PH1.44 Describe the first line antitubercular dugs, their mechanisms of action, side effects and doses. PH1.45 Describe the dugs used in MDR and XDR Tuberculosis

1. PH1.44 Describe the first line antitubercular dugs,
their mechanisms of action, side effects and doses.
PH1.45 Describe the dugs used in MDR and XDR
Tuberculosis
Dr Pankaj Kumar Gupta,
Assistant Professor,
Department of Pharmacology,
ESIC Medical College & hospital, Faridabad

2. What is Tuberculosis?

3. What is Tuberculosis?
Tuberculosis (TB) is an infectious
disease caused by the bacterium
Mycobacterium tuberculosis
(MTB)
Tuberculosis generally affects the
lungs, but can also affect other
parts of the body
One patient with infectious
pulmonary TB if untreated can
infect 10-15 persons in a year

4. Risk factors
o Malnutrition
o Diabetes
o HIV infection
o Low body weight
o Severe kidney disease
o Other lung diseases (silicosis)
o Substance abuse etc.
o Overcrowding
o Inadequate ventilation
o Enclosed living/working
conditions
o Occupational risks
Environmental
Medical

5. Epidemiology

6. • Chronic granulomatous disease
• Major health problem (developing countries)
• 1/3rd of world’s population infected with myco. Tuberculosis
• 9.4 million active TB cases globally (2.3 million cases – India –
highest contributor)-WHO-2010
• G.O.I 2012 declared TB – Notifiable disease

7. 7
40 crore infected
35 lakh estimated
TB patients annually
4.2 lakh deaths
Due to TB annually
In India…….

8. The TBthreat is REAL in India
28 Lakh
people fell ill from
TB
4.2 Lakh
people died from
TB
1.4 Lakh
people had drug-
resistant TB
Missing
million TB
patients
1 patient
dies every
minute
Less than
50% treated
successfully
WHO Global TB Report 2017

9. MDR-TB
• DR-TB has a rapid course, with worse outcomes
• In India-MDR-TB constitutes:
– 3% of all new TB-cases
– 17% of retreatment cases
• According to WHO global report (2015)- India has the
HIGHEST NUMBER of MDR-TB cases (Approx. 71,000 cases
annually)
• In 2015, WHO estimated 480,000 incident multidrug resistant
TB (MDR-TB; resistance of both isoniazid and rifampin) cases
globally.
World Health Organization. The Global Tuberculosis Report: 2016. Geneva,Switzerland: WHO, 2016. Available at
http://www.who.int/tb/publications/global_report/ en/. Last accessed 2019, January 23.

10. National Programme for TB

11. Health Programme
SN Year Programme Highlights
1 1962 National Tuberculosis Control Programme
was launched
•To control TB
2 1993 Revised National Control Programme was
launched (RNTCP)
•To implement WHO recommendations
3 1995 Short Course Chemotherapy under DOTS
programme introduced by WHO
•Introduction of 6-8 months multidrug
‘short course’ regimens
4 1997 RNTCP guidelines for treatment came into
existence
•Categorization of patients
•DOTS programme was launched in
India
5 2006 ‘STOP TB Strategy’ launched by WHO •MDR-TB was taken into account
6 2010 New WHO guideline with revised
categorization of patients
•New case OR Previously treated
•Drug resistant TB
7 2012 National Strategic Plan for Tuberculosis
Control 2012-2017
•TB was made ‘Notifiable Disease’
8 2016 ‘End TB Strategy’ launched by WHO •To eliminate TB from globe till 2030
9 2016 Revised RNTCP guidelines •Drug sensitivity testing introduced
https://www.nhp.gov.in/revised-national-tuberculosis-control-programme_pg
https://apps.who.int/iris/bitstream/handle/10665/44408/9789241500159_eng.pdf;sequence=1

12. Goal of RNTCP
“To implement WHO guidelines for TB & DOTS
therapy strategy in Indian scenario”

13. Diagnosis of TB

14. Identification of TB suspects
• Signs & symptom –
– Persistent cough, usually
with expectoration
– Others – weight loss,
tiredness, fever with
evening rise, night
sweats, chest pain,
shortness of breath,
anorexia and
haemoptysis

15. Sites of
extra-pulmonary
tuberculosis

16. A Pulmonary TB suspect is defined as
• An individual having a cough of 2 weeks or more
• Contacts of smear positive TB pts having cough of
any duration
• Suspected/confirmed extra-pulmonary TB having
cough of any duration
• HIV pts having cough of any duration

17. Definitive Diagnosis
• Microbiological confirmation (demonstration of AFB
on smear/culture of sputum/bronchial
secretions/NAAT (Nucleic Acid Amplification Test)
• Radiological Confirmation (Chest X-ray)
• Clinical Confirmation (signs & symptoms)
• Drug Sensitivity Testing

18. Biology of Tubercular Infection

19. Biology of Tubercular Infection
• M. Tuberculosis is an aerobic organism
• Several subpopulations
– Rapidly growing with High bacillary load-
• In wall of cavitary lesion where O2 tension is high, PH is neutral
• Highly susceptible to H, lesser extent to R, E, S
– Slow growing-
• Intracellular (inside macrophages) & at inflamed sites where PH is low
• Susceptible to Z & H,R,E-less active, S-inactive
• Spurters
• In caseous material where O2 is low & PH is neutral
• Intermittent growth
• R is most active on this subpopulation.
• Dormant
• Few remain totally inactive for prolonged periods
• No ATT (except Bedaquiline) is active against them
• Continuous shifting of bacilli between these populations

20. Classification of TB Cases
(RNTCP Concept)

21. Case Categories
Category of Treatment Type of Patient Regimens
Category I •New sputum smear-positive
•Seriously ill new sputum smear negative
•Seriously ill new extra pulmonary
2H3R3Z3E3 + 4H3R3
Category II •Sputum smear-positive relapse
•Sputum smear-positive failure
•Sputum smear-positive treatment after
default others
2H3R3Z3E3S3 +
1H3R3Z3E3 +
5H3R3E3
Category III New Sputum smear- negative, not
seriously ill
2H3R3Z3 + 4H3R3
• As per RNTCP (1997)
•Under RNTCP 2010 guidelines , only two categories are distinguished
Category 1 – new pts who have not been exposed to anti-tubercular agents earlier
(previous category 1 as well as 3 cases)
Category 2 – old cases who have been exposed to anti-tubercular drugs earlier
(treatment defaulters and relapse cases)

22. TB Cases
SN TB Case Definition
1 Drug-sensitive TB •Bacilli are susceptible to all 5 first line ATT
2 Multidrug resistant TB (MDR-TB) •Bacilli are resistant to both R & H with or
without resistance to any other first line
ATT.
3 Rifampin resistant TB (RR-TB) •Bacilli are resistant to R but not to H with
or without resistant to other ATT
4 Mono-resistant TB •Bacilli are resistant to one first line ATT but
not to R
5 Poly-drug resistant TB (PDR-TB) •Bacilli are resistant to more than one first
line ATT but not to R & H
6 Extensive drug resistant TB (XDR-TB) •MDR-TB + one FQ resistance + one 2nd line
injectable ATT
• As per RNTCP (2016)

23. ATT (Anti-Tubercular Therapy)

24. ATT
• Antitubercular therapy are a class of drugs
used to treat tuberculosis (TB).

25. Classification of ATT (RNTCP Concept)
Adopted from: treatment of tuberculosis guidelines; WHO,
Fourth edition (2010) and RNTCP, DOTS-plus Guidelines 2010

26. According to clinical utility – Anti-TB drugs can
be divided into first line and second line
 First line drugs –
1. ISONIAZID (H)
2. RIFAMPIN (R)
3. PYRAZINAMIDE (Z)
4. ETHAMBUTOL (E)
5. STREPTOMYCIN (S)
 Second line drugs –
 OTHER ORAL DRUGS
 Ethionamide (Eto)
 Prothionamide (Pto)
 Cycloserine (Cs)
 Terizidone (Trd)
 Para-Amino salicylic acid (PAS)
 Rifabutin
 Thiacetazone (Thz)
 FLUOROQUINOLONES
 Ofloxacin (Ofx)
 Levofloxacin (Lvx)
 Moxifloxacin (Mfx)
 Ciprofloxacin (Cfx)
 INJECTABLE DRUGS –
 Kanamycin (Km)
 Amikacin (Am)
 Capreomycin(Cm)

27. Alternative grouping of Anti-tubercular drugs
reflecting hierarchy in efficacy/priority in use
Group Line of
treatment
Drug Names Features
GROUP 1 First line oral
anti-TB drugs
Isoniazid, Rifampin,
Pyrazinamide, Ethambutol
(RIPE)
•Most potent
•Best tolerated oral drugs
•Used routinely
GROUP 2 Injectable anti-TB
drugs
Streptomycin, Kanamycin,
Amikacin, Capreomycin (SACK)
Potent
Bactericidal
Injectable in nature
GROUP 3 Fluoroquinolones Ofloxacin, Levofloxacin,
Moxifloxacin, Ciprofloxacin
(CLOM)
•Well-tolerated
•Bactericidal
•Oral drugs
•According to RNTCP guidelines-all
patients with drug-resistant TB SHOULD
RECEIVE ONE FLUOROQUINOLONE
GROUP 4 Second line oral
anti-TB drugs
Ethionamide, Prothionamide,
Cycloserine, Terizidone, PAS,
Rifapentin, Rifabutin
(PP-RR-ECT)
Less-effective
Bacteriostatic
More toxic than 1st line oral agents
GROUP 5 Drugs with
unclear efficacy
Thiacetazone, Clarithromycin,
Clofazimine, Linezolid,
Amoxicillin/clavulanate,
Imipenem/cilastatin,
Bedaquiline(CCC-LIB)
Not recommended for MDR-TB
May be used as RESERVE DRUGS (in
XDR-TB)

28. Isoniazid (Isonicotinic acid hydrazide, H)
 Primarily tuberculocidal
 Fast multiplying are rapidly killed, but quiescent ones
are only inhibited
 Acts on extracellular as well as on intracellular TB
 Equally active in acidic or alkaline pH
 One of the cheapest anti-tubercular drugs

29. Mechanism of Action
Inhibition of synthesis of mycolic acids
 Two gene products labelled ‘InhA’ and ‘KasA’, which
function in mycolic acid synthesis are targets of INH
action
 INH enters sensitive mycobacteria which convert it
by a catalase-peroxidase enzyme into a reactive
metabolite
 then forms adduct with NAD that inhibits InhA and
KasA

30.  INH enters bacilli by passive diffusion
 Drug is not directly toxic to the bacillus but must be
activated to its toxic form within the bacillus by KatG
(multifunctionary, catalase –peroxidase)
 KatG catalyzes the production from INH of an
isoNicotinoyl radical that subsequently interacts with
mycobacterial NAD and NADP to produce a dozen
adducts

31.  A nicotinoyl-NAD isomer, inhibits the activities of
enoyl acyl carrier protein reductase (InhA) and β-
ketoacyl acyl carrier protein synthase (KasA)
 Inhibition of these enzymes inhibits synthesis of
mycolic acid -- bacterial cell death
 Another Adduct, a nicotinoyl-NADP isomer, potently
inhibits mycobacterial DHFRase, thereby interfering
with nucleic acid synthesis

33.  Other products of KatG activation of INH include
superoxide, H2O2, alkyl hydroperoxides and NO
radical may also contribute to INH bactericidal effect

34. Resistance of INH
 About 1 in 106 tubercle bacilli is inherently resistant
to clinically attained INH concentration
 If INH given alone, such bacteria will proliferate
selectively and after 2-3 months, an apparently
resistant infection appears
 M/C mechanism which confers HIGH level
resistance – mutation of KatG (single point mutations
in heme binding catalytic domain of KatG, serine to
asparagine change at position 315)
 INH resistance may also involve mutation in InhA
and KasA genes
 Resistance due to efflux is also possible

35.  Combined with other drugs, INH has good resistance
preventing action.
 No cross resistance with other anti-tubercular drugs
occurs
 Overexpression of of the genes for InhA – confers
low level resistance to INH and some cross-
resistance to ethionamide
 KatG 315 mutants have a high probability of co-
occurrence with ethambutol resistance
 Mutation in KatG, ahpC, and inhA have also been
associated with rpoB mutations

36. Absorption, Distribution and Excretion
 Bioavailability of oral isoniazid is ~ 100% for 300 mg
dose
 INH is completely absorbed orally and penetrates all
body tissues , tubercular cavities, placenta and meninges
 Extensively metabolized in liver
 Most important pathway being N-acetylation by NAT2
 Acetylation endproduct is excreted in urine
 Rate of acetylation shows genetic variation

37.  Fast acetylators (30 – 40% of indians)-T1/2 of INH 1
Hr
 Slow acetylators (60 – 70% of indians )-T1/2 of INH
3 Hr
 Acetylator status does not matter if INH is taken
daily, but biweekly regimes are less effective in fast
acetylators
 INH induced peripheral neuritis > common in slow
acetylators
 A hepatotoxic minor metabolite is produced by
CYP2E1 from acetylhydrazine

38. Interactions
 Aluminium hydroxide inhibits INH absorption
 INH retards phenytoin, carbamazepine, diazepam,
theophylline and warfarin metabolism by inhibiting
CYP2C19 and CYP3A4 (Metabolism Inhibitor)
 Since rifampin is an enzyme inducer, its concurrent
use counteracts the inhibitory effect of INH
 PAS inhibits INH metabolism and prolongs its T1/2

39. Adverse effects
 Well tolerated
 Peripheral neuritis and a variety of neurological manifestations
(paresthesias, numbness, mental disturbances, mental disturbances, rarely
convulsions) – dose dependent toxic effects
 Interference with the production of the active co-enzyme pyridoxal
phosphate from pyridoxine -- increased excretion in urine – pyridoxine
given prophylactically (10 mg/dl)
 INH neurotoxicity is treated by pyridoxine 100 mg/day
 Hepatotoxicity (rare in children), but more common in older people and in
alcoholics (chronic alcoholism induces CYP2E1 – generates the hepatotoxic
metabolite)
 Others – lethargy, rashes, fever, acne and arthralgia

40. Rifampin (Rifampicin, R)
 Semisynthetic derivative of Rifamycin B obtained from streptomyces
mediterranei
 Bactericidal to M. Tuberculosis and many other gram(+) and gram (-)
bacteria like staph.aureus , N.meningitidis, H.influenza,
E.coli,Kleibsella , Pseudomonas,Proteus and legionella
 Against TB bacilli, it is as efficacious as INH and better than all other
drugs
 Bactericidal actions covers all subpopulations of TB bacilli, but acts
best on slowly or intermittenly dividing ones (spurters)
 Both extra and intracellular organisms are affected
 Good sterilizing and resistance preventing actions

41. Mechanism of action
 Interrupts RNA synthesis by binding to β subunit of
mycobacterial DNA dependent RNA polymerase
(encoded by rpoB gene )

42. RESISTANCE
 Prevalence of rifampin-resistant isolates are 1 in every
107 to 10 8 bacilli
 Rifampin resistance is nearly always due to mutation in
the rpoB gene reducing its affinity for the drug
(In 86% cases due to mutations at codons 526 and 531 of rpoB
gene)
 No cross resistance with any other anti-tubercular drug,
except rifampin congeners
 Rifampin monoresistance occurs at a higher rates when
pts with AIDS and multi-cavitary TB are treated with
either rifapentine or rifabutine

43. Pharmacokinetics
 Well absorbed orally
 Bioavailability ~70%, food decreases absorption
 Rifampin is to be taken in empty stomach
 Widely distributed in the body;
 Penetrates intracellularly, enters tubercular cavities,
caseous masses and placenta
 It crosses meninges, largely pumped out of CNS by P–
glycoprotein
 Metabolized in liver – active deacetylated metabolite –
excreted mainly in Bile , some in urine
 Rifampin and its deacetylated metabolite undergoes
enterohepatic circulation
 T1/2 – 2-5 hrs

44. Interactions
 Rifampicin is a microsomal enzyme inducer – increases
several CYP450 isoenzymes – CYP3A4 , CYP2D6, CYP1A2 ,
CYP2C subfamily
 Enhances its own metabolism (area under the plasma
concentration-time curve is reduced by ~ 35%) as well as that
of many drugs including warfarin, oral contraceptives,
corticosteroids, sulfonylureas, corticosteroids, HIV protease
inhibitors, NNRTIs, theophylline, metoprolol, fluconazole,
ketoconazole, clarithromycin, phenytoin etc.
 Contraceptives failure have occurred – advisable to switch
over to an OCP containing higher dose ( 50 µg ) of estrogen or
alternative method of contraception

45. Adverse effects
 Incidence of adverse effects is similar to INH
 Hepatitis, a major adverse effect, generally occurs
in pts with pre-existing liver disease and is dose
related
 Jaundice – discontinuation of drug – reversible
 Minors reactions, not requiring drug withdrawal and
more common with intermittent regimes
 Cutaneous syndrome
 Flu syndrome
 Abdominal syndrome
 Urine and secretions may become orange-red but
this is harmless

46. Other uses of rifampin
1. Leprosy
2. Prophylaxis of Meningococcal and H. influenza
meningitis and carrier state
3. Second/third choice drug for MRSA, Diptheroids
and legionella infections
4. Combination of doxycycline and rifampin is first line
therapy of brucellosis

47. Pyrazinamide (Z)
 Chemically similar to INH – Pyrazinamide was
developed parallel to it (1952)
 Weakly tuberculocidal
 More active in acidic medium and slowly replicating
bacteria
 More lethal to intracellular bacilli and at sites
showing inflammatory response
 Highly effective during the first 2 months of therapy
when inflammatory changes are present
 Inclusion enabled duration of treatment to be
shortened and risk of relapse to be reduced

48.  M.O.A – not well established
 Similar to INH – converted inside mycobacterial into
active metabolite pyrazinoic acid by pyrazinamidase
encoded by pncA gene
 Gets accumulated in acidic medium and probably
inhibits mycolic acid synthesis, but by interacting
with a different fatty acid synthase
 Pyrazinoic acid also appears to disrupt
mycobacterial cell membrane and its transport
function
 Resistance to Z develops rapidly if it is used alone,
and is mostly due to mutation in the pncA gene

49. Pharmacokinetics & ADRs
 Absorbed orally
 Widely distributed, good penetration in CSF
 Extensively metabolized in liver and excreted in
urine
 Plasma T1/2 ~ 6 hrs
 Adverse effects –
1. Hepatotoxicity
2. Hyperuricaemia
3. Others – abdominal distress
non-gouty arthralgia
fever

50. Ethambutol (E)
 Selectively Tuberculostatic
 Active against MAC as well as some other
mycobacteria
 Fast multiplying bacilli – more susceptible
 Added to triple regime of RHZ – hastens the rate of
sputum conversion and prevents development of
resistance
M.O.A
 Inhibits arabinosyl transferases (encoded by embAB
genes) involved in arbinogalactan synthesis
interfering mycolic acid incorporation in
mycobacterial cell wall

51.  Resistance to E develops slowly
 Most commonly associated with mutation in embB
gene,
 About 3/4th of oral dose is absorbed
 Distributed widely, but penetrates meninges
incompletely and is temporarily stored in RBCs
 Excreted in urine by GFR and tubular secretion
 Plasma T1/2 ~ 4 hrs

52. ADVERSE EFFECTS
1. Dose dependent and reversible visual disturbances
like Optic Neuritis - reduced visual acuity, central
scotoma and loss of ability to see Green, less
commonly Red - ? Due to its effect on Amacrine
and bipolar cells of retina.
2. Hyperuricemia
3. Peripheral neuritis

53. Streptomycin
 First clinically useful anti-TB drug
 Tuberculocidal but less effective than INH or rifampin
 Acts only on extracellular bacilli – poor penetration
 Penterates tubercular cavities, but does not cross to
CSF
 Poor action in acidic medium
 Not absorbed orally, must be administerd by IM inj.
 T1/2 is prolonged in renal failure
 NOT HEPATOTOXIC
 Use restricted to max. of 2 months- labelled as
‘supplemental’ 1st line drug

54. Daily Dose of First line ATT
based on WHO guideline 2010, body weight basis
Drugs Daily Dose
(mg/kg)
Daily Dose (Total)
INH 5 300
Rifampin 10 600
Pyrazinamide 25 1500
Etambutol 15 900
Streptomycin 15 900
PLEASE NOTE: If patient’s age > 50 years -maximum dose of streptomycin will be 0.75
g/day

55. Other drugs
 Thiacetazone – tuberculostatic
 Major A/E – hepatitis, bone marrow suppression and steven
johnson syndrome (not used in HIV pts due to risk of severe
hypersensitivity reactions including exfoliative dermatitis).
 PAS related to sulfonamides, acts by similar mechanism
–bacteriostatic.
 Ethionamide/prothionamide – tuberculostatic
 Major A/E–hepatitis, optic neuritis and hypothyroidism , can
also be used in leprosy.
 Cycloserine is a cell wall synthesis inhibiting drug
 neuropsychiatric adverse effects.

56.  Kanamycin and Amikacin are injectable
aminoglycosides
 used in treatment of MDR TB
 Capreomycin – injectable polypeptide
 Major A/E- ototoxicity, nephrotoxicity, hypokalemia and
hypomagnesemia
 FQs – Ofloxacin, Moxifloxacin and Levofloxacin
 effective against MAC in AIDS patients
 Newer macrolides like Azithromycin and
Clarithromycin
 against non-tubercular atypical mycobacteria

57.  Rifabutin
 more effective than Rifampicin against MAC,
 longer T1/2 ~ 45 hrs,
 less potential than rifampicin to induce microsomal
enzymes and thus, preferred in pts on anti-HIV drugs
(protease inhibitors or NNRTIs mainly nevirapine)
 Commonly causes – GI discomfort, Anterior Uveitis,
Hepatitis, clostridium associated diarrhoea, diffuse
polymyalgia syndrome, yellow skin discoloration.
 Rifapentine
 Similar to Rifampicin but more lipophillic and longer
acting.
 Not approved for adm. to HIV pts because of higher rate
of relapse

58. DELAMANID
 Drug class: “Nitroimidazole”
 Mechanism of action:
 Delamanid shows bactericidal effects in 2 ways:
 Drug blocks mycolic acid synthesis - prevents bacteria from creating
building blocks important for cell-walls
 Drug half-life: 36 hours
 One of the 2 drugs (other one being Bedaquiline) developed for
treatment of MDR & XDR-TB
 First approved by EMA in November 2014
 Indicated to be used
 As part of an appropriate combination regimen for Pulmonary MDR-TB, in
adults, adolescents, children and infants with a body weight of at least 10
kg when an effective treatment regimen cannot otherwise be composed
for reasons of resistance or tolerability.

59. Goals of ATT

60. Goals of ATT
Goals Rational Drugs
1 Kill dividing
bacilli
•Drugs with early bactericidal action rapidly
reduce bacillary load
•Achieve quick sputum conversion
•Makes patient non-contagious & provide quick
symptom relief.
•H & R
•S
2 Kill persisting
bacilli
•To effect cure (to sterilize patient)
•To prevent relapse
•Z
3 Prevent
emergence of
resistance
•To keep bacilli susceptible to the drugs •E

61. General Principles of ATT

62. General Principles of ATT
• Use of any single drug results in emergence of resistance & relapse in ¾
of cases.
– Combination of 2 or more must be used.
– Incidence of resistant bacilli is 10-8 to 10-6.
• H & R are most efficacious drugs and their combination is synergistic
– Duration of therapy is shortened form >12 to 9 months due to HR combination
– Addition of Z in initial 2 months reduces duration to 6 months.
• A single daily dose of all first line drugs is preferred.
• Response is fast in first few weeks as the fast dividing bacilli are
eliminated rapidly.
– Rate of improvement declines subsequently as slow multiplying organisms
respond gradually.
– Adequacy of any regimen is assessed by sputum smear/culture conversion
rates & 2-5 year relapse rates after completion of treatment.

63. ATT Regimens
Phase Duration No. of drugs Treatment Objective
1 Intensive
Phase (IP)
2-3 months (6-12
months in case of
resistance)
4-6 drugs •To rapidly kill bacilli
•Bring sputum conversion
•Fast symptomatic relief
2 Continuous
Phase (CP)
4-6 months (6-18
months in case of
resistance)
3-4 drugs •Remaining bacilli are
eliminated
•To prevent relapse

64. Difference of RNTCP Regimens between new &
previous guidelines
Old New
1 Intermittent Regimen Daily Regimen
2 Ethambutol in CP of category II
regimen only
Ethambutol in CP of both category I & II
regimen
3 No fixed dose, limited weight band FDCs as per weight band
4 Extension of IP for 1 month if
sputum is positive at the end of IP
No need of extension of IP
5 Follow up- Laboratory only Follow up- clinical, Laboratory both
6 No long-term follow-up Long term follow-up up to 2 years

65. Management of drug-sensitive TB

66. Treatment regimens for drug sensitive pulmonary TB
• Usually treated by 1st line ATDs
• Drug-sensitive TB includes 2 types:
A. Newly-treated patients: -
• Treatment involves:
– 2 months of HRZE (Intensive phase) + 4 months of HRE (Continuation phase)
– Total duration: 6 months
B. Previously-treated patients: -
• Treatment involves:
– [2 months of HRZES + 1 month of HRZE](Intensive phase) + 5 months of
HRE(Continuation phase)
– Total duration: 8 months.

67. Treatment regimens for drug sensitive pulmonary TB
Type of Patient Intensive Phase Continuation Phase Total Duration
New 2 months of HRZE 4 months of HRE 6 months
Previously-treated
Patients
2 months of HRZES
+ 1 month of HRZE
5 months of HRE 8 months

68. Management of MDR-TB

69. MDR-TB
• MDR-TB has a rapid course, with worse outcomes.
• Treatment involves complex multiple 2nd line drug
regimens, which confer the following demerits:
– Longer treatment duration
– Expensive
– High risk of toxicity

70. General principles of MDR-TB management
• Include 4 effective drugs in regimen (6 drugs can also be included,
provided efficacy regarding any of them is uncertain; back-up!)
• Avoid usage of cross-resistance drugs, chiefly: -
– 2 FQs
– Kanamycin with Amikacin
– Ethionamide with prothionamide
– Cycloserine with terizidone
– Ethionamide with INH (low-level resistance)
• When selecting drugs for treatment, select in a hierarchical order,
for example:
– 2 Group I drugs (Z, E) + one injectable drug (Group II) + One FQ (Group III) + 2
Group IV drugs

71. • Standard RNTCP regimen for MDR-TB consists of:
– 6 drugs in “intensive phase” (for 6-9 months)
– 4 drugs in “continuation phase” (for 18 months)
• Minimal 6 month of intensive phase can be extended by 1
month each time (to a total maximum of 9 months) provided,
sputum culture at 4th, 5th & 6th months of intensive phase
turns out to be positive.
• Pyridoxine (at dose of 100 mg/day) should be given to all
patients during therapy to avoid precipitation of neurotoxicity
(attributed to ATT)

72. Standard RNTCP Regimen for MDR-TB
Intensive Phase (6-9 months) Continuation Phase (18 months)
Pyrazinamide Ethambutol
Ethambutol Levofloxacine
Kanamycin Ethionamide
Levofloxacin Cycloserine
Ethionamide
Cycloserine
2 Group I drugs (Z, E) + one injectable drug (Group II) + One FQ (Group III) +
2 Group IV drugs
Pyridoxine 100 mg/day to be added to above regimen

73. Management of Rifampin-Resistant TB

74. Standard RNTCP Regimen for RR-TB
• RR-TB is treated as MDR-TB (WHO & RNTCP 2016)
• Since patients with RR-TB are sensitive to INH so INH is to be added to
‘Intensive Phase’
• RNTCP Regimen for RR-TB includes-
Intensive Phase (6-9 months) Continuation Phase (18 months)
INH INH
Pyrazinamide Ethambutol
Ethambutol Levofloxacine
Kanamycin Ethionamide
Levofloxacin Cycloserine
Ethionamide
Cycloserine
Pyridoxine 100 mg/day to be added to above regimen

75. Management of Mono-drug Resistant TB

76. Standard RNTCP Regimen for Mono-
drug Resistant TB
Intensive Phase (3-6 months) Continuation Phase (6 months)
Rifampin + two of first line drugs
(sensitive to bacilli) + One Injectable 2nd
line drug + 1 FQ
(Total 5 drugs for 3-6 months)
•Stop Injectable drug
•Continue with remaining 4 drugs for 6
months
Pyridoxine 100 mg/day to be added to above regimen

77. Management of Poly-drug Resistant TB

78. Standard RNTCP Regimen for Poly-
drug Resistant TB
Intensive Phase (3-6 months) Continuation Phase (6 months)
Rifampin + One any first line drug
(sensitive to bacilli) + One Injectable 2nd
line drug + 1 FQ + One of oral 2nd line
drugs
(Total 5 drugs for 3-6 months)
•Stop Injectable drug
•Continue with remaining 4 drugs for 6
months
Pyridoxine 100 mg/day to be added to above regimen

79. Management of INH Resistant TB

80. • In order to strategize treatment for INH-resistant TB, firstly an insight into
mechanisms of INH-resistance is important
• INH resistance can occur in 2 ways:
A. LOW-LEVEL INH RESISTANCE:
• inhA gene- plays role in activity of NAD-dependent enoyl-acyl carrier
protein reductase
• In low-level INH resistance-mutation occurs in the inhA gene
• In such situations:
– Focus on using HIGH DOSE OF INH (900 mg/day, for average body weight of
46-70 kg)
– Add pyridoxine to treatment regimen
– Monitor for potential neurotoxicity
– Avoid concurrent usage of Ethionamide (since it won’t be effective in low-level
INH resistance)

81. B. HIGH-LEVEL INH RESISTANCE:
• KatG gene- encodes for enzyme catalase peroxidase-helps in conversion of
INH to its active metabolite-shows antitubercular activity
• In high-level INH resistance-mutation in KatG gene occurs-conversion
doesn’t occur-drug is rendered ineffective!
• In such situations:
– Avoid usage of INH
– Ethionamide may be used (Since Ethionamide is effective in patients with
high-level INH resistance)

82. Management of Extensive Drug Resistant
TB (XDR-TB)

83. XDR-TB
• Extremely difficult to treat, necessitating use of Group-V drugs
• To prevent further progression of resistance- stop standard
MDR-regimen immediately
• Since Group-V drugs are both costly & toxic- an expert clinical
panel may decide on appropriate drug selection
• According to RNTCP(2016) guidelines:
– 7 drugs should be used in intensive phase(6-12 months)
– 6 drugs should be used in continuous phase(18 months)

84. Standard RNTCP Regimen for XDR-TB
Intensive Phase (6-12 months) Continuation Phase (18 months)
Capreomycin (1000 mg) Moxifloxacin (400 mg)
Moxifloxacin (400 mg) INH high dose (900 mg)
INH high dose (900 mg) PAS (12 g)
PAS (12 g) Clofazimine (200 mg)
Clofazimine (200 mg) Linezolid (600 mg)
Linezolid (600 mg) Amoxicillin-clavulanate (875+125 mg);
2 tabs in morning + 1 tab in evening
Amoxicillin-clavulanate (875 + 125
mg); 2 tabs in morning + 1 tab in
evening
Pyridoxine 100 mg/day to be added to above regimen

85. Tuberculosis in Pregnant Women
• H,R,E and Z safe to the foetus and recommends the standard
6 month (2HRZE + 4HRE)- WHO and British Thoracic Society
• S is C/I - ototoxic
In India, as per RNTCP (2016)
• Full course of TB treatment as in non-pregnant
• Treatment of TB should not be withheld or delayed because of
pregnancy.
• All pregnant women treated with INH should receive
Pyridoxine 10-25 mg/day.

86. Role of Corticosteroids
• TB is a relative C/I for use of glucocorticoids.
• In certain situations, Glucocorticoids may be used under the
cover of effective Anti-TB therapy –
1. Tuberculosis of serous membranes like pleura, pericardium, meninges etc. to
prevent fibrous tissue formation and its sequelae
2. Tuberculosis of the eye, larynx, genitourinary tract to prevent fibrosis and
scar tissue formation
3. In AIDS patients with severe manifestations of TB
4. To treat hypersensitvity reactions to anti-tubercular drugs
• Prednisolone is a preferred agent except in meningitis
(dexamethasone is preferred)
• Steroids C/I in intestinal TB – risk of perforation

87. Atypical Mycobacterial Infections
MAC (Mycobacterium Avium Complex)
• An opportunistic infection in HIV patients (develops when CD4 <50
cells/µl, viral load is high, other opportunistic infections are +nt)
• Disseminated & multifocal disease in HIV patients
Prophylaxis
• Objective- protecting the AIDs pts from developing active MAC
disease during the period CD4 <75 cells/ µl
• A single drug (Azithromycin 1200 mg/week OR Clarithromycin 500
mg twice daily)
Treatment
• Treatment of MAC requires REC regimen (Rifabutin + Ethambutol +
Clarithromycin/Azithromycin)

88. Treatment Regimen of MAC infection
Intensive phase
1. Clarithromycin 500 mg BD or Azithromycin 500 mg OD
2. Ethambutol 1000 mg/day (15 mg/kg) depends on
3. Rifabutin 300 mg/day the response
± till CD4 >100
Ciprofloxacin 500 mg BD and sympt relief
or Levofloxacin 500 mg OD (2- 6 months)
or Moxifloxacin 400 mg OD
Maintenance phase
1. Clarithromycin /azithromycin
2. Ethambutol /Rifabutin / 1 FQ doses – same min 12 mths

89. Thanks