zidovudine and Lzd may cause
peripheral nerve toxicity and are known to have myelosuppression cross-toxicity.
o These cases should be managed through consultation between the ART centre and DR-TB
centre.
 Anemia
• Patients with TB commonly have anemia of chronic disease. Many patients with TB also
suffer with nutritional deficiencies, and low Hb may also be a result of iron deficiency
and low iron stores.

• Iron deficiency may resolve naturally once effective TB treatment (even including Lzd)
leads to resolution of TB symptoms and improvement in the patient’s anemia, diet and
appetite.

• Extended use (≥ 2 weeks) of Lzd has been associated with reversible myelosuppression.
Therefore, the Lzd-containing regimen may be offered to patients with a pretreatment
serum Hb below 8 g/dL after corrections (>9gm%). However anaemia that cannot be
rapidly corrected (i.e. with blood transfusions) before starting MDR/RRTB treatment LZD
should not be offered, so avoid BPaLM.

• Similarly, owing to the morbidity associated with severe neutropenia and

 Anemia

• Some patients respond well to an initial blood transfusion that raises their Hb
above 8 g/ dL and allows them to at least start a Lzd-containing regimen. Lzd
will not necessarily cause myelosuppression in patients with baseline anaemia.

• Although blood transfusions may help to reverse anaemia following withdrawal

of Lzd, they may not resolve Lzd-induced myelosuppression with ongoing
exposure to the drug.

• Oral supplementation of iron is often not well tolerated and is not immediately
effective at the start of treatment, at a time when the pill burden can be
overwhelming and the risk of multiple drug side effects is high
 Work flow- Long term Follow up
• Post treatment 6-monthly follow-up must be performed strictly for two

years in every DR-TB patient

• More frequently, at least 3-monthly in the first year for patients in

whom BPaLM treatment was extended to 39 weeks.

• The follow-up must include clinical evaluation, smear, and extended

C&DST on appropriate specimen if available.

 6-9 months H mono/poly drug-resistant TB regimen

 6-9 months H mono/poly DRTB regimen- Lfx R Z E

 Total duration of H mono/poly DR-TB regimen is 6 months. It can be extended to 9 months –

 in patients with extensive disease; uncontrolled comorbidity; extra- pulmonary TB; if smear at the

end of month 4 is positive. There would be no monthly extensions in this regimen.

 In patients who remain sputum smear positive at the end of month 5 or later, the treatment outcome

will be declared as ‘treatment failed’ and the patient will be re-evaluated as per the diagnostic

algorithm as a non-responder.
 6-9 months H mono/poly drug-resistant TB regimen (2)
 The patients, not responding or failing in the H mono/poly DR-TB regimen-

a) If the resistance to Rifampicin is developed during treatment, the patient will be considered for BPaLM/ shorter MDR/RR-
TB regimen as per the eligibility.
b) Additional resistance to FQ/Z or both or intolerance or non-availability of any drug, use the replacement as given below:

Situation Sequence of using replacement drugs

1. If Lfx or Z can’t be used Replace with Lzd. If Lzd also cannot be given, replace with
Cfz* + Cs.
2. If both Lfx and Z can’t Add 2 drugs of the 3 – Lzd, Cfz*, Cs in order of preference
be used based on resistance, tolerability & availability.
3. If R resistance Switch to appropriate shorter or longer oral regimen.
c) The patients not responding or failing in the H mono/poly DR-TB regimen, demonstrating resistance to R, FQ or Z will be
considered as ‘probable MDR TB case’ and further evaluated for treatment with the MDR-TB regimen in the preferred
order of
 BPaLM if eligible,
 9-month shorter oral MDR/RR-TB regimen if eligible or
 longer oral M/ XDR-TB regimen.
ADR of BPaLM

Bedaquiline Pretomanid Linezolid Moxifloxacin

• QTc • Hematological • Peripheral • GI
prolongation events when neuropathy symptoms-
• Acneiform diarrhoea,
given with LZD • Myelosuppre vomiting
skin lesions ssion • Dizziness,
• Liver • QTC prolongation • Anemia convulsions
enzymes when given with • Phototoxicity
elevation • Optic neuritis ,
• Gastritis and BDQ • Lactic photosensitiv
ity
vomiting • Hepatitis when acidosis • Tendinitis
• Psychiatry & given with BDQ • Serotonin • Skin rash
Neurological syndrome • Arthralgia
complaints • Convulsions • QT
• Auditory and • Anaphylaxis prolongation
vision
problems • Arrhythmia
• Haemoptysis • Pseudomem
branous 28
colitis
 Adverse drug reactions to drugs
used in DR-TB
Adverse Drug Events Drugs Adverse Drug Events Drugs
QT prolongation Bdq, FQ, Cfz, Dlm, Pa Tendonitis and tendon FQ
Rash, allergic reaction and Any drug
anaphylaxis rupture
Gastrointestinal symptoms Eto, PAS, Z, E, Bdq, Cfz, Nephrotoxicity (renal toxicity) Am
Lzd, FQs Vestibular toxicity (tinnitus Am, Cs, FQs, Eto, Lzd
Diarrhoea and/or flatulence PAS, Eto and dizziness)
Hepatitis Z, Eto, PAS, Bdq Hearing loss Am
Giddiness Am, Eto, FQ and/or Z
Haematological abnormalities Lzd Optic neuritis E, Lzd, Eto, Cfz,
Hypothyroidism Eto, PAS Metallic taste Eto, FQs
Arthralgia Z, FQ, Bdq Electrolyte disturbances Am
Peripheral neuropathy Lzd, Cs, Am, FQ, rarely Eto, (Hypokalaemia and
E Hypomagnesaemia)
Headache Bdq, Cs
Depression Cs, FQ, Eto Gynaecomastia Eto
Psychotic symptoms Cs, H, FQ, Alopecia Eto
Suicidal ideation Cs, Eto Superficial fungal infection FQ
Seizures Cs, H, FQ
and thrush
Lactic acidosis Lzd
Dysglycaemia and Eto
Hyperglycaemia 29
 Peripheral Neuropathy: DAIDS criteria
Suspect agent(s): Lzd, Cs, H, Am, FQ, rarely Eto and E

30
Peripheral neuropathy screening tool

• The Annexure 2 – Peripheral neuropathy screening tool.

• Frequency – baseline, week 4, 8,12,16,20,26, 3month, 6-
month, 12-month, 24 month, (if on treatment ) 9- month,
week 30, week 34, week 39, or unscheduled (for new or
worsening peripheral neuropathy during treatment )
• Categorisation – minimal ; modest and severe. (based on
the interference to walking / sleeping caused by this
pain/ache or burning )

• Perception of vibration – using 128 hz tuning fork.

• Grading of vibration perception
• Deep tendon reflex
Module 1: TB preventive treatment 32