tuberculosis management as per new guidelines

1. Management of sensitive and resistant Tuberculosis – new
guidelines
By
Dr. Alka Bansal
Associate Professor,
Sawai Man Singh Medical College, Jaipur

2. Learning Objectives:
TB Burden in India-Incidence of MDR & XDR TB
Important-Abbreviations
• Anti TB drugs
• TB terminology
• Differences between OLD vs New regimen
• Classification of anti-tubercular drugs- OLD vs New
• Mono-drug Resistant TB
• Poly-drug Resistant TB
• Multi-drug Resistant TB (MDR)
• Pre-XDR TB
• XDR TB
• Mixed –drug Resistant TB
• Total - drug Resistant TB
• Bedaquiline based regimen
• Weight bands

3. TB Burden in India
• Annually, 1/4th of Global TB Incidence.
• Notifiable- for all new and relapse cases .
• The TB incidence is on declining trend.
• In India (2014), an estimated 2.2% of new cases
and 15% of previously treated cases have MDR-
TB.
• 9% of them being affected by extensively drug-
resistant (XDR) strains of Mycobacterium
tuberculosis..

4. More than half of the global burden of MDR-TB is in three
countries
• India
• China
• Russia

5. Important-Abbreviations-
• H-isoniazid
• R-rifampicin
• Z-pyrazinamide
• E –ehambutol
• S –streptomycin
• Km-kanamycin
• Lfx-levofloxacin
• Mfx-moxifloxacin
• PAS-para-aminosalicylic acid
• Eto- ethionamide
• Cys-cycloserine
• -Lzd- linezolid
• -Cfz-clofazimine
• Amx-clav- amoxycillin clavulinic acid

6. Anti TB Drugs

7. Repurposed Anti TB drugs
• Linezolid
• Clofazamine
• Imipenem/ Meropenem
• Amoxicillin – Clavulanate
• Thioacetazone
• Clarithromycin
All the above drugs belong to older category 5

8. New Anti TB drugs
• Bedaquiline
• Delamanid
In pre-clinical phase
• Pretomanid
• NC-002, NC-003
• Sutezolid
• SQ 109
• Benzothiazinones

9. Terminology
• Mono drug resistance-one drug from group 1 other than R.
• Poly drug resistance-two or more drugs from group 1 other than H+ R
combination.
• Multi drug resistance/RR-TB- resistance to ( H+ R) from group 1 . Rifampicin
resistance is treated as MDR.
• Pre –XDR-MDR with resistance to at least one from grp 2OR 3.
• XDR- MDR with resistance to at least one drug from grp 2 AND 3.
• Mixed DR- atleast two drugs from different groups with combinations other than
described above like from grp 1+3.
• TDR resistant to all first and second line drugs.
• Previous terms- relapse, recurrent, retreatment, after failure

10.  Cure: Completed treatment but consistently culture -ve (with at least
5 consecutive negative results in the last 12 to 15 months). If onefollow-
up +ve culture is reported during the last three quarters, patient will still be considered cured
provided this positive culture is followed by at least 3 consecutive negative cultures, taken at least
30 days apart, provided that there is clinical evidence ofimprovement.
 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 bacteriological results.
 Treatment failure: If >2 of 5 cultures recorded in the final 12-15
months are +ve, or if any of the final three cultures are +ve.
 Treatment default: A patient whose treatment was interrupted for 2
or >2 consecutive months for any reasons.

11. TB Management

12. Differences between
Old vs New (2016) Regimens

13. Rx of Drug sensitive TB:
Till 2015 2016
Thrice weekly regimen Once daily for all Paediatric & PLHIV
cases – 104 districts
Individual drug doses based on 3
weight bands for MDR TB Rx
FDCs based on weight bands (4 in
adult, & in child) for TB Rx
Continuation of IP for 1 month if
sputum positive
IP need not be continued
CP is with HR CP includes Ethambutol (HRE)
For EP TB cases, CP is for 7 mo For EP TB cases, CP is extended for
12-24 wks (3-6mo)
For TBM cases Inj SM added in IP No change in IP

14. • Classification of Anti-tubercular drugs-
OLD vs New

15. 1 First line
oral
HRZE
2 Injectable Streptomycin,
kana,amika,
capreomycin
3 FLQ Levo, moxifloxacin
4 Oral
bacteriost
atic
PAS, cycloserine,
ethionamide
5 Uncertain
efficacy
Linezolid,
clofazimine, amox-
clav, clarithro,
imipenam,
thioacetazone,high
dose isoniazid
A =3 FLQ Lfx ,Moxi, Gati
B =2 Inj. Amika, capreo,kana,
strepto
C =4+5 Core 2
line
Ethionamide (protion)
Cycloserine(terizidone)
Linezolid,clofazimine
add
on
D1
=1 FLD
oral
ZE high dose H
D2 New Bedaquiline
Delaminid
D3 4+5 PAS, Imipenam-
cilastatin, meropenam,
amox clav,
thioacetazone
Old
v/s
nw

16. New T/T for drug-sensitive TB is being followed in 104
districts of 5 states in India as pilot project
• Maharashtra
• Bihar
• Kerala
• Sikkim
• Himachal Pradesh
Rest country will follow intermittent regimen –
RNTCP-2010.

17. Treatment of Drug Sensitive Patients (2016)

18. Treatment of Drug Sensitive Patients (2010)
category patients IP CP
I New 2(HRZE) thrice
weekly
4(HR) thrice
weekly
II Old 2(HRZE)
+1(HRZE) thrice
weekly
5(HRE) thrice
weekly
Treatment of Drug Sensitive Patients (2016)
category patients IP CP
I New 2HRZE daily 4HRE daily
II Old 2HRZES+1HRZEdaily 5HREdaily

19. Mono drug resistant
Resistance to (EXCEPT R) IP CP
INH (3-6)RZE Lfx Km 6RZE Lfx (NO Km)
Z (3-6)HRE Lfx Km 6HRE Lfx (NO Km)
E (3-6)HRZ Lfx Km 6HRZ Lfx (NO Km)
All other FLD + one from group 2+ one from group 3

20. Poly drug Resistant
• Resistant to 2 or more First Line Drugs (other
than combined H &R)
Resistant to IP CP
Polydrug (3-6)R FLD Lfx Km
Eto
6(R FLD Lfx Eto)
same as mono drug resistant+ one from group 4

21. (
RR/MDR
Like poly drug resistant TB +Cs. Also add H if sensitive to it.
#total 7/6 in IP and 5/4 in CP(-Z &Km)

22. RR/MDR TB Mx
Drugs given are -
• Kanamycin
• Levofloxacin
• Ethionamide
• Pyrazinamide
• Ethambutol
• Cycloserine
For MDR TB cases, IP can be extended for 3months maximum
For all MDR TB cases with additional resistance, IP can be
extended for maximum 6months.

23. In case of Additional resistance (in addition to MDR)
• Resistance to E – Omit E
• Resistance to z – Omit Z
• Res to Z&E – Add PAS in IP & CP
• Res to any SLI – use the sensitive one
• Res to Lfx/Mfx – use PAS + the sensitive one among them
• Res to Lfx&Mfx – Clfz, Lz(5th grp), PAS in IP&CP(6-12mo)
• Res to all SLI - Clfz, Lz, PAS in IP&CP(6-12mo)
#Add PAS if resistant to all FLDs and SLI , any 3 group drug .
#5th group drugs(Clfz, Lz) are used if resistant to all drugs of group 2
OR 3..

25. PRE-XDR TREATMENT REGIMEN
• Pre XDR – MDR + resistance to any FQ or any second line injectable
(SLI)
1. FQ resistance
# If Oflox resistance-Add levoflox/Moxiflox (do not count as effective
drug)
• Add PAS
• Add 1 drug from group 5- Linezolid/Clofazimine
• Km-Mfx-Eto-Cs-PAS-Lzd-Z
# If resistant to all FQs
• Add PAS
• Add 2 drugs from group 5 –Linezolid and Clofazimine
• Km-Eto-Cs-PAS-Lzd-Cfz- Z
• Continue injectable for 12 months

26. PRE XDR
2. SLI Resistance (sensitive to FQ)
# If resistant to Am and Km
• Cm may be effective
• Add PAS
• Add 1 drug from group 5- Linezolid/Clofazimine
• Cm-Lfx-Eto-Cs-PAS-Lzd-Z
# If resistant to all SLIs
• Use Sm if sensitive
• Add PAS
• Add 2 drugs from group 5 – Linezolid and Clofazimine
• Lfx-Eto-Cs-PAS-Lzd-Cfz-Z

27. XDR TB Mx-
Drugs given are –
• Capreomycin
• Moxifloxacin
• Linezolid
• PAS
• Clofazamine
• Amoxi/Clav
• High Dose INH
XDR Definition- Resistant to atleast one FLQ, one
second line injectable with MDR (H+R) .It means
resistant to drugs from 3 groups
Add high dose H+ Amx/Clv to amikacin
resistant pre –XDR T/t. And use Mfx in
place of Lfx . NO Cs.

28. Management Guidelines for Patie nts with Documented
or Strongly Suspecte d Extensively Drug-Resista nt
Tuberculo sis (XDR-TB)
1. Use pyrazinamide and any first-line oral agents that may be
effective.
2. Use an injectable agent to which the strain is susceptible, and
consider an extended duration of use (12 months or possibly
the whole treatment period). If the strain is resistant to all
injectable agents, use of one that the patient has not
previously received is recommended.a
3. Use a later-generation fluoroquinolone, such as moxifloxacin,
high-dose levofloxacin, or possibly gatifloxacin.b
4. Use all second-line oral bacteriostatic agents (para-aminosalicylic
acid, cycloserine, and ethionamide or prothionamide) that have
not been used extensively in a previous regimen or any such
agents that are likely to be effective.
5. Add bedaquiline or delamanid and one or more of the
following drugsc:
clofazimine, linezolid, amoxicillin/clavulanic acid, clarithromycin,
and carbapenems such as imipenem/cilastatin and
meropenem.
6. The simultaneous use of bedaquiline and delamanid is
not recommended at the moment in view of the current
lack of information on the potential of adverse reactions
when these drugs are administered together.
7. Consider treatment with high-dose isoniazid if low-level
resistance to this drug is documented.
8. Consider adjuvant surgery if there is localized disease.
9. Enforce strong infection-control measures.
10. Implement strict directly observed therapy and full adherence
support as
well as comprehensive bacteriologic and clinical monitoring.

29. Mixed resistance TB

30. TDR TB
• No specific management guidelines mentioned by WHO/ RNTCP.

31. TOTALLY DRUG-RESISTANT TUBERCULOSIS/super extensively dr tb
• Tdr-tb is the term used for tb strains that showed in vitro resistance to all first and
Second line drugs tested.
• Even changing the treatment to reserve drugs namely co amoxiclav and
Clarithromycin showed little or no improvement in one study
• Center for disease control and prevention termed the disease “untreatable”
• In addition to mutation in the tdr strains,many morphological changes have been found like
budding or branching forms of MTB,MTB with thicker walls etc.

32. Bedaquiline (BDQ)
• New class of drug - Diarylquinone.
• Specifically targets Mycobacterial ATP Synthase.
• Strong Bactericidal and sterilizing activity.
• June 2013 – WHO published Interim policy guidance for use of BDQ
in conjunction with WHO recommended MDR-TB STRs.
• 2016 – RNTCP is introducing BDQ through conditional access
programme at 6 sites in India.

33. Criteria to receive BDQ (Apex Committee):
• Adults >18y with PTB
• Non pregnant females using non-hormonal birth controlmethods.
• Absence of arrhythmias or Controlled stable arrhythmiasas it prolongs QT interval.
Bedaquiline (400mg daily for 2 weeks, then2oomg thrice weekly for total 6 months )
with optimized background regimen (OBR) is indicated in-
a) MDR/RR-TB cases with resistance to all SLI OR FLQ(grp 2,3)
b) XDR-TB with resistance TO ANY OR ALL FLQ WITH ALL OR ANY SLI

34. Resistance Subgroup OBR for IP CP
MDR/RR All FLQ resistant 6-12 ZE(Km Eto Cs
Lzd)
18E Eto Cs Lzd
All SLI resistant 6-12 ZE(Lfx Eto Cs
Lzd
18E Eto Cs Lzd
Lfx
XDR All FLQ & all SLI
resistant
6-12 ZE Eto Cs Lzd
Cfz hINH Amx/Clv
18 E Eto Cs Lzd Cfz
hINH Amx/Clv (NO
Z)
All SLI & any FLQ
resistant
6-12 ZEMfx Eto Cs
Lzd Cfz
18EMfx Eto Cs Lzd
Cfz (NO Z)
All FLQ & any SLI
resistant
6-12 ZEMfx Eto Cs
Lzd Cfz Cm
18EMfx Eto Cs Lzd
Cfz (NO Z & Cm)

35. Shorter MDR-TB regimen – WHO issued it in 2016 to be used in
MDR/RR cases regardless of age and HIV status. Here give 7 drugs in IP and
treatment duration is 9-12 mths.
NOT for extra-pulmonary, pregnant, previous exposure or resistance to second
line drugs
Regimen IP CP
Shorter MDR-TB (4-6)hH ZE Mfx Km
Cfz Pto
5ZE Mfx Cfz Z is given
in CP but
not Hdrugs from
all groups are
used

36. Weight bands...
• Recommendation of drug doses according to weight have been
made since 2010 itself.
• New (2016) guidelines by Govt of India Central TB Division provides
number of FDCs according to weight bands.
• 4 weight bands for Adults, 7 for children.
• This is to prevent further drug resistance and assured bioavailability
by increasing drug compliance.

40. DOSES FOR REGIMEN OF MDR TB
s.no drugs 16-25 Kg 26-45 Kg 46-70 Kg >70kg
1 Kanamycin(500&1G) (IP) 500 mg 500mg 750mg 1000mg
2 Levofloxacin (250 &
500mg) (IP/CP)
250mg 750mg 1000mg 1000mg
3 Ethionamide
(250mg) (IP/CP)
375mg 500mg 750mg 1000mg
4 Ethambutol (200 &
800mg) (IP/CP
400mg 800mg 1200mg 1600mg
5 Pyrazinamide (500 &
750mg) (IP)
500mg 1250mg 1500mg 2000mg
6 Cycloserine(250mg)
(IP/CP)
250mg 500mg 750mg 1000mg
7 PAS (80%
Bioavailability)
5mg 10mg 12mg 12mg
8 Pyridoxine (100mg)
(IP/CP)
50mg 100mg 100mg 100mg

41. DRUGS
Dosage/day
<= 45kgs >= 45kgs
Inj. Capreomycin(cm) 750mg 1g
PAS 10gm 12gm
Moxifloxacin (Mfx) 400mg 400mg
High dose INH (High
dose-H)
600mg 900mg
Clofazimine (Cfz) 200mg 200mg
Linezolid (Lzd) 600mg 600mg
Amoxyclav(Amx/Clv) 875/125mg bd 875/125 mg bd
Pyridoxine 100mg 100mg
DRUGS USED FOR XDR-TB