PMDT guidelines 2021:

An update in management
of DR-TB

Dr. Kiran Rami/Dr. Meghna Patel/Dr.Kaushal Bhavsar

Dept of Respiratory Medicine,

GMERS Medical college and hospital,
Sola, Ahmedabad
Global and National magnitude of TB & DR-TB
Global India
Estimates of
TB Burden Numbers Numbers Rate % Global
(2019) (Lakh) (Lakh) (Per Lakh) burden

TB incidence 100 26.4 193 26%

TB mortality
(including TB- 14 4.45 33 32%
HIV)

Multi Drug
Resistant TB 4.65 1.24 9.1 27%

2
 Causes of DR-TB
Microbial
Drugs
Genetic mutation (Inadequate supply or
poor quality)
Caused by random • Non-availability of certain
chromosomal mutations at drugs (stock-outs or
predictable frequencies delivery disruptions)
• Poor quality
(H resistant bacilli 1 in 106, R • Poor storage conditions
1 in 108, HR 1 in 1014) * • Wrong dosages or
combination
*David HL. Drug-Resistance in M. tuberculosis and other mycobacteria. Clin Chest Med 1980; 1: 227-30.
*David HL. Probability distribution of drug resistant mutants in unselected population of Mycobacterium tuberculosis. Appl Mcrobiol 1970;20:810-814.
Programmatic
Providers/Programmes
(Inadequate regimen)
• Unsupervised treatment
• Absence of guidelines or
inappropriate guidelines
• Non-compliance with
guidelines
• Inadequate training of
health staff
• No monitoring of
treatment
• Poorly organized or funded
TB control programmes
Clinical
Inadequate drug intake
• Unobserved treatment
• Poor adherence
• Lack of information
• Non-availability of free
drugs
• Adverse drug reactions
• Social & economic barriers
• Malabsorption
• Substance abuse disorders
3
 Choice of diagnostic technology
DR diagnostic technology Choice
NAAT/LPA First
Liquid culture isolation and LPA DST Second

Liquid culture isolation and liquid DST Third

Turnaround time
Solid LJ media- of up to 84 days,
Liquid Culture (MGIT) up to 42 days,
LPA up to 72 hours
NAAT - 2 hours.
Grouping* of anti-TB drugs and other consideration
Groups & steps Medicine Abbreviation
Group A Levofloxacin or Lfx
Include all three medicines Moxifloxacin Mfx
Bedaquiline Bdq
Linezolid Lzd
Group B Clofazimine Cfz
Add one or both medicines Cycloserine or Cs
Terizidone Trd
Group C Ethambutol E
Add to complete the regimen and Delamanid Dlm
when medicines from Group A and Pyrazinamide Z
B cannot be used Imipenem-cilastatin or Meropenem Ipm-Cln
Mpm
Amikacin Am
(OR Streptomycin) (S)
Ethionamide or Eto
Prothionamide Pto
p-aminosalicylic acid PAS

* Reference: WHO Consolidated Guidelines for TB module 4: Treatment of DR-TB 2020

Annexure 11: evidences on efficacy and safety of the second-line anti-TB drugs 5
 Definitions
• Mono-resistant TB (MR-TB): A TB patient, whose biological specimen is resistant to
one first- line anti-TB drug only.

• Isoniazid-resistant TB (Hr-TB): A TB patient, in whose biological specimen resistance

to isoniazid and susceptibility to rifampicin has been confirmed.

• Poly-drug resistant TB (PDR-TB): A TB patient, whose biological specimen is resistant

to more than one first-line anti-TB drug, other than both H and R.

• Rifampicin resistant TB (RR- TB): A TB patient, whose biological specimen is resistant

to R, detected using phenotypic or genotypic methods, with or without resistance to other
anti-TB drugs. It includes any resistance to R, in the form of mono-resistance, poly-
resistance, MDR or XDR.
6
• Multidrug-resistant TB (MDR-TB): A TB patient, whose biological specimen is
resistant to both H and R with or without resistance to other first-line anti-TB drugs. MDR-
TB patients may have additional resistance to any/all FQ or any other anti-TB drug.

• Pre-extensively drug resistant TB (Pre-XDR-TB): TB caused by Mycobacterium

tuberculosis strains that fulfil the definition of MDR/RR-TB and are also resistant to any
fluoroquinolone.

• Extensively drug resistant TB (XDR-TB): TB caused by Mycobacterium tuberculosis

strains that fulfil the definition of MDR/RR-TB and are also resistant to any fluoroquinolone
(levofloxacin or moxifloxacin) and at least one additional Group A drug (presently to
either bedaquiline or linezolid [or both]).

7
Detection of drug resistant / susceptibility
Drug Resistance Testing (DRT)
• Genotypic tests – rapid molecular
diagnostic method that detect specific
genetic mutations that are associated with
drug resistance.
• Respiratory specimen, non-respiratory
specimen and culture isolates can be
subjected to DRT.
• Cannot be used for determining response
to the treatment
Drug Susceptibility Testing (DST)
• Phenotypic tests - wherein bacilli are
grown and subsequently tested for drug
susceptibility using various drug containing
and drug-free media.
• Used for determining response to the
treatment
• First-line LC-DST : R, H, E, Z
• Second-line LC-DST : S, Lfx, Mfx, Km, Cm,
Am, Lzd, Cfz*, Bdq*, Dlm* etc.
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 Integrated DR-TB diagnosis and treatment algorithm
All presumptive TB1 or
All TB patients Non-responders
key population2

NAAT3
FIRST SPECIMEN TESTED AT NAAT SITE
Rifampicin resistance detected Rifampicin resistance not detected

SECOND SPECIMEN TESTED AT C&DST LAB

FL-LPA 5 + SL-LPA 6 + LC DST7 – Z, Bdq8, Cfz8, Mfx, Lzd, Dlm8 FL-LPA 5 DS-TB regimen
No
After completing PTE, check on Nikshay or with C&DST lab, if LPA results are available Yes Stop DS-TB
H resistance detected4
YES NO YES regimen
Other exclusion criteria9 for shorter regimen Reflex testing for SL-LPA 6 +
LC DST7 – Mfx, Z, Lzd, Cfz8
• No additional resistance detected4 or • H resistance detected4 with both
• H resistance detected4 with KatG or
KatG and InhA mutation or
InhA mutation (not both) & FQ • FQ resistance detected4 H mono/poly DR-TB regimen
resistance not detected4
ABSENT PRESENT
Shorter oral Bedaquiline Additional resistance or
Longer oral M/XDR-TB regimen11
containing MDR/RR-TB regimen10 intolerance or non-availability Non-responders
of any drug in use or
Additional resistance or intolerance or non-availability of any drug in use emergence of exclusion criteria
or emergence of exclusion criteria

Longer oral M/XDR-TB regimen, modified if needed Modify H mono/poly DR-TB

as per replacement table regimen as per replacement table
 Isoniazid (H) mono/poly regimen
Rifampicin resistance not detected
FL-LPA 5
No
H resistance detected 4
Reflex testing for SL-LPA 6 + LC
DST7 – Mfx, Z, Lzd, Cfz8
H mono/poly DR-TB regimen
Additional resistance or
intolerance or non-availability of
any drug in use or emergence of
exclusion criteria
Modify H mono/poly DR-TB regimen
as per replacement table
• CBNAAT or Truenat. All EP-TB specimen except
FNAC of peripheral LNs & CSF to be sent directly
to C&DST laboratory for further processing.
DS-TB regimen Non-responders
• As per mutation pattern, includes resistance
Yes
Stop DS-TB inferred.
NAAT3
regimen
• Discordance in RR results between NAAT & FL-
LPA to be resolved with a repeat NAAT at C-DST
lab and microbiologists will provide the final
decision. inhA mutation associated with Eto
resistance. Use other exclusion criteria to decide
regimen if FL-LPA is done on culture isolates for
patients with smear negative specimen.
• To assess Lfx, Mfx and Am resistance.
Non-responders
• Start treatment based on LPA results & modify
based on LC-DST results later.
• Whenever DST is available.
 Pre-treatment evaluation (PTE)
• Pre-treatment evaluation for any TB patient must include a thorough clinical evaluation by a
doctor with
o History and physical examination
o Height/weight
o Random blood sugar (RBS)
o Chest X-ray
o HIV test
• No additional investigations are required unless clinically indicated.
• PTE carried out at the time of treatment initiation can be considered valid for 1 month from
the date of test result and patient can be re-initiated on subsequent regimen considering
the previously conducted tests
• Active drug safety management and monitoring (aDSM) treatment initiation form needs to
be completed for all DR-TB patients at the time of initiation of each new episode.
11
 Inclusion, exclusion criteria and
regimen & duration
H mono/poly No specific (6 or 9) Lfx R E Z 6 OR 9 months
Inclusion criteria

Regimen

Duration
Exclusion criteria
DR-TB with exclusion criteria In exceptional No separate
confirmed result situations of IP/CP
for rifampicin unavailability of
resistance not loose drug R or E
detected or Z, the use of 4
FDC (HREZ) with
Lfx loose tablets
may be considered
as an option

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 rather than not starting the H
mono/poly DR-TB patients on treatment. 12
 Dosage
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

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Duration of regimen
Regimen Intensive Extended Continuous Total
Phase Intensive Phase duration
Phase

All oral H mono-poly DR-TB

6 months 6 months
regimen
Extension of treatment in H mono/poly DR TB regimens

Total duration of H mono-poly DR TB regimen is 6 months

Treatment may be extended till 9 months
• In patients with extensive disease;
• uncontrolled comorbidity;
• extra-pulmonary TB and
• if smear at the end of 4th month is found positive; based on
smear microscopy and clinical monitoring.
In CNS, skeletal and milliary TB, treatment may be given up to
a year. In patients who remain sputum smear positive at the
end of 5-month or later of treatment, the outcome will be
declared as treatment failure.
To summarize…
• H mono-poly resistance regime
• When there is proven – Rif res NOT detected and H Res Detected
• Started at peripheral health facility level itself after PTE
• Regime 6 (or 9)m Lx R E Z
• Replacement as per replacement sequence when
• Additional resistance detected
• Adverse effects, non-availability, drug having to be excluded for medical reasons
• Same regime for children, PLHIV and pregnant women, longer regime for
EPTB
• Follow-up – clinically, monthly sputum microscopy (SM) from 3rd months
onwards and Culture at 3, 6, (9)m
• Failure if SM / Culture positive 5m or later
• Outcome declared based on culture results 16
Shorter oral Bedaquiline-containing
MDR/RR-TB regimen

• Transitioning from the current shorter injectable containing

MDR/RR-TB regimen to the shorter oral Bedaquiline-containing
MDR/RR-TB regimen in patients >5 years of age weighing 15kg or
more in a phased manner.
 Eligibility – inclusion criteria
1. DST based inclusion 2. Other inclusion criteria
criteria
• Rifampicin resistance • Children, aged 5 years to less than 18 years of age and weighing at
detected/inferred least 15 kg, given their special needs, in consultation with the
pediatrician
• MDR/RR-TB with H
• No history of exposure to previous treatment with second-line
resistance
medicines in the regimen (Bdq, Lfx, Eto or Cfz) for more than 1
detected/inferred based
month (unless susceptibility to these medicines is confirmed)
on InhA mutation only or
based on KatG mutation • No extensive TB disease
only (not both) • No severe extra-pulmonary TB
• MDR/RR-TB with FQ • Women who are not pregnant or lactating (further details in
resistance not detected subsequent sections)
18
 Eligibility – exclusion criteria
1. DST based exclusion criteria
• MDR/RR-TB patients with H resistance detected
with both Kat G and Inh A mutation; and
• MDR/RR-TB patients with FQ resistance detected
2. Other exclusion criteria
• If result for FL-LPA, SL-LPA and DST to Z, BDQ* &
Cfz* is not available after pre-treatment evaluation
is completed and it is a time to initiate the first dose
of the regimen, then, exclude those with history of
exposure for > 1 month to Bdq, Lfx, Eto or Cfz;
• Intolerance to any drug or risk of toxicity from a
drug in shorter oral Bedaquiline-containing
MDR/RR-TB regimen (e.g. drug–drug interactions);
2. Other exclusion criteria... Cont.
• Extensive TB disease found in presence of bilateral
cavitary disease or extensive parenchymal damage
on chest radiography. In children aged under 15
years, presence of cavities or bilateral disease on
chest radiography;
• Severe EP-TB disease where there is a presence of
miliary TB or TB meningitis or central nervous
system (CNS) TB. In children aged under 15 years,
extrapulmonary forms of disease other than
lymphadenopathy (peripheral nodes or isolated
mediastinal mass without compression);
• Pregnant and lactating women (for further details
refer 4.7.7.1); and
• Children below 5 years (for further details refer
4.6.6) 19
 Pre-treatment evaluation (PTE)
• In majority of MDR/RR-TB patients, PTE can be done on an outpatient basis
• DTO and MO-TU can arrange PTE at N/DDR-TBC or at sub-district level health
facility, wherever feasible
• PTE carried out at the time of treatment initiation can be considered valid for
1 month from the date of test result and patient can be re-initiated on
subsequent regimen considering the previously conducted pre-treatment
tests
• Active drug safety management and monitoring (aDSM) treatment initiation
form needs to be completed for all DR-TB patients at the time of initiation of
each new episode of treatment.
20
 PTE for shorter oral Bedaquiline-containing regimen for MDR/RR-TB
patients
Clinical evaluation Laboratory based evaluation
History and physical examination Random blood sugar (RBS)
Height HIV testing following counselling
Weight Complete blood count (Hb, TLC, DLC, platelet count)
Psychiatric evaluation if required Liver function tests (including serum proteins)
TSH levels
Urine examination – routine and microscopic
Serum electrolytes (Na, K, Mg, Ca)
Urine pregnancy test (in women of reproductive age)
Chest X-ray
ECG
21
 Regimen and duration
(4-6) Bdq (6 m), Lfx, Cfz, Z, E, Hh, Eto
(5) Lfx, Cfz, Z, E
Duration
• 9 – 11 months
• Initial phase (IP): 4 months
• IP can be extended up to 6 months
• Continuation phase (CP): 5 months
• Bedaquiline for 6 month
Points to note
 From start to end of 4 months: Bdq, Lfx,
Cfz, Z, E, Hh, Eto
 From start of 5 months to end of 6
months(If IP not extended): Bdq, Lfx, Cfz,
Z, E
 From start of 7 months to end of 9
months: Lfx, Cfz, Z, E
If the IP is extended up to 6 months then

all 3 drugs Bdq, Hh and Eto are stopped
together

Composition or the duration of the initial or continuation phase cannot be changed

22
 Treatment extension
IP should be given for at Follow up smear
least 4 months microscopy at 4th month

Negative Positive

Initiate CP with Extend IP

FL & SL-LPA and C&DST
Bedaquiline continued for another (for a maximum of 2 months)
2 months (5th & 6th months)
If additional resistant detected
Extend IP to 5th or 6th month
to Z/Cfz/FQ/both InhA & KatG,
based on smear result at the
Reassess patient at N/DDR-TBC
Duration of CP is fixed end of 4th and 5th month of
for switch to longer oral
for 5 months treatment
regimen,

23
 Points to remember
 Shorter oral Bedaquiline-containing MDR/RR-TB regimen (recommended by WHO) to be
introduced in a phased manner in adults (>18 years) as well as in children (5 years to 18
years) in individuals confirmed with pulmonary MDR/RR-TB, with uncomplicated extra-
pulmonary TB disease and in PLHIV in selected states to gain programmatic experience
to guide future expansion;
 Only those patients with mutations in both InhA and katG will not be eligible for shorter
oral Bedaquiline-containing MDR/RR-TB regimen. However, patients with only InhA or
only katG mutations will be eligible for the shorter oral Bedaquiline-containing MDR/RR-
TB regimen provided other conditions are met;
 Child-friendly formulations of second-line drugs including newer drugs are now available
under NTEP.
24
Longer oral M/XDR-TB regimen
• Recommended for MDR/RR-TB patients who are Excluded from shorter oral
Bedaquiline-containing MDR/RR-TB regimen including for the XDR-TB patient.

• In case of additional resistance or intolerance or non-availability of any drug in use or

emergence of exclusion criteria to shorter oral Bedaquiline-containing MDR/RR-TB
regimen or any longer regimen, the patient would be re-evaluated and initiated on
longer oral M/XDR-TB regimen at N/DDR-TBC with any modifications, if additional
resistance to any second-line drugs especially Lfx, Mfx, Bdq*, Lzd, Cfz*, Dlm* and Z
(*whenever available).
 Pre-treatment evaluation (PTE)
• In majority of M/XDR-TB patients, PTE can be done List of investigations
on an outpatient basis.
• The list of investigations
• DTO and MO-TU can arrange PTE at N/DDR-TBC or at enumerated for Shorter oral
sub-district level health facility, wherever feasible M/XDR-TB regimen
• PTE carried out at the time of treatment initiation • Additional investigations
can be considered valid for 1 month from the date specific to group C drugs as
of test result and patient can be re-initiated on needed
o Blood Urea & Serum Creatinine
subsequent regimen considering the previously
– if Am need to be added
conducted tests o Ophthalmologist opinion (for
• Active drug safety management and monitoring Linezolid)
(aDSM) treatment initiation form needs to be o Surgical evaluation for
completed for all DR-TB patients at the time of consideration after culture
initiation of each new episode of treatment. conversion is achieved
26
 Regimen and duration
(18-20) Lfx Bdq (6 month or longer) Lzd# Cfz Cs
#
dose of Lzd will be tapered to 300 mg after the initial 6–8 months of treatment
• Duration: 18 – 20 months
• No separate IP and CP
• Bdq will be given for 6 months & extended beyond 6 months as an exception
• Pyridoxine to be given to all DR-TB patients as per weight band
• For Pre-XDR-TB and XDR-TB patients the duration of longer oral XDR-TB regimen
would be for 20 months with appropriate modifications
27
 Dosages of M/XDR-TB drugs for adult in
longer oral M/XDR-TB regimen
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
8 Delamanid (Dlm)
100 mg twice 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 28mg
 Dosages of M/XDR-TB drugs for adult in
longer oral M/XDR-TB regimen
SN Drugs 16-29 kg 30-45 kg 46-70 kg >70 kg
12 Na - PAS (60% 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 (Imp-Cln) 3 2 vials (1 g + 1 g) bd (to be used with Clavulanic acid)

15 Meropenems (Mpm)3 1000 mg three times daily (alternative dosing is 2000 mg twice
daily) (to be used with Clavulanic acid)
Amoxicillin-Clavulanate 875/125 mg 875/125 mg 875/125 mg 875/125 mg
16 (Amx-Clv) (to be given bd bd bd bd
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
In patients of 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 29
Management of DR-TB in pregnancy
Thank you