Tuberculosis Pharmacotherapy (1)

Antitubercular Agents
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• Tuberculosis is a chronic granulomatous
disease
• In developing countries it is a major
health problem
• ≈ 30% of world population is infected
with Myc. Tuberculosis infection
• In India > 2 million people develop active
disease every year & half million die.
Tuberculosis
Mycobacterium tuberculosis
It is an infection difficult to
treat ??
Typical growth characteristics
Peculiar cell wall structure

(waxy appearance ) due to mycolic acid.
Resistance to infection emerges quickly.

Antitubercular Drugs
Mycobacterium Infections
Common infection sites
• Lung (primary site) - Intestines
• Brain - Lymph nodes
• Bone
• Liver
• Kidney
• Aerobic bacillus
• Passed from infected:
– Humans
– Cows (bovine) and birds (avian)
• Much less common
Mycobacterium Infections
• Tubercle bacilli are conveyed by droplets
• Droplets are expelled by coughing or sneezing,

then gain entry into the body by inhalation
• Tubercle bacilli then spread to other body organs

via blood and lymphatic systems
• Tubercle bacilli may become dormant, or walled

off by calcified or fibrous tissue
Tuberculosis - Pathophysiology
• M. tuberculosis – gram-positive, acid-fast
bacillus
• Spread from person to person via airborne

droplets
– Coughing, sneezing, speaking – disperse organism
and can be inhaled
– Not highly infectious – requires close, frequent, and
prolonged exposure
– Cannot be spread by hands, books, glasses,
dishes, or other fomites
Tuberculosis – Clinical Manifestations
• Early stages – free of symptoms
– Many cases are found incidentally
• Systemic manifestations:
– Fatigue, malaise, anorexia, weight loss, low-grade fevers, night
sweats
– Weight loss – occurs late
– Characteristic cough – frequent & produces mucoid or
mucopurulent sputum
– Dull or tight chest pain
• Some cases: acute high fever, chills, general flulike
symptoms, pleuritic pain, productive cough
• HIV Pt with TB: Fever, cough, weight loss –
– Pneumocystic carinii pneumonia (PCP)
Tuberculosis – Diagnostic Studies
• Tuberculin Skin Testing -- + reaction 2-12 weeks after the
initial infection
– PPD – Purified protein derivative – used to detect delayed
hypersensitivity response
• Two-step testing – health care workers
• 5mm > induration – Immunosuppressed patients
• 10 mm> “at risk” populations & health care workers
• 15 mm> Low risk people
– Chest X-ray -- used in conjunction with skin testing
• Multinodular lymph node involvement with cavitation in the upper
lobes of the lungs
• Calcification – within several years after infection
– Bacteriologic Studies –
• Sputum, gastric washings –early morning specimens for acid-fast
bacillus -- three consecutive cultures on different days
• CSF or pus from an abscess
M. tuberculosis: peculiar
features
• Rapid growers: In the wall of cavitary lesion,
extracellular.
• Slow growers: intracellular, within the
macrophages at inflamed sites.
• Spurters: intermittent growth spurts.
• Dormant: Do not grow for long time, become
active at times of low host resistance.
Bacilli continuously shift from one to other subpopulation.

Mycobacterial cell wall
Baron S (ed.) Medical Microbiology. 4th edition. Chapter 33

Chemotherapy in tuberculosis
• Goals of anti-tubercular chemotherapy
• Kill dividing bacilli: Patient is non-
contagious : transmission of TB is
interrupted.
• Kill persisting bacilli: To effect cure and
prevent relapse.
• Prevent emergence of resistance: so
that the bacilli remain susceptible to the
drugs.
• Now there is emergence of multidrug
resistant ( MDR ) TB . More than 0.4
million cases globally .
History
• First successful drug for treating TB was
PAS (Para- aminosalicylic acid) developed
by Lehman in 1943.
• Dramatic success came when Waksman
& Schutz discovered Streptomycin which

has made remarkable progress.
• Followed by Thiacetazone by Domagk in
in 1946
• In 1952 Isoniazid came into being
• Pyrazinamide by Kushner & colleagues
in 1952 & later on Rifampicin in 1957
by S. Margalith has totally changed the
strategy in the chemotherapy.
• Ethambutol came in 1961 by Lederle -
laboratories
• Fluoroquinolones , newer macrolides &
congener of Rifampicin →Rifabutin are
recent addition in antimycobacterial drugs
First line drugs:
Ionized ( H)
Rifampicin (R)
Ethambutol (E)
Pyrazinamide ( Z)
Streptomycin ( S) now reserved drug in
first line
Second line drugs:
Thiacetazone
Para aminosalicylic acid (PAS)
Ethionamide ( Etm)
Kanamycin
Cycloserine
Amikacin
Capreomycin
Newer Second Line drugs:
Ciprofloxacin
Ofloxacin
Levofloxacin
Clarithromycin
Azithromycin
Rifabutin
Drugs used in Tuberculosis
1st line drugs 2nd line drugs

high efficacy, low toxicity Low efficacy, high toxicity or both
• Isoniazid (INH) • Ethionamide

• Rifampin • Para aminosalicylic acid
• Pyrazinamide • Cycloserine
• Ethambutol • Amikacin/ Capreomycin
• Fluoroquinolones
• Streptomycin
• Rifabutin
Isoniazid (Isonicotinic acid hydrazide,H):
Essential component of all anti TB regimen
(except intolerance to H or resistance)
-It is tuberculocidal , kills fast multiplying
organism & inhibit slow acting organism
-Acts both on intracellular ( present in
macrophages ) & extracellular bacilli
-It is the cheapest AT Agent
-Atypical mycobacteria are not inhibited by
INH.
Not active against any other micro-orgs.
Mechanism of Action :
Inhibit synthesis of mycolic acid ( unique
fatty acid component of mycobacterial cell
wall .)
-INH enters the bacilli by passive diffusion. It
must be activated to become toxic to bacilli.
It became toxic by Kat G (multifunctional
Catalase - peroxidase , a bacterial enzyme )
which catalyzes the product from INH an
Isonicotinoyl radical that subsequently
inter-acts with mycobacterial NAD & NADP
to produce dozen of adducts , one of these
a nicotinoyl NAD isomer which ↓ the activity
of enoyl acyl carrier protein reductase
(Inh A) & β- ketoacyl carrier protein
synthase ( Kas A) , inhibition of these
enzymes↓ the synthesis of mycolic acid an
essential component of the mycobacterial
cell wall & causes cell death.
MOA of 1st line drugs
Isoniazid
Ethambutol
-
Mycolic Acid
-
Arabinogalactan
Peptidoglycan
Cell membrane
- Mitochondria
(ATP)
Rifampin
Pyrazinamide -
- Streptomycin
Cytoplasm
-
R
I Protein
B
O
S
O
M
e
(another adduct , a nicotinoyl –NADP isomer potentially mycobacterial

dihydrofolate reductase → interfere with nucleic acid synthesis .
These adducts also produce H2O2 , NO radical & other free radicals
which are toxic to bacilli )
- If INH is given alone , inherent resistant bacilli

proliferate selectively & after 2-3 months an
apparently resistant infection emerges .
(Mutation of the catalase –peroxidase gene in bacilli do
not generate the active metabolite of INH )
- Combination therapy with INH has good
resistance preventing action .
- There is no cross resistance .
Pharmacokinetics :
-Completely absorbed orally , penetrate all
body tissues, tubercular cavities , placenta
& meninges .
- Metabolized in liver by acetylation &
metabolites are excreted in urine .
- Rate of acetylation shows genetic variation
( fast acetylators > 30% Indians - t½ -1 hr
Slow acetylators >60% Indians -t ½- 3 hrs)
(daily regimen is not affected but biweekly
regimens are less effective in fast
acetylators )
Dose – 4-6 mg/ kg for >50 kg – 300 mg daily
- 600 mg bi-wkly
ISONIAZID (INH):
Pharmacokinetics
INH
Acetylation
(Phase II) N-acetyl transferase
N-acetyl Isoniazid
Hydrolysis
(Phase I) Isonicotinic acid Acetyl hydrazine
Genetic polymorphism affects INH metabolism

Slow acetylators are at higher risk of developing neuritis
ADRs -
Well tolerated drug
1.Peripheral neuritis & other neurological
manifestations- parasthesia , numbness,
mental disorientation & rarely convulsion
( due to interference with utilization of
pyridoxine & ↑ excretion in urine )
Due to this Pyridoxine given prophylactically
-10 mg/day which prevents neurotoxicities
(INH neurotoxicity treated with Pyridoxine-100 mg/ day )
2. Hepatitis – more common in older
patients & alcohlics ( reversible)
3. Rashes , fever , acne & arthralgia .
Rifampin ( Rifampicin , R ):
-Semisynthetic derivative of Rifamycin B
from Streptomyces mediterranei
-Bactericidal to M. Tuberculosis & others –
S. aureus Klebsiella
N. meningitidis Pseudomonas
H. influenzae Proteus
E. coli & Legionella
- Best action on slowly or intermittently
dividing bacilli on extracellular as well
as intracellular organisms
-Also act on many atypical mycobacteria
-Have good resistance preventing action
Mechanism:
Inhibit DNA dependant RNA Synthesis
(by ↓ bact RNA polymerase , selective because does not
↓ mammalian RNA polymerase )
- TB patient usually do not get primary
Rifampicin resistance – If occurs is due to
mutation in the repo -B gene (β subunit of
RNA polymerase ).
- No cross resistance
PKT –
Well absorbed orally widely distributed in the
body , penetrate cavities , caseous mass,
placenta & meninges .
-Metabolized in liver
-Excreted mainly in bile & some in urine
-t½- 2-5 hrs
ADR’s
1. Hepatitis – mainly in pts having
preexisting liver disease & is dose
related- Jaundice req. stoppage of drug
2. Respiratory syndrome –breathlessness
shock & collapse .
3. Purpura , hemolysis , shock , renal failure
4. Cutaneous syndrome – flushing , pruritis
& rashes ( face & scalp ), redness &
watering of eyes.
5. Flue syndrome – Nausea , vomiting,
abdominal cramps
( Urine & secretions may become red – which are
harmless & Pt should be told about this effect)
D/I
Rifampicin is microsomal enzyme inducer
-↑ several CYP 450 isoezymes
-↑ its own metabolism as well as of others
e.g.-Oral contraceptive Digoxin
Warfarin Theophylline
Steroids Metoprolol
Sulphonyl urea Fluconazole & Ketoconazole
etc.
(contraceptive failure can occur if given
simultaneously in child bearing age women taking
oral contraceptive)
Other uses –1. Atypical myc. Inf. (M. kansasii,
marinum , avium & intracellulare )
2. Leprosy
3. Prophylaxis of meningococcal & H. infl.
meningitis
4. MRSA , Diphtheroids & legionella inf.
5. Along with Doxycycline –first line therapy
in Brucellosis
Dose- 10 mg ( 8-12 mg / kg), for > 50 kg = 600 mg OD
3. Pyrazinamide ( Z)
Chemically≡ INH
-Weak tuberculocidal more active in acidic
medium
-More lethal to intracellular bacilli & to those
at sites showing an inflammatory response
( Therefore effective in first two months of therapy where
inflammatory changes are present )
-Good sterilizing activity
-It’s use enabled total duration of therapy to
be shortened & risk of relapse to be
reduced.
Mechanism ≡ INH - ↓ fatty acid synthesis but
by interacting with a different fatty acid
synthesis encoding gene .
PZA is thought to enter M. tub. by passive
diffusion and converted to pyrazinoic acid
(its active metabolite) by bact. pyrazinamidase
enz. .This metabolite inhibits mycobact. fatty
acid synthase -I enz. and disrupts mycolic
acid synthesis needed for cell wall synthesis
-Mutation in the gene (pcn A) that encodes
pyrazinamidase enzyme is responsible for drug resistance
( minimized by using drug combination therapy) .
PKT :
-Absorbed orally, widely distributed ,Good
penetration in CSF.
-Metabolized in liver & excreted in urine.
-t½ -6-10 hrs
ADRs :
-Hepatotoxic -dose related
-Arthralgia , hyperuricaemia, flushing ,
rashes , fever & anaemia
-Loss of diabetic control
Dose – 20-30 mg /kg daily , 1500 mg if > 50 kg
Ethambutol ( E) :
-Tuberculostatic , clinically active as
Streptomycin
-Fast multiplying bact.s are more sensitive
-Also act against atypical mycobacteria
-If added in triple regimen (RHZ) it is found
to hasten the rate of sputum conversion &
to prevent development of resist.
Mech. :
Not well understood . Found to ↓arabinosyl
transferase III involved in arabinogalactone
synthesis & also interfere with mycolic acid
incorporation in mycobacterial cell wall (this
is encoded by emb AB genes )
-Resistance develop slowly
- No cross resistance
PKT:
-3/4th of an oral dose of Ethm. is absorbed
-Distributed widely but penetrates in
meninges incompletely
-½ metabolized , excreted in urine
-caution is required in pts of renal disease
-Pts acceptability is good & S/Es are low
ADRs:
-Loss of visual acquity / color vision due
to optic neuritis ,which is most impt. dose
& duration dependent toxicity.
(children can not report this complaint easily therefore
not given below 6 yrs of age)
-Early recognition –reversible
Others- Nausea , rashes & fever
-Neurological changes
-Hyper uricaemia is due to interference
with urate excretion
Dose – 15-20 mg/kg , > 50kg -1000mg
Streptomycin (S):
-It was 1st clinically useful antibiotic drug
-It is protein synthesis inhibitor by combining
with 30S ribosome
-It is tuberculocidal , but less effective than
INH / Rifampicin
-Acts on extracellular bacilli only ( poor
penetration in the cells )
-It penetrates tubercular cavities but does
not cross BBB
- Resistance when used alone (in average
popul.1 in 10 to the power 8 bacilli are resistant to
streptomycin –they multiply & cause relapse
therefore stopped at the earliest .)
- Atypical mycobact.s are ineffective
- Popularity ↓ due to need of IM inj. & lower
margin of safety ( because of ototox. & nephrotox.).
- Dose- 15 ( 12-18 ) mg/kg, >50 mg- 1000mg
Thiacetazone (TZN) :
-First AT drug tested but weak
-Discarded due to hepatotoxicity
-In India revived in 1960s for oral use along
with INH as a substitute to PAS
-Tuberculostatic , does not add to the
therapeutic effect of H,S, R, E
ADRs -
Hepatotoxic
Exfoliative dermatitis
Stevenson Johnson’s syndrome
Can cause bone marrow depression
Others- Nausea , anorexia , abd. discomfort
Loose motions
Mild anemia
Pruritis
Dose- 150 mg OD (2-5 mg/ kg ) ,used in combined

tablet with INH
The Basis for Multi-Drug Therapy
• Prevent emergence of resistance

The Basis for Multi-Drug Therapy
2 INH Antibacterial attack
Rifampin against all
High Streptomycin subpopulations
INH of bacilli.
А
INH, Rifampin
Rapid
Continuous
(RIF, SM)PZ
Ethambutol,
growers
growth
PZ RIF
Rifampin
Speed of
bacteria
Slow A
growers No drug
growth
is effective
B C
D Acid Spurts
Spurtersof
Dormant inhibition metabolism
Low (No cure)
Mitchison, Tubercle 66: 219-226, 1985

Mechanism of Resistance
Relative activity of first line Drugs
• INH: potent bactericidal Combination is synergistic
• Rifampin: potent bactericidal
• Pyrazinamide: Weak bactericidal, active against
intracellular bacilli.
• Ethamutol: bacterisostatic, prevents resistance
development.
• Streptomycin: bactericidal, active against
extracellular rapid growers.
Never use a single drug for chemotherapy

in tuberculosis, a combination of two or
more drugs must be used.
PAS – Paraaminosalicylic acid:
-Related to sulfonamides chemically as well
as in mech. of action.
-Tuberculostatic , not add to therapeutic
value , only delay resistance
-Interfere with absorption of Rifampicin
S/E - Acceptability is poor due to frequent
anorexia , nausea & epigastric pain
Other use- Goitre
Liver dysfunction
& Blood dyscrasias
Dose- 10- 12 gm ( 200 mg/ kg) / day
Rarely used now

Ethionamide :
-Tuberculostatic , having moderate efficacy
-Acts both on extra as well as intracellular
bacterias
(Mycobacterial EthaA, an NADPH specific FAD- containing
mono- oxygenases converts Ethionamide to a sulfoxide, it ↓
mycobacterial growth by ↓ the activity of the inh A gene product,
the enoyl acyl reductase of fatty acid synthase II ,the same
enzyme which is ↓ by INH )
-Resistance develop readily & some cross
resistance to TZN
-Absorbed orally ,distributed all over including CSF
S/E- Anorexia
Nausea & vomiting,
Rashes
Hepatitis ,
Peripheral/ Optic neuritis
Dose- 1 gm / day, but more than 0.5 gm not tolerated.
- seldom used now , only used in resistance
cases .
Cycloserine (Cycs):
- Obtained from S. archidacces & is a chemical
analogue of D- alanine
-↓ Bacterial cell wall synthesis
-Tuberculostatic & ↓ other G -ve organisms
( E. coli , Chlamydia)
-Resistance develop slowly , no cross resist.
CNS toxicity is high , sleepiness , headache
tremor , psychosis & convulsions
-Rarely used (only in resistance cases)
Dose – 250 mg BD
Kanamycin , Amikacin & Capreomycin:
Used as reserved drug in severe cases not
responding to usual therapy
Newer drugs :
Ciprofloxacin
Ofloxacin
Levofloxacin
( all are used in TB & MAC )
Clarithromycin
Azithromycin
( used in MAC )
Rifabutin - > in MAC < in TB
Antitubercular Therapy
Treatment of Tuberculosis :
Remarkable change, conventional 1-1½yr
Tt – is replaced by more effective & less
toxic 6 month-8 month therapy
a) Rapidly growing with higher bacillary
load e.g. wall of the cavity region- highly
suscep. to INH & lesser extent to R,E,S
b) Slow growing – intracellular & at inflamed
sites – vulnerable to Z while H,R,E are
lesser active
c) Spurturs - with in caseous material
(where O2 tension is less ) the bacilli
grow intermittently.
R- is most active in this sub population
d) Dormant –bacilli remain totally inactive for
prolonged periods- No ATT is effective
Goals-
1. Killing of dividing bacilli- drugs with
bactericidal activity rapidly reduce the
bact. load in the Pt & achieve quick
sputum clearance – Pt become non con-
tageous to the community
- Transmission is interrupted
2. Killing of persistent bacilli for effective
cure & prevention of relapse
3. Prevent emergence of resistance
(Drug combination are selected to maximize the
above action together with consideration of cost &
convenience )
- H & R are most efficacious drugs ,their
combination is synergistic
Duration of therapy shortened from 12 to 9
months.
Addition of Z for initial 2 months further
reduces duration of treatment to 6 months
DOTs –Directly observed treatment short
course ,was recommended by the
WHO in 1995
Short course chemotherapy-
Regimen of 6-9 months treatment
In 1997 WHO framed clear cut guidelines
for different category of TB treatment .
All regimen have initial intensive phase -2
3 months to rapidly kill the TB bacilli & bring
sputum conversion & afford symptomatic
relief followed by continuation phase last
4-6 months for elementary remaining bacilli
t
Categories:
Category I
–New ( untreated ) smear +ve pulmonary TB
-New smear –ve pulmonaryTB with extensive
parenchymal involvement
-New cases of severe forms of extra- pulmonary
TB e.g.- meningitis , miliary TB , pericarditis
-B/L or extensive pl. effusion , intestinal or
genitourinary TB
(Revised National Tub. Control programme
In India in 1997— DOTs –follow thrice wkly
regimen to ↓ cost & it is more practical )
WHO :
- 2HRZE(S) (initial phase)-daily
- 4HR or 6HE (continuation phase,)daily
total duration 6-8 months
RNTCP :
2H3R3Z3E3 + 4H3R3 -total duration- 6month
Category II
-Smear +ve failure ,relapse & interrupted Tt cases
-Relapse- cured TB Patient again become sputum +ve
-Tt after interruption –interrupted Tt x 2month →return to
sputum + ve case
WHO: Initial phase –daily 2 HRZES +1 HRZE
Continuation phase –5HRE - total 8 month
RNTCP:
Initial phase -2H3R3Z3E3S3 +1H3R3Z3E3
Continuation phase -5H3R3E3 –total 8 months
Category III
New cases of smear –ve pulmonary TB with limited
parenchymal involvement or severe form of extra
pulmonary TB .
e.g.-Lymph node TB
Unilateral pleural effusion
Bone (excluding spine )
Peripheral joint & skin TB
WHO : Initial phase -2HRZ (daily)
Continuation phase - 4HR or 6HE (daily)
Total duration-6-8 months
RNTCP :
Initial phase -2H3R3Z3 ( daily )
Continuation phase -4H3R3 ( daily )
Total duration- 6 months
CATEGORY-WISE TREATMENT
(WHO1997 & RNTCP1997)
TB Initial Phase Continuation Total
Category (daily /3xper week) Phase Duration
(daily/3xper week)
i. 2 HRZE(S)/ 4 HR/ 4H3R3 or 6HE 6

2H3R3Z3E3 8
ii. 2 HRZES+ 5 HRE or 5H3R3E3 8

1HRZE / 8
2H3R3Z3E3S3+1H3R3Z3E
3
iii. 2 HRZ/ 4 HR/4 H3R3 or 6 HE 6
2H3R3Z3 8
DOTS PLUS:
Refers to DOTS programme which includes
component for multidrug resistance (MDR)
tuberculosis , its diagnosis , management &
treatment.
(It began in 2000 by WHO & implemented in India in 2010
& thus category IV is created) .
Cat IV –
Chronic cases who have remained or become smear
+ve after completing fully supervised Tt / close contact of
most likely MDR cases
MDR –TB –Resistant to both H& R & many
other anti -TB drugs
(Tt difficult because –one or more 2nd line drugs are to be
given for 12-24 months & they are less efficacious , less
convenient & more toxic & expensive )
Chronic – presence of association of
AIDS /Diabetes / Leukemia /Silicosis
-If sensitivity of drugs known then resistant
drugs are excluded
-For H resistance – RZE X 12 months
- For H+ R resistance- ZE+ S / Kanamycin /
Capreomycin/ + Ciprofloxacin or Ofloxacin ±
Ethionamide could be used
Extremely drug resistant ( XDR) TB :
Term applied to bacilli that are resistant to at
least 4 most effective cidal drugs i.e. H ,R
Ofloxacin , one of Kanamycin / Amikacin/
Capreomycin.
Global survey –reveals 20% TB isolates are
MDR out of which 2% are XDR .
TB in pregnant women :
WHO – H,R,Z –safe
(Recommended - – 2HRZ + 6HR regimen -8 month
-E can be added late
-S is C/I
In India Z is avoided
-(2HRE +7HR total 9 month regimen )
Breast feeding mother:
All ATT drugs are compatible ,baby should
be watched ,the infant should receive BCG
vaccination & INH prophylaxis
Indication of Glucocorticoids in TB:
-In TB Pts, glucocorticoids if at all used are always
used with AT drugs, they are considered in –
- Miliary TB
- Tuberculous Meningitis
- Rapidly filling Pleural effusion &
- Renal TB ( to reduce exudation & stricture formation)
( Its administration should be withdrawn gradually
when the G.C. of Pts improved ).
RECENT DRUGS
Three novel drugs currently under clinical
development which are active against
MDR-TB-
1. Linezolid
2. OPC-67683, a nitroimidazole
3. TMC207, a diarylquinoline
Newer Antitubercular Drugs in
Clinical Trials
1.LINEZOLID (Also known as 3rd line agent)
• Linezolid is an oxazolidinone used primarily for the
treatment of drug-resistant gram-positive infections.
• Also active against M. tuberculosis
• Mechanism of action is disruption of protein synthesis
by binding to the 50S bacterial ribosome.
• Linezolid has nearly 100% oral bioavailability, with
good penetration into tissues and fluids, including
CSF.
• Adverse effects may include optic and peripheral
neuropathy, pancytopenia, and lactic acidosis .
Clinical Trials
2.TMC207 (R207910 ) by Andries etal
in 2005 :
• TMC207 is a new diarylquinoline with a novel
mechanism of action: inhibition of the mycobacterial
ATP synthetase proton pump.
• TMC207 is bactericidal for drug-susceptible and MDR
strains of M. tuberculosis.
• Resistance has been reported and is due to point
mutations in the gene coding for the ATP synthetase
proton pump.
• A phase 2 randomized controlled clinical trial
demonstrated substantial improvement in rates of 2-
month culture conversion, with improved clearance of
mycobacterial cultures, for MDR-TB patients.
Clinical Trials
• This drug is metabolized by the hepatic
cytochrome CYP3A4.
• Rifampin lowers TMC207 levels by 50%, and
protease inhibitors also interact significantly
with this drug.
• The dosage is 400 mg/d for the first 2 weeks
and then 200 mg thrice weekly.
• Adverse effects are reported to be minimal,
with nausea and slight prolongation of the
QTc interval.
Clinical Trials
3. OPC-67683 AND PA 824 :
• The prodrugs OPC-67683 and PA 824 are
novel nitro- dihydro- imidazoxazole
derivatives.
• Antimycobacterial activity is due to
inhibition of mycolic acid biosynthesis.
• Early clinical trials of these compounds
are ongoing.
CHANGES IN RNTCP
GUIDELINES IN
2010-11
Changes in RNTCP
Guidelines
• Discontinuation of Cat III Regimen under
RNTCP
• The programme has now revised its
categorization of patients from the earlier 3
categories (Cat I, Cat II and Cat III) to 2
categories (New and Previously treated
cases)
NEW (CAT I)
New Sputum smear-positive
New Sputum smear-negative
New Extra-pulmonary
New Others
PREVIOUSLY TREATED (CAT II)

Smear-positive relapse
Smear-positive failure
Smear-positive treatment after default
Others
TREATMENT
Category Initial Phase Continuation Phase
• New (Cat I) 2H3R3Z3E3 4H3R3
• Previously 2H3R3Z3E3S3/ 5H3R3E3

Treated 1H3R3Z3E3
(Cat II)
CHEMOPROPHYLAXIS
Chemoprophylaxis of TB:
Prevention of active disease from latent inf.
& It is indicated by +ve Mantuox test.
Mantuox test / Tuberculin test – In this test purified protein derivative
(PPD) is injected by intradermal route . In normal person i.e. in
immunocompetent pts induration of > 5 mm & in immunocompromised Pts >10
mm induration is considered positive after giving 5 units of PPD .
Subjects require prophylaxis are –
- PPD +ve pts but no active disease
- -ve PPD but in close contact with TB Pts
-Immunocompromised Pts ( having leukemia ,HIV, taking corticosteroid) with
+ve MT
- HIV inf. Pts . exposed to MDR TB cases
Chemoprophylaxis
Standard drug is INH daily for 6-12 months.

OR: INH + Rifampin daily for 6 months.
If INH can not be used: Rifampin (4 months)/R+Z (2 months).
MDR: E+Z + FQ.
THE DEVELOPMENT PIPELINE
FOR NEW DRUGS, 2010
• Rifaximin : Newer non systemic rifamycin
approved for :
- Traveler's diarrhea,
- Hepatic encephalopathy
- Irritable bowel syndrome,
- Small intestinal bacterial overgrowth &
- Clostridium difficile infection
The goal of the new drugs component of the
Global
Plan to Stop TB 2011–2015
• To develop and introduce new TB drugs
and drug combinations that will result in-
 Shorter, safer, more effective and accessible
treatment regimens
Cure all forms of TB
Compatible with ART
Suitable for children
Easily managed in the field.
ACHIEVEMENTS EXPECTED BY
2015
• A new four-month TB treatment regimen
• Two new drugs will be approved by regulatory
authorities for drug sensitive TB
• At least one new drug for the treatment of drug
resistant TB will be introduced into the market
• A nine-month regimen for the treatment of drug
resistant TB including at least one new drug
ACHIEVEMENTS EXPECTED
BY 2015
• Fixed-dose combinations (FDCs) for first-
line drugs (including new drugs) will be
available and in use
• Child-friendly first-line TB drug formulations
will be under development
Anti- Leprotic agents
• Also known as Hansen’s disease
• It is a chronic granulomatous infection
caused by Mycobacterium leprae
• Attacks superficial tissues e.g. skin &
peripheral nerves
• Organism grow very slowly ( org.s can not
be cultured in artificial media but grows in
foot pad of Armedillon.)
• Disease is still considered as social stigma
but it needs a change in the attitude of
public to consider it just like any other
disease .
• Important is early diagnosis & Tt. which
makes it non infectious & prevents compl.s
Anti- Leprotic drugs :
Classification-
-Sulfone- Dapsone (DDS)
-Phenazine derivatives- Clofazimine
-Antitubercular drugs- Rifampicin
Ethionamide
-Other Antibiotics -
Ofloxacin , Minocycline & Clarithromycin
Sulfones -
Derivative of 4-4’ diamino diphenyl sulfone
(DDS)
Dapsone:
-Bacteriostatic
-High risk of resistance if used alone
Mechanism:
Similar to sulfonamide i.e. ↓ of dihydrofolate
synthase enzyme.( Anti-inflammatory effect occurs via ↓ of
tissue damage by neutrophils by ↓ neutrophil myeloperoxidase activity
,↓activity of neutrophil lysosomal enzyme , free radical scavanger ,↓ of
migration of neutrophils to the inflammatory sites )
ADRs:
-Nausea , vomiting , anorexia
-Allergic reaction
-Hemolysis in pts with G6PD deficiency
-Methemoglobinaemia
• Neurotoxicity & Psychosis
Sulphone Syndrome:
After 5/6 wks of Tt. in malnourished patients
there may be exacerbation of Lepromatous
Leprosy similar to Jerisch Hexheimer
reaction (seen with Penicillin ) ,characterized
by fever, malaise , exfoliative dermatitis ,
lymphadenopathy, Jaundice etc.
Indication –
-Leprosy
-Resistant Malaria ( with pyrimethamine)
-Toxoplasma encephalitis in AIDS
-Pneumocystis jirovecii in AIDS
Clofazimine :
It is a dye , weak bactericidal by ↓ the
function of DNA.
( membrane disruption ,↓of mycobacterial Phospholipase A2 , ↓ of
mycobacterial K+ transport , generation of H2O2 , interference with
the bacterial electron transport chain via ↓ of macrophages , T cells,
neutrophils & complement )
- Also having anti- inflammatory activity so
prevents Lepra reaction.
-used for common skin ulcers & MAC
S/E- Red discolouration of skin
- Eosinophilic enteritis
Rifampicin :
- Important antiTb drug also bactericidal to
M. Leprae.
- Rapidly make leprosy Pts noncontagious
- However not satisfactory if used alone-
some bacilli persist after prolonged Tt –
can cause resistance .
( The congener of Rifampicin - Rifabutin is
also bactericidal against M. leprae but not
superior to Rifampicin)
Ethionamide - Has significant antileprotic
activity but is hepatotoxic . It can be used
as an alternative to Clofazimine but other
substitutes are preferred.
Other Antibiotics:
-Fluoroquinolones : Ofloxacin , Pefloxacin,
Gatifloxacin are highly active against
M. leprae ( but not Ciprofloxacin )
-Minocycline: due to high lipophilicity, it is
active against M. leprae. , antibacterial
activity is less than Rifampicin but more
than that of Clarithromycin .
Clarithromycin :
Only macrolide antibiotic having significant
activity against M. leprae . It is being
included in alternative MDT regimens.
Diagnosis of Leprosy:
Diagnosed with any of the following-
- Skin lesions ( hypopigmented patches )
- Impaired or loss of sensation
- Acid fast bacilli in skin smears
- Nerve thickening
Treatment of Leprosy
• Leprosy primarily affect skin , mucous
membranes & nerves
• Prevalent in poors ( low socioeconomic
strata ) .
• National Leprosy Control Programme
launched in 1955
• It was changed to National Leprosy
Eradication Programme ( NLEP) in 1982
• India achieved elimination of Leprosy as
a public health problem .
• Incidence is less than 1 case/ 10,000
population .
Classification:
1. Indeterminate
2. Tuberculoid
3. Borderline
4. Lepromatous
5. Pure neuritis ( no skin lesion )
Tuberculoid:
Well defined skin lesion
-anesthetic patches
-Organism may or may not be found in skin
lesions.
-Lepromine test is positive (diagnostic for
Leprosy. It evaluate the immune system of
the patient & classify the type of disease.)
-prolonged remission occurs
Lepromatous:
-Ill defined skin lesions
-Skin is thickened , glossy & corrugated
-Disease progresses – large nerve trunks
get involved – anesthetic patches
-Atrophy of skin & muscles & absorption of
small bones e.g. phalanges of extremities,
ulceration & spontaneous amputation occurs
-Lepromine test is –ve ( as cell mediated
immunity is absent )
-Smear is +ve for organism .
For treatment purpose –leprosy is classified
as-
Multibacillary - It includes lepromatous,
borderline cases with +ve skin smear test
Tt- Rifampicin - 600 mg / month supervised
Dapsone-100 mg / day self administration
Clofazimine – 300 mg/ month supervised
+ 50 mg/ day self administration
X 2 years- relapse – repeat
Paucibacillary : ( small no. of organism)-
It includes indeterminate & tuberculoid
Tt- Rifampicin – 600 mg / month supervised
Dapsone – 100 mg / day self administration
X minimum for 6 months-repeat if relapse
Single lesion paucibacillary –single dose
ROM- Rifampicin-600 mg + Ofloxacin - 400mg +
Minocycline-100 mg
(MDT was introduced by the WHO in 1981& was implemented
under the NLEP ( National Leprosy Eradication Programme). It
includes Dapsone , Rifampicin & Clofazimine . The WHO in 1994
recommended a fixed duration therapy( FDT) of 2 years for MBL & 6
months for PBL . WHO expert committee On Leprosy in 1995
recommended shortening of MDT in MBL to 12 months & this was
implemented in our country since 1999 . The purpose of this is to
render the Pts noncontiguous & therefore cut down transmission
Alternative regimens :
Incorporating newer antileprotic drugs , but these are
used only in case of Rifampicin resistance or when MDT is
not advisable e.g.-
Clofazimine + any two of Ofloxacin / Minocycline/ Clarithromycin
for 6 months followed by Clofazimine + any one of Ofloxacin /
Minocycline x additional 18 months .
(PBL cases having few bacteria in the body & only one Skin lesion can
be treated with single dose of Rifampicin -600 mg + Ofloxacin-400 mg
+ Minocycline -100 mg. This has been recommended by the WHO for
solitary lesion of PBL.)
Two types of reactional state may occur
with therapy
1. Type I : Lepra reaction (reversal reaction)
In borderline leprosy due to increased in host
immunity- skin lesion & nerves become swollen
& tender without systemic manifestation –
Tt. –
Prednisolone (Thalidomide not effective)
Type II :Lepra reaction ( erythema nodosum
leprosum) –observed in lepromatous
leprosy – there is skin & nerve
manifestation with fever & systemic
involvement.
Tt.- by analgesic /antipyretic for mild cases,
in severe cases-Prednisolone or Thalidomide.
-Chloroquine & cytotoxic drugs are also
effective.
-Clofazimine require 3-4 wks so not suitable

for acute cases, but useful in chronic
cases & prevention of this reaction .
- No need to stop the antileprotic drugs .
MCQs
• 1. A middle aged man with chronic renal failure is diagnosed to have sputum +ve
• Pulmonary tuberculosis. His creatinine clearance is 25 mg/ min. All of the following
• Drugs need modification in doses EXCEPT :
• a) Isoniazid
• b) Streptomycin
• c) Rifampicin
• d) Ethambutol
• ( Ans- c ,Ref : Katzung 11/e p826)
•
• 2. A 30 year old pregnant women develops Tuberculosis. Which of the following
• antitubercular drug should not be given ?
• a) Rifampicin
• b) INH
• c) Streptomycin
• d) Ethambutol
• ( Ans- b ,Ref : KDT 6/e p748)
•
MCQs
• 3. A patient suffering from AIDS is on Zidovudine ,Lamivudine and Indinavir therapy.
• He develops Pulmonary tuberculosis for which treatment is started. Which of the
• Following should be avoided in him ?
• a) INH
• b) Ethambutol
• c) Pyrazinamide
• d) Rifampicin ( Ans- d ,Ref : KDT 6/e p741)
• 4. A patient of multidrug resistant Tuberculosis is on antitubercular drugs. After a few Months he
develops an inability to distinguish between red & green color. Most likely drug causing these
symptoms is :
• a) Rifampicin
• b) Ethambutol
• c) Cycloserine
• d) Ethionamide ( Ans -b ,Ref : KDT 6/e p742)
• 5. In multidrug resistant strains of M. tuberculosis which of the following drugs is likely
• to be effective, including those resistant to Streptomycin?
• a) Amikacin
• b) Gentamicin
• c) Spectinomycin
• d) Clarithromycin ( Ans- a ,Ref: Katzung 11/e p825)
•
MCQs
• 6. In atypical mycobacterial infection which of the following drug is active?
• a) Ethionamide
• b) Streptomycin
• c) INH
• d) Clarithromycin ( Ans- d , Ref: KDT 6/e p750)
• 7. Which of the following antitubercular drug DOES NOT cross blood brain barrier?
• a) Isoniazid
• b) Pyrazinamide
• c) Rifampicin
• d) Streptomycin ( Ans- d , Ref: KDT 6/e p743 )
• 8. Which of the following anti-tubercular drug is implicated in the causation of transient
• memory loss?
• a) Ethambutol
• b) Ethionamide
• c) Pyrazinamide
• d) Isoniazid ( Ans –d , Ref : Goodman & Gilman 10/e p1277 )
MCQs
• 9. Most effective drug for extracellular mycobacteria is:
• a) Ethambutol
• b) Rifampicin
• c) Isoniazid
• d) Pyrazinamide
• ( Ans –c , Ref : Goodman & Gilman 11/e p1205 ,1208,1211 )
• 10. In severe liver disease which of the following combination of antitubercular drug can
• be used ?
• a) Isoniazid + Streptomycin
• b) Rifampicin + Isoniazid
• c) Rifampicin + Ethambutol
• d) Streptomycin + Ethambutol
• ( Ans -d , Ref: KDT 6/e p 742-743 )
• 11. In Leprosy , the best bactericidal agent is :
• a) Rifampicin
• b) Clofazimine
• c) Dapsone
• d) Ethionamide
• ( Ans-a ,Ref : KDT 6/e p753)
MCQs
• 12. What is the side effect of Dapsone apart from hemolytic anaemia ?
• a) Infective mononucleosis like syndrome
• b) Flu like syndrome
• c) Lichenoid eruptions
• d) G-6-PD deficiency
• ( Ans -a , Ref: KDT 6/e p752 )
• 13. Dapsone is used in all EXCEPT :
• a) Dermatitis herpitiformis
• b) Leprosy
• c) Pneumocystis jiroveci pneumonia
• d) Tuberculosis
• ( Ans -d , Ref: KDT 6/e p752 )
• 14. In Lepra reaction , the drug useful is :
• a) Penicillins
• b) Clofazimine
• c) Dapsone
• d) Rifampicin
• ( Ans -a , Ref: KDT 6/e p752 )
•
MCQs
• 15. Treatment of Lepromatous leprosy is :
• a) Rifampicin + Dapsone
• b) Rifampicin + Clofazimine
• c) Rifampicin + Dapsone + Clofazimine
• d) Rifampicin + Ofloxacin + Minocycline
• ( Ans -c , Ref: KDT 6/e p755 )
•
Bibliography
1.Goodman & Gilman’s ,The Pharmacological Basis of
Therapeutics (12th Edition).
2. A complete Textbook of Medical Pharmacology by
S. K. Srivastava ( Latest Edition )
3.. Essentials of Medical Pharmacology by K. D. Tripathi
(7th edition)

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Antitubercular Agents

Peculiar cell wall structure

Resistance to infection emerges quickly.

• Droplets are expelled by coughing or sneezing,

• Tubercle bacilli then spread to other body organs

• Tubercle bacilli may become dormant, or walled

• Spread from person to person via airborne

Bacilli continuously shift from one to other subpopulation.

Baron S (ed.) Medical Microbiology. 4th edition. Chapter 33

& Schutz discovered Streptomycin which

1st line drugs 2nd line drugs

• Isoniazid (INH) • Ethionamide

(another adduct , a nicotinoyl –NADP isomer potentially mycobacterial

- If INH is given alone , inherent resistant bacilli

Genetic polymorphism affects INH metabolism

Dose- 150 mg OD (2-5 mg/ kg ) ,used in combined

• Prevent emergence of resistance

Mitchison, Tubercle 66: 219-226, 1985

Never use a single drug for chemotherapy

Rarely used now

i. 2 HRZE(S)/ 4 HR/ 4H3R3 or 6HE 6

ii. 2 HRZES+ 5 HRE or 5H3R3E3 8

PREVIOUSLY TREATED (CAT II)

• New (Cat I) 2H3R3Z3E3 4H3R3

• Previously 2H3R3Z3E3S3/ 5H3R3E3

Standard drug is INH daily for 6-12 months.

-Clofazimine require 3-4 wks so not suitable

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