The presentation included treatment principles of Tuberculosis with first line drugs as per the recent RNTCP guidelines in India on DAILY ATT.

1. Treatment of Tuberculosis
Dr. Gyanshankar Mishra
MD (Pulmonary Medicine) DNB(Respiratory Diseases) MNAMS
Associate Professor
Dept. of Respiratory Medicine, IGGMC Nagpur
Email address: gpmishra81@gmail.com

2. Case definitions
Diagnostic algorithm (RNTCP)
Treatment of TB (Drug Sensitive) –Principles ,
Drugs , Regimes
Drug resistant TB – Cause, types and
management (Introduction to PMDT)
INH Chemoprophylaxis

3. Case Definitions

4. Case Definitions..

5. Case definitions..

10. Bacteriologic Fundamentals
of TB Treatment
2. Long-term treatment
1. Drug combinations
3. Single-dose administration

11. Bacteriologic Fundamentals
of TB Treatment
1. Drug combinations
The combination of drugs prevents the
appearance of resistance,
because avoids
naturally resistant mutants selection

12. Appearance of resistance to INH administered as Monotherapy
Resistant Mutants
Sensitive Bacilli
Months after Start of TreatmentNo. of
viable bacilli
Mitchison DA. En: Heaf F, et al. Churchill, London, 1968
The fall and Rise Mechanism

13. Bacteriologic Fundaments
of TB Treatment
2. Long-term treatment
1. Drug Combinations
3. Single-dose Administration

14. Bacteriologic Fundaments
of TB Treatment
2. Long term treatment
This permits action on
all bacillary populations
(depending on
metabolic conditions)

15. ■ In a tuberculosis patient,
there are different bacillary
populations formed of
bacilli in different
situations
- Location
- pH
- Replication rate,
susceptibility to drugs,
Bacillary populations

16. Bacillary populations
1. Rapidly multiplying bacilli
- Optimum medium: Extracellular. pH 6.5-7, maximum
oxygenation (cavern wall)
- Large number of bacilli → High probability of spontaneous
natural mutations
Many Millions
Naturally Resistant Mutants
INH

17. 2. Slowly multiplying Bacilli
- Intramacrophagic location. Acid pH. Population<105
No Naturally Resistant Mutants
Bacillary populations
PZ

18. Bacillary populations
3. Intermittently growing bacilli
- Unfavourable conditions. Solid caseum. Extracellular
- Population <105 - Relapse capacity
No naturally resistant mutants
RIF

19. Bacillary populations
1. Rapidly multiplying bacilli → INH
- Optimum medium: Extracellular. PH 6.5-7, maximum oxygenation (cavern wall)
- Large number of bacilli → High probability of spontaneous mutations
2. Slowly multiplying bacilli → PZ
- Intramacrophagic location. Acid pH. Population<105
3. Intermittently growing bacilli → RIF
- Unfavourable conditions. Solid caseum. Extracellular
- Population <105. Relapse capacity
4. Bacilli in latent state: Not susceptible to drugs
- Reactivations and relapses

20. Which bacilli are acted upon by the ATT drugs?

21. Bacteriologic Fundaments
of TB Treatment
- Achieves blood level peaks
- Post-antibiotic effect
- Facilitates supervision
3. Single dose
administration

22. Ideal
Tuberculosis
Treatment
2 HRZE / 4 HRE

23. EMB must be given To
protect against the
possibility that the patient’s
organism may have
initial resistance to INH
How Long
(Throughout treatment)

24. Basis for Regimens
New case: New sputum smear Positive
patients, high bacillary population,
chances for naturally occurring resistant
mutants higher,therefore 4 drugs in
intensive phase
Retreatment Case: Because of previous
treatment, chances of harboring resistant
bacilli are higher; hence 5 drugs in IP and
total duration of treatment is 8 months.In
continuation phase lower bacterial
population;hence less chance of resistant
organisms, therefore 3 drugs are enough.

25. Standard 7: Treatment with first-line regimen
7.1 Treatment of New TB patients:
• The initial phase - H, R, Z, E for two months
• The continuation phase - H, R, E for at least four months
7.2 Extension of Continuation Phase: Extend CP by 3 to 6 months in special situations like Bone
& Joint TB, Spinal TB with neurological involvement and neuro-tuberculosis.
7.3 Drug Dosages: As per body weight in weight bands
7.5 Dosage frequency:
• Daily
7.6 Drug formulations: FDCs
7.7 Previously treated TB patients: No MDR :- 2HREZS/1HREZ/5HRE
Standards of TB Care in India..

26. What is a correct Anti TB prescription?
Mention the Patient’s Age / weight
At least 4 first Line anti TB drugs should be
prescribed (Unless Contra Indicated)
Duration - IP and CP / DAILY regime
All the drugs should be prescribed in doses as per
weight (WHO guidelines) All the drugs to be
prescribed to taken at once or at the same time
(within 15 to 20 minutes MAX)
The prescription should not contain any second line
anti TB drug in absence of confirmed resistance
/Other indication.

27. In RNTCP Daily regime….

28. 4FDC

29. 3FDC

30. Inj. Streptomycin
15 mg/kg (12–18 mg/kg) daily
 Maximum daily dose 1000 mg
Patients aged over 50 years may not be
able to tolerate more than 750 mg daily
Similarly, patients weighing less than 50 kg
may not tolerate doses above 500-750 mg
daily

31. RNTCP..Daily Dose Schedule for Adults
(as per weight bands)
Weight
band
Number of tablets Inj.
Streptomycin
Intensive phase Continuation
phase
HRZE HRE
75/150/400/275
mg
75/150/275
mg
gm
25-39 kg 2 2 0.5 gm
40-54 kg 3 3 0.75 gm
55-69 kg 4 4 1 gm
≥70 5 5 1 gm

32. Dosing in children is a bit different!
2014 WHO Guidelines…

33. Drug Dosage for Paediatric TB
Weight
category
Number of tablets
(dispersible FDCs)
Inj.
Streptomyci
n
Intensive phase Continuation
phase
HRZ E HRE
50/75/150 100 50/75/100 mg
4-7 kg 1 1 1 100
8-11 kg 2 2 2 150
12-15 kg 3 3 3 200
16-24 kg 4 4 4 300
25-29 kg 3 + 1A* 3 3 + 1A* 400
30-39 kg 2 + 2A* 2 2 + 2A* 500
*A=Adult FDC (HRZE = 75/150/400/275; HRE = 75/150/275)

34. DRUG RESISTANT TB

35. Drug resistance - types
 When drug resistance is demonstrated in a patient who has
never received anti-TB treatment previously, it is termed
primary (Initial) resistance, i.e. TB patient’s initial M.TB
population resistant to drugs
 Secondary (Acquired) resistance is that which occurs as a
result of specific previous treatment, i.e. Drug-resistant M.
TB in initial population, selected by inappropriate drug use
(inadequate treatment or non-adherence)

36. DRUG RESISTANT –TB (DR-TB)
 Drug resistant TB
 Mono resistance
 Poly resistance
 Multi Drug Resistant TB(MDR- TB)
 Extensive Drug Resistant TB (XDR-TB)

37. DRUG RESISTANT- TB(DR-TB)
Mono Drug Resistance
(Resistance to single first line ATT)
Poly Drug Resistance
(Resistance to two or more first line ATT except MDR-
TB)

38. DRUG RESISTANT- TB(DR-TB)
Multi-drug resistant tuberculosis (MDR TB) is defined as
resistance to isoniazid and Rifampicin (a laboratory diagnosis).
Extensively drug resistant TB (XDR-TB) is MDR + resistance to
any fluoroquinolone + resistance to at least one 2nd-line
injectable drug (amikacin, kanamycin, or capreomycin)

39. MDR TB
 Single Isoniazid or Rifampicin resistance is not MDR – TB.
 MDR TB is a laboratory diagnosis, Not a Clinical assumption.

40. Drug resistant TB

41. Diagnosis of DR TB
 Tests available are:
 Conventional LJ culture DST – Gold standard
 DST- modified proportion method. (4 to 6 weeks for culture
& 3 weeks post culture for dst).
 PCR based LPA (line probe assay) – DST result within 72 hours.
 Other methods – (Liquid cultures)BACTEC 460, MGIT 960 (14
days + 9 days for dst) , etc.

42. The Xpert MTB/RIF
 The Xpert MTB/RIF is a cartridge-
based, automated diagnostic test
that can identify Mycobacterium
tuberculosis (MTB)DNA and
resistance to rifampicin (RIF)by
nucleic acid amplification
technique(NAAT )
Result within 2
hours.

43. Choice of test
DR diagnostic technology Choice
CBNAAT/LPA First
Liquid culture isolation and
LPA DST
Second
Liquid culture isolation and
liquid DST
Third

44. MDR-TB Mechanisms of resistance distribution
INH
RMP
rpoB
KatG
inhA
Courtesy: F. Alcaide

45. Classes of Anti TB Drugs recommended for treatment of DR-TB
New Grouping of Drugs
A. Fluoroquinolones Levofloxacin
Moxifloxacin
Gatifloxacin
Lfx
Mfx
Gfx
B. Second-line injectable
agents
Amikacin
Capreomycin
Kanamycin
(Streptomycin)
Am
Cm
Km
(S)
C. Other core second-line
agents
Ethionamide / Prothionamide
Cycloserine / Terizidone
Linezolid
Clofazimine
Eto/Pto
Cs/Trd
Lzd
Cfz
D. Add-on agents (not
part of the core MDR-TB
regimen)
D1 Pyrazinamide
Ethambutol
High-dose isoniazid
Z
E
Hh
D2 Bedaquiline
Delamanid
Bdq
Dlm
D3 p-aminosalicylic acid
Imipenem-cilastatin
Meropenem
Amoxicillin-clavulanate4
(Thioacetazone)
PAS
Ipm/Cls
Mpm
Amx-Clv
(T)

46. Important principles of
MDR-TB regimen design
1. Use at least 4 reliable drugs .
2. Do not use drugs with cross resistance .
3. Eliminate drugs that are not safe for the patient.
4. Include drugs from Groups in a hierarchical order.
5. Monitor and manage adverse effects of drugs.
6. Never add a single drug to failing regime.

47. Advanced RNTCP Regimes
Drug Resistant TB (PMDT)

48. General Treatment Principles
 Provide 18-24 months’ treatment, always with intensive
phase of at least 6 months ( current WHO guidelines -8
months).
 Provide DOT therapy.
 Warn patients about possible side-effects.
 Manage side-effects appropriately.
 Perform cultures monthly.

49. Be aware of the possible culprits in case of
ADR
 Nausea and vomiting - Eto, PAS, Z, E
 Giddiness - Aminoglycosides, Eto, Fq and/or Z
 Ocular toxicity - E
 Renal toxicity - Aminoglycosides
 Arthralgia - Z and/or Fq
 Cutaneous reactions - pruritis or rash- any of the drugs
used.
 Hepatitis - Z & Eto ,H,R

50. Be aware of the possible culprits in case of
ADR..
 Peripheral neuropathy - Cs, Eto, H
 Seizures - Fq and/or Cs, H
 Psychiatric disturbances – Cs, Fq and/or Eto, H
 Vestibulo-auditory disturbances - Aminoglycosides
 Hypothyroidism - PAS and/or Eto

51. Isoniazid Preventive Therapy
 Children < 6 years of age, who are close contacts of a
smear positive TB patient, should be evaluated for
active TB by a medical officer/ paediatrician
 After excluding active TB he/she should be given INH
preventive therapy irrespective of their BCG or
nutritional status
 The dose of INH for preventive therapy is 10 mg/kg
body weight administered daily for a minimum period
of six months

52. Isoniazid Preventive Therapy..
INH preventive therapy should also be considered in following situations:-
 For all HIV infected children who either had a known exposure to an
infectious TB case or are Tuberculin skin test (TST) positive (>=5mm
induration) but have no active TB disease
 All TST positive children who are receiving immunosuppressive therapy
(e.g. Children with nephrotic syndrome, acute leukemia, etc.).
 A child born to mother who was diagnosed to have TB in pregnancy
should receive prophylaxis for 6 months, provided congenital TB has
been ruled out. BCG vaccination can be given at birth even if INH
preventive therapy is planned.

53. Take home message
Identify and screen TB suspects correctly
Use correct diagnostic aids -sputum examination /
chest xray /genexpert
Always prescribe correct anti TB therapy as per
weight – RNTCP /PMDT / Individualised
Do not use Fq /Linezolid initially in treatment of drug
sensitive TB