Pharmacotherapy of TB. Recommended regimen for TB under RNTCP(2016). New drugs under research and new targets.

1. Newly recommended regimens
(under RNTCP 2016) for treatment
of
Pulmonary Tuberculosis
and
Recent advances in anti-tubercular
drugs
Dr KG Bandekar
Dept of Pharmacology

2. Sub topics
• Introduction
• Current drugs and regimes
• New Regimens
• Need for newer drugs
• New targets, drugs/molecules under research

3. Introduction
• Tuberculosis is chronic granulomatous disease.
• Causative agent - Mycobacterium tuberculosis
bacterium.
• M. tuberculosis is aerobic.
• In India – 2.3 million cases.
• TB – a notifiable disease in India.
• RNTCP(Revised National Tuberculosis Control
Programme) – launched to control and treat.

4. Mechanism of actions

5. Drugs currently used
1st line drugs .docx
2nd line drugs.docx
1st line drugs – High efficacy and low toxicity
2nd line drugs – Either low efficacy or higher
toxicity or both – are reserved drugs.

6. ADRs 1st line drugs
• Non hepatotoxic drugs – E and S
• Safe drug in Renal failure – R ( as it is secreted
in bile) – No dose adjustment in RF
• Least toxic drug – R

7. ADRs 1st line drugs
• H is metabolised by acetylation. Slow
acetylators - peripheral neuritis; fast
acetylators - hepatotoxicity
• Hepatotoxicity due to R is uncommon unless
pre existing liver disease is present and
presents as ‘hyperbilirunemia without SGPT
elevation’.
• E – optic neuritis ( low visual acuity, red/ green
colour blindness – green more than red)

8. Rifabutin and rifapentine
• Supplementary 1st line drugs
• Rifabutin is less effective against M.
tuberculosis than ‘R’.
• Rifabutin is used in HIV patients who are on
protease inhibitors / NNRTIs – less enzyme
induction compared to ‘R’. (Rifapentine is not
used)
• No dose adjustment in liver disease

9. 2nd line drugs

10. Fluroquinolones (FQ)
• Ciprofloxacin(Cfx), ofloxacin (Ofx),
moxifloxacin (Mfx) and levofloxacin (Lfx)
• Mfx the most effective.
• Effective in HIV patients.

11. Kanamycin (Km) and Amikacin (Am)
• Bacteriocidal.
• Less vestibular toxicity than hearing loss.
• Equally nephrotoxic.
• Am lesser toxic than Km.

12. Ethionamide (Eto)
• Mechanism similar to H
• Causes hepatitis, optic neuritis,
hypothyroidism
• Used also in leprosy

13. Cycloserine(Cs)
Inhibition of cell wall synthesis – inhibits
recemizing enzyme.
Causes neuropsychiatric disorders.
Capreomycin (Cm)
Injectable polypeptide.
Causes ototoxicity, nephrotoxicity, low K+
and
low Mg2+ .

14. PAS
• Related to sulfonamides.
• Affects folate synthesis.
• Least active drug.
• Only delays resistance.
• Causes kidney, liver, thyroid dysfunction.

15. Kanamycin and amikacin
• Injectable aminoglycosides.
• Can be used in Multi Drug Resistant -MDR
cases

16. Linezolid
• Oxazolidinone gp synthetic antibiotic.
• Inhibition of protein synthesis –unique binding
site 23 S of 50 S.
• Use in TB – off label use.

17. Bedaquiline
• Newer approved drug.
• Inhibits mycobacterial ATP synthase.
• Long half life.
• Used in MDR-TB.
• Pregnancy is a contraindication.
• Causes QT prolongation.

18. Chemotherapy
• Objective – Cure - elimination of both, fast
and slowly multiplying bacilli (including
persisters)
• Effectiveness evaluation – elimination of bacilli
from patient’s sputum.
• Correct drugs, correct dose, and for correct
length of time.

19. Rational of combination anti
tubercular drugs
• To prevent resistance.
• Resistant mycobacterial population (in
normally susceptible) -1 bacillus in 106
• Normally lesion contains > 108 bacilli.
• Hence – resistant strain readily selected if only
single drug is used.

20. Rational of combination anti
tubercular drugs contd…
• Two independently acting drugs in
combination are more effective.
• Probability of bacillus resistant to both drugs
initially – 1 in 106 X 106 = 1012 .

21. Dose

22. Wt-band dose recommendations

23. Regimens
• Long course – classical regimen - 18 months
H + 1/2 bacteriostatic drug/s
Sterilisation mainly dependent on H
• Short course chemotherapy - 6-8 months
Rapid bacteriological conversion
Low failure rates
Lower incidences of drug resistance
 Intensive phase (2/3 months)+ Continuation
phase (4 – 5 months)

24. DOTS - Directly Observed Treatment
Shot course Chemotherapy
• By WHO
• Strategy to ensure cure by providing the most
effective medicine and confirming that it is
taken.

25. Current Regimen
Cat Intensive phase Continuation
phase
Duration
(months)
Remark
Cat I
New patient
(2) HRZE daily (4) HR daily 6 Optional
(2) HRZE daily (4)HR 3/week 6 If DOTS
ensured
(2) HRZE
3/week
(4) HR 3/week 6 DOTS ensured
or No HIV inf
Cat II
Previously
treated
(2) HRZES daily
+ (1) HRZE daily
(5) HRE daily 8 Low/medium
risk of MDR-TB
Empirical
(standardised)
MDR-TB
regimen –
country specific
Empirical
(Standardised)
MDR-TB
regimen –
country specific
18-24 or
Sensitivity test
is avl
High risk MDR-
TB

26. Chemotherapy of TB in pregnancy
• Except S continue all 1st line drugs
• Breast feeding mothers – full course ( breast
feeding to be continued)
• Mothers receiving H and breastfed baby – Vit
B6 supplementation daily

27. Drug regimen recommended in
RNTCP(2016)
1. Daily dose regimen
2. MDR/RR-TB cases (without additional
resistance)
3. XDR-TB
4. H resistant TB
5. BDQ containing regimen
6. Shorter MDR-TB regimen(as per WHO 2016)

28. 1. Daily dose regimen
• 2 categories
a) New
b) Previously treated
Type of TB case Regimen in
Intensive phase
(IP)
Regimen in
Continuation
phase (CP)
New (2) HRZE (4) HRE
Previously
treated
(2) HRZES + (1)
HRZE
(5) HRE

29. FDC daily dose regimen doses

30. Drug resistance
• Multi drug resistance (MDR) – Resistance to H
and R and may be to any 1st line drug/s.
• Extensively drug resistance (XDR) – Resistance
to H,R,FQ and either aminoglycoside or Cm or
both.

31. 2. MDR/RR-TB cases (without
additional resistance)
Type of TB case Regimen
during IP
Regimen
during CP
R resistant + (H
sensitive or
unknown)
(6-9) km Lfx
Eto Cs ZEH
(18) Lfx Eto cs
E H
MDR TB (6-9) km Lfx
Eto Cs Z E
(18) Lfx Eto Cs
E

32. 3. XDR-TB
Type of TB case Regimen in IP Regimen in CP
XDR (6-12) Inj Cm,
PAS , Mfx, high
dose H, Cfz Lzd,
Amx/Clv
(18) PAS , Mfx,
high dose H,
Cfz Lzd,
Amx/Clv

33. 4. H resistant TB
Type of TB case Regimen in IP Regimen in CP
R sensitive ad
H resistant
(3-6)km Lfx R E
Z
(6) Lfx R E Z

34. 5. BDQ containing regimen
• Eligibility for BDQ regimen – Either of -
a) MDR/Rifampicin TB + res to all FQs
b) MDR/Rifampicin TB + res to all 2nd line drugs
c) XDR TB
Dose and duration
1. 0-2 week – Tab BDQ 400 mg daily + optimised
background regimen (OBR)
2. 3-24 week – Tab BDQ 200 mg 3/week + OBR
3. 25 week – to end of treatment – Continue OBR

35. BDQ containing regimen contd…

36. 6.Shorter MDR-TB regimen(as per
WHO 2016)

37. New anti-tubercular drugs

38. Pretomanid
• Stage 3 clinical trial
• Bacteriocidal.
• Interferes - ATP synthesis and mycolic acid
synthesis.
• 6 months regimen for pulmonary XDR-TB–
Linezolid + bedaquiline + pretomanid.
• PaMZ (Pretomanid+ Z + Moxiflox) regimen – RCT
in new pul TB patients.
• PRACTICAL study

39. Delamanid
• Stage 3 clinical trial
• Interferes synthesis of methoxy and keto mycolic
acid. (Unlike ‘H’ which inhibits alfa mycolic acid)
• Bacteriocidal.(Comparable to ‘R’)
• Only against mycobacteria.
• No cross resistance with H,R,E,S
• In MDR TB – [Delamanid + levofloxacin +
linezolid+ Z] – (‘A5343’ trial at Korea)

40. Sutezolid
• Stage 2 clinical trial
• Linezolid analogue.
• Bacteriocidal.

41. SQ109
• Stage 2 clinical trial
• Bacteriocidal
• Acts by inhibiting mmpl3.(Mmpl3, an inner
membrane protein, responsible for transport
of lipids to outer membrane to synthesise
mycolic acid)

42. Sudoterb
• Stage 2 clinical trial
• Inhibits protein synthesis.

43. INH derivative LL-3835
• Incorporation of lipophilic moieties (INH
hybrids)into framework of INH can increase
permeation into bacterial cell therby
increasing anti –TB action.
• LL-3835 – INH pyrrole hybrid-in stage 2 clinical
trial.
• (Few pyrrole compounds have been shown to
have in vitro anti tubercular activity)

44. Aptamers
• Bind targets with great affinity.
• No immunogenicity.
• Mtb-Apt1 and Mtb-Apt-6 – shoed in vitro
activity.
• Binds to ?polyphosphate kinase2(PPK2) as
target. {PPK2- role in synthesis of mycolic acid}

45. New targets

46. New targets

47. A. Targeting actively growing Mtb
• 1. Maltosyltransferase (GIgE) – Utilises
‘maltose 1 phosphate’ to elongate 1,4- glutan
chains.
• Accumulation of maltose 1 phophate – toxic
to Mtb
• Affects respiratory electron transport in Mtb.
• Humans lack proteins homologous to GlgE –
suitable target.

48. 2. Mycolic acid cyclopropanation
• Affects mycolic acid metabolism.
• Dioctylamine – inhibitor of cyclopropanation.

49. 3.DprE1/DprE2
• Decaprenylphosphoryl-beta-D-ribose2’-
epimerase.
• Biosynthesis of decaprenylphosphoryl-D-
arabinose(DPA) – cell wall synthesis.
• Also required for growth and survival.
• Inhibitors – nitrobenzothiazinones (BTZs).

50. 4. Mycothiol ligase (MshC)
• Mycothiol – LMW thiol that protects Mtb from
toxicity of drugs.
• Genes encoded – MshA,B,C,D.
• MshC important amongst them.
• Inhibitor – Dequalinium chloride - prevents
growth of Mtb.

51. 5. HisG
• ATP phosphoribosyl transferase (HisG).
• Histidine biosynthesis.
• Inhibitors of HisG – cidal

52. 6. ATP synthase
• 3 subunits for enzyme a,b,c.
• Inhibitors of C subunit have shown growth
inhibition.
• Inhibitor – R207910 – 20000 times more
affinity than human ATP synthase.

53. 7. Deformylase (def and fmt) and
methionine aminopeptidase)
• mRNA translocation begins with incorporation
of formylated methionine at N terminus.
• This residue is removed in 2 steps –
deformylation by deformylase followed by
hydrolysis of methionine by methionine
aminopeptidase.
• Protein synthesis.

54. B. Targeting dormant Mtb
• Dormancy – Physiological state characterised
by cessation in proliferation in in vitro and in
vivo
• Persistence – Tolerance by subpopulation of
bacteria to cidal effects of drugs.

55. 8. Isocitrate lyase (Icl)
• Icl-1 and Icl-2
• Inhibitors – growth inhibition, loss of
virulence.
• Inhibitors also act against persistent bacteria
in population.

56. 9. Proteasome complex
• Inhibition of proteasome activity increases
susceptibility of Mtb to nitrogen
intermediates which are antimicrobial
molecules secreted by macrophages.

57. 10. L,D-traspeptidase
• Interferes peptidoglycan metabolism
11 . DosR(DevR)
Hypoxia is sensed and transduced via DosR
which activates ‘dormancy regulon’ leading to
physiological adaptation.
Inhibitors of DosR affects dorancy.

58. 12. CarD
• Interacts with beta subunit of RNA polymerase
and regulates stringent response.
• Inhibting CarD – limits ability of Mtb to initiate
stringent response and to enter into
dormancy.

59. 13. UDP-GlcNAc pathway

60. UDP-GlcNAc pathway
• Uridine diphospho-N-acetyl-glucosamine
(UDP-GlcNAc) – key component of bacterial
cell peptidoglycan.
• Glmu (N acetylglucosamine-1-phosphate
uridyltransferase) involved in last step in
synthesis of UDP-GlcNAc.

61. 14. Mmpl3
• Mmpl3, an inner membrane protein,
responsible for transport of lipids to outer
membrane to synthesise mycolic acid.

62. Host directed therapies (HDT)
• Adjuvant treatment.
• Potentiate immune defenses against
M.tuberculosis.
• Reduce inflammation
• Helps preserving lung fn
• Enhance ATT
• Target host proteins – less likely to develop
resistance.

63. HDT contd…
• Examples –
• Bone marrow derived mesenchymal stromal
cells
• Repurposing commonly used drugs for-
epilepsy, diabetes, hypercholestrolemia,
immune modulators

64. Repurposing commonly used drugs
• Valproic acid and vorinostat – Trials in HIV + TB
• Metformin – against intracellular
m.tuberculosis - in vitro
• Thalidomide and its analogue – in TB
meningitis (as immunomodulators)

65. References
• KDT
• Park PSM text book (2017 edition)
• Katzung
• Novel targets in M.tuberculosis:search for new
drugs. Gyanu Lamichhane.
• M.AlMatar et al./Biomedicine& Pharmacotherapy
91(2017) 546- 558
• UDP-GlcNAc pathway : potential target for
inhibitor dicovery against M.tuberculosis. Chitra
Rani

66. Thank you !