Foot Notes to Diagnostic Algorithm:

1. Includes TB patients diagnosed based on smear microscopy, clinical/ radiological assessment, and
histopathology on appropriate specimen
2. Presumptive TB includes a person with any of the symptoms, signs or any chest X-ray abnormalities
suggestive of TB. States to accelerate upfront use of chest X-rays for screening and use of NAAT for TB
diagnosis.
3. Sputum (two specimens), gastric lavage (GL), induced sputum (IS), broncho-alveolar lavage (BAL), other
respiratory specimen and extra pulmonary specimen like fine needle aspiration cytology (FNAC) of
peripheral lymph nodes (LNs) and cerebrospinal fluid (CSF), to be sent to NAAT site for M.tb/Rif, followed
by
i. NAAT for H, FQ resistance detection among M.tb detected using the same specimen, wherever the
test is available and as per algorithm.
ii. Until NAAT for H, FQ resistance detection is available for the district, send second specimen for
FL-LPA for H resistance detection among M.tb detected followed by SL-LPA for FQ, SLI resistance
detection among H or R resistance detected
iii. Baseline culture to be done for specimen from MDR-TB patients received at C&DST lab for baseline
liquid culture (LC) DST to Bdq*, Lzd, Pa*, Dlm*, Z, Mfx 1.0 (*whenever available) and for specimen
from H mono/poly DR-TB patients received at C&DST lab for baseline (LC) DST to Mfx 1.0, Lzd, Z.
iv. All EP-TB specimens except FNAC of peripheral LNs and CSF preferably to be sent directly to C&DST
laboratory for further processing. (3).
v. Start treatment based on NAAT for H, FQ resistance detection / LPA and modify based on LC-DST
results whenever available.
vi. InhA mutation is associated with Eto resistance and KatG mutation is associated with Hh resistance.
If FL-LPA is done on culture isolates for patients with smear negative specimen, till the time the result
of indirect FL-LPA is available, use other exclusion criteria to decide regimen. Results of Mfx, Am and
Eto will be interpreted as per the mutation pattern of rapid molecular test/ LPA.
4. Eligibility criteria for BPaLM has been mentioned in the respective section of Chapter-3.
5. Implementation considerations/ Extension criteria for BPaLM (Details have been mentioned in section
BPaLM respective section of Chapter-3).
6. Eligibility criteria for 9-11 month shorter oral MDR/RR-TB regimen have been mentioned in the
respective section of Chapter-3)
7. At follow-up, offer LC-DST for Bdq*, Lzd, Pa*, Dlm*, Z, Mfx 1.0 (*whenever available).
● All states must ensure the availability of all NTEP-endorsed diagnostic technologies or appropriate
linkages with public or private laboratories to ensure adequate diagnostic and follow-up capacity in
consultation with CTD for all notified TB patients, including those seeking care in the private sector.
● In a new case, if M.tb detected is low or very low and RR-TB detected, NAAT to be repeated and an opinion
from a microbiologist may also be sought. If there is a discordance in R resistance between NAAT and
FL LPA, a second NAAT is to be performed at the C&DST laboratory using the decontaminated deposit,
or fresh sample to be sent if culture deposits are not available. The final result will be on consensus of
the 3 tests (2 NAAT and 1 LPA). If 2 of 3 are R resistant then the final result will be R resistant; if 2 of 3
are sensitive, then the final result will be sensitive to R and the treatment will be started as based on
best of three results. Further, the C&DST report whenever available may be reviewed by N/DDR-TBC
committee to decide on the treatment regimen. (3).

NOVEMBER 2024 17
18 National Guidelines for Management of Drug Resistant TB
3 TREATMENT OF DRUG-
RESISTANT TB

This chapter describes

I. Evidence on newer oral drugs and regimens for treatment of drug-resistant TB
II. Shorter regimens general considerations
III. The new 6-month shorter oral regimen BPaLM for the treatment of MDR-TB
IV. Highlights the key changes in 9-11 month shorter oral MDR/RR-TB regimen,
V. Highlights the key changes in18-20 month longer oral M/XDR-TB regimen,
VI. 6-month H mono/poly DR-TB regimen.
VII. Switching between regimens
VIII. Supply chain management
IX. Management of DR-TB in special situations
X. Adverse Events
XI. Treatment interruptions and follow ups
The decisions for enrolment on the BPaLM or 9-11 month shorter MDR/ RR-TB regimen or 18 month longer
M/ XDR-TB regimen will be made by the nodal DR-TB centre (NDR-TBC) or district DR-TB centre (DDR-
TBC) in consultation with respective N/DDR-TBC committee, as deemed necessary, based on the results of
the molecular and/ or LC-DST (a single breakpoint concentration based for FQ) for second- line anti-TB drugs
(SLD) for individual patient and the eligibility criteria. All DR-TB patients need to be assessed at the time of
treatment initiation as per the guidance document for differentiated TB care.
Decisions on appropriate regimens should be made considering the results of DRT/ DST, clinical assessment,
patient treatment history, risk of adverse events, severity, and site of the disease. To assess regimen
effectiveness, all treatment services under NTEP should be delivered including patient- centered care and
support, informed decision-making process where necessary, principles of good clinical practice, active drug
safety monitoring and management (aDSM), and regular monitoring of patients (12).

3.1. Evidence on newer oral drugs and regimens for treatment of

drug-resistant TB
● The NIX-TB trial (13) with three drugs Bdq, Pretomanid (Pa) and Lzd [BPaL] has shown 90% treatment
success rate in patients with Pre-XDR-TB (erstwhile XDR-TB) patients and MDR-TB patients with
treatment intolerance or nonresponse to standard treatment. The toxic effects of Lzd (1200 mg) include
peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common,
were manageable, often leading to dose reductions or interruptions in treatment with Lzd.
● Two more studies viz, TB PRACTECAL trial (14) and ZeNix trial (15) were published and reviewed by
the WHO guidelines development group (GDG). It was recommended the optimal dosing of Lzd is 600
mg daily to ensure optimal efficacy (91% treatment success rate), with the possibility of dose reduction

NOVEMBER 2024 19
 in the event of toxicity or poor tolerability (peripheral neuropathy occurred in 24%, myelosuppression
occurred in 2%, and the Lzd dose was modified i.e., interrupted or reduced in 13%) (11).
● TB PRACTECAL trial (14) with the 6-month BPaLM regimen – comprising Bdq, Pa, Lzd (600 mg) and
Mfx – showed favourable efficacy (treatment success rate 88.7%) and safety (19.4% grade > 3 adverse
events as against 58.9% in the prevailing WHO standard of care) when compared with the regimens in
the control arm of the TB-PRACTECAL trial. Evidence has largely revealed that the optimal dosing of Lzd
is 600 mg daily. It also alleviated previous concerns on reproductive toxicities observed in animal studies
(11).
● Modified BPaL (mBPaL) trial, a pragmatic randomized clinical trial, randomized participants to the three
arms with Bdq, Pa and different Lzd doses; arm 1 had Lzd 600 mg for 26 weeks; arm 2 had Lzd 600 mg
for 9 weeks & 300 mg for 17 weeks and arm 3 had Lzd 600 mg for 13 weeks & 300 mg daily for 13 weeks.
At the end of the treatment, the effectiveness (cure) was similar across the three arms; 93% in BPaL in
arm 1, 94% in BPaL in arm 2 and 93% in BPaL in arm 3. The study observed that the median (interquartile
range) time for the occurrence of anemia was 4 weeks (2-6 weeks) and peripheral neuropathy was 11
weeks (4-16 weeks). Severe anemia (grade 3 or 4) was more in patients in arm 1 (13%) compared to arms
2 & 3 (4%, 6%). The anemia events were manageable in all the three arms. Grade 3 peripheral neuropathy
was observed in 7 patients in arm 1 compared to one each in arms 2 & 3. The study showed that Lzd
related toxicity could be reduced with structured dose reduction of Lzd from 600 mg to 300mg after 9/
13 weeks while maintaining similar treatment effectiveness as Lzd 600mg when given along with Bdq
and Pa for 26 weeks (16).
● The study for cost-effectiveness found that in most settings, BPaL-based regimens are cost-saving (17). It
has been appreciated that BPaL would reduce workload and financial burden on the health care system,
expressed concerns regarding BPaL safety (monitoring), long-term efficacy, and national regulatory
requirements, and stressed the importance of addressing current health systems constraints as well,
especially in treatment and safety monitoring systems (18).
● The Indian Council of Medical Research (ICMR) conducted Health Technology Assessment (HTA) for
cost- effectiveness of BPaLM/ BPaL treatment regimen for MDR/RR-TB and following key observations
were reported:
i. Emerging global evidence suggests that 6-month Bedaquiline containing regimens BPaL and BPaLM
are cost-effective, and improve compliance and clinical outcomes in drug resistant TB patients.
ii. As compared with currently deployed treatment protocols, the BPaL/BPaLM regimens are cost
effective.
iii. Pragmatic uptake of the above regimen could improve treatment success rate for MDR/RR-TB and
free up resources for investment in other areas of TB programme.
iv. Introduction of BPaL and BPaLM regimens in the TB elimination mission merits consideration on
priority.
● Routine data from the South African NTP for a 9-11 month shorter oral MDR/RR-TB regimen containing
Bdq, FQ and Lzd (600 mg) combined with other medicines used in MDR/RR-TB patients without
resistance to FQ without previous exposure to SLDs was compared with the existing recommended 9-11
month, all- oral, Bdq-containing regimen (which contains Eto instead of Lzd) or longer regimens in the
same group of patients. It included mostly adult patients (96%) and a high proportion of PLHIV (67%).
The data showed that replacing four – six months of Eto with two months of Lzd in this regimen resulted
in similar treatment efficacy and safety. The outcomes were similar, irrespective of HIV status. (11).
● Based on data reviewed from TMC207-C211 and IMPAACT P1108 trials, corresponding the use of
Bdq in children aged 5–18 years and aged 0–6 years, respectively, the WHO GDG concluded that in
children 0–6 years of age, cardiac safety signals were not distinct from those reported in adults. Data
from pediatric MDR/RR-TB individual patient data (IPD) were analyzed descriptively (24,231 records
from all six WHO regions, the majority from India and South Africa) in April 2020, including 40 children
aged below six years and 68 children aged 6–12 years who received Bdq as part of DR-TB treatment.

20 National Guidelines for Management of Drug Resistant TB

 The moderately desirable effects of Bdq in all-oral regimens for children will allow the construction of
regimens that are more child- and family-friendly, with shorter durations. The WHO GDG determined
that the balance between desirable and undesirable effects probably favoured the use of Bdq in children
aged below six years and was probably feasible to implement (19).
● On review of data on the use of Dlm in children from cohorts 1 (age 12–17 years), 2 (age 6–11 years),
3 (age 3–5 years) and 4 (age 0–2 years) for both protocols (protocol 242–12–232 and 233), the WHO
GDG noted that exposures in the 0–2 year age group were lower than those of children aged three years
and older, necessitating a modelling/simulation approach to dosing. No cardiac safety signals, distinct
from those reported in adults, were observed in children 0–2 years of age. However, pharmacodynamic
simulations suggested that clinically meaningful changes in QT (i.e. prolongation) would be unlikely in
children under three years of age, even if higher doses were used to reach drug exposures comparable
to those achieved in adults. The GDG concluded that the balance between desirable and undesirable
effects probably favours the intervention (19).
● The chronology of events for introduction of Pa containing regimen in India can be found in annexure 1.

3.2 General consideration for treatment of drug resistant TB

● For MDR/RR-TB, in patients aged 14 years or more, 26-39 weeks BPaLM is the first preference and in
patients aged <14 years 09-11 month shorter oral is first preference based on the eligibility criteria
(described in the relevant section for BPaLM and 9-11 month shorter oral MDR/RR-TB regimen) (3).
● Patients who are not eligible for the BPaLM regimen should be assessed for the eligibility of the 9-11
month shorter oral MDR/RR-TB regimen, and if found ineligible, they should be considered for longer
oral M/XDR-TB regimen based on the DST pattern.
● The DR-TB regimens will be provided by the N/DDR-TBC committee in the designated public sector
facilities and engaged private sector facilities once the patient has been confirmed as eligible. Each of
the N/DDR-TBCs must ensure that laboratory capacity and consultancy services from various specialists
are available, either in-house, supported under institutional/ state government mechanisms or through
an outsourced mechanism. The engagement with private facilities as per guidance document on
partnerships 2019 should also be undertaken for investigations and specialist consultations that are not
available in public health facilities (20).
● Selection of the treatment regimen is to be based on comprehensive analysis of lab report for NAAT/
LPA/ LC-DST, pre-treatment evaluation, Inclusion-exclusion criteria, past h/o drug use, absolute and
relative contra-indication.
● All patients are to be assessed for selection of appropriate regimen and for hospital admission using
differentiated TB care approach.

NOVEMBER 2024 21
3.2.1 Pre-treatment evaluation
All MDR/RR-TB patients would be subjected to a thorough pre-treatment evaluation (PTE) at the N/DDR-
TBCs as per table 3.1 below.

Table 3.1: The list of the PTE for MDR/RR-TB patients

Clinical evaluation Laboratory-based evaluation

● History and physical examination (including ● Random blood sugar (RBS)
previous drug use, alcohol/ substance abuse, ● HIV testing following counselling
family planning methods etc)
● Complete blood count (Hb, TLC, DLC, platelet
● Previous history of ATT taken, especially Bdq, count)
Pa, Dlm and Lzd (defined as more than one
month exposure) ● Liver function tests#

● A thorough clinical examination ● Renal function tests

● Assess nutritional status [Height (m), Weight(kg), ● Serum electrolytes (Na, K, Mg, Ca)
BMI] ● Urine pregnancy test (in women of reproductive
● Neurological evaluation, if required age group)

● Ophthalmic evaluation, visual acuity, and color ● Chest X-ray

vision test ● ECG
# HBsAG and other viral markers (Hepatitis A, C and E) to be done in case of jaundice

● A brief peripheral neuropathy screening tool, annexure-3, is to be used to assess the peripheral
neuropathy (21). “Division of AIDS (DAIDS) table for grading the severity of adult and paediatric adverse
events” 2017, by National Institutes of Health, US Department of Health and Human Services, may be
referred for grades of neuropathy and anemia (22).

3.2.2 Treatment initiation

● All patients diagnosed as MDR/RR-TB using various technologies will be evaluated and initiated on an
appropriate regimen with eligibility criteria as per the integrated diagnostic and treatment algorithm for
DS and DR-TB.
● Once a patient is identified as per the eligibility criteria, the N/DDR-TBC committee will start the patient
on BPaLM or 9-11 month shorter oral MDR/RR-TB regimen or 18-20 months longer oral regimen.
● Till Bdq is available for the use in children below five years and evidences for the use of Pa among below
14 years, the other regimens as applicable will be used.
● The decision to initiate treatment will be taken by the nodal DR-TB centre (NDR-TBC) or district DR-TB
centre (DDR-TBC) in consultation with respective N/DDR-TBC committee.
● All eligible patients will be offered thorough counselling along with educational material in the local
language, which will give details of the nature and duration of treatment, including information on the
BPaLM or 9-11 month shorter oral MDR/RR-TB regimen or 18-20 month longer oral regimen, the need
for regular treatment, possible side effects of the drugs in the regimen, the drugs which are to be avoided
and the consequences of irregular treatment or premature termination of treatment. Female patients in
reproductive age-group will receive additional counselling on family planning. The patient-wise box with
bottles and strips for the entire course will remain under the custody of the treatment supporter for the
entire duration of treatment.
● As Bdq has a longer half-life (calculated half-life is 24 to 30 hours and terminal half-life of 5.5 months
due to extensive tissue distribution post stopping BDQ), any interruption in treatment may lead to early
washing out of other drugs while Bdq remains in the body leading to monotherapy with Bdq with higher

22 National Guidelines for Management of Drug Resistant TB

 risk of Bdq resistance amplification. Hence, it is strongly recommended that all treatment regimens,
including BPaLM doses are to be administered under direct observation (minimum 6 days per week) by
a trained treatment supporter (health care provider, community volunteer) identified by the community
health officer (CHO) of the respective Ayushman Arogya Mandir (AAM, erstwhile health & wellness
centre, HWC). The treatment supervision may be supplemented by suitable digital adherence monitoring
technology (3). It will be preferable for the treatment supporters to accompany the patient/ contacts for
the screening and follow-up visits and liaise with the clinical staff.

Monitoring indicator:
Administer at-least 85% of doses under direct physical
supervision by the treatment supporter.

● It is recommended to avoid taking magnesium supplements or magnesium-containing antacids for two

hours before and two hours after taking any regimen as it can bind the FQs and make them ineffective
(23).

3.3 BPaLM regimen

BPaLM regimen must be the first choice of treatment in eligible patients ≥14 years age with MDR/RR- TB
regardless of their FQ resistance status or HIV status.

3.3.1 Eligibility criteria

The eligibility criteria for BPaLM regimen includes.

Inclusion Criteria

i. Person with age 14 years & above with new microbiologically confirmed MDR/ RR-
TB requiring a new course of treatment or probable MDR-TB who failed H mono/
poly DR-TB treatment
ii. H/o of Drug Exposure: Person with exposure of less than one month intake of Bdq,
Lzd and/ or Pa in the past
or
Person with exposure of more than one month intake of Bdq, Lzd and/ or Pa and
documented sensitivity to these drugs
or
Person who had not failed treatment with Bdq or Lzd containing shorter or longer
regimen, and sensitivity to these drugs are documented
iii. QTcF in ECG is ≤450 ms in males and ≤470 ms in females
or
when serum electrolytes are abnormal and QTcF is >450 ms in males & QTcF is >470
ms in females in baseline ECG, after correcting the electrolytes, QTcF in repeat ECG
is ≤450 ms in males and ≤470 ms in females
iv. Non-lactating women, lactating women but not breast-feeding, non-pregnant
women, pregnant women with <20 or <24 weeks gestation and who is willing
for medical termination of pregnancy (as per latest MTP gazette notification, as
applicable)

NOVEMBER 2024 23
 Exclusion criteria & Contra-indications

i. Person with age below 14 years

ii. Person with documented resistance to Bdq, Lzd and/ or Pa.
iii. Person with significant liver dysfunction [LFT (Liver enzymes and/ or total bilirubin);
AST/ALT>3.0 x ULN and Total Bilirubin >2.0 x ULN]
iv. People with severe forms of extrapulmonary-MDR-TB like CNS TB, spinal/ skeletal
TB, or disseminated TB (miliary TB or TB with multiorgan involvement)
v. Person with significant Cardiac conduction abnormalities in the heart- including
structural heart disease, syncope, long QT syndrome, AV blocks, Reentry arrhythmias
etc.
i. Person currently having uncontrolled cardiac arrhythmia that requires
medication
ii. Person with history of additional risk factors for Torsade de Pointes, e.g. heart
failure, hypokalemia, family history of long QT syndrome.
iii. Baseline QTcF is >450 ms in males & QTcF is >470 ms in females in baseline
ECG, and if electrolytes are normal.
Or
Baseline QTcF is >450 ms in males & QTcF is >470 ms in females in baseline
ECG, electrolytes are abnormal and even after correcting the electrolytes QTcF
in repeat ECG, is not ≤450 ms in males and ≤470 ms in females.

Note:
● In case of extensive pulmonary TB, BPaLM regimen may be given, if eligible.
● If at baseline, the results of the serum chemistry panel, hematology or urinalysis are outside the normal
reference range (including above listed parameters), the patient may still be considered if the physician
judges that the abnormalities or deviations from normal to be not clinically significant or to be appropriate
and reasonable. Hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to a patient
receiving any QTc prolonging drugs.
In addition to the eligibility criteria for BPaLM, the relative contraindications, requiring careful selection of
patients after a detailed history of the patient (drug, comorbidity, concurrent use of any drugs, etc.), physical
assessment in combination with PTE test, are detailed in Table 3.2.

24 National Guidelines for Management of Drug Resistant TB

Table 3.2: Relative contraindications for BPaLM

Relative
Notes
Contraindications
Concurrent use of ● Use of strong inhibitors or inducers of cytochrome P450 enzyme*
medications that have ● Drugs that prolong the QT interval (anti-fungals, antiarrhythmics,
known interactions or
antipsychotics etc.)
overlapping toxicities
with BPaLM ● Drugs that increase serotonin levels and other serotoninergic
● Monoamine Oxidase Inhibitors (MAOIs) or prior use within two weeks of
treatment
● Currently on serotoninergic antidepressants/ tricyclic antidepressants or
prior use within three days of treatment
● Concomitant use of any drug known to induce myelosuppression
● If a patient requires an oral magnesium-containing substance e.g. magnesium
trisilicate, magnesium sulphate this must be dosed two hours separate from
the fluoroquinolone.
Severe anaemia, ● Haemoglobin (Hb) level < 8.0 g/dL
thrombocytopenia or ● Platelet count < 75 000/mm3
leukopenia
● Absolute neutrophil count < 1000/mm3
Severe renal failure ● Serum creatinine > 3.0 × ULN
● Owing to limited experience with the use of this regimen, caution should be
exercised in patients with severe renal failure
Severe neuropathy ● Peripheral neuropathy of grade 3 or grade 4
ALT: alanine transaminase; AST: aspartate transaminase; ULN: upper limits of normal.
* Exceptions may be made for patients that have received three days or less of one of these drugs or substances if there has
been a wash-out period before administration of Bdq to at least five half-lives of that drug or substance.

3.3.2 Regimen, dosage, and administration

● BPaLM regimen is to be administered orally with food (avoid magnesium supplements or magnesium
-containing antacids before and after 2 hrs) and adequate water intake.
● 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.

NOVEMBER 2024 25
● The dosages of the drugs in the regimen are as follows (14,16,24,25):

i. Bedaquiline
ƒ Weeks one to two: 400 mg once daily
ƒ Weeks three to 26/39*: 200 mg three times a week; plus
ii. Pretomanid:
ƒ Weeks one to 26/39*: 200 mg daily; plus
iii. Linezolid:
ƒ Weeks one to 26/39*: 600 mg once daily; plus
iv. Moxifloxacin:
ƒ Weeks one to 26/39*: 400 mg once daily
* Extension criteria has been described in subsequent section.

Pyridoxine (Pdx) to be given as per weight band:

Body weight 16-29kg >30 kg
Dose 50mg 100mg

● All patients aged 14 years and above would receive the above standard dosage. There is no weight band
wise dosing.

3.3.3 Dose Reduction of Lzd (16):

● All the efforts are to be made to continue the regimen with Lzd 600 mg throughout the course.
i. If Lzd 600 mg can’t be continued, because of grade 03/ grade 04 toxicity, up to 09 weeks, the regimen
is to be declared as treatment failed.
ii. The dose reduction of Lzd to 300 mg, because of grade 03/ grade 04 toxicity, can be considered only
after 09 weeks.
iii. If dose of Lzd is reduced to 300 mg the period of the regimen will be extended upto 39 weeks
● In the initial days of treatment, myelosuppression due to Lzd sets earlier compared to peripheral
neuropathy. If, Hb falls less than 8g/dl and responds to blood transfusion, the patient can be continued
with Lzd 600 mg with intensive monitoring.

3.3.4 Regimen Change as per DST:

● Since Bdq and Lzd resistance levels in India are low, the NTEG recommended that BPaLM regimen can be
initiated in all the eligible MDR-TB patients while awaiting baseline DST to these drugs.
● In case the baseline DST shows resistance to any of the Bdq / Pa/Lzd, the outcome will be declared as
"Treatment regimen changed" and the patient is considered for 18-20 months longer oral M/XDR-TB
regimen, after assessment at N/DDRTBC.

3.3.5 Moxifloxacin in BPaLM:

● Mfx is a part of BPaLM regimen for full course, irrespective of resistance pattern to FQ at baseline or
during the course of the regimen. The following are the supporting evidence for the continuation of
Moxifloxacin in BPaLM regimen irrespective of FQ resistance pattern:
A. TB PRACTECAL study:
ƒ TB PRACTECAL trial had 3 arms including BPaLM, BPaLC, BPaL compared with the WHO standard
of care. In the BPaLM arm 32/138 participants (23%) were FQ resistant and Mfx continued
throughout the treatment duration in all 138 patients irrespective of FQ resistance status.

26 National Guidelines for Management of Drug Resistant TB

 ƒ Culture conversion: Culture conversion at 12 weeks was observed for 99/121 (82%) patients
for whom conversion could be defined in the standard care group and 107/120 (89%) patients in
the BPaLM group (risk difference 7.3 percentage points [95% CI −1.5 to 16.2] (26). In stage 1 of
the trial, the percentages of patients with culture conversion in liquid medium at 8 weeks after
randomization were 77%, 67%, and 46% in the BPaLM, BPaLC, and BPaL groups, respectively. 78 of
99 patients in the standard-care group (79%) and 85 of 96 patients in the BPaLM group (88%) had
culture conversion at 12 weeks (14).
ƒ Comparable time to culture conversion: Median time to culture conversion was 56 days (IQR
28 to 83 days) in the standard care group and 55 days (IQR 28 to 57 days) in the BPaLM group
(unadjusted hazard ratio 1.38 [95% CI 1.05 to 1.81] (26).
ƒ Low recurrence and probable protection against amplification of bedaquiline resistance: In TB
PRACTECAL trial, disease recurrence was observed in 5/115 (4%) participants in the BPaLC group,
4/111 (4%) participants in the BPaL group and 1/138 (1%) participants in BPaLM group. New
resistance to bedaquiline was observed in three of four isolates from the participants with disease
recurrence, all were in the BPaL group; of these, an isolate from one participant also showed
resistance to clofazimine (26). At week 48, there were no recurrences of tuberculosis in the BPaLM
group (14). Also sustained treatment success was observed with BPaLM at 108 weeks (94%) after
randomization in patients resistant to FQ (26).
ƒ Better treatment outcome: The network meta-analysis found successful outcomes in 55/62 (89%)
patients treated with BPaLM compared with 46/60 (77%) patients of those treated with BPaL
(absolute risk reduction 1.15 [95% CI 0.95–1.38]) (26).
ƒ The safety outcomes also favoured BPaLM, with lower percentages of patients with adverse events
of grade 3 or higher or serious adverse events for all outcomes (at week 72, at week 108, and during
treatment) (14).
ƒ The QTcF interval at week 24 was lower in the BPaLM group than in the standard-care group and
more closely resembled the QTcF in the BPaL group. The QTcF in the BPaLC group was similar to
that in the standard-care group. This finding corroborates evidence suggesting that clofazimine is a
primary driver of QTcF prolongation in bedaquiline-containing regimens (14).

B. US programmatic data (27)

ƒ CDC report compares patients who were initiated on the BPaLM regimen in the USA between
2019 and 2022, with patients receiving BPaL, a regimen previously documented to have uptake in
US tuberculosis programmes, as a complement to the randomised TB-PRACTECAL study.
ƒ 84/116 (72%) patients with BPaL regimen and 29/36 (81%) patients with BPaLM regimen
completed treatment
ƒ TB relapse reported was 3% in BPaL regimen and 0% in BPaLM regimen in the above cohort.
ƒ TB death reported was 1% in BPaL regimen and 3% in BPaLM regimen in the above cohort.

3.3.6 BPaLM regimen implementation considerations/ extension criteria/ regimen

modification
i. Folllow up cultures are to be done at the month 9,13, 18, 22, 26, and 39 in case of extension. However,
if patients on BPaLM show clinical deterioration or no improvement by 9 weeks, send an additional
specimen for smear, rapid molecular test, C&DST to all drugs at 9 weeks.
ii. At any point, after 9 weeks, if the patient is not improving clinically or radiologically, send sputum/ EPTB
specimen for C&DST and refer the patient to N/DDR-TBC.
iii. Interruptions: All possible efforts should be made to support the patient and manage the adverse events
to ensure uninterrupted treatment and intake of all medicines in the regimen. However, when severe
toxicity occurs, the medicine should be stopped.

NOVEMBER 2024 27
 a. In case of treatment interruptions and extended treatment duration to make up for missed doses,
it is necessary for patients to complete the 26 weeks of prescribed doses within 30 weeks and for
patients in whom treatment is extended, it is necessary to complete 39 weeks of prescribed doses
within 43 weeks.
b. If above conditions are not fulfilled, the patient may be declared as treatment failed and considered
for an appropriate treatment regimen change at the N/DDR-TBC.
iv. Missed Doses: Patient must complete 26 weeks (182 days) / 39 weeks (273 days) of treatment period
with all core medicines i.e., B, Pa, L. In case of missed doses in BPaLM regimen, the following general
guidance should be considered:
a. Patient must be resumed and complete the BPaLM course by prolonging the treatment duration for
number of missed doses of any core drugs in the regimen i.e., B, Pa, L in the following conditions:
Š Consecutive treatment interruption of up to two weeks or
Š Non-consecutive cumulative treatment interruption of up to four weeks
In the event of treatment interruption of the regimen, re-introduction of the regimen could be considered
post-cessation within 4 weeks after re-assessment of the patient by the N/DDR TBC.
b. In following conditions of missed doses of any core drugs i.e., B, Pa, L, the regimen is not resumed.
Š >2-weeks of consecutive treatment interruption; or
Š >4-weeks cumulative of nonconsecutive treatment interruption.
Further,
ƒ treatment outcome to be declared as treatment regimen changed.
ƒ the patient to be sent for clinical review and assessment at NDR-TBC to consider for 18-20 months
longer oral M/ XDR-TB regimen. The outcome of only the changed regimen would be reported.
v. Dose modification of Bdq, Pa, and Mfx is not recommended during treatment.
vi. For intolerance (grade 3-4) to FQ: Drop Mfx, complete the rest of the regimen as BPaL and extend the
treatment to 39 weeks.
vii. For intolerance (grade 3-4) to LZD Dose: All efforts must be made to ensure that the dosage of Lzd
600mg daily to be continued for the entire duration of treatment.
a. Within the first 9 weeks of treatment initiation, if Lzd (600 mg daily) need to be discontinued, due to
severe/ grade 03 toxicity (myelosuppression and/or peripheral neuropathy or optic neuritis), despite
efforts to restart Lzd at 600 mg, then discontinue the BPaLM regimen and declare the outcome as
'treatment failed'. The patient must be sent to the NDR-TBC for further evaluation and management.
b. For grade 03/ grade 04 toxicity/ intolerance due to Lzd (600 mg daily) in patients after 9 weeks of
treatment initiation: -
Š All efforts must be made to ensure that the patient consumes Lzd at full or lower dose up to at
least 26-39 weeks of treatment.
Š The patient must be sent to the N/DDR-TBC for detailed assessment regarding the temporary
interruption, reintroduction of Lzd at full dose. If reintroduction at full dose is not possible,
lower dose of Lzd to 300 mg.
Š In case of reduction in the dose of Linezolid, the treatment must be extended upto 39 weeks
and the patient must be followed up, more frequently by the physician clinically, radiologically
and microbiologically.

28 National Guidelines for Management of Drug Resistant TB

In general, action for Lzd toxicity should be taken in the following manner:
● for optic neuritis diagnosed at any grade, permanent discontinuation of linezolid is indicated;
● for peripheral neuropathy Grade 2, reduce the dose of linezolid to 300 mg per day with a possible drug
holiday for 1-2 weeks before dose reduction;
● for peripheral neuropathy Grade 3 or 4, in most cases permanent suspension of linezolid will be needed;
in some cases, after a 1-2-week drug holiday and reversion to Grade 2, the linezolid can be restarted and
tolerated, provided it does not revert back to a Grade 3 or 4 (caution is warranted with this approach
because patients can be left with a severe painful and disabling permanent peripheral neuropathy); and
● myelosuppression (even of Grade 3 or 4) is often reversible with a short 1-to-2-week drug holiday
followed by reducing the dose of linezolid to 300 mg per day; severe anaemia may need to be treated
with transfusions or erythropoietin.
An example of changes in Lzd dosing within the BPaLM regimen are given in Box 3.1 below-

Box 3.1. Example of changes in linezolid dosing within the BPaLM regimen
A patient diagnosed with MDR/RR-TB (based on NAAT results) completes four weeks
of treatment with BPaLM, with 600 mg of Lzd, when she/he experience symptoms of
severe paresthesia in the feet, preventing her/his from completing daily life activities.
This adverse event necessitates the cessation of Lzd within the first 9 weeks of therapy.
Because permanent discontinuation of Lzd was needed, the entire regimen had to be
discontinued, the treatment outcome to be declared as failed and a new regimen as
applicable to be started.

viii. After all efforts, in case the side-effects are worsening, the regimen must be stopped and the patient
must be shifted to longer oral M/XDR-TB regimen by the N/DDR TB Center. In the event of intolerance
(grade 3 or 4) to Bdq, Pa or Lzd, when re-challenge is not possible within 4 weeks of de-challenge to
address the intolerance or when resistance is detected, discontinue BPaLM regimen permanently and
declare the outcome as ‘treatment failed. Permanent discontinuation of Bdq, Pa or Lzd because of grade
3 or 4 ADR, drug resistance at any point of time, the patient must be declared as ‘treatment failure’ and
referred to NDR-TBC for evaluation.
ix. Patients’ screening for Lzd ADR: Patients must be actively screened for any early development of
Linezolid induced adverse events especially myelosuppression and neuropathy.
a. This is done more frequently in patients with any of the following high risk groups.
Š patients with co-morbidities like Diabetes mellitus, PLHIV, history of substance abuse,
hypothyroidism, and abnormal baseline electrolytes.
Š low BMI < 18.5 kg/m2
Š pre-existing anemia (Hb <8 gm/dl).
Š nutritional deficiencies
Š Lack of gain in appetite or weight or weight loss.
b. To screen peripheral neuropathy for neuromuscular weakness and neurosensory alteration and
grade, “the DAIDS Table for grading AE & peripheral neuropathy screening tool in annexure-3” is
to be referred. The table 3.3 has been suggested by the national experts for screening of peripheral
neuropathy which can be used at the peripheral health institution/ community level.
c. The indicator for myelosuppression:
Š >10% drop in hemoglobin from baseline or reduction in the TLC or platelet count should,
prompt more frequent follow ups and additional monitoring of the patients.

NOVEMBER 2024 29
Table 3.3 Signs/ symptoms for grading of peripheral neuropathy

Grade 4 /
Sr Grade 1 / Grade 2 / Grade 3 / Potentially
Symptoms
No. Mild Moderate Severe life-
threatening
1. Numbness, burning, prickly (pins and
needles) feelings in the feet
2. Feel hurt when bed covers touch the
skin
3. Cramps in the muscles of the leg or
muscle weakness.
4. Inability to distinguish hot or cold
water.
5. Worsening of symptoms at night or
increase in leg pain while walking.
6. Slipping off of footwear without
knowledge
7. Inability to place his soles on the
ground.
8. Frequent sores or ulcers on the feet
9. Diminution in the vision

x. Once a patient is declared as ‘treatment failed’, all attempts should be made to take opinion of state DT3C
clinics and the person to be assessed for an longer oral M/XDR-TB regimen, appropriate modifications
using replacement drug sequence (3).
xi. Extension Criteria:
a. The dose reduction of the Lzd to 300, because of grade 3-4 intolerance, can be considered after 09
weeks. If dose of Lzd is reduced to 300 mg the period of the BPaLM regimen will be extended upto
39 weeks
b. In case of grade 3-4 intolerance to Mfx, drop Mfx, complete the rest of the regimen as BPaL and
extend the treatment up to 39 weeks.
c. Extension of treatment upto 39 weeks should be done with strict clinical evaluation and smear and
culture microbiological follow-up at monthly interval.

3.3.7 Follow-up monitoring

● Once the BPaLM regimen is started, the patient will be monitored with regular clinical, bacteriological,
radiological, ECG, biochemical investigations and specialist consultation if needed, as shown in table 3.4.
● Monitoring neuropathy symptoms and Hb levels may help guide Lzd dosing to avoid toxicities. A decrease
in Hb level of 10% or more after four weeks of treatment initiation, may help to identify those at high risk
for severe anaemia.
● All patients initiated on BPaLM regimen need to be followed up as per the prescribed schedule. The
results of the above follow-up assessments would be used to guide necessary modifications or change of
the regimen.

30 National Guidelines for Management of Drug Resistant TB

Table 3.4: List and frequency of follow-up assessments for patient initiated on BPaLM
regimen

Follow-up
Timeline
assessments
Duration 26 weeks (extended up to 39 weeks)
Clinical review,
including weight and
BMI, concomitant
medication, Monthly
adherence, signs/
symptoms suggesting
adverse events
CBC (with Hb,
Day 15, 30, then monthly till month six, and more frequently if clinically indicated
platelets)^, and ECG
Visual acuity, and
Week 09, 13, 26 and more frequently if clinically indicated
color vision test
Smear microscopy@ With culture at the C&DST lab
Monthly from month two onwards (i.e., at month 2, 3,4,5,6). If the culture results
of month four or later are positive, collect one repeat specimen immediately and
Culture@ 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.
NAAT for H, FQ resistance detection or FL and SL LPA (Lfx, Mfx, Am, Eto) and LC-
DST@ DST Bdq*, Lzd, Pa*, Dlm*, Z, Mfx 1.0 (*whenever available) if culture +ve at the end
of month four, 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 three, the end of treatment, as and when clinically indicated
S. Electrolytes (Na, K,
As and when clinically indicated in case of any QTcF prolongation
Mg, Ca)
Specialist
(Ophthalmic,
As and when clinically indicated
Neurological)
consultation
Surgical evaluation After culture conversion
At 06, 12, 18, and 24 months after completion of treatment (Clinical, CXR, Smear
Long term follow-up 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
@ 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 for amplification of resistance. 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

NOVEMBER 2024 31
● Sociological/ psychological evaluation for treatment adherence, reasons for non-adherence, mental
health status, quality of life, motivation and counselling are to be done. Referral services for care and
rehabilitation will be provided if required.

3.3.8 Management of patients found to be ineligible for BPaLM regimen

● Patients who cannot be initiated on a BPaLM regimen will be assessed for and be managed with a 9-11
month shorter oral MDR/RR-TB regimen if eligible.
● If the patient is ineligible for both shorter regimens, then the patient will be managed with longer oral M/
XDR-TB regimen with appropriate modifications based on the decision of the N/DDR-TBC committee.
● If a clinical decision support is still needed, the state/national difficult to treat TB clinic (DT3C) may be
consulted on a case-to-case basis (3).

3.4 9–11-month shorter oral MDR/RR-TB regimen

● 9-11 month shorter oral MDR/R-TB regimen is to be used in eligible persons as per integrated algorithm.
● In patients 14 years or above with MDR/RR TB, BPaLM is first preference.
● The 9-11 month shorter oral MDR/RR-TB regimen is to be preferred over 18-20 months longer M/XDR-
TB regimen in adults and children with MDR/RR-TB.
● Till Bdq is available for the use in children below five years, Bdq is replaced by inj Amikacin, and other
modifications as per the PMDT guidelines 2021.
● Access to rapid DRT/ DST for ruling out FQ resistance is required before starting a patient.
● The program has adopted 9-11 month shorter oral regimen "with Lzd" for two months replacing "4
months of Eto" in IP phase, the rest of the medicine and duration of treatment remains same as earlier.

3.4.1 Eligibility criteria:

The eligibility criteria for the 9-11 month shorter oral MDR/RR-TB regimen is mentioned below:
i. Rifampicin resistance detected.
ii. MDR/RR-TB with FQ resistance not detected.
iii. 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)
iv. No extensive TB disease
v. No severe forms of extra-pulmonary MDR - TB like CNS TB, spinal/ skeletal TB (miliary TB or TB with
multiorgan involvement or disseminated TB)
vi. As Eto has been replaced by Lzd in the regimen therefore the 9-11 month shorter oral MDR/RR- TB
regimen with Lzd can be given to pregnant women irrespective of the gestational age with appropriate
safety monitoring in consultation with the patient (3). Further, if Z resistance is detected during initial
phase (IP), the patient will be switched to longer oral M/XDR-TB regimen.
vii. For the Lzd containing regimen, thyroid function test is not required in pre-treatment evaluation.
viii. InhA mutation and/or KatG mutation:
ƒ Lzd containing shorter oral MDR/RR-TB regimen can be given even in case of both KatG & InhA
mutations are present.
ƒ In case of both KatG & InhA mutation, Eto containing shorter oral MDR/RR-TB regimen cannot be
given
ix. Non-lactating women, non-pregnant women, pregnant women with <20 or <24 weeks gestation and
who is willing for medical termination of pregnancy (as per latest MTP gazette notification), if Eto is to be
used.

32 National Guidelines for Management of Drug Resistant TB

3.4.2 Regimen, dosage, and administration
● The regimen with Lzd or Eto would be as follows:

(2) Lzd (4-6) Lfx Cfz Z E Hh (6-9) Bdq (5) Lfx Cfz Z E
(4-6) Lfx Cfz Eto Z E Hh (6-9) Bdq (5) Lfx Cfz Z E

Table 3.5 The dosage of Lzd is 600 mg for 14 years & above. Table 3.5 Lzd dose for children
<14years is as per weight band as given below:

Weight bands among patients under 15 years

Weight- old Usual
Formula-
Medicine based upper
tion 5–6 7–9 10– 16– 24– 31– >34
Daily dose Daily dose
kg kg 15 kg 23 kg 30 kg 34 kg kg

15 mg/kg
20 mg /mL 6 20
od in 1–15 4 mL 8 mL 11 mL 14 mL 15 mL
susp mL mL
kg
Linezolid 600 mg
10–12 mg/
kg od in 600 mg tab 0.25 0.25 0.25 0.5 0.5 0.5 0.75
>15 kg

● Clinical and haematological monitoring are crucial to detect early Lzd-associated AEs, particularly
sudden or significant drop in Hb(>10%), neutrophils or platelets.
● If sputum smear microscopy is positive by the end of the month 04, then FL-LPA and SL-LPA, culture &
DST should be offered and the IP should be extended. IP can be extended to month 05 or 06 based on
smear results at the end of month 04 or 05 of treatment. This will be done for a maximum of 2 months
(i.e., total duration of IP is not more than 6 months).
● If additional resistant to Z is detected in the baseline sample on C&DST or FQ/InhA & KatG mutation is
detected in month 04 sample, the patient needs to be reassessed at N/DDR-TBC for stopping shorter
oral Bedaquiline-containing MDR/RR-TB regimen and initiation of longer oral M/XDR-TB regimen,
immediately on receiving the report

Table 3.6 Dosage of drugs 9-11 month shorter oral MDR/RR-TB regimen for adults

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

1 High dose H (Hh) 300 mg 600 mg 900 mg 900 mg
2 Ethambutol (E) 400 mg 800 mg 1200 mg 1600 mg
3 Pyrazinamide (Z) 750 mg 1250 mg 1750 mg 2000 mg
4 Levofloxacin (Lfx) 250 mg 750 mg 1000 mg 1000 mg
5 Bedaqulline (Bdq) Week 0-2 Bdq 400 mg daily
Week 3-24: Bdq 200 mg 3 times per week
6 Clofamizine (Cfz) 50 mg 100 mg 100 mg 200 mg
7 Ethionamide (Eto)* 375 mg 500 mg 750 mg 1000 mg
8 Pyridoxine (Pdx) 50 mg 100 mg 100 mg 100 mg
*Drugs can be given in divided doses in a day in the event of intolerance

NOVEMBER 2024 33
3.4.3 Baseline and follow-up monitoring
While using the 9-11 month shorter oral MDR/RR-TB regimen with Lzd, the following modification would be
considered in baseline and follow up monitoring:
● Ophthalmic evaluation, including visual acuity and colour vision test, need to be done at baseline and
week 09, 13, 26 and more frequently if clinically indicated.
● CBC, including Hb and platelets, needs to be done at baseline followed by week 2, week 4 and week 8
● If Eto is not used, there would be no need for monitoring TSH
● Repeat NAAT for H, FQ, SLI, Eto resistance detection or FL and SL LPA (Lfx, Mfx, Am, Eto) and LC DST
(Mfx 1.0, Lzd, Z, Bdq, Pa*, Dlm*) (*whenever available) if culture is positive at the end of month three or
later and end of treatment or smear is positive at the end of IP, end of extended IP and end of treatment

3.4.4 Regimen modification

Based on the recent evidence, the following regimen modifications are permissible in the modified 9-11
month shorter oral MDR/RR-TB regimen with Lzd (23):
i. Bdq is usually given for six months but can be extended to 11 months, particularly if IP is extended from
four to six months due to a positive sputum smear result at month 4.
ii. Lzd is only given for two months (instead of 4-6 months of Eto). In case of missed doses of Lzd upto 14
days, the missed doses may be added at the end of 2 months if resistance to FQ, Hh, Z has been ruled out.
iii. To reduce the severity of AEs, Lzd dose should not be reduced to less than 600 mg.
iv. In case of Lzd intolerance leading to permanent discontinuation of Lzd 600 mg within the initial two
months period, replace Lzd with four-six months of Eto to complete the regimen, Suppose person has
consumed Lzd for six weeks and develops intolerance, Eto needs to be started. The period for Eto will be
04 months minus 6 weeks, i.e period of Eto (4 months) minus the period of Lzd(6weeks) consumed at the
time of replacement. Still if the regimen cannot be continued because of any reason, declare the outcome
as “treatment failed” and switch to longer oral M/XDR-TB regimen without Lzd after reassessment.
v. If, for any reason, a patient is unable to tolerate Z or E, then drop one (but only one) of these drugs
during CP and complete the treatment duration. If two or more of these drugs or any of the other drugs
(Bdq, Lfx/Mfx, Lzd/Eto, or Cfz) are stopped due to intolerance or emergence of drug resistance, declare
the outcome as “treatment failed” and switch the patient to longer oral M/ XDR-TB regimen after
reassessment.(3).

3.5 18-20 months longer oral M/XDR-TB regimen

● (6 or longer) Bdq (18-20) Lfx Lzd Cfz Cs
● To be given to eligible person as per integrated algorithm in chapter 2.
● The patients who cannot be initiated on BPaLM or 9-11 month shorter oral MDR-TB regimen due to
reasons of ineligibility, additional resistance, intolerance, non-availability of any drug in use or emergence
of exclusion criteria will be managed with longer oral M/XDR-TB regimen modified in accordance with
the replacement sequence.
● After month 06 of treatment, the patient must be reviewed based on month 05 culture results. If month
05 culture result is not available at the end of month 06, decision to taper the dose of Lzd to 300 mg
will be based on month 04 culture result. If the month 05 or 04 culture result (whichever applicable)
remains positive, after initial 06 months, Lzd 600 mg may be extended by one month and maximum for
two months based on month 06, month 07 culture reports and clinical/radiographic response. If the 8th
month culture is positive, declare the outcome as treatment failed, subject the culture isolate to FL-LPA,
SL-LPA and C&DST. If any additional resistant to Group A, B or C drugs in use is detected, the patient
needs to be reassessed at N/DDR-TBC for modification of longer oral M/XDR-TB regimen immediately
on receiving the report.

34 National Guidelines for Management of Drug Resistant TB

● The duration of Bedaquiline is limited to 6 months. Extension beyond 6 months is to be considered in
patients in whom an effective regimen cannot otherwise be designed if only 2 of 5 drugs are available
from Groups A & B and adequate number of Group C drugs are not available due to high background
resistance, non-availability or unreliability of DST.
● Maximum duration of treatment is not more than 20 months.
● Till the Bdq use is approved for use in children below five years in India, the existing guideline for
management of MDR TB in children below five years will be followed, Bdq is replaced by Dlm)
● Repeat NAAT for H, FQ, SLI, Eto resistance detection or FL and SL LPA (Lfx, Mfx, Am, Eto) and LC-DST
Bdq*, Lzd, Pa*, Dlm*, Z, Mfx 1.0 (*whenever available) if culture is positive in sample collected at the end
of month 06 or any time beyond.
● For XDR-TB patients the duration of longer oral XDR-TB regimen would be for 20 months.(3).

Table 3.7 Dosage of M/XDR-TB drugs for adults in longer oral M/XDR-TB regimen (with
replacement drugs)

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

1 Levofloxacin (Lfx) 250 mg 750 mg 1000 mg 1000 mg
2 Moxifloxacin (Mfx) 200 mg 400 mg 400 mg 400 mg
3 High dose Mfx (Mfxh) 400mg 600mg 800mg 800mg
Week 0–2: Bdq 400 mg daily
4 Bedaquiline (Bdq)
Week 3–24: Bdq 200 mg 3 times per week
5 Clofazimine (Cfz) 50 mg 100 mg 100 mg 200 mg
6 Cycloserine (Cs)3 250 mg 500 mg 750 mg 1000 mg
7 Linezolid (Lzd) 300 mg 600 mg 600 mg 600 mg
50 mg twice daily (100 mg) for 24 weeks in 6-11 years of age 100 mg twice
8 Delamanid (Dlm)
daily (200 mg) for 24 weeks for ≥12 years of age
9 Amikacin (Am)1 500 mg 750 mg 750 mg 1000 mg
10 Pyrazinamide (Z) 750 mg 1250 mg 1750 mg 2000 mg
11 Ethionamide (Eto) 3
375 mg 500 mg 750 mg 1000 mg
Na - PAS (60%
12 10 gm 14 gm 16 gm 22 gm
weight/vol)2,3
13 Ethambutol (E) 400 mg 800 mg 1200 mg 1600 mg
Imipenem-Cilastatin
14 2 vials (1g + 1g) bd (to be used with Clavulanic acid)
(Imp-Cln)3
1000 mg three times daily (alternative dosing is 2000 mg twice daily) (to be
15 Meropenems (Mpm)3
used with Clavulanic acid)
Amoxicillin-
Clavulanate (Amx-
16 875/125 mg bd 875/125 mg bd 875/125 mg bd 875/125 mg bd
Clv) (to be given with
carbapenems only)
17 Pyridoxine (Pdx) 50 mg 100 mg 100 mg 100 mg
1
For adults more than 60 yrs of age, dose of SLI should be reduced to 10mg/kg (max up to 750 mg)
2
Patients receiving PAS with 80% weight/volume the dose will be changed to 7.5gm (16-29 kg); 10 gm (30- 45 Kg); 12 gm (46-70 Kg) and 16 gm (>70
kg)
3
Drugs can be given in divided doses in a day in the event of intolerance

NOVEMBER 2024 35
3.6 Isoniazid (H) mono/poly drug-resistant TB regimen
● Regimen - (06) LxREZ, to be given to eligible persons as per integrated algorithm in chapter 2.
● H mono/poly DR-TB regimen is of 06 or 09 months with no separate IP/CP. In exceptional situations of
unavailability of loose drug R or E or Z, the use of 4 FDC (HREZ) with Lfx loose tablets may be considered
as an option for starting the H mono/poly DR-TB regimen.
● It can be extended directly to 9 months in certain conditions. In patients with extensive disease;
uncontrolled comorbidity; extra- pulmonary TB; if smear at the end of month 4 is found positive and
when regimen is modified, the treatment may be directly extended to 9 months. There would be no
monthly extensions in this regimen.
● The patients not responding or failing in the H mono/poly DR-TB regimen demonstrating & no additional
resistance to R 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, 9-11 month shorter oral MDR/
RR-TB regimen if eligible or longer oral M/ XDR-TB regimen with appropriate modification as per the
programme guidelines.

Table 3.8 Dosages for drugs used in H mono/poly DR-TB regimen by weight bands for adults

S.N Drugs 16-29 kg 30-45 kg 46-70 kg >70 kg

1 Rifampicin (R) 300mg 450mg 600mg 750mg
2 Ethambutol (E) 400 mg 800 mg 1200 mg 1600 mg
3 Pyrazinamide (Z) 750 mg 1250 mg 1750 mg 2000 mg
4 Levofloxacin (Lfx) 250 mg 750 mg 1000 mg 1000 mg

Table 3.9 Replacement sequence of drugs to modify Hr-TB regimen

Situation Sequence of using replacement drugs

Replace with Lzd. If Lzd also cannot be given, replace with
1. If Lfx or Z can’t Be Used
Cfz* + Cs.
Add 2 drugs of the 3 – Lzd, Cfz*, Cs in order of preference
2. If both Lfx and Z can’t be used
based on resistance, tolerability & availability.
3. If R resistance Switch to appropriate shorter or longer oral regimen.
*whenever DST is available

3.7 Switching between treatment regimens

This section describes the management of patients while switching between shorter and longer regimens
(23).
● Patients who are required to be shifted from BPaLM or 9-11 month shorter oral MDR/RR-TB regimen to
longer oral M/XDR-TB regimen due to reasons of resistance, tolerability, availability, Interruptions and
the emergence of exclusion criteria, need to be re-evaluated for necessary modification of longer oral M/
XDR-TB regimen and initiated on a full course of longer oral M/XDR- TB regimen after discussion with
state difficult-to-treat TB clinic.
● Similarly, patients who are placed on a longer oral M/XDR-TB regimen based on the history of exposure
to SLDs for more than one month awaiting DST results and later found to be eligible for the BPaLM
or 9-11 month shorter oral MDR/RR-TB regimen (and in whom resistance is not detected on baseline
specimen to H, i.e. both InhA and KatG or to FQ or Z, Bdq, Pa*, Dlm*) can be switched to any of these
shorter regimens, provided that treatment has not lasted for more than one month. If patients are

36 National Guidelines for Management of Drug Resistant TB

 switched in this way, the BPaLM or 9-11 month shorter oral MDR/RR-TB regimen is given for the full
duration without any changes to its composition or duration.
● If a new episode of treatment is being started while switching over from BPaLM or 9-11 month shorter
oral MDR/RR-TB regimen to longer oral M/XDR-TB regimen or vice versa, and if Bdq is sensitive or the
patient is not exposed to Bdq for more than one month, Bdq needs to be continued in the new regimen
till the treatment duration is completed.
● At the time of switching between regimens, if the loading dose of Bdq (first 14 days)
i. is still ongoing with no dose interruption, then complete the loading dose and shift to the thrice-
weekly doses after 14 days to complete the treatment duration.
ii. is over, there is no need to repeat the loading dose. Start Bdq with a fresh bottle/strip with the thrice-
weekly doses along with the first dose of other medicines in the new regimen and continue the thrice-
weekly doses to complete the treatment duration.
● In all the above situations, the remaining drugs (except a bottle of Bdq) of the regimen stopped should be
returned for reconstitution, and a new box of the changed regimen should be initiated.
● In such patients with a change in regimen from BPaLM or 9-11 month shorter oral MDR/RR-TB regimen
to longer or vice-versa in the initial months either due to delay in receiving the baseline DST results or
before any definitive treatment outcome can be applied, the outcome the “Treatment regimen changed”
needs to be reported. The patient needs to be removed from the denominator of the previous regimen
while assessing the treatment outcome.

3.8 Supply chain management of anti-TB drugs and logistics

This section describes procedures and supply chain management of second-line anti-TB drugs.

3.8.1 Drug procurement

NTEP will supply patient courses of drugs for the DR-TB regimens to the respective treatment initiating sites
through the respective state drug store (SDS), district drug store (DDS), TB unit drug store (TUDS) along
with the routine supply of rest of the drugs. The procurement and supply management (PSM) will be through
the regular mechanisms of NTEP, like other FL and SLDs, and will be monitored using Ni- Kshay (https://
nikshay.in/) / Ni-Kshay Aushadhi (https://nikshayaushadhi.in/) online portals.

3.8.2 Supply chain management

● The drugs of the DR-TB regimens will be supplied to the SDSs, DDSs and subsequently to identified
treatment initiating sites (DR-TB centres) through NTEP as a part of regular drug supply.

3.8.2.1. BPaLM regimen

● Pa 200 mg tablet is packaged in either white, round, high-density polyethylene bottles with polypropylene
child-resistant closure or child-resistant blister packages consisting of a polyvinyl chloride film with foil
and paper backing.
● The tablets dispensed outside the container should be stored in a tight, light-resistant container with an
expiry date that should not exceed three months. It will have a shelf-life of 24 months and will need to be
stored at 25 ºC (15–30 ºC).
● BPaLM regimen will be issued as a complete box containing 26 weeks course. One Bdq bottle contains
24 weeks course of 100 mg x 188 tablets plus 12 loose tablets or Bdq 100 mg is available in strips 10
tablets in a single strip, thus leading to a need of 20 strips to complete the 26 weeks course, One Pa
bottle contains 200 mg x 26 tablets & Lzd is available in 600 mg X 10 tablets per strip, and Mfx is available
in 400 mg X 10 tablets per strip.

NOVEMBER 2024 37
● Since there are no weight bands, the patient-wise boxes (PwB) with 26 weeks’ complete duration of the
drugs in the regimen will be prepared by the SDS and issued to the DDS as per the stocking norms and
subsequently to identified treatment initiating sites (DR-TB centres) on a caseload basis. The composition
of a PwB for the entire BPaLM course of 26 weeks is given in table 3.10, and for its extension of 27-39
weeks (13 weeks) is given in table 3.11.

Table 3.10: Composition of one PwB for the entire BPaLM course of 26 weeks

Drug Strength Total tablets No. of bottles/ strips/ tablets

Bedaquiline (Bdq) 100 mg 200 One bottle plus 12 loose tablets /20 strips
Pretomanid (Pa) 200 mg 182 7 bottles / 19 strips
Linezolid (Lzd) 600 mg 182 18 strips plus 2 tablets
Moxifloxacin (Mfx) 400 mg 182 18 strips plus 2 tablets
Pyridoxine (Pdx) 50/100 mg 182 18 strips plus 2 tablets

● PwB has a Bdq pouch with 12 tablets (which needs to be taken for the first 3 days of loading doses) and a
Bdq bottle with 188 tablets. The batch number and expiry date are to be mentioned on the pouch.
● Pyridoxine (Pdx) will be administered for the entire duration of treatment.
● The complete PwBs will be stored at the DDS and issued as per the monthly case load basis to the N/
DDR TBC respectively. At the time of treatment initiation, the N/DDR TBC will open a fresh complete
PwB to initiate the treatment with using Bdq loose drugs available from the zip-lock pouch for the first
three days (12 loose tablets) and the rest of the drugs directly from the PwBs.
● If the treatment is initiated on an out-patient basis, the first dose of all medicines will be given under
observation at the N/DDR TBC, and the rest of the PwB will be provided to the treatment supporter or
the patient. The patient is counselled to take 2nd and 3rd day dose from the pouch (pouch has 12 tablets
for 3 days). Further treatment supporter and the patient will be directed to utilize remaining Bdq doses
from the Bdq bottle provided in the PwB from day four onwards to continue the Bdq daily loading dose
upto day 14 and shift to thrice-weekly dose from day 15 till the end of 26 weeks.
● Pa (200 mg), Lzd (600 mg) and Mfx (400 mg) are to be taken as one tablet per day for the entire duration
of treatment.
● After treatment initiation, respective DTO to be informed by the N/DDR-TBC and sr. DR-TB TB-HIV
supervisor/ STS is responsible for handing over treatment box from the patient/relative to the trained
treatment supporter.
● If the N/DDR-TBC directs to reduce the dose of Lzd 300 mg once daily dose, half a tablet of 600 mg will
be consumed by the patient, and the remaining half to be discarded.
● In case of an extension of treatment beyond 26 weeks, an additional PwB to cover the drug requirement
from 27-39 weeks (13 weeks) will be issued from the DDS based on the decision conveyed by N/DDR-
TBC. These additional drug requirements will be covered using loose drugs supplied from SDS to DDS
and may be adjusted against the drugs returned from the patients who died, LTFU or whose regimens
were changed.
● The patient should be encouraged to submit empty bottles to the health facility and eventually store
them at DDS. If required, a new bottle of Bdq or Pa may be opened for reconstitution.

38 National Guidelines for Management of Drug Resistant TB

Table 3.11: Composition of One extension PwB for the BPaLM course of 27-39 weeks (13
weeks)

Drug Strength Total tablets No. of bottles/ strips/ tablets

Bedaquiline (Bdq) 100 mg 78 One reconstituted bottle with 78 tablets / 8 strips
Three full bottles (26 tablets per bottle) and one
Pretomanid (Pa) 200 mg 91
reconstituted bottle with 13 tablets
Linezolid (Lzd) 600 mg 91 9 strips plus one tablet
Moxifloxacin (Mfx)
400 mg 91 9 strips plus one tablet
(if indicated)
Pyridoxine (Pdx) 50/100 mg 91 9 strips plus one tablet

● In case the patient has been continued BPaL regimen, all Mfx (400 mg) tablets will be removed by the
SDS/DDS before issuing the PwB or by the respective treatment supporter/supervisor from the ongoing
PwB during an immediate home visit and the patient as well as treatment supporter informed about the
change in the daily dosing. The remaining Mfx (400 mg) tablets will be returned to the concerned DDS/
SDS for reconstitution. The change should be reflected in the dispensation module of Ni-Kshay by the N/
DDR-TBC or concerned treatment supervisor as per advice of the N/DDR-TBC.

3.8.2.2 9 -11 month shorter oral MDR/RR-TB regimen

● The constitution of the IP box of the 9-11 month shorter oral MDR/RR-TB regimen will be the same as
detailed in respective section (3), except replacement of four months of Eto with two months of Lzd in
the IP, as applicable. Thus, 63 tablets of Lzd (600 mg) to cover the initial nine weeks are to be added to the
initial monthly PwBs in place of the entire quantity of Eto(3).
● A child-friendly formulation of Bdq (20 mg scored uncoated dispersible tablet [DT]) is approved by DCGI
for children and adults. Indirect bioequivalence testing of Bdq 20 mg DT child friendly and Bdq 100 mg
adult formulations showed that both tablets have the same bioavailability and can be used interchangeably
at the same total dose. Findings from the Bdq crush study also showed that the bioavailability of Bdq
tablets suspended in water was the same as for tablets swallowed whole (28)(29).
● If any regimen modification is advised by N/DDR-TBC in accordance with section 3.4.4., the patient as
well as treatment supporter/supervisor must be informed about the change in the daily dosing while
the next month’s PwB will be modified and issued by the respective DDS/SDS for the respective patient.
The remaining drugs will be returned to the concerned DDS/SDS for reconstitution by the treatment
supporter/supervisor. The change should be reflected in the dispensation module of Ni-Kshay by the N/
DDR-TBC or concerned treatment supervisor as per the advice of the N/DDR-TBC.

3.8.2.3 Longer oral M/XDR-TB regimen

● Patients who cannot be initiated on BPaLM or 9-11 month shorter oral MDR-TB regimen due to
any reasons will be managed with longer oral M/XDR-TB regimen modified in accordance with the
replacement sequence.
● PwBs of the longer oral M/XDR-TB regimen with appropriate modifications will be prepared and issued
by DDS to the concerned N/DDR TBC (3).
● Delamanid 25mg DT was approved by DCGI for use as part of an appropriate combination regimen for
pulmonary multi-drug resistant tuberculosis (MDR-TB) in adults, adolescents, children, and infants with
a body weight of at least 10 kg when an effective treatment regimen cannot otherwise be composed for
reasons of resistance or tolerability (30). However, adult Dlm tablets can be split, crushed or dissolved to
ease administration in children without potentially altering bioavailability (28)(31).

NOVEMBER 2024 39
● All the drugs in the PwB issued to be consumed by the patient as per the dosing schedule of the respective
regimen till the end of treatment. The patient should be advised to visit the N/DDR-TBC for end of
treatment evaluation and further actions including updating the treatment outcome on Ni-Kshay.
● If MERM boxes are being used, the empty box and the device need to be returned to the concerned DDS/
SDS for resetting and reissuing the box to a new patient.

3.9 Management of special situations

This chapter deals with the management of patients eligible for BPaLM or 9-11 month shorter oral MDR/
RR-TB regimen and longer oral M/XDR-TB regimen in special populations.

3.9.1 Pregnancy and lactation

● Pregnancy is not a contraindication for the treatment of drug-resistant TB but poses a great risk to both
the mother and foetus.
● SLIs are contraindicated throughout the pregnancy due to their effect on the 8th cranial nerve of the
foetus. Eto is contraindicated during the first 32 weeks of pregnancy due to teratogenic effects.
● There is an experience of using Lzd during pregnancy. For pregnant and lactating women, it is therefore
recommended to use the regimen with Lzd instead of Eto in the 9-11 month shorter oral MDR/RR-TB
regimen.
● The use of 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 (32).
● 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 obstetrician while treating such patients.
● All women of childbearing age who are awaiting results of C&DST as well as those receiving DR-TB
treatment, should be advised, and counselled intensively to use birth control measures because of the
potential risk to both mother and foetus. It should be remembered that oral contraceptives might have
decreased efficacy due to vomiting and drug interactions with DR-TB drugs.
● All women of childbearing age should be tested for pregnancy as part of the PTE and whilst on treatment.
DR-TB patients found to be pregnant prior to treatment initiation or whilst on treatment must be
evaluated in consultation with an obstetrician, considering factors such as risks and benefits of DR-TB
treatment; severity of DR-TB; gestational age, and potential risk to the foetus.
● In pregnant women, strict counselling needs to be done for MTP, especially regarding the risk of delaying
treatment, potential effects of new drugs on the foetus, including foetal abnormalities (if MTP is not
opted) and the need for more intense maternal-foetal-neonatal follow-up. Appropriate counselling and
an informed decision-making process for consent need to be undertaken in each case with electronic
data management in Ni-Kshay, including aDSM.
● Pregnant women with MDR-TB should be jointly managed by an obstetrician and a pulmonologist or
physician at DR-TBC. Management of DR-TB patients who are pregnant prior to initiation of treatment
or whilst on treatment is based on the duration of pregnancy and regimen being considered as follows:
1. BPaLM regimen may be considered if the pregnant women with <20 or <24 weeks gestation and who is
willing for medical termination of pregnancy (as per latest MTP gazette notification)
2. As Lzd is an option in place of Eto, all pregnant women would be eligible for the 9-11 month shorter oral
MDR/RR-TB regimen after considering other eligibility criteria. Eto based regimen may be considered
after 32 weeks’ gestation, if Lzd based regimen can’t be used.

40 National Guidelines for Management of Drug Resistant TB

3. If the pregnant woman is not eligible for both above regimens, the 18-20 month longer oral M/XDR-
TB regimen may be considered. Modify regimen if one or more drugs cannot be used due to reasons of
resistance, tolerability, contraindication, availability etc.
ƒ in the order of Z E PAS
ƒ Eto may be considered after 32 weeks’ gestation, if required
ƒ Am may be considered in post-partum period only. Am can not be considered as a replacement drug
in the final 12 months of treatment
● In women of reproductive age who have been initiated on BPaLM or 9-11 month shorter oral MDR/
RR-TB regimen or longer oral M/XDR-TB regimen and who become pregnant, the risk to the mother and
foetus needs to be explained clearly. If the pregnancy is < 24 weeks, the decision to continue the BPaLM
regimen would depend upon the willingness of the patient to opt for an MTP as per MTP (amendment)
act, 2021.
● Lactating mother should be encouraged for breastfeeding, if she is smear/ culture negative and not on
Pa containing regimen.
● If she is unwilling for MTP or has a pregnancy > 24 weeks duration, she needs to be treated with or
shifted from BPaLM (if already initiated), based on eligibility and in the given order of preference, to
9-11 month shorter oral MDR/ RR-TB regimen or longer oral M/XDR-TB regimen. In such patients, the
risk to the mother and foetus needs to be explained clearly, and the pregnant DR-TB patients need to
be monitored carefully, both in relation to the treatment and progress of the pregnancy. This approach
should lead to good results since the patient should be smear/culture negative at the time of parturition,
and the mother and infant do not need to be separated.

NOVEMBER 2024 41
● The following additional monitoring is recommended for pregnant women managed with any MDR-TB
regimens:
i. These mothers should deliver in a tertiary care institute or at least at a place where a pediatrician is
available.
ii. CBC, including Hb, need to be monitored monthly and more frequently if clinically indicated.
iii. USG foetal anomalies scan at 18 weeks and USG growth scan at 32 weeks. A fetal echo is to be done
only if there is an abnormality on the scan.
iv. More frequent ECG and serum electrolytes may be considered as clinically indicated.
v. The option of 2nd trimester MTP can be considered if the mother is fit for it, based on a fetal scan of
2nd trimester.
vi. Strict aDSM is to be done.
vii. ANC registration and obstetrician follow-up are to be done regularly.
viii. If Eto is considered in the regimen, and if the basal TSH in PTE is deranged, then TSH must be done
monthly and once it is normal (less than 2.5), then quarterly during treatment. Check the infant for
early evidence of hypothyroidism.
ix. In case para-aminosalicylic acid (PAS) and Eto are given (which cause hypothyroidism) and Lzd (which
causes myelosuppression) to a newborn who has been exposed to a cocktail of drugs, certain baseline
investigations at birth like CBC and TSH should be done.

3.9.2 Children
● Safety and effectiveness of BPaLM regimen with Pa in children < 14 years have not been established.
Thus, children below 14 years should be treated with 9-11 month shorter or longer oral regimens as per
eligibility in consultation with the paediatrician available or linked to the N/DDR-TBC.
● Bdq has been approved by the regulatory authority for use in children 5 years and above. Bdq may be used
in shorter or longer regimen in children less than 5 years of age whenever approved by the regulatory
authority.

3.9.3 Older people

● Clinical studies of the combination regimen of Pa, Bdq, and Lzd did not include sufficient numbers of
subjects aged 65 years and over to determine whether they respond differently from younger subjects.
Hence, health status and underlying co-morbidities must be assessed carefully before considering
patients aged 65 years and over for BPaLM regimen, and if included, they would need much closer
monitoring.

3.9.4 People living with HIV

Management of DR-TB patients in people living with HIV should be done in consultation with ART centre.
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.
i. Efavirenz induces metabolism of Bdq, so its co-administration with Bdq may result in reduced Bdq
exposure and loss of activity; therefore, co-administration is to be avoided. Efavirenz also reduces Pa
exposures significantly; therefore, an alternative antiretroviral agent (potentially dolutegravir (DTG),
although there is currently insufficient evidence for this) should be used if the BPaLM regimen is
considered.
ii. Ritonavir may increase Bdq exposure, which could potentially increase the risk of Bdq-related adverse
reactions; however, increased risk has not been noted in studies administering both drugs concurrently.
Individuals who are prescribed both Bdq and ritonavir should be monitored closely for adverse events,
including QTc prolongation.
42 National Guidelines for Management of Drug Resistant TB
iii. Zidovudine (no longer commonly used or recommended for HIV treatment in adults and adolescents)
should be avoided, if possible, because both zidovudine and Lzd may cause peripheral nerve toxicity and
are known to have myelosuppression cross-toxicity (23).
These cases should be managed through consultation between the ART Centre and DR-TB Centre.(3).

3.9.5 People with renal insufficiency

● Generally Bdq, Lnz and Mfx are considered safe in renal insufficiency
● Renal insufficiency may be caused by TB infection itself or by previous use of aminoglycosides. Patients
with renal insufficiency and initiated on BPaLM or 9-11 month shorter oral MDR/RR-TB regimen or
longer oral M/XDR-TB regimen may develop severe anaemia and electrolyte imbalance.
● Patients with renal insufficiency should be carefully evaluated before the start of any MDR/RR-TB
regimen if the PTE rules out the exclusion criteria. Owing to limited experience with the use of this
regimen, caution should be exercised in patients with severe renal failure.

3.9.6 People with liver disorders

● In various DR-TB regimens under NTEP, R, H, Z, PAS, Eto, Bdq and Pa are potentially hepatotoxic drugs.
Hepatitis rarely occurs with the FQs.
● The potential for hepatotoxicity is increased in the elderly, alcoholics, malnourished and in patients
with pre-existing liver disease. In general, most SLDs can be safely used in the presence of mild hepatic
impairment, as they are relatively less hepatotoxic than FLDs.
● For patients on BPaLM regimen, routine liver function test (LFT) is recommended at month three in
all patients and then as and when clinically indicated. DR-TB patients having deranged LFT during PTE
should be strictly monitored and more frequently as clinically indicated while on treatment. Once a
patient on SLDs develops hepatitis, other etiologies should be excluded, such as viral hepatitis, alcoholic
hepatitis, drug- induced hepatitis by non-TB drugs etc.
● Close monitoring of liver enzymes is recommended, and the drugs may need to be stopped if significant
liver inflammation is apparent.

3.9.7 People with diabetes mellitus

● Blood sugar levels may be difficult to control in patients with MDR/RR-TB and diabetes, and insulin may
be required to gain adequate blood sugar control during treatment.
● Patients with diabetes are also at increased risk of peripheral neuropathies, which may be further
exacerbated following exposure to Lzd and Hh. These patients must be counselled to report symptoms
of peripheral neuropathies early because such symptoms may necessitate a change in regimen – either
to the Eto-containing 9-11 month shorter oral MDR/RR-TB regimen (bearing in mind this will still include
Hh in the IP), or longer oral M/XDR-TB regimen without Lzd.
● The concomitant use of metformin at high doses and Lzd may increase the risk of lactic acidosis. Also, the
long-term use of Lzd, Hh and cycloserine (Cs) in patients with diabetes can lead to an increased risk of
peripheral neuritis. Baseline optic neuropathy or retinopathy or maculopathy may worsen after Lzd use;
hence, eye evaluation is recommended before and during treatment. Regarding potential baseline renal
damage in diabetics, Am or Sm should be used with caution. Patients with DR-TB and diabetes may need
close follow-up and support, with quick identification of drug–drug interactions and adverse events (23).

NOVEMBER 2024 43
3.9.8 People with anaemia
● 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. This
deficiency may resolve naturally once effective TB treatment (even including Lzd) leads to resolution of
TB symptoms and improvement in the patient’s anaemia, diet and appetite.
● Extended use (≥ 2 weeks) of Lzd has been associated with reversible myelosuppression and requires
intensive monitoring.
ƒ Therefore, the Lzd-containing regimen must not be offered to patients with a pretreatment serum
Hb below 8 g/dL that cannot be rapidly corrected (i.e. with blood transfusions) before starting
MDR/RR- TB treatment.
ƒ Some patients respond well to an initial blood transfusion that raises their Hb above 8 gm/
dL and allows them to at least start a Lzd-containing regimen. Lzd will not necessarily cause
myelosuppression in patients with baseline anaemia.
ƒ 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. Therefore, if Lzd
toxicity leads to a drop in Hb below 8 g/dL during the first two months of treatment, Lzd should be
withdrawn, and the regimen switched appropriately.
ƒ More research is needed on the role of iron supplementation to treat anaemia during MDR/RR- TB
treatment; however, 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 (23).
● Similarly, owing to the morbidity associated with severe neutropenia and thrombocytopenia, the Lzd-
containing regimen is not suitable in patients with neutrophils below 0.75 × 109/L (or 750/mm3) or
platelets below 150 × 109/L (or 1,50,000/mm3) before starting treatment. Some patients respond well
to an initial blood transfusion that raises their Hb above 8 gm/ dL and allows them to at least start a Lzd-
containing regimen. Lzd will not necessarily cause myelosuppression in patients with baseline anaemia,
although a baseline Hb below 10.5 g/dL has been reported as a risk factor for Lzd-induced anaemia.
● If Lzd toxicity leads to a drop in Hb below 8 g/dL during the first two months of treatment, Lzd should be
withdrawn, blood transfusions may help to reverse anaemia. The Lzd reintroduction may be tried after
Hb is above 9 g/dL. More research is needed on the role of iron supplementation to treat anaemia during
MDR/RR- TB treatment; however, 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 (23).

3.10 Adverse events

● Identification of adverse drug reactions (ADR) should be a part of patient interaction at the time of
treatment initiation as well as treatment supporters should be involved in sensitization sessions for
common ADR. N/DDR- TBC initiating the treatment should be informed immediately once any ADR is
reported by the patient in the field.
● If the treatment is stopped in the field due to any reason, the N/DDR-TBC should be informed immediately
to take the necessary action to reintroduce the treatment, modify or replace the regimen and/or manage
the ADR.
● The most common adverse reactions observed in patients treated with Pa in combination with Bdq and
Lzd are peripheral neuropathy, hematological abnormalities, visual impairment and cardiotoxicities.
● Other adverse reactions included acne, nausea, vomiting, headache, increased transaminases, dyspepsia,
rash, pruritus, abdominal pain, pleuritic pain, increased gamma-glutamyl transferase, lower respiratory
tract infection, hyperamylasemia, hemoptysis, back pain, cough, hypoglycemia, abnormal loss of weight,
and diarrhoea (33).

44 National Guidelines for Management of Drug Resistant TB