Download Antitubercular Agents

Antitubercular Agents
Dr. Rajendra Nath
Professor
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
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Lung (primary site)
Brain
Bone
Liver
Kidney
- Intestines
- Lymph nodes
• Aerobic bacillus
• Passed from infected:
– Humans
– Cows (bovine) and birds (avian)
• Much less common
Antitubercular Drugs
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
Antitubercular Drugs
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
Antitubercular Drugs
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)
Antitubercular Drugs
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 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
Drugs used in Tuberculosis
1st line drugs
2nd line drugs
high efficacy, low toxicity
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Isoniazid (INH)
Rifampin
Pyrazinamide
Ethambutol
Streptomycin
Low efficacy, high toxicity or both
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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
Antitubercular Agents
-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 .)
Antitubercular Agents
-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
Antitubercular Agents
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
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Mycolic Acid
Arabinogalactan
Peptidoglycan
Cell membrane
Pyrazinamide
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Mitochondria
(ATP)
Rifampin
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Streptomycin
R
I
B
O
S
O
M
e
Protein
Cytoplasm
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(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 .
Antitubercular Agents
(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
ISONIAZID (INH):
Pharmacokinetics
Acetylation
(Phase II)
INH
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
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 Pyridoxine-100 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
N. meningitidis
H. influenzae
E. coli
Klebsiella
Pseudomonas
Proteus
& 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
Steroids
Sulphonyl urea
etc.
Theophylline
Metoprolol
Fluconazole & Ketoconazole
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:
-3/4th 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
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 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 )
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
The Basis for Multi-Drug Therapy
1
• Prevent emergence of resistance
The Basis for Multi-Drug Therapy
2
High
INH
INH, Rifampin
(RIF,
SM)PZ
Ethambutol,
А
Rapid
Continuous
growers
growth
Speed of
bacteria
growth
Slow
growers
D
Low
Antibacterial attack
against all
subpopulations
of bacilli.
INH
Rifampin
Streptomycin
Dormant
(No cure)
PZ
A
RIF
Rifampin
No drug
is effective
B
Acid
inhibition
Mitchison, Tubercle 66: 219-226, 1985
C
Spurts
Spurtersof
metabolism
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.
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 use- Goitre
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
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
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 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
Antitubercular Therapy
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
Antitubercular Therapy
Goals1. 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 chemotherapyRegimen 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
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
genitourinary TB
, intestinal or
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
CATEGORY-WISE TREATMENT
(WHO1997 & RNTCP1997)
TB
Category
Initial Phase
(daily /3xper week)
Continuation
Phase
(daily/3xper week)
Total
Duration
i.
2 HRZE(S)/
2H3R3Z3E3
4 HR/ 4H3R3 or 6HE
6
8
ii.
2 HRZES+
1HRZE /
2H3R3Z3E3S3+1H3R3Z3E
3
5 HRE or
5H3R3E3
8
8
iii.
2 HRZ/
2H3R3Z3
4 HR/4 H3R3 or 6 HE
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 2nd 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 resistance- ZE+ 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-TB1. 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
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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 .
Newer Antitubercular Drugs in
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 2month culture conversion, with improved clearance of
mycobacterial cultures, for MDR-TB patients.
Newer Antitubercular Drugs in
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.
Newer Antitubercular Drugs in
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
• New (Cat I)
2H3R3Z3E3
• Previously
Treated
(Cat II)
2H3R3Z3E3S3/
1H3R3Z3E3
Continuation Phase
4H3R3
5H3R3E3
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 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-Sulfone-Phenazine derivatives-Antitubercular drugs-
Dapsone (DDS)
Clofazimine
Rifampicin
Ethionamide
-Other Antibiotics Ofloxacin , Minocycline & Clarithromycin
Anti- Leprotic agents
Sulfones Derivative of 4-4’ 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.( 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
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
asMultibacillary - It includes lepromatous,
borderline cases with +ve skin smear test
Tt- Rifampicin - 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
Tt- Rifampicin – 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 + Ofloxacin-400 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 cases-Prednisolone 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 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
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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
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
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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
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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
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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
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
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15. Treatment of Lepromatous leprosy is :
a)
b)
c)
d)
Rifampicin + Dapsone
Rifampicin + Clofazimine
Rifampicin + Dapsone + Clofazimine
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)