pharmacotherapy of tuberculosis

1. PHARMACOTHERAPY
OF TUBERCULOSIS
Dr.Suchanda Gadre(MD,Pharmacology)
Dr.D.Y.Patil School of Medicine,Nerul,Navi
Mumbai.

2. INTRODUCTION
• Tuberculosis is a chronic
granulomatous disease caused
by M.tuberculosis.
• ⅓ of world’s population affected by TB.
• India is major contributor with 2.3 million cases and
1000 people dying from TB every day.

3. Epidemiology
• India is the highest burden country in the world in
terms of absolute number of cases occurring every
year.
• In 2010 India accounted for one fourth of estimated
global TB cases.
• In 2011 prevalence and incidences of estimated TB
cases were 256 and 185 cases per 100,000
population respectively.

5. • Tuberculosis-M.tuberculosis.
• Bovine strain-cattle and animals.
• Affects the lungs causing pulmonary tuberculosis.
• Extra Pulmonary Tuberculosis-Intestine ,meninges,
bones and joints, lymph ,glands and other tissues of
body.
• Some Atypical Mycobacterium causing disease
similar to tuberculosis are- M.Kansasii,
M.Scrofulaceum,M.Intercellulare,M.Fortuitum.

6. RISK FACTORS OF TUBERCULOSIS
• Low socioeconomic status
• Crowded living conditions
• Diseases that weakens immune system like HIV
• Person on immunosuppressant like steroid
• Health care workers
• Migration from a country with a high number of cases
• Recent Tubercular infection(within last 2 year)
• HIV infection
• Children exposed to high risk adults
• Close contacts of persons known or suspected to have active
disease
• Low body weight .

8. SIGNS AND SYMPTOMS
• Productive, prolonged cough for > 2 weeks.
• Systemic symptoms- fever, chills, night
sweats, appetite loss, weight loss(5% over 3
months), pallor.
• Symptoms in Extrapulmonary tuberculosis-
pleuritis, meningitis, scrofula of the neck, urinary
stricture and Pott's disease of the spine.

10. Transmission
• Droplet infection
• Coughing, sneezing.
• Depends on closeness and time of contact
.The bacilli multiply in 4 -6 weeks and
spreads throughout the body.

12. PATHOGENESIS
• Sputum positive is the most infectious.
• 1 smear +ve case infects 10-15 person per year if
untreated.
• Risk of infection to disease is 10-15% in lifetime.
• Cell mediated immunity responsible for
hypersensitivity to mycobacterial antigen.
• Formation of caseating granuloma and cavitation in
lungs.
• Macrophages are the primary cells affected.

13. DIAGNOSIS
A)Tuberculin Test(Mantoux test)- Discovered by
Von Pirquet in 1907.It estimates the
prevalence of disease.(1TU of PPD in 0.1 ml)
Induration formed is measured.
Interpretation.
• 10 or >10mm- Positive
• <6mm-Negative
• 6-9mm-Doubtful.

14. Method to measure induration

15. B)Chest X Ray- Useful for diagnosis of smear negative
pulmonary TB and TB in children.
• It is a valuable tool for diagnosis of pleural and
pericardial effusion in early stage of disease when
clinical signs are minimal.
• Essential in diagnosis of Miliary TB.
• Abnormalities often seen in apical or posterior
segments of upper lobe or superior segments of
lower lobe.

16. Pulmonary TB Miliary TB

17. C)Sputum Test-A pulmonary tuberculosis
suspect should submit two sputum samples.
Day 1 sample 1 Patient provides “on the spot” sample
Day 2 sample 2 Patient brings an early morning sample.

18. .
Sputum test
Both samples
negative
Symptomatic
treatment and broad
spectrum antibiotic
for 10-14 days
Symptoms
persist
cured
Repeat sputum
test
Both samples
positive or If any
one sample
positive
Pulmonary TB
confirmed
Contd..

19. Repeat sputum
test
If one or more
samples positive
Pulmonary TB
confirmed
If both samples
negative
Chest XRay
Findings not
consistent
Rule out TB
Findings
consistent
with TB
Sputum negative
pulmonary Tb

20. Other Diagnostic Tests
D) Sputum culture-It is second in importance.It
takes 6-8 weeks,expensive and needs special
training and expertise.
E) Blood culture- LJ, Liquid MGIT 960.Results are
obtained after 2 weeks.

21. Treatment and RNTCP
• Chemotherapy is indicated in every active case of
tuberculosis . The objective is cure.
• RNTCP- In 1992 National TB Programme was
reviewed and in 1993 Revised National Tuberculosis
Control Programme was implemented as a pilot
study.
• In 1997 RNTCP was launched as a National
Programme.

22. • DOTS- Directly Observed Treatment Short Course.
Implemented under RNTCP is a comprehensive
package for Tb control.
• India adapted DOTS in 1993 and by march 2003
nation wide coverage has been achieved
• DOTS strategy has 5 components.
a. Political and administrative commitment.
b. Good quality diagnosis.
c.Good quality drugs. An uninterrupted supply of
good quality anti-TB drugs.
d.Supervised treatment to ensure the
right treatment.
e.Systematic monitoring and accountability.

24. Stop TB Strategy- Launched by WHO in 2006.
• Its strategy is to be implemented over 10
years under Global Plan to stop TB 2006-2015.
• It focuses on 5 principles- case detection,
treatment success, incidence, prevalence and
deaths.
RNTCP/DOTS treatment divides patients in
categories and according to the category the
treatment is decided.

25. • First Line Drugs:- 1. Isoniazid (H) 2. Rifampicin (R)
3. Pyrazinamide (Z)
4. Ethambutol (E)
5. Streptomycin (S)
• Second Line Drugs:- 1)Ethionamide(Eto)
2)Prothionamide(Pto)
3)Cycloserine(Cs)
4)Terizidone(Trd)
5)Para aminosalicylic acid(PAS)
6)Rifabutin
7)Thiacetazone(Thz)
contd..

26. Flouroquinolones- 1) Ofloxacin
2)Levofloxcin
3)Ciprofloxacin
4)Moxifloxacin
Injectable Drugs- 1)Kanamycin
2)Amikacin
3)Capreomycin.

27. Alternative Grouping of Antitubercular
Drugs.
Group 1 First line oral anti T b
drugs
Isoniazid, Rifampicin, Pyrazinamide, Ethambutol
Group 2 Injectable anti tb drugs Streptomycin, Kanamycin , Amikacin, Capreomycin.
Group 3 Flouroquinolones Ofloxacin, Levofloxacin, Ciprofloxacin,
Moxifloxacin.
Group 4 Second line oral anti tb
drugs
Ethionamide, Prothionamide, Cycloserine,
Terizidone, Para aminosalicylic acid.
Group 5 Drugs with unclear
efficacy
Thiacetazone, Clarithromycin, Clofazimine,
Linezolid, Amoxicillin/Clavulanate,
Imipenem/Cilastatin.

28. • Isoniazid-
 Excellent and cheapest anti tubercular drug.Bactericidal.
 Acts onExtracellular+Intracellular bacilli
 Inhibition of mycolic acid synthesis.
 Active metabolite formed by carboxylase peroxidase enzyme.
 Pharmacokinetics- well absorbed orally and reaches all body fluids.
It can cross BBB for treatment of tubercular meningitis.
Metabolised by N-acetylation NAT2.
 Plasma half life- 3hrs.

29.  Resistance- INH has high resistance.
1. mutation of catalase peroxidase gene (KAT G)
2. mutation of InhA and KasA gene.
3. d/t efflux of INH from bacterial cell wall.
 Adverse effects- Peripheral Neuritis
Hepatotoxicity.

30. Drug Interactions-1.INH inhibits metabolism of
Phenytoin,Carbamazepine,diazepam,thiophyllin and
warfarin by inhibiting CYP2C19 and CYP3A4.
2. Aluminium Hydroxide inhibits INH.
Dose- 300mg OD or 5mg/kg/day orally.
600mg thrice weekly i.e. 10mg/kg/day.
 Serious Infections- 600mg OD orally.

31. Rifampicin-
Obtained from streptomyces mediterranei.
Bactericidal.
Acts best on intermittently or slowly dividing bacilli called
as Spurters.
Effective against intracellular+extracellular bacilli.
Has good resistance preventing and sterlising property.

32. Mechanism of Action- Inhibition of DNA dependant RNA
polymerase.
Pharmacokinetics- well absorbed orally. BA-70%.
food decreases its absorption.
Metabolised in liver to active deacytylated
metabolite,excreted in bile and urine.
Plasma half life-2-5 hours.
Resistance- Point mutation in rpoB gene.

33. Adverse Effects- Hepatitis is major adverse effect but is dose
dependent and reversible.
Orange Red discolouration of urine is seen.
Drug Interactions- It is an enzyme inducer. Induction of
cytochrome P-450 and its isomers.
Increases metabolism of many drugs e.g. OCPs,
anticoagulants, protease inhibitors used in HIV.

34. Dose- 600mg daily single dose before breakfast or
600mg single dose thrice weekly.
Other Uses- 1.Leprosy.
2. Prophylaxis of Meningococcal and H.Influenzae meningitis
and carrier state.
3. Prosthetic valve endocarditis.
4. Combination with doxyclyline for Brucellosis.(DOC)
5. 2nd/3rd choice drug for MRSA diphtheroids and Legionella.

35. Pyrazinamide- Developed in 1952. It is similar to INH
chemically. 3rd most important antitubercular drug.
Weakly Bactericidal.
Most effective during first 2 months of infection.
Good sterlising property.
Mechanism of Action- Enters Mtb by passive diffusion and
converts to pyrazinoic acid (active metabolite) by
pyrazinamidase enzyme and inhibits synthesis of mycolic
acid synthesis.
By inhibition of mycolic acid synthase 1 enzyme.

36. Plasma half life- 9-10hours.
Resistance- Gene mutation in pnc A gene.
Adverse Effects- Hepatotoxicity(15%).Hyperuricemia and
acute gouty arthritis.
Contraindicated in pregnancy.
Dose- 25-30mg/kg/day.(1500mg)
If given thrice a week then 35mg/kg/day(2000mg).

37. Ethambutol- Synthetic BACTERIOSTATIC drug.
Mechanism Of Action- Inhibits arabinosyl transferase
enzyme. Prevents polymerisation of
arabinoglycans.(essential component of mycobacterial cell
wall).
Pharmacokinetics-less than ⅟ is metabolised.
Plasma Half Life- ~4hrs.

38. Resistance- Point mutation is emb B gene.
Adverse Effects- Retrobulbar neuritis impairing visual acuity
and red green colour discrimination.(25mg/kg/day
;>9months).C/I in children < 5yrs of age
Dose- 800-1000mg orally; 15mg/kg/day. Orally.
1600mg/day;30mg/kg/day thrice a week.
It is safe in pregnancy.

39. Streptomycin- Bactericidal.
Acts only on Extracellular bacilli.
Resistance is rapidly developed.
Admistered i.m and has low margin of safety.
Adverse effects- Vestibular Defects and nephrotoxicity.
Use is restricted to tuberculosis and labelled as
‘Supplemental Drug’ .

40. Second line anti TB drugs
• Kanamycin(km),Amikacin(Am):-
 Aminoglycoside- Similar to streptomycin.
 Ototoxic and Nephrotoxic.
 Streptomycin resistant-Mostly sensitive to
Amikacin.
 Dose-15mg/kg/day i.m or i.v 5 days a week for 2
months.
0.75-1gm/day thrice weekly for 4 months.

41. • Capreomycin (Cm):- Cyclic peptide antibiotic.
 Ototoxicity, Nephrotoxicity, eosinophilia, fever and rashes.
 Administered i.m causes pain at inection site.
 Alternative to aminoglycoside.
 Streptomycin and Amikacin resistant and MDR TB- sensitive
to Capreomycin.
 Dose- 0.75-1gm/day.

42. • Ethionamide (Eto):-
 Introduced in 1956 with moderate efficacy. Similar to INH
 Intracellular + Extracellular bacilli. Inhibition of mycolic acid
synthesis.
 Resistance- mutation in gene for Eto activating enzyme.
 Adverse effects- hepatitis , behavioural changes (pyridoxine
100mg), menstrual irregularities , impotence.
 Dose- initial 250mg/day and increased every 5-6 days upto
750 mg/day.
 Used only drug resistant TB cases.

43. • Cycloserine (Cs):-
 Obtained from S.orchidaceus. Inhibits cell wall synthesis.
Bacteriostatic.
 1/3rd metabolised, rest excreted in urine.
 Plasma half life-9hrs.
 Adverse effects-neurological disorder-neuropyschiatric
symptoms, fall in BP noted.
 Pyridoxine 100mg/day.
 Used for drug Resistant TB cases.MDR TB.
 Dose- initial 250mg/day,if tolerated increase to 750mg/day
for patients with body wt >45kg.

44. • Para-amino salicylic acid (PAS)-
 Introduced in 1946. Bacteriostatic.
 Inhibition of folate synthase.
 Delays resistance by inhibiting episomal resistance transfer.
 Competes with aceylation of INH.50% of PAS is acetylated.
 Tolerance is poor-anorexia, nausea,epigastric pain.
 Used in drug resistance TB.MDR TB.
 Dose-10-12gm(200mg/kg)/day in divided dose.

45. • Fluoroquinolones (FQs)- {Levofloxacin(Lfx),ofloxacin(ofx),
ciprofloxacin(Cfx),moxifloxacin(Mfx)}
 New potent bactericidal drugs, active against MAC.
 Mfx more active against MTB.
 Penetrate cells and kill bacteria lodged in macrophages.
 Addition of Mfx in RHZ – possibility of reducing treatment
duration.
 FQs –key component in MDRTB.
 Resistance development- Lfx->Ofx->Cfx by mutation of DNA
gyrase gene.
 Dose- Ofx-800mg OD
Lfx-750mg OD
Mfx-400mg OD

46. RNTCP Treatment Categories
Intensive Phase Continuation Phase
• Duration- 2-3 months
• Rapid Killing of Bacteria
• Sputum conversion
• Symptomatic Relief
•Duration 4-7 months
•Elimination of remaining Bacteria
•Prevention of Relapse.

47. category Type of Patient Drugs Given Duration Colour
of box
F/U
Sputum
Test
CAT 1
ALL NEW
PULMONARY AND
EXTRA PULMONARY
CASES
2(HRZE) + 4(HR) IP- 2
MONTHS
CP-4
MONTHS
RED 2,4,6
MONTHS.
CAT 2
ALL RE TREATMENT
PULMONARY AND
EXTRA PULMONARY
CASES
2(HRZES) +1(HRZE)
+5(HRE)
IP-
3MONTHS
CP-
5MONTHS
BLUE 3,5,8
MONTHS
CAT 3 DISCONTINUED
CAT4 MDR TB CASES
INJ KANAMYCIN,TAB
LEVOFLOX,TAB ETO,TAB
CS,TAB Z, TAB E,(PAS
SUBSTITUTE DRUG)
IP-6-9
MONTHS
CP-18-24
MONTHS
3,4,5,6,7,9,
12,15,18,21
,24
MONTHS
CAT 5 XDR TB CASES
INJ CAPREOMYCIN,TAB
MOXIFLOX,HIGH DOSE
INH,CLOFAZIMINE,LINIZOLI
D,PAS,AMOXICLAV,(RESERV
E DRUGS
CLARITHROMYCIN,THIACET
IP-6-12
MONTHS
CP-18
MONTHS.
3,4,5,6,7,9,
12,15,18,21
,24
MONTHS.

48. Resistance to Antitubercular Drugs
• Resistance may be of 2 types
Primary/Pretreatment Secondary/Acquired
Resistance shown by Resistance acquired
bacteria. during course of
treatment.

49. MDR TB- MDR case is defined as one that is atleast resistant
to Isoniazid and Rifampicin , with or without resistance to
any other anti TB drugs based on DST results from an
RNTCP accredited laboratory.
MDR-TB suspect is divided into 3 criterias:-
1. Criteria A- All failures of new TB cases (CAT1),s+ve RT cases
who remain s+ve at 4th month onwards in CAT2 and all PTB
cases who are contacts of known MDR TB cases.
contd....

50. 2. Criteria B- Criteria A + all sm +ve Re-Treatment cases at
diagnosis and any sm+ve followup in new or RT cases.
3. Criteria C- Criteria B + Sm –ve Re Treatment PTB cases at
diagnosis and HIV TB co- infected cases.
According to 2013 survey by WHO , India has highest no. Of
MDR cases.
3.7% of new TB cases have MDR TB.
Principles of Treatment of MDR:-
1. Regimen should have atleast 4 drugs effective drugs.
2. Reliance about efficacy

51. 3. Avoid combination of cross reacting drugs.
4. Include drugs from group 1 to 4 in hierarchial manner.
RNTCP initiated DOTS-plus programme in the year 2000 to
cover diagnosis and treatment of MDR TB.
2010- Updated to Revised DOTS-Plus guidelines.
According to revised programme rifampicin resistance is
also MDR TB.

52. Pyridoxine 100mg/day prescribed to all patients to avoid
adverse drug reaction.
Standardised Treatment Regimen
This standardised regime under DOTS plus has been very
successful.
Intensive phase Continuation phase
Kanamycin, ofloxacin/
levofloxacin, ethionamide,
cycloserine, pyrazinamide,
ethambutol
Ofloxacin/levofloxacin,
ethionamide, cycloserine ,
ethambutol

53. Tests to confirm MDR TB
• DST- Drug susceptibility test. Done in RNTCP
accredited laboratory. Long and Tedious
process.
• GeneXpert- Rapid test detecting
mutation.Results in 48hrs.
• CBNAAT- PCR technique.

54. Recent Article on MDR TB
• 30,000 patients detected with MDR TB every year in
mumbai.
• 288 patients registered with XDR TB since 2012.
• 6,701 patient registered with MDR since august 2010.
• The Private Provider Interface Agency(PPIA)initiated in
mumbai. Subsidy provided on the basis of chest X-Ray.

55. XDR TB- Extensively Drug Resistant Tb.
• Resistance to MDR + FQs as well as one of second line
injectable drugs
• Bacilli resistant to atleast 4 bateriocidal drugs.
• Rapid growth and fast mortality.
• Once detected standardised MDR regimen is stopped.
• Group 5 drugs with uncertain efficacy may be included
under supervision.
• Tests done- DST, GenXpert.

56. Total Drug Resistant TB- First case detected in South Africa in
April 2013 and was termed “virtually untreatable” by
“Centres For Disease Prevention And Control”.
It is resistant to all first line and second line drugs.
According to some studies even high doses of INH and
coamoxiclav (625mg/day) or clarithromycin (1000mg/day)
was not effective.
Bacilli in TDR has more thicker cell wall than MDR,they are
multiple branching and shows budding. Mechanism and
transfering of resistant genes is still under study.

57. TDR TB BACILLI

58. Recent Advances in TB.
• Bedaquiline- FDA approved on 28/12/2012.
Used in 24weeks treatment of MDRTB.
Renal Impairment seen.
Dose- 400mg with food OD for 2 weeks.
f/b- 200mg tds/week for 22 weeks.
• Delaminid- (OPC-67683)-Inhibits mycolic acid
synthesis.

59. On Going Clinical Trials
NC-03/Phase 3 (Early) NC-002/Phase 3
(Advanced)
ReMOXTB
JCPa- Bedaquilline
/Clofazimine/PA-824
PA-
824/Moxifloxacin/Pyrazina
mide.(PAMz)
HRZM-
Isoniazid/Rifampicin/Pyrazi
namide/Moxifloxacin.
JPaZ- Bedaquiline /
Pyrazinamide / PA-824
ERZM-
Ethambutol/Rifampicin/Pyr
azinamide/Moxifloxacin.
JCZPa- Bedaquiline /
Clofazimine /
Pyrazinamide / PA-824
JCZ- Bedaquiline /
Clofazimine / Pyrazinamide

60. Tuberculosis in pregnant women
• WHO and British Thoracic Society consider HRZE safe
to the foetus and standard regimen recommended
(2HRZE+4HR).
• In India pyrazinamide is not recommended and
2HRE+7HR for 9 months is recommended.
• Treatment should not be withheld or delayed
because of pregnancy.
• Streptomycin is contraindicated. It causes Ototoxicity
in foetus.

61. Treatment of Breast Feeding Women-
• All anti TB drugs are compatible with breast feeding and full
course should be given.
• Infant should receive BCG vaccine and 6 month Isoniazid
preventive treatment after ruling out active TB.

62. TB and HIV
• TB and HIV make a lethal
Combination.
TB is the most common opportunistic infection in
HIV .
Epidemiological Impact-a) Reactivation of latent
infection.
b) Primary Infection
c) Recurring Infection
d) In the community.

63. • Extra pulmonary symptoms are more common.(CD4
count < 150 cells/microltr).
• Treatment regime-2HRZE+ (4-7)HR/(HRE).
• Drug Interactions- 1)Rifampicin + NNRTIs.(Rifabutin
prescribed as alternative/Dose alteration)
2) Rifampicin with NRTI.(No dose alteration required)
3) If 2NRTIs + NNRTI used then Effaverenz is selected.
• MDR TB in HIV treatment is same as Non HIV.

64. Diagnosis of TB in HIV patients-
• Diagnosis is difficult in
advanced HIV.
• Higher frequency of –ve sm
• Failure of Tuberculin Test.
• Chest X-ray less cavitation.
Recommendations- Sputum smear microscopy.
Sputum culture.

65. According to some studies in HIV and TB co-infection
when CD4 counts are <200 then less cavitations and
atypical shadows are seen.
Pulmonary TB HIV+TB co-infection

66. Sputum smear
microscopy
+ ve - ve
Sputum culture
But Suspect of
TB
- ve + ve
But signs of TB
TB treatment

67. CHILDHOOD TUBERCULOSIS
• Cases mostly 10-20%
• Mainly due to failure of treatment in adults.
• Most common age group-1-4yrs.
• Diagnosis difficult.
• Gastric lavage/BAL(Bronchioalveolar lavage)
used for microscopy when sputum not
avalaible.

68. Dosage chart
Drugs Therapy per dose (Thrice a week)
1) Isoniazid
2) Rifampicin
3) Pyrazinamide
4) Streptomycin
5) Ethambutol
10-15mg/kg
10mg/kg
35mg/kg
15mg/kg
30mg/kg

69. Sm + ve
contact
Symptoms + Symptoms -
Montoux not
available
Montoux
available
Preventive
chemophrophylaxis
INH/5mg/kg/daily
INH 3months
Tuberculin test
<6mm
Stop chemo, BCG
vaccine
>6mm,
Continue INH fr
3 months
Full course CAT1

70. New TB Vaccine
• Developed by McMaster University.
• McMaster vaccine is an additional boost to
BCG Vaccine.
• Clinical Trial done in 2009 on 24 Human
Volunteers.
• 2012 approved of safety and efficacy.
• It is a part of Global TB vaccine initiative.

71. THANK YOU