B (PMDT) can be defined as “all associated functions related to providing services based in the TB strategy in order to achieve the targets set for drug-resistant TB in the Global Plan to Stop TB 2011–2015”
1. Programmatic management of drug resistant tuberculosis
Guidelines in India 2019
Treatment of Drug –Resistance Tuberculosis in Adults
Dr.Darshna Sarvaiya
1st Year resident
Community Medicine
2. • PMDT :
- Implementation commenced : 2007,Nationwide Coverage : 2013
- Laboratory network
- ADR treatment
- Standards second –line regimen with supply chain based on monthly patient wise boxes
• In 2012, Revision on PMDT guidelines
• In 2012-13 : phased expansion by geography and lab capacity based DST offer by risk group
- Failure and contacts
- Previously treated TB patients and follow up smear positives
- HIV positive TB patients
• In 2013 , Nationwide coverage of PMDT services
• In 2014, Base line second line DST
History of PMDT in India
3. • In 2015, National Drug Resistant Survey
• In 2016,
- Revised Technical and operational Guidelines
- BDQ CAP implementation
- Mono and poly resistance
• In 2017,
-Revised Guidelines for PMDT in India -2017
- Universal DST
• In 2018,
- Roll out of Shorter MDR regimen
- Nationwide Bedaquiline access
- Introduction of Delamanid and access for 6 to 17 years
• In 2019 – Revised Guidelines for PMDT in India
- All oral Regimen
4. TB Burden :Global V/S India V/S Gujarat
Estimation
of TB Burden
Global India % of Global Gujarat % against
India
Incidence of
TB Cases
100 lakhs 27.9 lakhs 27 % 1.55 lakhs 5.5 %
Mortality of
TB
13 lakhs 4.23 lakhs 34 % 5591 1.3 %
MDR-TB 6 lakhs 1.47 lakhs 27% 3422 2.2 %
TB –HIV
Deaths
3 lakhs 11000 4% 429 3.9 %
WHO Global Report 2018
TB Burden : Global V/S India V/S Gujarat
5. GROUPS & STEPS DRUGS
Group A:
Include all three medicines
Levofloxacin OR
Moxifloxacin
Lfx
Mfx
Bedaquiline Bdq
Linezolid Lzd
Group B:
Add one or both medicines
Clofazimine Cfz
Cycloserine OR
Terizidone
Cs
Trd
Group C:
When medicines from
Group A and B cannot be
used
Ethambutol E
Delamanid Dlm
Pyrazinamide Z
Imipenem-cilastatin OR
Meropenem
Ipm-Cln
Mpm
Amikacin
(OR Streptomycin)
Am
(S)
Ethionamide OR
Prothionamide
Eto
Pto
Classes of Anti TB Drugs recommended for treatment of DR TB
6. Drugs analysed Benefits/harms
Lfx,Mfx,Lzd,BDQ Greater treatment success, reduced
deaths
Cfz,Carbapenems Greater Treatment Success, No reduced
deaths
Z Lower mortality if susceptible
Sm,Am,Cs/Trd Modest benefits
Km*,Cm higher failures, relapses, deaths & toxicity
Eto/Pto,PAS,Macrolides,Amx-Clv No significant benefits or worse
outcomes
Evidence to revised drug classification
7. • 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.
Principles of designing a WHO recommended all oral longer MDR TB
regimen (WHO-2019)
8. 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
Pyridoxin to be given to all DR TB patients as per weight band.
Under RNTCP, the following are the standard DR TB regimens:
All oral longer MDR TB regimen Guidelines for PMDT in India 2019
9. Guideline - 2018 Guideline – 2019 update
DST Guided
Regimen class
Intensive Phase Continuation
Phase
MDR/RR +
resistance to FQ
class
(6-9) Km Eto Cs Z
Lzd3 Cfz + (6) Dlm
(18) Eto Cs Lzd3
Cfz
MDR/RR+
resistance to SLI1
class
(6-9) Lfx Cm1 Eto
Cs Z Lzd3 Cfz + (6)
Dlm
(18) Lfx Eto Cs Lzd3
XDR-TB
(6-12) Cm1 Eto Cs
Z Lzd3 Cfz E + (6)
Dlm
(18) Eto Cs Lzd3
Cfz E
MDR/RR-TB + res
to FQ / SLI1 + Lzd3
or more
Modify the Regimen with New drugs
for XDR-TB as per the footnotes
All oral longer regimen for 18-
20 months
6-8 Dlm(6)* Lfx Lzd Cfz Cs/ 12 Lfx
Lzd (l) Cfz Cs
6-8 Bdq(6)* Lfx Lzd Cfz Cs/ 12 Lfx
Lzd (l) Cfz Cs
After DCG(I) approval
• Bdq in 6 to 17 yrs
• Dlm in 3-6 yrs
Regimen as per the recommendation of NTEG on Rx
10.
11. 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 DR-TB patients
12. Standard DR TB
regimen
Inclusion criteria Exclusion criteria
All oral H mono/poly
regimen
Isoniazid-resistant TB with
confirmed result for Rifampicin-
resistance not detected (RS)
No specific criteria except drug interaction/intolerability with
any other drug used concomitantly
Shorter MDR TB
regimen
Patient with Rifampicin-resistant
pulmonary or extra pulmonary TB
DST based criteria:
If DST/DRT result for FQ or SLI is resistant or
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
regimen for MDR/
RR TB
Patients in whom shorter MDR TB
regimen cannot be considered
due to any reason
None
Criteria to receive standard DR TB regimen
13. • Bdq can be provided to the patient ≥ 18 yrs.
• Dlm can be provided to age group 6 to 17 years.
• Non-pregnant females or females not on hormonal birth control methods are eligible. Post-
menopausal for past 2 year.
• Patients with controlled stable arrhythmia can be considered after obtaining cardiac
consultation.
Inclusion criteria for new drugs (Bdq/Dlm)
14. • 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 cardio toxic
drugs.
• History of additional risk factors, e.g. heart failure, hypokalemia, family history of long QT
syndrome;
• If results of the serum chemistry panel, hematology or urinalysis are outside the normal
reference range (including above listed parameters),
• Hypokalemia, hypomagnesaemia and hypocalcaemia should be corrected prior to a patient
receiving any QTc prolonging drugs.
Exclusion criteria for new drugs (Bdq/Dlm)
15. 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
Pre-treatment evaluation for MDR/RR TB patients
16. • Lzd may cause anemia, thrombocytopenia, peripheral neuritis and optic
neuritis.
• Cs should be used carefully in pre-existing seizure disorders not adequately
control with medication.
• Cs can cause depression and suicidal tendency.
• Cfz causes dark brown discoloration of the skin.
Caution to be exercised in choosing other group A and B drugs
17. Weight bands for DR-TB treatment
All oral H mono/poly regimen,
Shorter MDR-TB regimen,
All oral longer MDR TB regimen
<16 kg
(according to per
kg doses)
16-29
Kgs
30-45
Kgs
46-70
Kgs
>70 Kgs
Standardized
monthly
treatment boxes
will be prepared
at State/District
Patient wise boxes & loose drugs will be provided to Nodal and District DR TBC
18. • Week 0–2: BDQ 400 mg (4 tablets of 100 mg) daily (7 days per week)+ Other
drugs
• 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 +Other drugs
• 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 would be as per the weight bands in
accordance to the RNTCP PMDT guidelines.
Bedaquiline: Dosage
20. • Age >12 years : Tab.Delamanid 100 mg (two tablets of 50 mg )orally twice a day
for 24 weeks + Other drugs
• Age 6 to 11 years : Tab.Delamanid 50 mg (one tablet of 50 mg ) twice a day for
24 weeks + other drugs
• Week 25 (start of month 7) to end of treatment: Continue other second-line
anti-TB drugs only as per RNTCP recommendations
Delamanid : Dosage
21.
22.
23. Regimen Sequence of using replacement drug to modify the regimen
All oral H
mono/poly
If SL LPA shows Lfx resistance - Replace Lfx with Mfxh if SL LPA 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 TB
regimen
If there is a need for stopping/replacing any drug, stop the regimen and
evaluate the patient to switch to all oral longer regimen.
Sequence of using replacement drugs to modify the regimen
24.
25.
26. Regimen Intensive Phase Extended
Intensive Phase
Continuous
Phase
Total duration
All oral H mono-
poly DR-TB
regimen
6 months 6 months
Shorter MDR-TB
regimen
4 months +2 months 5 months 9-11 months
All oral longer
MDR TB
regimen
6 months +2 months 12 months 18-20 months
Duration of regimen
27. 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 one 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.
28. 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”,
29. 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”,
• For XDR TB patients the duration of all oral longer MDR TB regimen would be for 20 months.
30. • 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 injectable 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.
Keynotes
31. 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 revised schedule.
32. Missing Bedaquiline/Delamanid doses and reload after interruption
Initial 2 weeks of BDQ/Dlm 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/Dlm 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
33. 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
34. 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
35. 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 IPand 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
36. 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
37. Nausea/vomiting: Eto, Pto, PAS, Z,
E, Bdq
Abdominal pain :PAS, Eto, Pto, Cfz,
FQs, H, E, and Z
Metallic Taste :Eto/Pto, FQs
Diarrhoea: PAS, Eto/Pto Optic Neuritis:): E, Lzd, Eto/Pto,
Cfz, Rifabutin, H, S
Seizures :Cs, H, FQ
Arthralgia :Z, FQ, Bdq Gastritis :PAS, Eto, Pto, Cfz, FQs, H,
E, and Z
Hypothyroidism :Eto/Pto, PAS
Dizziness/Tinnitus
:Aminoglycosides, Eto, FQ and/or Z,
Cs, FQs, H, Eto, Lzd
Peripheral neuropathy :Cs, Lzd, H,
S, Km, Am, Cm, FQ, rarely Pto/Eto,
E
Psychosis :Cs, H, FQ,
Hearing disturbances :S, Km, Am,
Cm
Depression :Cs, FQ H, Eto/Pto Suicidal ideation :CS, H, Eto/Pto
Headache :Bdq, Cs Tendonitis :FQ Hepatitis: Z, H, R, Pto / Eto, PAS,
Bdq
Alopecia: H, Eto/Pto Allergic reaction: Any drug Renal failure:S, Km, Am, Cm
Electrolyte disturbances:Cm, Km,
Am, S
Gynecomastia: Eto/Pto QT prolongation: Bdq, Dlm, FQ, Cfz
Notable
adverse
reactions
to
drugs
used
for
DR-TB
patients
38. ADRs Suggested Drugs to manage the ADR
Nausea, vomiting, upset Stomach Metoclopramide, dimenhydrinate, prochlorperazine
Heartburn, acid indigestion, sour stomach, ulcer H2-blockers (ranitidine, cimetidine, famotidine, etc.),
Proton pump inhibitors(omeprazole, lansoprazole, etc.)
Avoid antacids because they can decrease absorption of
fluoroquinolone eg. alumniumhydroxide
Oral candidiasis (non-AIDS patient) Fluconazole, clotrimazole lozenges, Nystatin suspension,
itroconazole liquid
Diarrhoea Loperamide
Depression Selective serotonin reuptake inhibitors (fluoxetine,
sertraline), tricyclic antidepressants (amitriptyline)
Severe anxiety Lorazepam, diazepam, clonazepam
Insomnia Any hypnotic
Drugs
used
in
management
of
adverse
event
