Management of DR-TB

PMDT Guideline
Dr Subhankar Roy, Junior Resident, Department of Medicine, IPGME&R
Chairpersons- Dr Avas Chandra Ray, Associate Prof, Dept of Medicine, IPGME&R
Dr Amitabha Sengupta, Professor, Dept of Pulmonary Medicine, IPGME&R
Few Terminologies

 Mono-resistance (MR)- Biological specimen is resistant to only one 1 st line ATD

 Poly-Drug resistance (PDR)- Biological specimen is resistant to >1 1 st line ATD
other than INH & Rifampicin
 Multi-drug resistance (MDR)- Resistance to INH+R +/- other 1st line ATD, based
on the results from a quality assured laboratory. MDR-TB may have additional
resistance to any/all FQ or any/all SLI
 Rifampicin resistance (RR)- Resistance to R detected by phenotypic/genotypic
methods +/- resistance to other 1st line ATD except INH
 Pre-extensively drug resistant TB (Pre-XDR-TB)- MDR/RR-TB + FQ resistance
 Extensive Drug resistance (XDR)- MDR TB+ additional resistance to any FQ
(Lfx/ Mfx) + at least one additional group A drug resistance (Bdq/Lzd/both)
Evolution of PMDT
Detection of Drug Resistance

 Rapid molecular methods/ Genotypic tests-

1. Xpert MTB/RIF
2. Xpert MTB/XDR
3. Truenat MTB & Truenat MTB-Rif
4. LPA- FL LPA detects R, H and Eto resistance
SL LPA detects FQ & SLI resistance
 Growth-based drug susceptibility test (DST)/ Phenotypic test-
 DST on BACTEC-MGIT 960
 Quality assured DST to R ,H, Z, Mfx, Lfx, Lzd, Am, Km & Cm are available across
the country
Genes for Drug Resistance

Drug Resistance Target Region

Isoniazid inhA promotor, katG, fabG1, oxyR-ahpC
intergenic region
Ethionamide InhA promotor
Fluroquinolone gyrA, gyrB
Amikacin, Kanamycin, Capreomycin rrs, eis promotor
Who are to be tested for NAAT?

 Presumptive TB/ Key population-

Key population includes
 PLHIV
 Children
 EP-TB
 Smear Negative/Not available with CXR suggestive of TB
 Contacts of DR-TB
 Other vulnerable groups
 All TB patients & Non-responders to DS-TB regimen
Who are to be tested for NAAT?

 Subsequent time points when NAAT is offered for determining

additional/acquired Rifampicin resistance-
 Bacteriologically positive during course of DS-TB or H mono/poly DR-TB treatment
 Failure to respond to treatment
 Patients retrieved after loss to follow-up
 As per physician’s advice
Classification of Drugs used in DR-TB

 Group A-  Group C-
 Levofloxacin/Moxifloxacin  Delamanid
 Bedaquiline  Amikacin/Streptomycin
 Linezolid  Pyrazinamide
 Group B-  Ethionamide/Prothionamide
 Clofazimine  PAS
 Cycloserine/Terizidone  Ethambutol
 Imipenem-Cilastatin/Meropenem
Pre-Treatment Counselling
Information
on lab
result
Importance
TPT of early
initiation

Nature &
Family
duration of
planning Pre- treatment
Treatment
Counselling

Infection Possible
control change in
precaution treatment

Care and
Reassurance
support
to family
services
Treatment of MDR/RR-TB

 Transition from current shorter injectable regimen to shorter Oral

Bedaquiline-containing regimen in phased manner within 2021
 Pre-Treatment evaluation:

Clinical Evaluation Laboratory based evaluation

History & Physical examination RBS
Weight HIV testing
Height CBC
Psychiatric evaluation if required LFT, TSH
Electrolytes (Na,K,Mg,Ca)
UPT, Urine R/E, M/E
CXR, ECG
Inclusion criteria

 Rifampicin resistance detected/inferred

 MDR-TB with H resistance detected/inferred based on InhA OR KatG mutation
only (NOT BOTH)
 MDR/RR-TB with FQ resistance not detected
Exclusion Criteria
 DST based exclusion criteria-
1. MDR TB with H resistance detected with BOTH KatG & InhA mutation
2. MDR/RR-TB with additional FQ resistance
 Other exclusion criteria-
1. H/O exposure for >1month to Bdq, Lfx, Eto or Cfz when results of FL-LPA, SL-LPA & DST to
Bdq, Cfz, Z unknown
2. Intolerance/toxicity from a drug in shorter Bdq containing MDR/RR-TB regimen
3. Extensive TB disease (B/L cavitary ds, miliary TB)
4. Severe EP-TB ( TB meningitis, CNS TB), any EP-TB in <15yr children except TB
lymphadenopathy
5. Pregnant & lactating women
6. Children <5years
7. Uncontrolled cardiac arrhythmia that requires medication
8. QTcF>500 at baseline & normal electrolytes, repeat ECG after 6 hours shows the same
9. Family h/o long QT syndrome
Regimen & Duration

 Initial phase (IP): 4 months which can be extended up to 6months, Bdq is used
for 1st 6 months.
 Continuation phase (CP): 5months
 Total Duration: 9-11 months

IP: (4-6)Bdq(6m),Lfx,Cfz,Z,E,Hh,Eto CP: (5) Lfx, Cfz, Z, E

Dosage of shorter oral Bdq regimen
Drugs Dosage per day according to weight (mg)
16-29Kg 30-45Kg 46-70Kg >70Kg
High dose H 300 600 900 900
Ethambutol 400 800 1200 1600
Pyrazinamide 750 1250 1750 2000
Levofloxacin 250 750 1000 1000
Bedaquiline Week 0-2: 400mg daily
Week 3-24: 200mg 3 times weekly

Clofazimine 50 100 100 200

Ethionamide 375 500 750 1000
Pyridoxine 50 100 100 100
Follow-up Evaluation Schedule

 Clinical+weight: Monthly in IP, quarterly in CP

 Smear microscopy: Monthly from 3 rd month onwards till end of IP, Extension of IP
if previous SM is +ve
 Culture: At end of 3rd month, 6th month & end of treatment. If culture is +ve at
6th month, collect 1 repeat sample to ascertain bacteriological
conversion/reversion
 DST: FL-SL LPA, LC&DST if
1. Culture +ve
2. Smear +ve at end of IP/extended IP & end of treatment
 CXR: At end of IP, as & when clinically indicated
 ECG: At 2weeks, then monthly in 1st 6months, then as & when clinically indicated
 Most important evidence of response to DR-TB treatment is conversion of sputum
smear & culture to negative
Special Situations
 Pregnancy & Lactation: Shorter oral Bdq containing MDR/RR-TB regimen can’t be
administered before 32wks due to teratogenicity of Eto
 PLHIV: Can be used in PLHIV including those receiving ART. Efavirenz, Ritonavir
may potentially increase risk of Bdq related ADR
 Renal impairment:
Dose adjustment required No dose adjustment required
Z – 25-35mg/kg per dose thrice weekly INH
E- 15-25mg/kg per dose thrice weekly Moxifloxacin
Levofloxacin- 750-1000mg per dose Eto
thrice weekly
Bdq in Severe renal impairment Clofazimine
Bdq in mild/mod renal impairment
 Pre-existing liver disease: if persistently deranged LFT, shorter oral Bdq based
regimen avoided due to presence of H, Z & Eto
Shorter Injectable containing Regimen
 Inclusion criteria:
1. MDR TB
2. RR TB
 Exclusion criteria:
1. H/O exposure >1m to Km/Am, Mfx h, Eto or Cfz when results of LPA & DST not
available
2. Intolerance/Toxicity to any drug
3. Extensive TB (B/L cavitary ds)
4. Miliary TB, Severe EP-TB like CNS TB, TB meningitis
5. Any EP-TB in children <15years except TB lymphadenopathy
6. Pregnant & Lactating women
7. Additional resistance to FQ or SLI
8. H resistance with both KatG & InhA mutation
 PTE:
1. Baseline audiometry & then every 2 monthly till SLI course is completed
2. Serum creatinine: baseline & then monthly till SLI course is completed
 Regimen & Duration:

IP: (4-6) Mfxh, Km/Am, Eto, Cfz, Z, Hh, E CP: (5) Mfxh, Cfz, Z, E

 If IP is prolonged injectable agent is only given thrice weekly in extended IP

Treatment of XDR-TB: Longer Bdq
regimen
 All three group A & atleast one group B drug should be included
 If only 1 or 2 group A drug are used, both group B agents to be included
 If regimen can’t be composed with agents from group A & B alone, group C
agents are added
 In India, we start with all 5 drugs of group A & B and continue with 4 drugs in
the latter part of the regimen (beyond 6-8 months)
 Longer oral M/XDR-TB regimen is of 18-20 months with no separate IP or CP
 Preferred regimen: (18-20)Lfx Bdq(6m) Lzd Cfz Cs
 Lzd to be tapered to 300mg after initial 6-8 months of treatment
 Bdq will be given for initial 6 months
Inclusion Criteria

1. XDR-TB patients
2. MDR/RR-TB patients who are excluded from shorter oral Bdq containing regimen
3. Additional resistance or intolerance or non-availability of any drug in use or
emergence of exclusion criteria
4. Return after LTFU
5. Failure of shorter oral Bdq containing regimen
6. MDR-TB in pregnant patients who are unwilling for MTP
Treatment Extension

 If month 5 or 4 culture result is positive, dose of Lzd (600mg) & the regimen
to be extended by 1month to month 7 ( for a maximum of 8months)
 If month 8 culture is positive, FL-LPA, SL-LPA & culture-DST to be done

If any additional resistance detected, the patient needs to be reassessed at

N/DDR-TBC for modification of regimen
 Bdq to be extended beyond 6 months ONLY when an effective regimen cannot
be designed due to non-availability of adequate group A/B drugs &
background resistance of most group C drugs
Replacement sequence of drugs

 According to efficacy, resistance pattern, prior use, side-effect profile

 At least 4-5 drugs to be used in initial 6-8 months
 At least 3-4 drugs required in last 12 months
 Dlm & Am not started in final 12months of treatment
 Replacement of group C drugs done in following order
Dlm Am Z Eto PAS Ethambutol Penems
Follow-up Evaluation Schedule

 Clinical + Weight monitoring: Monthly upto 6 (upto 7/8th month depending on

smear/culture positivity), quarterly from month 7 or 9 onwards
 Smear Microscopy: Any smear positivity beyond >6months warrants checking
for bacteriological conversion/reversion
 Culture: monthly from 3rd month onwards to end of 6months ( upto 8th month
is extended) and then quarterly
 DST: FL & SL-LPA and LC-DST if culture +ve beyond 6 months
 CBC: at D15, monthly for 6months, then as & when clinically indicated
 LFT: quarterly
 CXR: at end of 6th month, end of treatment and as & when clinically indicated
 ECG: at 2 wks, then monthly till 6month (till Bdq/Dlm is extended) then as
when clinically indicated
Special Situations
 Pregnancy:

Duration of Pregnancy

<20 weeks >20 weeks

Advise MTP Pt unwilling for MTP

MTP done >32 weeks <32 weeks

Start/Continue shorter oral Bdq Start/Continue longer oral Bdq

containing MDR/RR-TB regimen containing MDR-TB regimen
 HIV-TB co-infection: same as MDR TB
 Renal impairment: Dose modification of Pyrazinamide, Ethambutol, Amikacin,
Levofloxacin, Cycloserine, Penems, PAS
 Pre-existing liver disease: H,Z,PAS,Eto & Bdq are potentially hepatotoxic
drugs and alterative regimen to be formed
BPaL Regimen

 For MDR-TB with additional FQ resistance

 ONLY to be used under operational research conditions
 Initial hospitalisation for 15 days mandatory at NDR-TBC ward for monitoring
of tolerability
 Dosage & Duration:
 Bedaquiline- 400mg daily (0-2 wks), 200mg three times in a week (2-24 wks)
 Pretomanid- 200mg daily for 26 wks
 Linezolid- 1200mg OD for 24 wks
H mono/poly DR-TB regimen

 PTE:
1. History & physical examination
2. Height/Weight
3. RBS
4. CXR
5. HIV test
 Treatment Regimen: ( 6 or 9) Lfx R E Z
 In exceptional cases due to unavailability of loose drug, use of 4FDC (HRZE)
with Lfx loose tablets may be considered rather than not starting treatment
Replacement sequence

Situation Sequence of replacement

Lfx can’t be used Replace with Mfxh
Mfxh or Z can’t be used Replace with Lzd, If Lzd also can’t be
used, then Cfz+Cs
Mfxh +Z can’t be used Use 2 drugs from Lzd, Cfz, Cs in order of
preference on resistance, tolerability &
availability

R resistance Shorter/Longer Bdq regimen

Follow-up Evaluation Schedule

 Clinical + weight: monthly till end of treatment

 Smear microscopy: monthly from 3 months till end of treatment
 Culture: At end of 3rd month & end of treatment (6th/9th month). If culture at
3rd month is positive, repeat the test to rapidly ascertain bacteriological
conversion/reversion
 DST: NAAT, SL-LPA & LC-DST if smear/culture positive at 3rd month or end of
treatment
 Colour vision test: once every 2months
 CXR: as and when clinically indicated, end of treatment
Special Situations

 Pregnancy & Lactation : can be started/ continued

 Extensive TB: prolongation of the regimen upto maximum of 12 months
 PLHIV: recommended in HIV reactive TB patients
Prophylaxis for contacts of DR-TB
Chemoprophylaxis regimen

Regimen Dose
6Lfx for contacts of R resistant FQ 1.Age>14yr
sensitive patients BW<45kg- 750mg/day
BW>45kg- 1000mg/day
2. Age<14yr 15-20mg/kg/day
4R for contacts of H resistant R Age >10yrs- 10mg/kg/day (Max 600mg)
sensitive patients Age <10yrs- 15mg/kg/day
6H can be used for RR-TB with FQ & H sensitive patients
Management of adverse drug reaction
 QTcF Prolongation
 Normal M<450 ms, F<470 ms
 Culprit drugs- Bdq, FQ, Cfz, Dlm

QTc <480 QTc 480-500 QTc >500

Cont Drugs, Check Withhold Cfz,FQ Dlm &

electrolytes, monitor Normal Low Bdq, correct
Electrolytes Electrolytes electrolytes. Monitor
ECG closely
QTcF daily. When
electrolytes are normal
& QTc<470 add the
drugs sequentially Bdq,
FQ, Cfz & Dlm
 Myelosuppression -
 Culprit Drug- Lzd
 Stop the drug if myelosuppression occurs
 Restart with lower dose (300mg) if myelosuppression resolves

 Nephrotoxicity-
 Culprit drug- SLI
 Discontinue suspected agent
 Restart the drug @2-3 times/wk if the drug is essential to the regimen
 Adjust all TB drugs according to CrCl
 Hearing loss-
 Culprit Drug- Aminoglycosides
 If early symptoms- reduce the dose twice/thrice per week
 Hearing threshold >40 dB <8000 Hz- Stop Aminoglycoside
 Optic neuritis-
 Culprit Drug- E, Lzd, Eto, Cfz, H, S
 STOP E & LZD, Do not restart
 Usually reverses with cessation of drug
 Hepatotoxicity
 Culprit Drugs- Z, H, R, Eto, PAS, Bdq
 If the patient is very sick (Meningitis, smear 3+), then administer ATT
 For not so serious patients, introduction of ATT can be delayed
 Rule out other potential causes of hepatitis ( Viral hepatitis, alcohol induced, other
medications)
 AST/ALT >5*UNL with normal Bil OR
AST/ALT <5 *UNL with normal
AST/ALT >3*UNL with Bil>2*UNL OR
Bil & Asymptomatic patient
Symptomatic patient

Stop all hepatotoxic drugs

Continue all drugs, monitor
Monitor clinical symptoms, AST/ALT & Bil
clinical symptoms, AST/ALT, Bil
once a week
every 2 wks till resolution

Improvement No Improvement

1. H mono/poly DR-TB: substitute with

If AST/ALT <2*UNL, restart full doses of withheld
replacement drug, extend treatment up to 9
drugs in following order
months
1. R, Z in H mono-poly DR-TB regimen
2. Shorter regimen MDR-TB: Shift to longer regimen
2. Hh,Z, Eto in shorter MDR-TB regimen
3. Longer regimen MDR-TB: modify regimen from
3. BDQ, Z, Eto & PAS in longer MDR-TB regimen
replacement sequence
Monitor AST/ALT every 3 days after each
reintroduction to ensure no deterioration before
re-introducing the next drug
Outcome
 Interim outcomes
1. Bacteriological conversion- 2 consecutive cultures (DR/DS TB) or smears (DS TB)
taken at least 7 days apart are found to be negative after bacteriological
confirmation
2. Bacteriological reversion- at least 2 consecutive cultures (DR/DS TB) or smears (DS
TB) taken at least 7 days apart are found to be positive after initial conversion or
for patients without bacteriological confirmation of TB
 Final outcomes
1. Treatment failed- Regimen terminated/ permanently changed to a new regimen
2. Cured- Bacteriologically confirmed TB at beginning of treatment with evidence of
bacteriological response at the end of treatment
3. Treatment completed- A patient who completed treatment but doesn’t meet the
criteria for cure or treatment failed
4. Lost to follow-up- A patient who did not start the treatment or whose treatment
was interrupted for >2 consecutive months
Integrated algorithm for DR-TB
Thank you