recent advances in Treatment of TB

1. DR.RAVIRAJ SUDHIR JAGDHANI
JR-3
DEPT. OF PHARMACOLOGY
SHRI V.N.G.M.C. YAVATMAL, MAHARASHTRA
RECENT ADVANCES IN ANTI-TUBERCULAR
DRUGS
RECENT ADVANCES IN ANTI-
TUBERCULAR
DRUGS
DR.RAVIRAJ SUDHIR JAGDHANI
JR-3
DEPT. OF PHARMACOLOGY
SHRI V.N.G.M.C. YAVATMAL, MAHARASHTRA

2. CONTENT
• INTRODUCTION
• HISTORY
• DRUGS IN CURRENT USE
• NEED FOR NEW DRUG THERAPIES
• NEWER DRUGS APPROVED BY FDA
• DRUGS IN PIPELINE
• CONCLUSION
• REFERENCES

3. INTRODUCTION
• Chronic granulomatous disease
• M.tuberculosis
• World
• India > Indonesia > China > Nigeria > Pakistan > South Africa
• Tuberculosis
Microbiologically diagnosed Clinically diagnosed

4. Classification based on anatomical site of TB:
• Pulmonary
• Extrapulmonary
Classification based on history of TB treatment
• New case
• Previously treated:
o recurrent TB case
o treatment after failure
o treatment after loss to follow up
o other previously treated patient
• Transferred in:

5. Classification based on drug resistance
• Mono-resistance
• Poly-resistance
• Multi-drug-resistance
o Rifampicin resistance
• Extensive drug resistance

6. HISTORY
• Consumption, Phthisis, Scrofula, Pott’s disease and the White plague
• 1946: Medical Research Council (MRC) TB unit in the United Kingdom ->
randomized, controlled clinical trial, which was designed to compare
streptomycin plus bed rest versus bed rest alone
• 1950s: para-amino salicylic acid, isoniazid, pyrazinamide, cycloserine and
kanamycin
• 1960 – 1990: In collaboration with the United States Public Health Service
(USPHS): developed current short course treatment regimen (Rifampicin and
Pyrazinamide)

7. • 1970s – 1980s: The technical strategy for DOTS was developed by Karel
Styblo of the International Union Against TB & Lung Disease primarily in
Tanzania
• 1994: DOTS
• 2000: DOTS Plus

8. INDIA
• 1997: The large scale implementation of the Indian government's Revised
National TB Control Program (RNTCP) (RNTCP I) was started.
• March 2006: The RNTCP was then expanded  entire nation was covered
by the RNTCP in March 2006. (RNTCP II)
• 2012: Notifiable disease
• 2012-2017: National strategic plan
• 2017-2025: National strategic plan for tuberculosis elimination

9. MDR TB
• MDR TB management:
• Guidelines for management
• ATS: 1965, 1966, 1994, 2003
• BTS: 1990, 2000
• WHO: 1997, 2003, 2006, 2008, 2011, 2014 and 2016
• No controlled trials to compare various regimens or drugs
• Personal experiences and expert opinion

10. GOAL OF TB TREATMENT (WHO 2016)
1. To decrease case fatality and morbidity by ensuring relapse free year
2. To minimise and prevent development of drug resistance
3. To render patient non infectious, break the chain of transmission and to
decrease the pool of infection

11. DRUGS IN CURRENT USE

12. • Anti-tuberculosis (TB) drugs are CLASSIFIED into five groups based on
evidence of efficacy, potency, drug class and experience of use
First-line anti-TB drugs
• Group 1. Oral: isoniazid (H/Inh), rifampicin/rifampin (R/Rif), pyrazinamide
(Z/Pza), ethambutol (E/Emb), rifapentine (P/Rpt) or rifabutin (Rfb).
Second-line anti-TB drugs
• Group 2. Injectable aminoglycosides: streptomycin (S/Stm), kanamycin
(Km), amikacin (Amk). Injectable polypeptides: capreomycin (Cm), viomycin
(Vim).
• Group 3. Oral and injectable fluoroquinolones: ciprofloxacin (Cfx),
levofloxacin (Lfx), moxifloxacin (Mfx), ofloxacin (Ofx).
• Group 4. Oral: para-aminosalicylic acid (Pas), cycloserine (Dcs), terizidone
(Trd), ethionamide (Eto), prothionamide (Pto)
• Third-line anti-TB drugs
• Group 5. Thioacetazone (Thz), Clofazimine (Cfz), linezolid (Lzd), amoxicillin
plus clavulanate (Amx/Clv), imipenem plus cilastatin (Ipm/Cln),
clarithromycin (Clr).

13. DRUG SENSITIVE TB

15. DR-TB / MDR-TB

17. SHORTER MDR-TB TREATMENT REGIMEN
• In patients with RR-TB or MDR-TB who were not previously treated with
second-line drugs and in whom resistance to floroquinolones and second-
line injectable agents was excluded or is considered highly unlikely, a shorter
MDR-TB regimen of 9–12 months may be used instead of the longer
regimens

19. MDR TB WITH MIXED PATTERN OF RESISTANCE

23. XDR-TB
• Very difficult to treat -> rapid course and high mortality
• Standard MDR regimen ?
• Group V drugs

25. TB IN PREGNANT WOMEN
• Treatment of TB should not be withheld or delayed because of pregnancy
• H
• R
• E
• Z
• S
• Pyridoxine

26. TREATMENT OF BREASTFEEDING WOMEN
• All anti-TB drugs are compatible
• Baby should be watched
• BCG
• H

27. CHEMOPROPHYLAXIS
i. Contacts of open cases who show recent Mantoux conversion.
ii. Children with positive Mantoux and a TB patient in the family.
iii. Neonate of tubercular mother.
iv. Patients of leukaemia, diabetes, silicosis, or those who are HIV positive but
are not anergic, or are on corticosteroid therapy who show a positive
Mantoux.
v. Patients with old inactive disease who are assessed to have received
inadequate therapy.
• MDR-TB ???

28. ROLE OF CORTICOSTEROIDS
i. In seriously ill patients (miliary or severe pulmonary TB) to buy time for
drugs to act.
ii. When hypersensitivity reactions occur to antitubercular drugs.
iii. In meningeal/renal/pericardial TB or pleural effusion—to reduce exudation,
prevent its organisation and strictures, etc.
iv. In AIDS patients with severe manifestations of tuberculosis.
• Contraindications???

29. TB IN AIDS PATIENTS
• When CD4 count is <150 cells/μL, extrapulmonary and dual TB is more
commonly encountered
• Drugs used are same as in non-HIV cases
• Pyridoxine
• Cotrimoxazole
• Drug interactions?
• MDR-TB?

30. NEED FOR NEW DRUG THERAPY

31. • To reduce adverse effect
• To reduce duration of treatment
• To increase compliance / to reduce defaulters
• To increase efficacy / to reduce treatment failure / to prevent relapse
• To reduce cost
• For treatment of MDR and XDR TB

32. NEWER DRUGS APPROVED BY FDA

33. BEDAQUILINE (DEC’ 2012)
• Diarylquinoline
• Specifically targets ATP synthase, an enzyme essential for the supply of
energy to M.tuberculosis
• Strong bactericidal and sterilizing activity  preclinical, laboratory and
animal studies
• Highly plasma protein bound
• Metabolized in liver by CYP3A4
• Extended half life
• No cross resistance

34. • In June 2013, WHO published interim policy guidance in conjunction with the
WHO recommended MDR-TB treatments
• RNTCP has introduced BDQ through conditional access programme at 6
sites in country initially
• Compassionate use programme
• Common side effects include nausea, joint pains, headaches, and chest
pain.
• Serious side effects include QT prolongation, liver dysfunction, and an
increased risk of death.
• While harm during pregnancy has not been found, it has not been well
studied in this population

35. DELAMANID (OPC 67683)
• Nitroimidazole
• Approved for medical use in 2014 in Europe, Japan, and South Korea
• Works by blocking the manufacture of mycolic acids thus destabilising the
bacteria's cell wall.
• Delamanid is metabolised by the liver enzyme CYP3A4
• Common side effects include headache, dizziness, and nausea.
• Other side effects include QT prolongation.
• It has not been studied in pregnancy as of 2016.

36. LINIZOLID
• Available evidence presents Linezolid as a viable option in the treatment of
MDR/XDR TB although patients ought to be monitored closely for the
incidence of major adverse events such as myelosuppression and
neuropathy.
• Additionally, highly powered randomized controlled trials including
participants from endemic regions are urgently needed to better inform the
magnitude and significance of Linezolid treatment effect in MDR and XDR TB
patients.
• Dose: 600mg

37. • Other antibiotics:
• Clarithromycin (500mg BD)
• Clofazimine (200mg)
• Amoxi-clav (875/125mg)
• Imipenam/cilastatin

38. DRUGS IN PIPELINE

39. PRETOMANID (PA-824)
• Nitroimidazole
• Phase III clinical trial
• The aerobic killing mechanism of this drug appears to involve inhibition of cell
wall mycolic acid biosynthesis.
• The respiratory poisoning through nitric oxide release seemed to be a crucial
element of anaerobic activity by pretomanid.
• The 14-day EBA of PaMZ (n=13; mean±SD 0.233±0.128) was significantly higher
than that of bedaquiline (n=14; 0.061±0.068), bedaquiline– pyrazinamide (n=15;
0.131±0.102), bedaquiline– Pa (n=14; 0.114±0.050) but not PaZ (n=14;
0.154±0.040) and comparable with that of standard treatment (n=10; 0.140±0.094).
• Treatments were well tolerated and appeared safe.
• One patient on PaMZ was withdrawn because of corrected QT interval changes
exceeding pre-specified criteria

40. SUTEZOLID (PNU-100480)
• Oxazolidone
• The 90% CI for bactericidal activity in sputum over the 14-day interval.
• There were no treatment-related serious AEs, premature discontinuations or dose
reductions due to laboratory abnormalities.
• There was no effect on the QT interval. Seven (14%) sutezolid-treated patients had
transient, asymptomatic ALT elevations to 173±34 U/dl on day 14 that subsequently
normalised promptly; none had serious liver injury.
• The mycobactericidal activity of sutezolid 600 mg twice daily or 1200 mg once daily
was readily detected in sputum and blood.
• Both schedules were generally safe and well tolerated.

41. SQ 109
• Ethylenediamine
• Study to determine safety, tolerability, pharmacokinetics and bacteriological
effect of different doses of SQ109 alone and in combination with rifampicin
when administered over 14 days.
• SQ109 was safe and generally well tolerated.
• Mild-to-moderate dose-dependent gastrointestinal complaints were the most
frequent AE.
• No relevant QT prolongation was noted.
• Exposure to SQ109 (AUC0– 24 ) increased by drug accumulation upon
repeated administration in the SQ109 monotherapy groups.

42. • Co-administration of SQ109 150 mg with R resulted in decreasing SQ109
exposures from day 1 to day 14.
• A higher (300 mg) dose of SQ109 largely outweighed the evolving inductive
effect of R.
• Treatments with SQ109 alone showed no significant activity. SQ109 alone or
with rifampicin was safe over 14 days.
• Upon co-administration with R, 300 mg of SQ109 yielded a higher exposure
than the 150-mg dose.
• SQ109 did not appear to be active alone or to enhance the activity of
rifampicin during the 14 days of treatment.

43. BENZOTHIAZINONES (BTZ043)
• Pre-clinical developmental stage
• Studied the interaction profiles of BTZ043 with several anti-TB drugs or drug
candidates against M. tuberculosis strain H37Rv, namely, R, H, E,
delamanid, Pa, M, meropenem with or without clavulanate and SQ-109.
• No antagonism was found between BTZ043 and the tested compounds, and
most of the interactions were purely additive.
• BTZ043 acts synergistically with delamanid
• Synergy between two new antimycobacterial compounds (delamanid and
BTZ043) with novel targets offers an attractive foundation for a new anti-TB
regimen

44. NATIONAL STRATEGIC PLAN FOR
TUBERCULOSIS ELIMINATION 2017–2025

45. • VISION: TB-Free India with zero deaths, disease and poverty due to
tuberculosis.
• GOAL: To achieve a rapid decline in burden of TB, morbidity and mortality
while working towards elimination of TB in India by 2025.
• New, comprehensively-deployed interventions are required to hasten the rate
of decline of incidence of TB many fold, to more than 10-15% annually.
• The requirements for moving towards TB elimination have been integrated
into the four strategic pillars of “Detect – Treat –Prevent – Build” (DTPB)

48. CONCLUSION

49. • In spite of the progress achieved so far, much needs still to be done to
improve our approach to clinical trials of new anti-TB drugs and regimens.
• The surrogate markers currently adopted to measure the efficacy of a given
drug are old and need complicated statistical approaches to interpolate the
scientific evidence
• Furthermore, the time necessary to assess the pharmacological profile of a
new drug is still very long and the possibility of enrolling vulnerable persons
into the trials is a barrier we need to overcome soon

50. REFERENCES
• Tripathi KD. Essentials of Medical Pharmacology. 7th Ed. Antitubercular
drugs:765-79
• Lia D’Ambrosio and et al. New anti-tuberculosis drugs and regimens: 2015
update. ERJ Open Res 2015; pg.01-15
• WHO updates 2016
• www.tbcindia.nic.in
• Sharma HL, Sharma KK. Principles of Pharmacology. 3rd Ed. Chemotherapy
of TB and Leprosy:764-77
• Efficacy and safety profile of linezolid in the treatment of multidrug-resistant
(MDR) and extensively drug-resistant (XDR) tuberculosis: a systematic
review and meta-analysis

51. THANK YOU…