Antitubercular Agents
Dr. Rajendra Nath
Professor

Antitubercular Agents
• 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.
??

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

• 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

• 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

• 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)

• 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

• 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: P atient is noncontagious : 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.

Antitubercular Agents
• 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

Antitubercular Agents
& 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

Antitubercular Agents 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

Antitubercular Agents
First line drugs:
Ionized ( H)
Rifampicin (R)
Ethambutol (E)
Pyrazinamide ( Z)
Streptomycin ( S) now reserved drug in first line

Antitubercular Agents
Second line drugs:
Thiacetazone
Para aminosalicylic acid (PAS)
Ethionamide ( Etm)
Kanamycin
Cycloserine
Amikacin
Capreomycin

Antitubercular Agents
Newer Second Line drugs:
Ciprofloxacin
Ofloxacin
Levofloxacin
Clarithromycin
Azithromycin
Rifabutin

1 st line drugs high efficacy, low toxicity
• Isoniazid (INH)
• Rifampin
• Pyrazinamide
• Ethambutol
• Streptomycin
2 nd line drugs
Low efficacy, high toxicity or both
• Ethionamide
• Para aminosalicylic acid
• Cycloserine
• Amikacin/ Capreomycin
• Fluoroquinolones
• Rifabutin

Antitubercular Agents
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.

Isoniazid
-
Mycolic Acid
st
Ethambutol
-
Arabinogalactan
Peptidoglycan
Cell membrane
-
Pyrazinamide
-
Mitochondria
(ATP)
-
Rifampin
-
Streptomycin
Cytoplasm
S
O
M e
I
R
B
O
Protein

( 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 .

Antitubercular Agents
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 )

Antitubercular Agents
(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

Acetylation
(Phase II)
Hydrolysis
(Phase I)
INH
N-acetyl transferase
N-acetyl Isoniazid
Isonicotinic acid Acetyl hydrazine
Genetic polymorphism affects INH metabolism
Slow acetylators are at higher risk of developing neuritis

Antitubercular Agents
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 )

Antitubercular Agents
Due to this Pyridoxine given prophylactically
10 mg/day which prevents neurotoxicities
(
INH neurotoxicity treated with Pyridoxine100 mg/ day
)
2. Hepatitis – more common in older patients & alcohlics ( reversible)
3. Rashes , fever , acne & arthralgia .

Antitubercular Agents
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

Antitubercular Agents
- 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

Antitubercular Agents
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

Antitubercular Agents
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

Antitubercular Agents
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

Antitubercular Agents
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
)

Antitubercular Agents
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.

Antitubercular Agents
( contraceptive failure can occur if given simultaneously in child bearing age women taking oral contraceptive
)

Antitubercular Agents
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

Antitubercular Agents
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
)

Antitubercular Agents
-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 .

Antitubercular Agents
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)
.

Antitubercular Agents
PKT :
-Absorbed orally, widely distributed ,Good penetration in CSF.
-Metabolized in liver & excreted in urine.
t½ -6-10 hrs

Antitubercular Agents
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

Antitubercular Agents
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.

Antitubercular Agents
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

Antitubercular Agents
PKT:
-3/4 th 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

Antitubercular Agents
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

Antitubercular Agents
-Neurological changes
Hyper uricaemia is due to interference with urate excretion
Dose – 15-20 mg/kg , > 50kg -1000mg

Antitubercular Agents
Streptomycin (S):
-It was 1 st 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 )

Antitubercular Agents
-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

Antitubercular Agents
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

Antitubercular Agents
-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

Antitubercular Agents
Loose motions
Mild anemia
Pruritis
Dose- 150 mg OD (2-5 mg/ kg ) ,used in combined tablet with INH

1
• Prevent emergence of resistance

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

• 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.

Antitubercular Agents
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

Antitubercular Agents
Other useGoitre
Liver dysfunction
& Blood dyscrasias
Dose- 10- 12 gm ( 200 mg/ kg) / day
Rarely used now

Antitubercular Agents
Ethionamide :
-Tuberculostatic , having moderate efficacy
-Acts both on extra as well as intracellular bacterias
(
Mycobacterial EthaA, an NADPH specific FAD- containing monooxygenases 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

Antitubercular Agents
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 .

Antitubercular Agents
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.

Antitubercular Agents
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

Antitubercular Agents
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 11½yr
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 regionhighly suscep. t o INH & lesser extent to R,E,S b) Slow growing – intracellular & at inflamed sites – vulnerable to Z while H,R,E are lesser active

Antitubercular Therapy c) Spurturs - with in caseous material
(where O
2 tension is less ) the bacilli grow intermittently.
Ris most active in this sub population d) Dormant –bacilli remain totally inactive for prolonged periodsNo ATT is effective

Antitubercular Therapy
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 contageous to the community
- Transmission is interrupted

Antitubercular Therapy
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

Antitubercular Therapy
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

Antitubercular Therapy
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 t
4-6 months for elementary remaining bacilli

Antitubercular Therapy
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

Antitubercular Therapy
( 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

Antitubercular Therapy
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

Antitubercular Therapy
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

Antitubercular Therapy
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

TB
Category i.
ii.
iii.
Initial Phase
(daily /3xper week)
2 HRZE(S)/
2H3R3Z3E3
2 HRZES+
1HRZE /
2H3R3Z3E3S3+1H3R3Z3E
3
2 HRZ/
2H3R3Z3
Continuation
Phase
(daily/3xper week)
4 HR/ 4H
3
R
3 or 6HE
5 HRE or 5H
4 HR/4 H
3
R
3
3
R
3
E
3 or 6 HE
Total
Duration
8
8
6
8
6
8

Antitubercular Therapy
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 )
.

Antitubercular Therapy
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 2 nd line drugs are to be given for 12-24 months & they are less efficacious , less convenient & more toxic & expensive )

Antitubercular Therapy
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 resistanceZE+ S / Kanamycin /
Capreomycin/ + Ciprofloxacin or Ofloxacin ±
Ethionamide could be used

Antitubercular Therapy
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 .

Antitubercular Therapy
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
)

Antitubercular Therapy
Breast feeding mother:
All ATT drugs are compatible ,baby should be watched ,the infant should receive BCG vaccination & INH prophylaxis

Antitubercular Therapy
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

1.
LINEZOLID ( Also known as 3 rd 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 .

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 2month culture conversion, with improved clearance of mycobacterial cultures, for MDR-TB patients.

• 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
QT c interval.

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
• 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) 2H
3
R
3
Z
3
E
3
4H
3
R
3
• Previously 2H
3
R
3
Z
3
E
3
S
3
/ 5H
3
R
3
E
3
Treated 1H
3
R
3
Z
3
E
3
(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.

•
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.

• 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 firstline 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 .)

Anti- Leprotic agents
• 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 agents
Anti- Leprotic drugs :
Classification-
SulfoneDapsone (DDS)
Phenazine derivativesClofazimine
Antitubercular drugsRifampicin
Ethionamide
Other Antibiotics -
Ofloxacin , Minocycline & Clarithromycin

Anti- Leprotic agents
Sulfones -
Derivative of 44’ diamino diphenyl sulfone
(DDS)
Dapsone:
-Bacteriostatic
-High risk of resistance if used alone

Anti- Leprotic agents
Mechanism:
Similar to sulfonamide i.e. ↓ of dihydrofolate synthase enzyme.(
Antiinflammatory 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

Anti- Leprotic agents
• 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.

Anti- Leprotic agents
Indication –
-Leprosy
-Resistant Malaria ( with pyrimethamine)
-Toxoplasma encephalitis in AIDS
-Pneumocystis jirovecii in AIDS

Anti- Leprotic agents
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

Anti- Leprotic agents
Rifampicin :
- Important antiTb drug also bactericidal to
M. Leprae.
- Rapidly make leprosy Pts noncontagious
- However not satisfactory if used alonesome bacilli persist after prolonged Tt – can cause resistance .
( The congener of Rifampicin - Rifabutin is

Anti- Leprotic agents 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.

Anti- Leprotic agents
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 .

Anti- Leprotic agents
Clarithromycin :
Only macrolide antibiotic having significant activity against M. leprae . It is being included in alternative MDT regimens .

Anti- Leprotic agents
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

Treatment of Leprosy
• India achieved elimination of Leprosy as a public health problem .
• Incidence is less than 1 case/ 10,000 population .

Treatment of Leprosy
Classification:
1. Indeterminate
2. Tuberculoid
3. Borderline
4. Lepromatous
5. Pure neuritis ( no skin lesion )
Tuberculoid:
Well defined skin lesion

Treatment of Leprosy
-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

Treatment of Leprosy
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

Treatment of Leprosy
-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
TtRifampicin -
600 mg / month supervised

Treatment of Leprosy
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
TtRifampicin –
600 mg / month supervised
Dapsone –
100 mg / day self administration
X minimum for 6 months-repeat if relapse

Treatment of Leprosy
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

Treatment of Leprosy

Treatment of Leprosy
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 + Ofloxacin400 mg
+ Minocycline -100 mg. This has been recommended by the WHO for solitary lesion of PBL .)

Treatment of Leprosy
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 )

Treatment of Leprosy
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 casesPrednisolone or Thalidomide.
Chloroquine & cytotoxic drugs are also effective.

Treatment of Leprosy
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 anti- leprotic drugs .

MCQs
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• 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 a) Isoniazid
EXCEPT : b) Streptomycin c) Rifampicin d) Ethambutol
( Ans- c ,Ref : Katzung 11/e p826)
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• 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
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• 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
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• 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)
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• 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
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• 6. In atypical mycobacterial infection which of the following drug is active?
a) Ethionamide b) Streptomycin c) INH
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• 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
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• 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
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• d) Pyrazinamide
( Ans –c , Ref : Goodman & Gilman 11/e p1205 ,1208,1211 )
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• 10. In severe liver disease which of the following combination of antitubercular drug can be used ?
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• 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
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• 12. What is the side effect of Dapsone apart from hemolytic anaemia ?
a) Infective mononucleosis like syndrome b) Flu like syndrome c) Lichenoid eruptions
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• d) G-6-PD deficiency
( Ans -a , Ref: KDT 6/e p752 )
• 13. Dapsone is used in all EXCEPT : a) Dermatitis herpitiformis
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• b) Leprosy c) Pneumocystis jiroveci pneumonia
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• 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
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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 )

1.Goodman & Gilman’s ,The Pharmacological Basis of
Therapeutics (12 th Edition).
2. A complete Textbook of Medical Pharmacology by
S. K. Srivastava ( Latest Edition )
3.. Essentials of Medical Pharmacology by K. D. Tripathi
(7 th edition)