New PMDT

Guideline 2019
Global TB Burden -2018

Global India

Incidence 100 lakhs 27.4 Lakh

Deaths 13 lakh 4.1 lakh

HIV TB cases 9.2 lakh 86,000

HIV TB
deaths 3 lakh 11,000

Estimated
MDR/RR 5.58 lakh 1.35 lakh
cases
The End TB Strategy:
3 pillars and 4 principles

3
 Vision, goal, targets, milestones

Vision:
(2.2 lakh)
A world free of TB
Zero TB deaths,
Zero TB disease, and
Zero TB suffering (2,2 million)

Goal:
End the Global TB
epidemic

4
Diagnostic methods in DR TB
 Vision
• To provide Universal DST to all notified TB patients
• Offering an upfront NAAT to certain type of presumptive
TB patients among key populations.

• A staggered testing algorithm utilizing newer rapid

diagnostic technologies such as NAAT (CBNAAT/
TruNAAT), first and second-line LPA in line with WHO
guidelines.
Diagnostic Aspects:
Drug Resistance TB

PHENOTYPING GENOTYPING/ MOLECULAR

SOLID (L J MEDIUM) LPA
CBNAAT (Gene Xpert)/Ultra
LIQUID (MGIT 960)
Gen/Tru NAAT/Gene Sequencing

• VIABLE BACILLI • RAPID TEST

• BSL II & III • DNA BASED
• LABOURIOUS PROCESS • BSL – I FACILITY
• TIME CONSUMING • 95 % CONCORDANSE

No Single Test is Ideal for Drug Resistant TB

 Specimen collection and transportation to labs

• Obtaining good quality specimens of adequate volume are critical

to ensure correct diagnosis.
• Collection of specimens: Programme recommends collection of
sputum
one spot and one morning,
OR
2 spot specimens collected with a gap of at least one hour
(if the patient is coming from a long distance OR s/he is unlikely to
return to give the second specimen).
Line Probe Assay –MTBDR Plus
3 steps:
1.Sample preparation:
Decontamination
DNA extraction

2. Amplification :PCR

3. Hybridization : membrane strip

Results: within 48 hrs

 CBNAAT- (GeneXpertMTB RIF)

• Automated NAT, specific for TB, RIF resistance through rpoB

• multiplex PCR, as sensitive as culture
• One tube reaction
• Only one step sputum processing
• Less than 2 hrs for results
• One day training for technologists
Xpert™ MTB assay

Concentrates bacilli &

removes inhibitors

Sample is Ultrasonic lysis of filter-

End of hands on work automatically captured organisms to
4
3 filtered & washed release DNA

DNA molecules are

mixed with dry PCR
reagents

Transfer of 2 ml GeneXpert
after 15 min

2 Time-to-result: 1 h 45 min 6

Nested real-time
1 amplification & detection
with internal process
Sputum liquefaction &
inactivation with 2:1 SR control
 Collection of EP Samples

• Samples for culture should never be collected in formalin.

• If histo pathological examination is required, two samples should

be collected

• No preservative should be used for any extra-pulmonary specimen

for culture. Necessary instructions are to be given to the concerned
staff for sending the biopsy specimen in normal saline for culture
and NOT IN FORMALIN as it will kill the bacilli.

• Extra pulmonary specimens should never be collected or

transported in CPC.
 Extra Pulmonary samples process by
Gene X- pert (CBNAAT)
• Gastric Lavage
• BAL
• CSF
• Pericardial fluid
• Synovial fluid
• Pleural & Ascitic fluid
( Without Blood)
MTB
 Extra Pulmonary samples send to
C & DST Lab.
• Lymphnode
• PUS
• Tissue
• Bone
• Bloody samples
• Urine
• Stool
MGIT 320

Any Swab Required to be MGIT 920

Culture
 Methods for drug susceptibility testing

Rapid molecular Drug Resistance Testing Growth-based

(DRT) - Genotype phenotypic drug
susceptibility
testing (DST)
first-line drugs: R,
Nucleic Acid
Line Probe Assay H, E, Z
Amplification Test
(LPA) second-line
(NAAT)
drugs: S, Lfx, Mfx,
Km, Cm, Am
cartridge other drugs: Lzd,
Second
based chip based
First line line (Lfx, Cfz, Bdq*, Dlm*
Gene- TruNAAT
(H & R) Mfx, Km,
Xpert platform
Cm, Am) PAS etc.,
platform

Genotypic testing is much faster than phenotypic methods.

 DST and DRT
Growth-based phenotypic drug susceptibility testing
• Culture though a highly sensitive and specific method for TB
diagnosis, requires 2-8 weeks to yield results.
• automated Liquid culture systems e.g. BACTEC MGIT 960,
BacTAlert or Versatrek etc and solid (Lowenstein Jensen) media.
Rapid molecular drug resistance testing
• LPA provides rapid diagnosis of R and H resistance as well as
resistance to FQs and SLIDs. LPA can yield results in 72 hours.
• NAAT provides accurate and rapid diagnosis of TB by detecting
M.tb and R resistance conferring mutations. The test can be
performed in both respiratory and non respiratory specimens and
yields results in 2 hours.
 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.
 Laboratory services required for PMDT

State level IRL or C & DST laboratory should provide:

• Culture on liquid / solid media, and identification of M.

tuberculosis by Immuno-chromatographic assay
• testing for resistance/susceptibility to at least
rifampicin by RNTCP approved genotypic or phenotypic
methods

Clinical laboratory services include:

• basic haematology, biochemistry, serology, and urine

analysis.
Definitions and classification of DR-TB patients

Presumptive DR-TB: It refers to the following patients

in order of their risk:

– All Notified TB patients (Public and private)

– Follow-up positive on microscopy including
treatment failures on standard first line
treatment and all oral H mono/poly regimen;
– Any clinical non-responder including
paediatric (if specimen available)
Definitions and classification of DR-TB patients

Presumptive TB refers to a person with any of the symptoms or signs

suggestive of TB.

Diagnosis of TB is difficult (key population)

• Extra-pulmonary,
• PLHIV,
Upfront
• Smear -ve/NA with x-ray suggestive of TB
NAAT
including paediatric TB, vulnerable groups
as defined in TOG-2016 and
• DR TB contacts, NAAT is offered upfront for
diagnosis of TB among these presumptive
TB patients.
 DR-TB Diagnostic Algorithm
Presumptive TB All notified TB patients Non responder to treatment

• PLHIV
• EPTB
• DS TB
• Smear -ve/NA with X- • H mono/poly
ray suggestive of TB
including paediatric
NAAT##
• Vulnerable populations
• Contact of DR TB
patient

R resistance detected R resistance not detected

FL LPA$$
FL – LPA$$,
SL – LPA$$ and
DST for Mfx(1.0),
Lzd*, Cfz*, Z*, Bdq*, H resistance detected H resistance not detected
Dlm*
SL LPA$$
DST for Z*
# NAAT include CBNAAT & TruNAAT
*whenever available
$ Culture isolates to be subjected to LPA for smear negative DST for Mfx (1.0) & Lzd only if FQ
specimens or Z resistance detected
For discordance resolution – see text
Definitions and classification of DR-TB patients

• Universal DST refers to rapid DST for at least rifampicin among all
notified TB patients (preferably before initiation of treatment to
maximum within 15 days of diagnosis), and further DST for at
least fluoroquinolones and Second line injectables among all TB
patients with rifampicin resistance.
• Drug-susceptibility testing (DST) refers to in-vitro testing using
either phenotypic methods to determine susceptibility or
genotypic methods to determine resistance. 
• Drug resistance testing (DRT) refers to in-vitro testing using
genotypic methods (molecular techniques) to determine
resistance.
 Classification and Definitions of DR-TB

• Mono-resistance TB (MR): A TB patient, whose biological specimen

is resistant to one first-line anti-TB drug only.

• Poly-Drug Resistance TB (PDR): A TB patient, whose biological

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

• Rifampicin Resistance (RR): 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.
 Classification and Definitions of DR-TB

• Multi Drug Resistance (MDR) : A TB patient, whose biological

specimen is resistant to both H and R with or without resistance to
other first line drugs. MDR-TB patients may also have additional
resistance to any/all FQ OR any/all SLI anti-TB drug.

• Extensive Drug Resistance (XDR) : A MDR TB patient, whose

biological specimen is additionally resistant to a fluoroquinolone
(Ofx, Lfx, or Mfx) and a second-line injectable anti TB drug (Km, Am
or Cm).
RNTCP request form – Patient information &
reason for testing
RNTCP request form – CBNAAT & Culture
report
RNTCP request form – FL-LPA and SL-LPA
Lab request form- DST report
 Rifampicin resistance not detected

For all TB patient in Rifampicin resistant not detected

For all H mono/poly resistance detected
FL LPA (H mono For H + FQ or Z
resistance SL LPA resistance detected
detection)
DST for Z
DST to Mfx (1.0) &
Lzd
 Considerations
• Any discordance in test results for Rifampicin between NAAT and
FL LPA, repeat NAAT will be carried out at C-DST lab.
• The final result will be based 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 resistance is not detected in 2 of 3 specimen, then
the final result will be resistance not detected.
• In case of LPA result is found to be invalid, the sputum specimen
is inoculated on culture immediately. If the culture result is found
to be positive, LPA test carried out for confirming MDR/RR TB.
• DST to Lzd, Z, Cfz would be available as soon as the proficiency
testing exercise is completed and Bdq and Dlm would be
introduced soon
 Specimen process algorithm at CDST lab

Smear Reported to
Valid
LPA concerned
+Ve results
health facility
Smear
microscopy

Smear - Liquid Invalid

Ve culture results

At the C-DST laboratory, smear microscopy is done on the second specimen

received from NAAT lab. LPA will be carried out for smear positive specimen
while smear negative specimen will be managed as mentioned
 Operational process of specimen referral

Specimen handling Nikshay

Specimen Two specimen in conical

tubes, collected, packed Generate Test
collection & transported in cool ID
centres chain
One specimen will be
utilized to perform Update NAAT
NAAT result and create
NAAT and second
Test ID for tests
sites specimen will be expected at C-
transported to C-DST DST lab
lab
Second specimen will be
tested for FL and/or SL Update test
C-DST lab LPA and further DST as results
applicable
Methods for drug susceptibility testing

Rapid molecular Drug Resistance Testing Growth-based

(DRT) - Genotype phenotypic drug
susceptibility
testing (DST)
first-line drugs: R,
Nucleic Acid
Line Probe Assay H, E, Z
Amplification Test
(LPA) second-line
(NAAT)
drugs: S, Lfx, Mfx,
Km, Cm, Am
cartridge other drugs: Lzd,
Second
based chip based
First line line (Lfx, Cfz, Bdq*, Dlm*
Gene- TruNAAT
(H & R) Mfx, Km,
Xpert platform
Cm, Am) PAS etc.,
platform

Genotypic testing is much faster than phenotypic methods.

 Rifampicin Resistant detected

• FL LPA (for Eto)

• SL LPA and (for FQ or SLI)
• DST to Mfx (1.0), Lzd*, Cfz*, Z*, Bdq*,
Dlm*(*whenever available) will be set up on liquid
culture using the decontaminated deposits only for
RR TB patients (Base line SL DST).
 Diagnosis of DR-TB in children - 1
• Primary transmission of drug-resistant TB to the child and less likely to be acquired from exposure to TB
treatment.

• Paediatric DR-TB is likely to reflect DR-TB in adults, so DR-TB is common in children in settings with
higher prevalence, mortality and morbidity of DR-TB in adults compared to drug-sensitive TB .

• Children with recurrent TB, treatment after lost to follow-up and treatment after failure are presumed
patients of DR-TB.
• Children usually have pauci-bacillary disease and are sputum negative. So, definitions are to be used in
conjunction with clinico-radiological picture.

• Children who are at high risk of DR-TB could be :

 contacts of DR patients

 paediatric non responders.

 Probable MDR-TB among children - 2

• Criteria for diagnosis of “probable MDR-TB” include

children with signs and symptoms of active TB
disease who in addition have the following risk
factors.

 close contact with a known case of MDR-TB;

close contact with a person who died whilst on TB treatment;
close contact with a person who failed TB treatment;
failure of a first-line regimen, recognizing that both
bacteriological and clinical definitions of failure should be
used; and
previous treatment with second-line medications.
 Algorithmic approach to diagnosis of DR-TB in children
New child TB patient

Treat as Confirmed Confirmed Treat as

DRT/DST known
DR-TB DR-TB DS-TB DS-TB
No

Contact with infectious TB patient ?

Yes Yes Yes or No

DRT/DST of source patient not known &

Source is a Source is a known DS-TB patient
Source is retreatment TB patient &/or
DR-TB patient or not known or no risk factor
Child is failing 1st line treatment

Probable DR-TB Presumptive DR-TB Probable DS-TB

Do DRT/DST of child or source’s specimen

Do DRT/DST on an appropriate
specimen from the child.
Consult pediatrician to treat as
DR-TB according to DST of child If poor response to If DRT/DST If DRT/DST
OR source’s isolates, if child’s treatment, consult shows DS-TB, shows DR-TB,
specimen can’t be obtained pediatrician to treat as treat as DS- TB treat as DR- TB
Probable DR-TB
 Initiative for promoting affordable and quality TB
test (IPAQT)

• IPAQT brought together various private labs with the support of test
manufacturers to bring down the price for quality TB tests for up to
50% in the private sector.

• It is an initiative of non profit stakeholders and over 100 private

sector labs/hospitals with a pan-India presence that have come
together to provide WHO approved tests for TB.

• Each patient diagnosed by these IPAQT labs must notify to the

programme surveillance system.
 RNTCP PMDT Treatment Register
• Each episode/change in the regimen is entered in separate row
against a new episode ID with patient ID in remarks column.
• Senior DR TB and TB HIV supervisor of the respective district is
expected to coordinate with all NAAT sites, C-DST labs and
compile all the DR TB patients diagnosed to enter it in PMDT
treatment register maintained at district level.
• Information about DR TB patients notified from private sector
can be extracted from Nikshay.
• NDR TBC are also expected to update this register for the
patients initiated on treatment at the centre.
• As far as possible, patients should be entered consecutively by
their date of diagnosis.
RNTCP PMDT Treatment Register
RNTCP PMDT Treatment Register
RNTCP PMDT Treatment Register
 Pre- treatment evaluation &
Treatment of Drug Resistant TB
Referral for pre-treatment evaluation

• Patients diagnosed with DR-TB be referred for

treatment as soon as possible
• If RR-TB/ H mono-poly DR-TB is confirmed, the
patient should be traced in the field, with help
of
– Medical Officers – TB Control (MO-TC) & PHI,
– Senior DR-TB TB-HIV Supervisor and
– Senior Treatment Supervisor (STS)
• Counselled by the counsellor
RNTCP PMDT referral for treatment form

• Patient
details
• Disease
classification
• Reason for
testing
• Current
regimen
RNTCP PMDT referral for treatment form

• Lab result
details
• DR TB site
details
• Reason for
referral
 Initial counselling
• If RR-TB / H mono-poly DR-TB is confirmed, district team
should begin process of treatment initiation at district level
• Inform patient about
– lab results & their reliability
– Need for additional treatment
– Importance of rapid initiation of treatment and adherence
– PMDT services under RNTCP
– What to do next
– Infection control
• Re-assurance to the family against panic or unnecessary
stigmatization of the patient.
Pre-treatment evaluation for DR-TB patients
Pretreatment evaluation for any TB patient including DR
TB patients should include, a thorough clinical
evaluation by a physician including
• history and physical examination,
• height/weight,
• random blood sugar (RBS),
• chest X-ray and
• HIV testing
No additional investigations are required for H
mono/poly DR TB patients unless clinically indicated.
Pre-treatment evaluation for MDR/RR TB patients
1. Complete Blood Count (Hb, TLC, DLC, Platelet count)
2. B. Urea & S. Creatinine
3. Audiometry (only if on injectable)
4. Liver Function Tests
5. Thyroid Stimulating Hormone levels to assess the thyroid function
(TSH levels alone are usually sufficient to assess the thyroid function of
the patient)
6. Urine examination – Routine and Microscopic
7. Psychiatric evaluation if required
8. Serum electrolytes (Na, K, Mg, Ca) only for new drugs
9. S. protein (Albumin, Globulin and total proteins) (only if on Dlm)
10.ECG (if on Mfx, Bdq, Cfz or Dlm)
11.urine pregnancy test (in women of reproductive age group)
12.Ophthalmologist opinion – rule out chorioretinitis/uveitis (only if on
Linezolid)
13.Surgical evaluation should be done at appropriate time
Points of consideration for pre-treatment evaluation
• In majority of MDR/RR TB patients, pretreatment
evaluation can be done on an outpatient basis.
• The physician may decide for admission for initiation
of treatment or get it done on an outpatient basis.
• A specialist consultation along with reports of pre-
treatment evaluation tests can be arranged, if
required.
• Must ensure that laboratory capacity and specialists
for consultation are available, either in-house or
through an outsourced mechanism
• For infection control purposes, a separate space for
specimen and blood collection should be identified
 Treatment initiation

The concerned DR TBC committee provides

• counselling,
• initiates activities related to active drug safety monitoring (aDSM) like,
• assessing the baseline history of known adverse/serious adverse
events (AE/SAE),
• biochemical investigations,
• ECG,
• Audiometry and
• initiates the patient on an appropriate treatment regimen.

Pre-treatment evaluation reports are valid till 1 month for any regimen
change unless clinically indicated
 Treatment initiation
All eligible patients need to be counseled on:
• Details of nature and duration of treatment
• Information on new drug Bdq/Dlm (treatment booklet)
• Possible change in the treatment regimen based on the SL LPA and DST
results
• Need of treatment adherence
• Possible side effects of the drugs and consult to doctor immediately for
it
• Consequences of irregular treatment or pre-mature termination of
treatment
• Counseling on family planning
• No written informed consent from patients is required for
administration of any new drug
 Patient Flow for DR-TB Patients
District and nodal DR-TB centres should be involved actively in
management of all DR-TB patients.
• District DR-TB centre will be the reporting unit for the
respective district and will register all MDR/RR TB and H
mono/poly DR-TB patients of respective districts initiated on
standard regimen in PMDT treatment register.
• Nodal DR-TB centre will work as DR TBC for the district where
it is located and referral centre for all respective districts
linked to it.
• Patient details would be entered and regularly updated on
Nikshay ID against each episode ID.
 Referral to NDR TBC if required

All regimen can be initiated at DDR TBC if all facilities are available
If required, DDR TBC may refer patient to the NDR TBC for
• Diagnosed with additional drug resistance,
• Drug intolerance,
• Contraindication,
• Failing regimen,
• Return after treatment interruption of >1 month,
• Emergence of exclusion criteria for standard regimen,
• For expert opinion,
• Management of any complications warranting regimen change
 Patient Flow for DR-TB Patients
• PMDT treatment card of DR-TB patients managed at the concerned
district or nodal DR-TB centre
• Issue fresh treatment card to all patients that are re-registered at
NDRTBC which will be changed and updated at all subsequent levels
where it is maintained. Attach the previous treatment card to the
freshly issued one.
• After initiation of treatment, the patient should be referred back to the
PHI with up to a maximum of one week’s supply of drugs,
arrangements for injections in transit, and a copy of the PMDT
treatment book and referral form.
• The respective DTO / MO-PHI should be informed about referral in
advance by the concerned DR-TB centre via email or mobile phone.
• Drugs provided to the patients for transit period
• The DTO arranges for availability of the monthly IP drug box & patient
records at the treatment supporter (via the TU and PHI staff)
Treatment of DR TB
 Classes of Anti TB Drugs recommended for treatment of DR-TB

GROUPS & STEPS DRUG

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 Delamanid Dlm
regimen and when Pyrazinamide Z
medicines from Group A Imipenem-cilastatin OR Ipm-Cln
and B cannot be used Meropenem Mpm
Amikacin Am
(OR Streptomycin) (S)
Ethionamide OR Eto
Prothionamide Pto
p-aminosalicylic acid PAS
 Classes of Anti TB Drugs recommended for treatment of DR-TB

• Kanamycin and Capreomycin, which were associated with poorer

outcomes when used and are therefore no longer recommended
for use in MDR TB regimens;
• Gatifloxacin and high-dose Isoniazid were used in very few patients
and thioacetazone was not used at all.
• Thioacetazone is unlikely to have a role in contemporary longer
regimens and is not currently available in a quality-assured
formulation.
• Clavulanic acid should be included in MDR/RR TB regimens only as
a companion agent to the carbapenems (Imp-Cln and Mpm). When
used in this way, it should be given with every dose of carbapenem
and should not be counted as an additional effective TB agent.
 Newer anti-TB drugs

• The risk–benefit considerations for the use of

Bdq in patients aged 6–17 years and Dlm in
patients aged 3-5 years are similar to those
considered for adults.
• On the basis of findings in adults and on the
pharmacological and safety data reviewed,
extrapolations on efficacy and safety should be
restricted to children aged 3–5 years but not to
children younger than 3 years.
Principles of designing a WHO recommended all oral
longer MDR TB regimen (WHO-2019)
• In MDR/RR TB patients on longer regimens, all three Group
A agents (Lfx/Mfx, Bdq &Lzd) and one Group B agent (Cfz
&Cs) should be included to ensure that treatment starts with
at least four TB agents likely to be effective, and that at least
three agents are included for the rest of the treatment after
Bdq is stopped.
• If only one or two Group A agents are used, both Group B
agents are to be included.
• If the regimen cannot be composed with agents from Groups
A and B alone, Group C agents are added to complete it.
 All oral longer MDR TB regimen
Guidelines for PMDT in India 2019
As the likelihood of stopping Lzd due to toxicity is greater, the all oral
longer MDR TB regimen for India would include the fifth drug Cs
upfront to prevent the need for replacing Lzd or Cfz, if dropped.
Under RNTCP, the following are the standard DR TB regimens:
Regimen class Intensive phase Continuation phase

H mono/poly DR TB (R resistance not detected and H resistance)

All oral H mono-poly DR TB regimen@ (6) Lfx R E Z 

MDR/RR TB

Shorter MDR TB regimen@ (4-6) Mfxh Km/Am* Eto Cfz Z Hh E (5) Mfxh Cfz Z E

All oral longer MDR TB regimen@ (18-20) Bdq(6) Lfx Lzd# Cfz Cs
 Keynotes

*If the intensive phase is prolonged, the injectable agent is only given three times a
week in the extended intensive phase.
# Reduce Lzd to 300 mg/day after 6 to 8 months.
@ Pyridoxin to be given to all DR TB patients as per weight band.
All oral H mono/poly DR TB regimen is of 6 months with no separate IP/CP. Shorter
MDR TB regimen is of 9-11 months with 4-6 months of IP containing injectables and
5 months of CP. If the IP is prolonged, the injectable is only given three times a
week in the extended intensive phase. All oral longer MDR TB regimen is of 18-20
months with no separate IP/CP. New drugs like Bdq and Dlm would be given for 6
months duration while the dose of Lzd will be tapered to 300 mg after the initial 6-8
months of treatment. This regimen will also be used for treatment of XDR TB
patients with 20 months duration.
 Integrated Drug Resistant TB Algorithm
Presumptive TB All notified TB patients Non responder to treatment
• PLHIV
• EPTB • DS TB
• Smear -ve/NA with X-ray • H mono/poly
suggestive of TB including NAAT #
paediatric
• Vulnerable populations
• Contact of DR TB patient

R resistance detected R resistance not detected

FL, SL – LPA & LC DST* First-line treatment

FL LPA
Presence of non DST based criteria &/ or
Resistance to Lfx/Mfx(h), Km/Cm/Am, DST to Z*/Cfz &/or InhA
mutation detected
No Unknown Yes
H resistance detected H resistance not detected
History of use for > 1 month/intolerance to
Mfx(h), Km, Eto or Cfz
SL LPA & LC DST*
No Yes
In case of addl. resistance,
Shorter failing regimen, drug All oral All oral H mono/poly Continue first-line
MDR TB intolerance, return after longer MDR DR TB regimen treatment
regimen interruption (>1 m) or TB regimen
emergence of any
exclusion criteria Modify regimen

# NAAT include CBNAAT & TruNAAT

*LC DST will be done as per the diagnostic algorithm ** Refer table of exclusion criteria for shorter MDR-TB regimen
 Criteria for patients to receive standard DR TB regimen
Standard DR TB
regimen Inclusion criteria Exclusion criteria
All oral H Isoniazid-resistant TB with No specific criteria except drug
mono/poly confirmed result for interaction/intolerability with any other drug used
regimen Rifampicin-resistance not concomitantly
detected (RS)
Shorter MDR TB Patient with Rifampicin- DST based criteria:
regimen resistant pulmonary or extra  If DST/DRT result for FQ or SLI is resistant or
pulmonary TB  presence of InhA mutation (for Eto) or
 Resistance to Z (whenever available)
 History of use for > 1 month/intolerance to
Mfx(h), Km, Eto or Cfz
Non-DST based criteria:
 Pregnancy
 Any extrapulmonary disease in PLHIV
 Disseminated, meningeal or central nervous
system TB
 Intolerance to any drug in the shorter MDR TB
regimen or risk of toxicity from a drug in the
shorter regimen (e.g. drug–drug interactions)
All oral longer Patients in whom shorter None
regimen for MDR TB regimen cannot be
MDR/ RR TB considered due to any
reason
 Inclusion criteria for new drugs
(Bdq/Dlm)
• Bdq/Dlm can be provided to the patient ≥ 18 yrs.
• Dlm can be provided to age group 6 to 17 years.
• Use of Bdq for 6 to 17 yrs and Dlm for 3 to 6 yrs
may be considered only after approval of DCGI.
• non-pregnant females or females not on hormonal
birth control methods are eligible. They should be
willing to continue practicing birth control methods
throughout the treatment period or have been
post-menopausal for past 2 years; and
• patients with controlled stable arrhythmia can be
considered after obtaining cardiac consultation.
 Exclusion criteria for new drugs
(Bdq/Dlm)
• Pregnancy & lactating mother
• currently having uncontrolled cardiac arrhythmia that requires medication;
• QTcF interval characteristics at base line:
– QTcF ≥ 500 at baseline & normal electrolytes, ECG to be repeated after 6
hours and If both ECGs show QTcF>500 then the patient should not be
challenged with cardiotoxic drugs.
• history of additional risk factors for Torsade de Pointes, e.g. heart failure,
hypokalaemia, family history of long QT syndrome;
• If results of the serum chemistry panel, haematology or urinalysis are outside
the normal reference range (including above listed parametres), 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.
• Hypokalaemia, hypomagnesaemia and hypocalcaemia should be corrected
prior to a patient receiving any QTc prolonging drugs.
Bdq/Dlm is not added to a failing regimen in any MDR/RR TB patient
Caution to be exercised in choosing other group
A and B drugs
• Lzd may cause anaemia, thrombocytopenia, peripheral
neuritis and optic neuritis. Adequate precaution may be
taken accordingly.
• Cs should be used carefully in pre-existing seizure
disorders not adequately control with medication.
Neurologist consultation should be taken prior to
initiation of Cs in such patients, also psychiatrist opinion
should be taken in severe depression as Cs can cause
depression and suicidal tendency.
• Cfz causes dark brown discoloration of the skin.
Accordingly, the patient should be counselled prior to
initiation of treatment with Cfz
 Newer anti-TB drugs
• After almost five decades of discovery of
Rifampicin, the two new drugs named Bedaquiline
and Delamanid with anti-TB effect were approved
for treatment of multidrug resistant TB by The
Central Drugs Standard Control Organization
(CDSCO).
 Bedaquiline

– New class of drug, Diarylquinoline

– Targets mycobacterial ATP synthase,
– Strong bactericidal
– Extensive tissue distribution up to 5.5 months
post stopping BDQ.
– Significant benefits in improving the time to
culture conversion in MDR-TB patients.
– Active drug safety monitoring (aDSM)
– Cross-resistance with Clofazimine.
 Patient Flow for DR-TB Patients

District or Nodal DR TBC

NAAT RR TB
MDR/RR
DS TB

Shorter MDR TB regimen All oral longer

FL LPA MDR TB regimen

In case of addl.
Continue H SL-LPA resistance, failing
first line mono/p DST regimen, drug
oly intolerance, return
after interruption (>1
m) or emergence of Modify regimen
any exclusion criteria All oral longer MDR
All oral H mono/poly
Patient Flow for H mono/poly resistance
• If H is found to be resistant, the patient will be initiated on all oral H
mono-poly DR TB regimen at the PHI level while awaiting the
results of SL LPA
• Modify the regimen appropriately at the N/DDR TBC if Lfx/Mfx(h)
resistance is detected on SL LPA.
• The patients with RR TB will be considered for shorter MDR TB
regimen at N/DDR TBC after ruling out the exclusion criteria for
shorter MDR TB regimen. Decision to start shorter MDR TB regimen
will be based on non-DST and DST based exclusion criteria
mentioned in table 6.4. The patients excluded from shorter MDR TB
regimen would be initiated on all oral longer MDR TB regimen at
N/DDR TBC. In case of additional resistance on LC DST, the all oral
longer MDR TB regimen would be appropriately modified.
 Patient Flow for MDR RR TB
• The patients with RR TB will be considered for shorter MDR TB
regimen at N/DDR TBC after ruling out the exclusion criteria for
shorter MDR TB regimen.
• Decision to start shorter MDR TB regimen will be based on non-
DST and DST based exclusion criteria.
• The patients excluded from shorter MDR TB regimen would be
initiated on all oral longer MDR TB regimen at N/DDR TBC.
• In case of additional resistance on LC DST, the all oral longer
MDR TB regimen would be appropriately modified.
Treatment initiation on outpatient basis
• All oral longer MDR TB regimen can be initiated on outpatient basis if
the patient is satisfying all following risk assessment criteria:
– QTcF < 450 ms in males and <470 ms in females at baseline.
– Normal serum K, Mg, Ca at baseline.
– No history of structural cardiac abnormalities (LVH or RVH secondary to
hypertension can also cause ECG changes, however mere presence of LVH
need not be an exclusion criteria) or ECG abnormalities.
• Patients with QTcF between >450 to 500 ms in male and > 470 to 500
ms in female upto 500ms require daily monitoring of ECG for 3 days
along with evaluation and correction of any electrolyte abnormalities. A
cardiologist opinion may need to be taken.
• The first dose is given under supervision at the treatment initiating
facility for ambulatory patients.
• Patient should be initiated from Monthly patient wise box
• Entire one-month box needs to be handed over at the time of
discharge.
Replacement drugs in sequence of preference
• Replacement of drugs required in following conditions
– adverse drug reaction,
– poor tolerance,
– contraindication
– resistance detected on baseline LC DST.

Principles apply for replacement of drugs

Five drugs are to be used in the initial 6 to 8 months and at least 4
drugs in the last 12 months.
Replacement of one of either Lzd, Cs or Cfz without replacement of
Bdq or FQ, there is no need to add another drug as there will still be
minimum 4 effective drugs in the first 6-8 months and 3 drugs in the
last 12 months as per the WHO principles.
For replacement of Bdq or FQ, the scenarios have been given in the
table below.
 Other principles apply for replacement of drugs
• The drugs are replaced according to their efficacy, no
demonstrable resistance, prior use, side-effects profile and
background resistance to the replacement drug in the country
• The regimen should preferably be fully oral. However, in
certain circumstances, an Injectable may have to be used for
the need of efficacy and side-effect profile.
• Dlm and Am will not be used in the final 12 months of
treatment.
• One group A drug will be replaced by two group C drugs.
• Though Imp-Cln is 4th in the sequence of drugs of group C, it
will only be used as the last resort for designing the regimens,
operational issues of a Peripherally Inserted Central Catheter
(PICC) placement for the entire duration of its use, need for
admission to a NDR TBC.
Sequence of using replacement drugs to modify the
regimen
Regimen Sequence of using replacement drug to modify the regimen
All oral H  If SL LPA shows Lfx resistance - Replace Lfx with Mfxh if SL LPA
mono/poly pattern suggests. Do LC DST for detection of resistance to
Mfxh and Z.
 If Mfxh or Z can’t be used – Replace with Lzd. If Lzd cannot be
given, replace with Cfz. If both Lzd and Cfz cannot be given,
add Cs.
 If both Mfxh and Z can’t be used – Add 2 drugs of the 3 - Lzd,
Cfz, Cs (in the order of preference).
 Treat for 9 months in any of the above 3 situations.
 If R resistance – Switch to appropriate regimen.

Shorter MDR  If there is a need for stopping/replacing any drug, stop the
TB regimen regimen and evaluate the patient to switch to all oral longer
regimen.
Sequence of using replacement drug to modify the all oral longer MDR TB regimen
 If Bdq is excluded in the first 6 months, then:
i. Use Dlm*, If Dlm cannot be used, use Z* + Am* OR Eto*
ii. If both Dlm and Z cannot be used, use Am* + Eto*
 If Lfx needs to be stopped in the first 6 months, replace it with Mfx h if SL LPA pattern suggests. Do LC DST for
detection of resistance to Mfxh.
 If no FQ can be used
i. in first 6 to 8 months, then:
 Use Dlm*, If Dlm cannot be used, use Z* + Am* OR Eto*
 If Z cannot be used, use Am* + Eto*
ii. Beyond 6-8 months
 Use Z + Eto
 If two or more drugs is stopped in initial 6-8 months, then:
i. Use Eto* + Z* + Dlm*
ii. If Dlm cannot be used, use Eto* + Z* + Am*
iii. If Dlm, Z cannot be used, use Eto* + E + Am*
iv. If Dlm, Z and Am cannot be used, use Eto* + E + PAS
v. If 3 drugs cannot be used out of E, Z, Am, Eto or PAS, use Imp-Cln + Amx-clv. The patient will need
admission to the NDR TBC.
 If a regimen with minimum number of effective drugs can still not be constituted initially, use drugs in order
with E, PAS, Imp/Cls + Amx-clv.
 If at least 3 drugs from group A or B are not available in the last 12 months of treatment, then
i. use 2 drugs out of E, Z*, Eto* or PAS

* Use Dlm – if available, no history of prior use and no exclusion criteria for its use, Z – if resistance not
detected, Eto – If InhA mutation not present, Am – if SL LPA pattern suggests
 Bedaquiline: Dosage
• Week 0–2: BDQ 400 mg (4 tablets of 100 mg) daily (7 days per
week) + OBR

• Week 3–24: BDQ 200 mg (2 tablets of 100 mg) 3 times per

week (with at least 48 hours between doses) for a total dose
of 600 mg per week + OBR

• Week 25 (start of month 7) to end of treatment: Continue

other second-line anti-TB drugs only as per RNTCP
recommendations

The dosage of BDQ would apply to all weight bands while the dosage of other drugs in the
OBR would be as per the weight bands in accordance to the RNTCP PMDT guidelines.
 Dosage of DR-TB drugs for adults
S.No Drugs 16-29 Kgs 30-45 Kgs 46-70 Kgs >70 Kgs
1 Rifampicin(R) 1
300mg 450mg 600mg 600mg
2 High dose H (Hh) 300 mg 600 mg 900 mg 900 mg
3 Ethambutol(E) 400 mg 800 mg 1200 mg 1600 mg
4 Pyrazinamide(Z) 750 mg 1250 mg 1750 mg 2000 mg
5 Kanamycin(Km) 2 500 mg 750 mg 750 mg 1000 mg
6 Capreomycin (Cm) 500 mg 750 mg 750 mg 1000 mg
7 Amikacin (Am) 500 mg 750 mg 750 mg 1000 mg
8 Levofloxacin(Lfx) 4 250 mg 750 mg 1000 mg 1000 mg
9 Moxifloxacin (Mfx) 4 200 mg 400 mg 400 mg 400 mg
10 High Dose Mfx (Mfxh) 4 400mg 600mg 800mg 800mg
11 Ethionamide(Eto) 4 375 mg 500 mg 750 mg 1000 mg
12 Cycloserine(Cs)4 250 mg 500 mg 750 mg 1000 mg
13 Na-PAS (60% weight/vol) 3,4 10 gm 14 gm 16 gm 22 gm
14 Pyridoxine(Pdx) 50 mg 100 mg 100 mg 100 mg
15 Clofazimine (Cfz) 50 mg 100 mg 100 mg 200 mg
16 Linezolid (Lzd) 300 mg 600 mg 600 mg 600 mg
17 Amoxyclav(Amx/Clv) 875/125 mg 875/125 mg 875/125 mg 875/125
(In child: WHO 80mg/Kg in 2 BD BD (2 morning +1 (2 morning +1 evening)
evening)
divided doses)
18 Bedaquiline (Bdq) Week 0–2: Bdq 400 mg daily
Week 3–24: Bdq 200 mg 3 times per week
1
For H mono/poly resistant TB; 2For adult more than 60 yrs of age, dose of SLI should be reduced to 10mg/kg (max up to 750 mg) 3In
patient of PAS with 80% weight/volume the dose will be changed to 7.5gm (16-29Kg); 10 gm (30-45 Kg); 12 gm (46-70 Kg) and 16 gm
(>70 Kg) 4 drugs can be given in two divided doses in a day in the event of intolerence
 Weight bands for DR-TB treatment

All oral H mono/poly regimen, Standardized

monthly
Shorter MDR-TB regimen, treatment
boxes will be
All oral longer MDR TB regimen prepared at
State/District

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

(according to
per kg doses) Kgs Kgs Kgs Kgs
Patient wise boxes & loose drugs will be provided to Nodal and District DR TBC
 Patient Flow for DR-TB Patients
Nikshay data entry
• DST result update at CBNAAT or C&DST site
• Treatment initiation detail – N/DDR TBC and District
• Follow up sample and adherence details – District/TU/PHI
 Dosage of DR-TB drugs for children*
(< 30 kg body weight)
DRUGS Daily Dose (Pediatric till the age of 18 yrs)
7–15 mg/kg for patients less than 30 kg; max dose 300 mg daily
Isoniazid1
High dosage: 15-20 mg/kg
Rifampicin 10–20 mg/kg for patients less than 30 kg; max dose 600 mg daily
Pyrazinamide 30–40 mg/kg for patients less than 30 kg; max dose 2000 mg daily
Ethambutol 15-25 mg/kg once daily
Levofloxacin 5 years and under: 15–20 mg/kg split into two doses (morning and evening) Over 5 years: 10–15 mg/kg once daily
7.5–10 mg/kg
Moxifloxacin
High dose: 10-15 mg/kg
Ethionamide/ Protionamide 15–20 mg/kg
Cycloserine 15–20 mg/kg
p-aminosalicylic acid 200–300 mg/kg for patients less than 30 kg in two divided doses
<6 years age: 10-12 mg/kg/d;
Linezolid
>6 years age: 15 mg/kg/d
2-5 mg/kg
Clofazimine 50 mg capsule: Use thrice a week in children weighing upto 5 kg and every alternate day in children between 5-9
years age
80 mg/kg (based on the amoxicillin
Amoxicillin clavulanic acid
component) in two divided doses
Kanamycin 15–20 mg/kg once daily (Max 1000mg)
Amikacin 15–20 mg/kg once daily (Max 1000mg)
Capreomycin 15–20 mg/kg once daily (Max 1000mg)
Imipenem cilastatin Meropenem is preferred in children.
 20–40 mg/kg intravenous every eight hours. Meropenem is given with Amoxicillin- clavulanate* 40mg/kg given twice
Meropenem
daily based on the amoxicillin component
Bedaquiline Dose not yet determined in children
50 mg twice daily (100 mg) for 24 weeks in 6-11 years of age
Delamanid
100 mg twice daily (200 mg) for 24 weeks for 12-17 years of age.

* as per Companion handbook to the WHO guidelines for the programmatic management of drug-resistant TB 2014
#
till the time data are available, adult dose is used
 Treatment of NTM

• Prerogative of the nodal DR-TB centers

• In vitro susceptibilities for many NTM do not
correlate well with clinical response to anti-
mycobacterial drugs
• Empiric therapy for suspected NTM lung disease is
not recommended
• MAC and M. kansasii - continue therapy for at least
12 months after the last negative sputum culture
• Resectional surgery
 Suggested treatment regimen for MAC

1. Rifampicin 450-600 mg OD
2. Ethambutol 800 – 1200 mg OD
3. Clarithromycin 1gm OD (Split into two doses).
4. Amikacin (Inj.) 750mg-1gm thrice weekly for the first 2-3 months.
Intensive phase is for 3- 6months
Continuation phase same drugs except Injectable, continued for 12 months
after sputum culture conversion.
Doses as per the standard weight bands
If the patient does not culture covert by end of 3 months, then species
identification and DST is required for further management by the NDR-
TBC committee based on expert consultations.
Note:- As the proportion of the patients estimated is very low, drugs will not
be available through RNTCP but will have to be made available through
the general health system.
 Note for treatment of NTM-1
• For nodular/bronchiectatic MAC lung disease is a three-times
weekly regimen including clarithromycin 1,000 mg or Azithromycin
500 mg, ethambutol 25 mg/kg, and rifampicin 600 mg administered
three times per week.
• For fibrocavitary or severe nodular/bronchiectatic MAC lung
disease includes clarithromycin 500–1,000 mg/day or azithromycin
250 mg/ day, ethambutol 15 mg/kg/day, and rifampicin 10
mg/kg/day (maximum, 600 mg). An initial 2 months of ethambutol at
25 mg/kg/day is no longer recommended.
• Intermittent drug therapy is not recommended for patients who
have cavitary disease, patients who have been previously treated, or
for patients who have moderate or severe disease.
 Note for treatment of NTM-2
• The primary microbiologic goal of therapy is 12 months of negative sputum
cultures while on therapy; therefore follow up Culture and Smear
microscopy : monthly basis in IP and quarterly basis in CP after culture
conversion is achieved
• Macrolides should not be used as mono-therapy for MAC because of the
risk for developing macrolide-resistant MAC isolates.
• A macrolide with a single companion drug, ethambutol, may be adequate
for nodular/bronchiectatic MAC disease but should not be used in patients
with fibrocavitary disease because of the risk of emergence of macrolide
resistance
• Patients receive recommended multidrug therapy for MAC in first attempt.
• Expert consultation should be sought for patients who have difficulty
tolerating MAC treatment regimens or who do not respond to therapy.
 Counselling for DR-TB patients

• Counselling offers an opportunity to explore and heal past and

present difficulties faced by patients
• A counsellor can help the patient to better understand
importance of regular treatment
• His/her role is to empower patients with disease related
information and enable him to take informed decision related to
treatment adherence.
• Documentation is an essential part of counselling.
• The DR-TB counselling register that is available with the
counsellor serves the purpose of documentation
• RNTCP provides a counsellor at every NDR-TB centre for this
purpose
 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

Shorter MDR-TB regimen 4 months +2 months 5 months 9-11 months

18-20
All oral longer MDR TB regimen 6 months +2 months 12 months months
 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.
 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.
 Extension of treatment in Shorter MDR TB regimen
• Total duration of shorter MDR TB regimen is for 9-11 months
• IP should be given for at least four months. After fourth month of treatment, if the
result of sputum microscopy is negative then CP should be initiated.
• If sputum smear microscopy does not become negative by the fourth month of
treatment, subject the patient to FL LPA and SL LPA and culture DST.
• If no additional resistance is detected, the IP should be prolonged until sputum smear
converts maximum till 6 months.
• If the intensive phase is prolonged, the injectable agent is only given three times a
week.
• IP should be extended to 5th or 6th month based on smear results. This will be done
for a maximum of 2 months
• If the patient remains smear positive at the end of 6th month of treatment, the patient
will be declared as “Treatment Failure”, re-evaluated as per integrated DR TB algorithm
and initiated on an appropriate modified regimen based on the extended DST.
 Extension of treatment in All oral longer MDR TB regimen

• Total duration of all oral longer MDR TB regimen is 18-20 months.

• After the 6th month of treatment, the dose of Lzd will be tapered to 300
mg if the 4th or 5th month culture result is negative.
• If the 4th or 5th month culture result remains positive, the dose of Lzd
(600 mg) and the regimen is extended by 1 month. However, the duration
of new drugs (Bdq or Dlm) is limited to 24 weeks only.
• Extension of treatment with Lzd (600 mg) and the regimen beyond 6
months maximum upto 8 months
• If the patient continues to remain culture positive or reverts back to
culture positive after 8 months of treatment, the patient is declared as
“Treatment failed”, re-evaluated as per integrated DR TB algorithm and
initiated on an appropriate modified regimen based on the extended DST.
For XDR TB patients the duration of all oral longer MDR TB regimen would
be for 20 months.
 Management of DR-TB patients with Treatment
Interruptions and Loss to Follow up

All the missed doses during IP must be completed prior to switching

the patient to CP.
Similarly all missed doses during CP must be administered prior to
ending treatment.
Patients who interrupt treatment for less than one month during IP:
• Resume IP treatment, however the duration of treatment will be
extended to complete IP. The follow up cultures will be done as
per the revised schedule.
Patients who interrupt treatment for less than one month during CP:
• Resume CP treatment, however the duration of treatment will be
extended to complete the CP. The follow up cultures will be done
as per the revised schedule.
Management of DR-TB patients with Treatment
Interruptions and Loss to Follow up continue….

Patients who are Loss to Follow up (interrupt treatment

continuously for one month or more) and return back for
treatment:
• Such patients will be given an outcome of “loss to follow up”.
• The patient would be subjected to repeat FL-SL LPA and LC as
per the diagnostic algorithm to restart with appropriate DST
guided regimen with or without newer drug for a fresh episode
of treatment.
MDR-TB patients who do not respond to the Shorter MDR-
TB regimen or who interrupt treatment
• Interrupt treatment continuously for one month or more of
shorter MDR-TB treatment then the episode is classified as “Loss
to follow up”. s/he is not restarted on a shorter MDR-TB regimen
but on an appropriate DST guided DR-TB regimen.
• If there are interruptions of less than one month (e.g. medical
indication in the patient of adverse events, patient decision) then
the shorter MDR-TB regimen can be continued and the missed
doses added to the rest of the treatment.
• Signs of impending treatment failure patient should be
considered for an appropriate DST guided DR-TB regimen
 Missing Bedaquiline doses and reload after
interruption
Initial 2 weeks of BDQ course and returns to resume the treatment:

 If interruption is up to 7 days:
BDQ containing regimen will be continued to complete the doses and the duration
of treatment will be extended to complete IP..
 If interruption is more than 7 consecutive days
BDQ course will be re-loaded (started afresh) if returns within 1 month and a
sputum sample will be collected for culture.

3-24 weeks of BDQ course and returns to resume the treatment:

 If interruption is up to 1 month:
BDQ containing regimen will be continued to complete the doses
 If interruption is more than 1 months:
BDQ will be permanently discontinued. Such patients will be given an outcome of
“Lost to follow up” (LTFU) based on the duration of LTFU
culture isolate must be stored for BDQ DST in future
 Transfers of DR-TB patients
• Move within DR TB site serving area
– Continue on same regimen with same Patient ID.
• Move out of DR TB site serving area
– Transfer with 7 days treatment & continue on the
same treatment. Register patient with a same patient
ID at the receiving district DR-TB centre.
– Change the DR TB centre for the patient (feature
currently not live under Nikshay)
 Managing referrals from other sectors

• DST results from private laboratories will be considered

acceptable under the following situations:
– CB-NAAT : Annual calibration of the machines.
– C-DST labs : Annual proficiency testing through NRLs

• Other patient DST would be offered under RNTCP as per the

integrated DR-TB algorithm

• Prior treatment : Quality or quantity and duration of drugs

consumed prior in other sector will not have any effect on
RNTCP treatment unless DR TB center insists for (well-
documented and adequate information available)
Treatment follow up & monitoring
 Clinical monitoring
• After initiation of Rx from the DR-TB Centre, MO
D/NDR TB center
– at monthly intervals during the IP, and
– at 3-monthly intervals during the CP until the end of
treatment
• Assess clinical, microbiologic, and radiologic response
to treatment
• Measure weight
• Assess possible adverse drug reactions (ADR)
• Encourage the patient to continue treatment
• Verify treatment card
 Follow up schedule
Regimen Class All oral regimen for H Mono /Poly DR TB
Duration 6 months (no separate IP/CP)
Clinical + Wt. Monthly
Smear Microscopy Monthly from 3rd month onwards

Culture At end of 3rd, 6th and 9th month (if applicable)

DST NAAT, SL LPA and LC DST as per algorithm if smear/ culture +ve at
3rd,6th or 9th month
UPT As and when clinically indicated
CBC/platelets^ As and when clinically indicated
TSH & LFT# As and when clinically indicated
CXR As and when clinically indicated and at end of Rx
ECG$ As and when clinically indicated
S. Electrolytes (Na, K, Mg, Ca) As and when clinically indicated
Specialist consultation As and when clinically indicated
Colour vision test^ Once in two months (in children)
^ Lzd containing regimen to rule out bone marrow suppression
# HBsAG and other viral markers (Hepatitis A, C & E) to be done in case of Jaundice
$ In case of baseline ECG abnormality or QTcF ≥450ms for regimen contains Mfx(h), Bdq, Dlm or Cfz, ECG must be done on daily basis for
initial 3 days or as suggested by cardiologist. Repeat ECG with long II lead after an hour to reconfirm abnormal ECG.
* DST whenever available
 Follow up schedule
Regimen Class Shorter MDR TB Regimen
Duration 9 – 11 months (4-6m IP, 5m CP)
Clinical + Wt. Monthly in IP, Quarterly in CP
Smear Microscopy Monthly from 3rd month onwards till end of IP, Monthly in extended IP
only if previous month S+ve.
Culture End of IP, end of extended IP and end of Rx
DST FL & SL LPA and LC DST (Mfx 1.0, Lzd*, Cfz* & Z*) if smear /culture +ve
at end of IP, end of extended IP and end of Rx
S. Creatinine Monthly till SLI course is completed
Audiometry Every 2 months till SLI course is completed and as and when clinically
indicated
UPT As and when clinically indicated
CBC/platelets^ As and when clinically indicated
TSH & LFT# At end of IP, as and when clinically indicated
CXR At end of IP, end of treatment, as and when clinically indicated
ECG$ At 2 wks, monthly in IP, as and when clinically indicated
S. Electrolytes (Na, K, Mg, Ca) As and when clinically indicated
Specialist consultation As and when clinically indicated
Colour vision test^ Once in two months (in children)
^ Lzd containing regimen to rule out bone marrow suppression
# HBsAG and other viral markers (Hepatitis A, C & E) to be done in case of Jaundice
$ In case of baseline ECG abnormality or QTcF ≥450ms for regimen contains Mfx(h), Bdq, Dlm or Cfz, ECG must be done on daily basis
for initial 3 days or as suggested by cardiologist. Repeat ECG with long II lead after an hour to reconfirm abnormal ECG.
* DST whenever available
 Follow up schedule
Regimen Class All oral longer regimen for MDR/RR
Duration 18-20 months
Clinical + Wt. Monthly in first 6 months, Quarterly beyond 6 months
Smear Microscopy With culture at C-DST lab
Culture Monthly from 3rd month onward to end of 6 months, Quarterly beyond 6
months, 2 consecutive monthly culture if any culture +ve from 12m
onwards
DST FL & SL LPA and LC DST (Mfx 1.0, Lzd, Cfz*, Bdq* & Dlm*) if any time
culture +ve at end of 6 months or beyond 6 months.
S. Creatinine If Injectable is used, monthly till SLI course is completed
Audiometry If Injectable is used, every 2 months till SLI course is completed and as and
when clinically indicated
UPT As and when clinically indicated
CBC/platelets^ 15th day, monthly in first 6 months, then as and when clinically indicated
TSH & LFT# LFT quarterly, as and when clinically indicated
CXR At end of 6 months, end of treatment, as and when clinically indicated
ECG $
At 2 wks, monthly in first 6 months, then as and when clinically indicated
S. Electrolytes (Na, K, Mg, Ca) As and when indicated and in case of any QTcF prolongation
Specialist consultation As and when clinically indicated
Colour vision test^ Ophthalmic exam once in 3 months
^ Lzd containing regimen to rule out bone marrow suppression
# HBsAG and other viral markers (Hepatitis A, C & E) to be done in case of Jaundice
$ In case of baseline ECG abnormality or QTcF ≥450ms for regimen contains Mfx(h), Bdq, Dlm or Cfz, ECG must be done on daily basis for
initial 3 days or as suggested by cardiologist. Repeat ECG with long II lead after an hour to reconfirm abnormal ECG.
* DST whenever available
 Moving from IP to CP
Shorter MDR TB regimen
(less than 12 months Rx)
• Monthly Smear till end of IP
• If negative, initiate CP
• If positive, extend IP for one
more month till conversion
or end of extended IP
• Follow-up culture will be
done at the end of IP, end of
extended IP and end of
treatment.
All oral longer MDR TB regimen
(more than 12 months Rx)
• Monthly culture from 3rd
month onwards to end of IP
• If 4th /5th months culture is
negative, initiate CP
• If 4th /5th months culture is
positive, extend IP for one
more month till conversion or
end of extended IP
 Follow-up microscopy
• Smear examination would be used on a monthly basis from 3rd month onwards
to guide the decision on moving from IP to CP in shorter MDR TB regimen and
extension of treatment from 6 months to 9 months and treatment outcome for
all oral H mono/poly regimen.
• For H mono/poly regimen,
– positive smear result at 4th month, treatment will be extended to 9 months.
– Follow up positive at end of 5th month, declare as treatment failed.
– Follow up culture would be done at 3rd, 6th and 9th month (if applicable). If found culture
positive, DST will be done.
• For shorter MDR TB regimen,
– If smear remains positive at the end of IP and/or extended IP, a fresh specimen/culture isolate
of that time will be subjected to FL/SL-LPA to check for amplification of resistance to FQ/ SLI or
InhA mutation.
– If the patient is found to be susceptible to both FQ and SLI at end of IP, the intensive phase will
be extended on monthly basis up to a maximum of six months.
– At end of extended IP or later, if any resistance is detected by SL-LPA OR InhA mutation
detected on FL-LPA OR if found to be culture positive, the patient will be declared as treatment
failure.
– The patient is then re-evaluated for all oral longer MDR TB regimen with appropriate
modification if required.
 Follow-up culture
• should be done using liquid culture.
• final treatment outcome of all MDR-TB patients will be declared on the
basis of follow-up culture results only
• For all oral longer MDR TB regimen
– In case of extension of IP, the follow-up culture months will shift by every
month of extension of IP till maximum limit of IP for all regimen classes.
– Extension of treatment is based on the follow up culture result of 5th month or
4th month culture result is negative at the end of 6 months of treatment,
reduce the dose of Lzd for subsequent period of treatment. If 5th month culture
result is not available, decision should be based on the 4th month culture result.
– If the follow up culture result (5th or 4th month) is positive, continue the
regimen for one more month and extend the total duration of treatment for
one more month.
– Extend the treatment maximum for 2 more months based on the follow up
culture results of 6th or 7th month, beyond this, reduce the dose of Lzd to half
for subsequent period in all the weight bands.
– Patient should have received minimum 8 months of treatment before declaring
the patient as treatment failed if the patient is not converted.
 Interim outcomes
• Culture  conversion: Patient is considered to have culture converted when
two consecutive cultures, taken at least 1 month apart, are found to be
negative. In such a case, the specimen collection date of the first negative
culture is used as the date of conversion.
• Culture reversion: Patient is considered to have culture reverted when, after
an initial culture conversion, two consecutive cultures, taken at least 1
month apart, are found to be positive. For the purpose of defining
Treatment failed, reversion is considered only when it occurs in the
continuation phase.
• Smear  conversion: Patient is considered to have smear converted when two
consecutive smears, taken at least 1 month apart, are found to be negative.
In such a case, the specimen collection date of the first negative smear is
used as the date of conversion.
• Smear reversion: Patient is considered to have smear reverted when, after
an initial smear conversion, two consecutive smears, taken at least 1 month
apart, are found to be positive. For the purpose of defining Treatment failed,
reversion is considered only when it occurs in the continuation phase.
 Interim outcomes
• Time-to-culture conversion is calculated as the
interval between the date of DR TB treatment
initiation and date of the first of these two
negative consecutive cultures (date of sputum
specimens collected for culture should be
used).
• Follow up schedule for the patient should be
adjusted to the months equivalent to the
dosage consumed by the patient if he has
missed the dosage during the course of
treatment.
Outcomes for all oral H mono/ poly DR TB patients
• Cured: A microbiologically confirmed patient at the beginning of treatment
who was smear negative at the end of the complete treatment and on at
least one previous occasion.
• Treatment completed: A patient who has completed treatment according
to guidelines but does not meet the definition for cure or treatment failure
due to lack of microbiological results.
• Treatment failed: A patient whose biological specimen is positive by smear
at 5 months or later
• Died: A patient who has died due to any reason during the course of anti-
TB treatment
• Lost to follow up: A patient whose treatment was interrupted for
continuous 1 month or more.
• Not Evaluated: A patient for whom no treatment outcome is assigned. This
includes former “transfer-out” & “still on treatment”
• Regimen Changed: A need for permanent discontinuation of existing
regimen and initiation of new regimen with change of at least one or more
anti-TB drugs prior to being declared as failed.
 Outcomes for shorter MDR TB regimen
• Cured: A microbiologically confirmed MDR/RR TB patient who has completed treatment
without evidence of failure and was culture negative at end of treatment and on at least
one previous occasion.
• Treatment completed: A patient who has completed treatment according to guidelines but
does not meet the definition for cure or treatment failure due to lack of microbiological
results.
• Treatment failed: Treatment terminated or need for permanent regimen change of any
anti-TB drugs in CP because of
– lack of microbiological conversion by the end of extended IP or
– microbiological reversion in CP after conversion to negative or
– evidence of additional acquired resistance for drugs in regimen or
– adverse drug reactions (ADR).
• Died: A patient who dies for any reason during the course of anti TB treatment.
• Lost to follow-up: A patient whose treatment was interrupted for continuous one month
or more.
• Not evaluated: A patient for whom no treatment outcome is assigned, this includes
former “transfer-out” & “still on treatment”.
• Regimen changed: A need for permanent discontinuation of existing regimen and
initiation of new regimen with change of at least one or more anti-TB drugs prior to being
declared as failed.
Outcomes for all oral longer regimen for MDR/RR TB
• Cured: A microbiologically confirmed MDR/RR TB patient who has completed
treatment without evidence of failure and three or more consecutive cultures
taken at least 1 month apart from 8 months onwards are negative including
culture at the end of treatment.
• Treatment completed: A patient who has completed treatment according to
guidelines but does not meet the definition for cure or treatment failure due
to lack of microbiological results.
• Treatment failed: Treatment terminated or need for permanent regimen
change of at least two or more anti-TB drugs from 8th months onwards because
of
– lack of microbiological conversion by the end of the 8 th month of treatment or
– microbiological reversion in the 8 th month or later after conversion to negative or
– evidence of additional acquired resistance for drugs in regimen or
• Died: A patient who dies for any reason during the course of anti TB treatment.
• Lost to follow-up: A patient whose treatment was interrupted for one month
or more for any reasons prior to being declared as failed.
• Not evaluated: A patient for whom no treatment outcome is assigned, this
includes former ‘transfer- out’ & “still on treatment”.
 Outcomes schedule

Interim When to report Treatment When to report

outcome (from initiation outcome (from initiation
of treatment) of treatment)
All oral H 4th month 6 months 6-9 months 12 months
mono/poly status
regimen
Shorter MDR TB 4th month 6 months 9 - 11 months 14 months
regimen (end of IP)
All oral longer 6th month 9 months 18-20 months 24 months
MDR TB regimen (end of IP)
PMDT Treatment Card – Page 1
PMDT Treatment Card – Page 2
PMDT Treatment Card – Page 3
PMDT Treatment Card – Page 4
PMDT Treatment Card – Page 5
PMDT Treatment Card – Page 6 & 7
PMDT Treatment Card – Page 8
THANK YOU
Non-tuberculous Mycobacteria (NTM)…1
• There are a large number of mycobacteria other than
Mycobacterium TB, which are now being increasingly
recognized as a cause of human disease.

• NTM are also known as atypical mycobacteria, anonymous

mycobacteria or MOTT. Ubiquitously distributed in the
environment and hence also known as environmental
mycobacteria.

• They are distinct from M.TB in their characteristics that

they can survive outside the human or animal host.
 Non-tuberculous Mycobacteria (NTM)…2

• They are generally non pathogenic or opportunistic pathogens and

most commonly cause disease when there is immunosuppression or
injury, except for few species which infect immune-competent
humans.

• Often these bacteria inhabit the respiratory passages in the form of

commensal organisms. Pulmonary infection from NTM though rare,
can cause disease similar to TB.

• They more commonly infect the skin, soft tissue, lymph nodes,
implant devices, wounds, bones and joints. Disseminated NTM
disease is mostly seen in patients who are immunosuppressed or
who have AIDS.
 Non-tuberculous Mycobacteria (NTM)…3
• Though NTM are widely distributed in the environment, the
clinical infection is rare. They may be falsely recovered from
clinical specimens due to laboratory contamination or
contamination of medical instruments.

• Chronic pulmonary infection due to M. avium complex and M.

kansasii generally occurs in elderly persons especially males who
are smokers or who have pre existing lung lesions.

• Cervical lymphadenopathy occurs in children due to M.

scrofulaceum, while skin and soft tissue infections may develop
from M. fortuitum, M. chelonei, M. xenopi and M. ulcerans.
 Non-tuberculous Mycobacteria (NTM)…4

• Exposure of humans to NTM may occur while bathing,

swimming and drinking and the organism can also gain
entry through cuts and abrasions.

• However, the risk of infection is generally less.

Disseminated lesions are found in immunocompromised
patients due to infection from M. avium complex.

• Sometimes, M. chelonei may cause very indolent

pulmonary infection.
 Diagnosis of NTM
• Because of their omnipresence in our environment, isolation
of NTM from nonsterile body sites does not imply true
infection or disease, per se.

• Repetitive isolation, signs of clinical disease, radiological

abnormalities, the exact species isolated and predisposing
conditions of the patient involved, are all helpful in
determining whether the isolated mycobacteria are to be
considered causative agents of the patient’s disease.

• In normally sterile sites, isolation of NTM, preferably backed up

by histological evidence of granulomatous inflammation,
suffices for the diagnosis of NTM disease.
Table 4.1 Most frequently isolated non-TB
Mycobacteria and their sites of infection
Species Main site of infection Growth rate
M. avium complex Pulmonary, lymph nodes, disseminated Slow
(M. aviaum, M. disease
intracellulare, minor
species)
M. kansasii Pulmonary, disseminated disease Slow
M. xenopi Pulmonary Slow
M. malmoense (NW Europe) Pulmonary Slow
M. ulcerans Skin Slow
M. marinum Skin Intermediate
M. abscessus Pulmonary, skin Rapid
M. chelonae Skin, soft tissues, disseminated disease Rapid
M. fortuitum Skin, soft tissues, pulmonary Rapid
M. scrofulaceum Lymph nodes  
M. haemophilum Disseminated disease  
 Evaluation for NTM lung disease
Clinical
– pulmonary symptoms include cough, hemoptysis, fever, weight
loss or organ specific signs and symptoms etc;
– exclusion of any other etiologies.

Radiological
– radiological findings pertain to nodular or cavitary opacities on
chest radiograph; and
– Or an HRCT scan that shows multifocal bronchiectasis with
multiple small nodules.

Microbiological (mentioned in next page)

 Microbiologic criteria for diagnosis of
NTM lung disease
Specimen Result
At least three sputum Two positive cultures regardless of the
results available with:OR results of AFB smear
Single available bronchial One positive culture regardless of the
wash or lavage with OR results of AFB smear

Compatible histopathology-
(granulomatous inflammation) and a
positive biopsy culture for NTM
Tissue biopsy with: Compatible histopathology-
(granulomatous inflammation) and a
positive sputum or bronchial wash
culture for NTM
Guidelines for making the diagnosis of
NTM-pulmonary disease…1
• Clinical features of an indolent, respiratory disease include cough,
expectoration, fever and other constitutional symptoms;

• Positive smear for AFB and/or heavy growth of NTM (at least 1+ on
solid media) on culture in respiratory specimens with the same
species being identified repeatedly;

• Histopathological features of mycobacterial/granulomatous disease or

culture of NTM from biopsy specimens;

• Radiological features of nodular infiltrates with or without cavitation

and/or bronchiectatic lesions;
 Guidelines for making the diagnosis of
NTM-pulmonary disease…2
• Underlying host conditions include immunosuppression, AIDS,
alcoholism, COPD, cystic fibrosis, diabetes, malignancies, prior TB,
oesophageal motility disorders etc;

• Absence of other Chapter

causes4 Laboratory
of pulmonary
services for lesions, such as TB,
aspergillosis, etc.

• Persistence of AFB after anti-TB treatment for two weeks or more

with CBNAAT or LPA report not detecting MTB; and

• Smear positive, CBNAAT negative, LPA TUB band negative with or

without R resistance in patients of presumed DR at diagnosis also
need to be evaluated.