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Antitubercular AgentsAntitubercular Agents

Dr. Rajendra NathDr. Rajendra Nath

Professor


• 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.

TuberculosisTuberculosis

It is an infection difficult to treat

Mycobacterium tuberculosis

??Typical growth characteristics

Peculiar cell wall structure (waxy appearance ) due to mycolic acid.

Resistance to infection emerges quickly.

http://www.ispub.com/ispub/ijtm/volume_1_number_2_62/tuberculous_mastitis_masquerading_as_carcinoma_breast/mastitis-fig1.jpg

Antitubercular DrugsAntitubercular DrugsMycobacterium Mycobacterium InfectionsInfections

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

Antitubercular DrugsAntitubercular DrugsMycobacterium Mycobacterium InfectionsInfections

• 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 DrugsAntitubercular DrugsTuberculosis - PathophysiologyTuberculosis - Pathophysiology

• M. tuberculosisM. 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 DrugsAntitubercular DrugsTuberculosis – Clinical ManifestationsTuberculosis – 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 DrugsAntitubercular DrugsTuberculosis – Diagnostic StudiesTuberculosis – 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 M. tuberculosis: peculiar featuresfeatures

• 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.Bacilli continuously shift from one to other subpopulation.

Mycobacterial cell wallMycobacterial cell wall

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

Chemotherapy in tuberculosisChemotherapy 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 .

HistoryHistory

• First successful drug for treating TB was

PAS (Para- aminosalicylic acid) PAS (Para- aminosalicylic acid) developed by Lehman in 1943.

• Dramatic success came when Waksman


& Schutz discovered Streptomycin which has made remarkable progress.

• Followed by ThiacetazoneThiacetazone by Domagk in in 1946• In 1952 IsoniazidIsoniazid came into being • PyrazinamidePyrazinamide by Kushner & colleagues in 1952 & later on RifampicinRifampicin in 1957


by S. Margalith has totally changed the

strategy in the chemotherapy.

• EthambutolEthambutol came in 1961 by Lederle -laboratories

• Fluoroquinolones , newer macrolides &

congener of Rifampicin →Rifabutin are

recent addition in antimycobacterial drugs


First line drugs:First line drugs:

Ionized ( H)

Rifampicin (R)

Ethambutol (E)

Pyrazinamide ( Z)

Streptomycin ( S) now reserved drug in

first line


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


Newer Second Line drugs:Newer Second Line drugs:

Ciprofloxacin

Ofloxacin

Levofloxacin

Clarithromycin

Azithromycin

Rifabutin

Drugs used in TuberculosisDrugs used in Tuberculosis

1st line drugshigh efficacy, low toxicity

• Isoniazid (INH)• Rifampin• Pyrazinamide• Ethambutol• Streptomycin

2nd line drugsLow efficacy, high toxicity or both

• Ethionamide• Para aminosalicylic acid• Cycloserine• Amikacin/ Capreomycin• Fluoroquinolones• Rifabutin


Isoniazid (Isonicotinic acid hydrazide,H):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 AgentIt is the cheapest AT Agent


-Atypical mycobacteria are not inhibited by INH.Not active against any other micro-orgs.Mechanism of Action :Mechanism of Action :Inhibit synthesis of mycolic acid ( uniquefatty acid component of mycobacterial cellwall .)


-INH enters the bacilli by passive diffusion. Itmust be activated to become toxic to bacilli.It became toxic by Kat G (multifunctionalCatalase - peroxidase , a bacterial enzyme ) which catalyzes the product from INH anIsonicotinoyl radical that subsequentlyinter-acts with mycobacterial NAD & NADPto 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 1MOA of 1stst line drugs line drugs

Mycolic Acid

ArabinogalactanPeptidoglycan

Cell membrane

DNA RNA

polymerase

mRNA RIBOSOMe

Protein

Isoniazid

-

Pyrazinamide

- Mitochondria(ATP)

- Rifampin

-

Ethambutol

-

Streptomycin

- Cytoplasm


(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 Mutation of the catalase –peroxidase gene in bacilli do

not generate the active metabolite of INHnot generate the active metabolite of INH )

- Combination therapy with INH has good resistance preventing action .

- There is no cross resistance .


PharmacokineticsPharmacokinetics :-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 )DoseDose – 4-6 mg/ kg for >50 kg – 300 mg daily

- 600 mg bi-wkly

ISONIAZID (INH): ISONIAZID (INH): PharmacokineticsPharmacokinetics

Acetylation (Phase II)

Hydrolysis (Phase I) Isonicotinic acid

INHN-acetyl transferase

N-acetyl Isoniazid

Acetyl hydrazine

Genetic polymorphism affects INH metabolismGenetic polymorphism affects INH metabolism

Slow acetylators are at higher risk of developing neuritisSlow acetylators are at higher risk of developing neuritis


ADRs -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 10 mg/day which prevents neurotoxicities

(INH neurotoxicity treated with Pyridoxine-100 mg/ day100 mg/ day )

2. Hepatitis – more common in older patients & alcohlics ( reversible)

3. Rashes , fever , acne & arthralgia .


Rifampin ( Rifampicin , R ):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:Mechanism: Inhibit DNA dependant RNA Synthesis (by ↓ bact RNA polymerase ↓ 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 –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’sADR’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 D/I Rifampicin is microsomal enzyme inducer-↑ several CYP 450 isoezymes-↑ its own metabolism as well as of otherse.g.-Oral contraceptive Digoxin

Warfarin Theophylline Steroids Metoprolol Sulphonyl urea Fluconazole & Ketoconazole

etc.


(contraceptivecontraceptive failure can occur if given failure can occur if given

simultaneously in child bearing age women takingsimultaneously in child bearing age women taking

oral contraceptiveoral contraceptive)


Other uses Other uses –1. Atypical myc. Inf. (M. kansasii, marinum , avium & intracellulare )

2. Leprosy3. Prophylaxis of meningococcal & H. infl. meningitis4. MRSA , Diphtheroids & legionella inf.5. Along with Doxycycline –first line therapy in BrucellosisDoseDose- 10 mg ( 8-12 mg / kg), for > 50 kg = 600 mg OD


3. Pyrazinamide ( Z)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.MechanismMechanism ≡ INH - ↓ fatty acid synthesis butby interacting with a different fatty acid synthesis encoding gene .


PZA is thought to enter M. tub. by passivediffusion and converted to pyrazinoic acid(its active metabolite) by bact. pyrazinamidaseenz. .This metabolite inhibits mycobact. fattyacid synthase -I enz. and disrupts mycolicacid 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 :PKT :

-Absorbed orally, widely distributed ,Good

penetration in CSF.

-Metabolized in liver & excreted in urine.

-t½ -6-10 hrs


ADRs :ADRs :

-Hepatotoxic -dose related

-Arthralgia , hyperuricaemia, flushing , rashes , fever & anaemia

-Loss of diabetic controlDoseDose – 20-30 mg /kg daily , 1500 mg if > 50 kg


Ethambutol ( E) :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. :Mech. :

Not well understood . Found to ↓↓arabinosylarabinosyl

transferase IIItransferase 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: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: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 –reversibleOthers- Nausea , rashes & fever


-Neurological changes

-Hyper uricaemia is due to interference

with urate excretion DoseDose – 15-20 mg/kg , > 50kg -1000mg


Streptomycin (S):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.). - DoseDose- 15 ( 12-18 ) mg/kg, >50 mg- 1000mg


Thiacetazone (TZN) :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, EADRs -ADRs - Hepatotoxic Exfoliative dermatitisStevenson Johnson’s syndrome Can cause bone marrow depressionOthers- Nausea , anorexia , abd. discomfort


Loose motions

Mild anemia

Pruritis

DoseDose- 150 mg OD (2-5 mg/ kg ) ,used in combined tablet with INH

The Basis for Multi-Drug TherapyThe Basis for Multi-Drug Therapy

• Prevent emergence of resistance

1

The Basis for Multi-Drug TherapyThe Basis for Multi-Drug Therapy

Antibacterial attackagainst all

subpopulations of bacilli.

Mitchison, Tubercle 66: 219-226, 1985

Rapid growers

Slowgrowers

INHRifampin

Streptomycin

INH, RifampinEthambutol, PZ

No drug is effective

Rifampin

Spurters

2

Mechanism of ResistanceMechanism of Resistance

Relative activity of first line DrugsRelative activity of first line Drugs

• INH: potent bactericidal• 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 Never use a single drug for chemotherapy in tuberculosis, a combination of two or in tuberculosis, a combination of two or

more drugs must be used.more drugs must be used.

Combination is synergistic


PAS – Paraaminosalicylic acid: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 RifampicinS/E S/E - Acceptability is poor due to frequent anorexia , nausea & epigastric pain


Other use- Goitre

Liver dysfunction

& Blood dyscrasiasDoseDose- 10- 12 gm ( 200 mg/ kg) / day

Rarely used now


Ethionamide :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 CSF


S/ES/E- Anorexia

Nausea & vomiting,

Rashes

Hepatitis ,

Peripheral/ Optic neuritisDoseDose- 1 gm / day, but more than 0.5 gm not tolerated.

- seldom used now , only used in resistance

cases .


Cycloserine (Cycs):Cycloserine (Cycs):

- Obtained from S. archidacces 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 Dose – 250 mg BD

Kanamycin , Amikacin & Capreomycin:

Used as reserved drug in severe cases not

responding to usual therapy


Newer drugsNewer drugs :CiprofloxacinOfloxacinLevofloxacin( all are used in TB & MAC )ClarithromycinAzithromycin( used in MAC )Rifabutin - > in MAC < in TB

Antitubercular TherapyAntitubercular Therapy

Treatment of Tuberculosis :Treatment of Tuberculosis : Remarkable change, conventional 1-1½yr Tt – is replaced by more effective & less toxic

6 month-8 month therapya)a) Rapidly growingRapidly growing with higher bacillary load

e.g. wall of the cavity region- highly suscep. to INH INH & lesser extent to R,E,Sb) Slow growing Slow growing – intracellular & at inflamed

sites – vulnerable to Z while H,R,E are lesser active


c) SpurtursSpurturs - with in caseous material (where O2 tension is less ) the bacilli grow intermittently.

R- R- is most active in this sub population

d) DormantDormant –bacilli remain totally inactive for

prolonged periods- No ATT is effective


Goals-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 relapse3. Prevent emergence of resistance (Drug combination are selected to maximize the above action together with consideration of cost & convenience )

- H & R H & R are most efficacious drugs ,their combination is synergistic


Duration of therapy shortened from 12 to 9therapy shortened from 12 to 9

months.months.

Addition of Z 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-Short course chemotherapy-Regimen of 6-9 months treatmentIn 1997 WHO framed clear cut guidelines for different category of TB treatment .All regimen have initial intensive phase -23 months to rapidly kill the TB bacilli & bringsputum conversion & afford symptomaticrelief followed by continuation phase last4-6 months for elementary remaining bacillit


Categories:Categories:Category I –New ( untreated ) smear +ve pulmonary TBNew ( untreated ) smear +ve pulmonary TB

-New smear –ve pulmonaryTB with extensiveNew smear –ve pulmonaryTB with extensive parenchymal involvementparenchymal involvement -New cases of severe forms of extra- pulmonary-New cases of severe forms of extra- pulmonary

TB e.g.- TB e.g.- meningitis , miliary TB , pericarditismeningitis , miliary TB , pericarditis -B/L or extensive pl. effusion , intestinal or B/L or extensive pl. effusion , intestinal or

genitourinary TB genitourinary TB


((Revised National Tub. Control programmeRevised National Tub. Control programme In India in 1997— DOTs –follow thrice wklyIn India in 1997— DOTs –follow thrice wkly regimen to ↓ cost & it is more practicalregimen to ↓ cost & it is more practical )WHO WHO : - 2HRZE(S) (initial phase)-daily - 4HR or 6HE (continuation phase,)daily total duration 6-8 months 6-8 months

RNTCP :RNTCP :

2H3R3Z3E3 + 4H3R3 -2H3R3Z3E3 + 4H3R3 -total duration- 6month6month


Category II -Smear +ve failure ,relapse & interrupted Tt casesSmear +ve failure ,relapse & interrupted Tt cases

-Relapse- cured TB Patient again become sputum +ve-Relapse- cured TB Patient again become sputum +ve -Tt after interruption –interrupted Tt x 2month →return to -Tt after interruption –interrupted Tt x 2month →return to

sputum + ve casesputum + ve case WHO: WHO: Initial phase –daily Initial phase –daily 2 HRZES +1 HRZE2 HRZES +1 HRZE

Continuation phase Continuation phase –5HRE - 5HRE - total 8 month otal 8 month

RNTCP:RNTCP:

Initial phase -2H3R3Z3E3S3 +1H3R3Z3E3 2H3R3Z3E3S3 +1H3R3Z3E3

Continuation phase -5H3R3E35H3R3E3 –total 8 months


Category III New cases of smear –ve pulmonary TB with limitedNew cases of smear –ve pulmonary TB with limited

parenchymal involvement or severe form of extraparenchymal involvement or severe form of extra pulmonary TB .pulmonary TB .e.g.-Lymph node TB Unilateral pleural effusion Bone (excluding spine ) Peripheral joint & skin TB


WHO :WHO : Initial phase Initial phase -2HRZ (daily)

Continuation phase Continuation phase - 4HR or 6HE (daily)

Total duration-6-8 monthsTotal duration-6-8 months

RNTCP :

Initial phase -Initial phase -2H3R3Z3 ( daily )

Continuation phase -Continuation phase -4H3R3 ( daily )

Total duration- 6 monthsTotal duration- 6 months

CATEGORY-WISE TREATMENTCATEGORY-WISE TREATMENT (WHO1997 & RNTCP1997 (WHO1997 & RNTCP1997)

TB TB

Category Category

Initial Phase Initial Phase

(daily /3xper week) (daily /3xper week)

Continuation Continuation

Phase Phase

(daily/3xper week)(daily/3xper week)

TotalTotal

DurationDuration

i. 2 HRZE(S)/

2H3R3Z3E3

4 HR/ 4H3R3 or 6HE 6

8

ii. 2 HRZES+

1HRZE /

2H3R3Z3E3S3+1H3R3Z3E3

5 HRE or 5H3R3E3 8

8

iii. 2 HRZ/

2H3R3Z3

4 HR/4 H3R3 or 6 HE 6

8


DOTS PLUS: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 2010in 2010

& thus category IV is createdcategory IV is created) .


Cat IV – Chronic cases who have remained or become smear Chronic cases who have remained or become smear

+ve after completing fully supervised Tt / close contact of +ve after completing fully supervised Tt / close contact of most likely MDR cases most likely MDR cases

MDR –TB –Resistant to both H& R H& R & many other anti -TB drugs(Tt difficult because –one or more 2Tt difficult because –one or more 2ndnd line drugs are to be line drugs are to be given for 12-24 months & they are less efficacious , lessgiven for 12-24 months & they are less efficacious , less convenient & more toxic & expensive convenient & more toxic & expensive )


Chronic – presence of association of

AIDS /Diabetes / Leukemia /SilicosisAIDS /Diabetes / Leukemia /Silicosis

-If sensitivity of drugs known then resistant

drugs are excluded -For HH resistance – RZE RZE X 12 months

- For H+ R H+ R resistance- ZE+ S / Kanamycin / ZE+ S / Kanamycin / Capreomycin/ Capreomycin/ + Ciprofloxacin or Ofloxacin ± + Ciprofloxacin or Ofloxacin ± Ethionamide Ethionamide could be used


Extremely drug resistant ( XDR) TB :Extremely drug resistant ( XDR) TB :

Term applied to bacilli that are resistant to at

least 4 most effective cidal drugs 4 most effective cidal drugs i.e. H ,R

Ofloxacin , one of Kanamycin / Amikacin/

Capreomycin.Global survey –reveals 20% TB isolates areMDR out of which 2% are XDR .


TB in pregnant women :TB in pregnant women :WHO WHO – H,R,ZH,R,Z –safe(Recommended - – 2HRZ + 6HR 2HRZ + 6HR regimen -8 month

-EE can be added late -S is C/IS is C/IIn India ZZ is avoided

-(2HRE +7HR total 9 month regimen2HRE +7HR total 9 month regimen )


Breast feeding mother:Breast feeding mother:

All ATT drugs are compatible ,baby should

be watched ,the infant should receive BCGBCG

vaccination & INH prophylaxisvaccination & INH prophylaxis


Indication of Glucocorticoids in TB:Indication of Glucocorticoids in TB: -In TB Pts, glucocorticoidsglucocorticoids if at all used are always

used with AT drugs, they are considered in – - Miliary TBMiliary TB - Tuberculous Meningitis- Tuberculous Meningitis - Rapidly filling Pleural effusion &- Rapidly filling Pleural effusion & - Renal TB ( to reduce exudation & stricture formation- Renal TB ( to reduce exudation & stricture formation) ( Its administration should be withdrawn gradually

when the G.C. of Pts improved ).

RECENT DRUGSRECENT DRUGS

Three novel drugs currently under clinical

development which are active against MDR-TBMDR-TB-

1. Linezolid1. Linezolid

2. OPC-67683, a nitroimidazole2. OPC-67683, a nitroimidazole

3. TMC207, a diarylquinoline3. TMC207, a diarylquinoline

Newer Antitubercular Drugs in Newer Antitubercular Drugs in Clinical TrialsClinical Trials

1.1.LINEZOLIDLINEZOLID ((Also known as 3Also known as 3rdrd line agent 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 .


2.2.TMC207 (R207910 ) by Andries etalTMC207 (R207910 ) by Andries etal in 2005 :in 2005 :• TMC207TMC207 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.


• This drug is metabolized by the hepatic cytochrome CYP3A4.

• Rifampin lowers TMC207 levels by 50%, 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 400 mg/d for the first 2 weeks and then 200 mg thrice weekly.and then 200 mg thrice weekly.

• Adverse effects are reported to be minimal, with nausea and slight prolongation of the QTc interval.


3. OPC-67683 AND PA 824 :OPC-67683 AND PA 824 :

• The prodrugs OPC-67683OPC-67683 and PA 824 PA 824 are novel nitro- dihydro- imidazoxazole derivatives.

• Antimycobacterial activity is due to inhibition of mycolic acid biosynthesisinhibition of mycolic acid biosynthesis.

• Early clinical trials of these compounds are ongoing.

CHANGES IN RNTCP CHANGES IN RNTCP GUIDELINES IN GUIDELINES IN

2010-112010-11

Changes in RNTCP Changes in RNTCP GuidelinesGuidelines

• Discontinuation of Cat III Regimen under RNTCP

• The programme has now revised its The programme has now revised its categorization of patients from the earlier 3 categorization of patients from the earlier 3 categories (Cat I, Cat II and Cat III) to 2 categories (Cat I, Cat II and Cat III) to 2 categories (New and Previously treated categories (New and Previously treated cases)cases)

NEW (CAT I)NEW (CAT I)New Sputum smear-positiveNew Sputum smear-negativeNew Extra-pulmonaryNew Others

PREVIOUSLY TREATED (CAT II)PREVIOUSLY TREATED (CAT II)Smear-positive relapseSmear-positive failureSmear-positive treatment after defaultOthers

TREATMENTTREATMENT

Category Initial Phase Continuation PhaseCategory Initial Phase Continuation Phase

• New (Cat I)New (Cat I) 2H2H33RR33ZZ33EE3 3 4H 4H33RR33

• Previously 2HPreviously 2H33RR33ZZ33EE33SS33/ 5H/ 5H33RR33EE33

Treated Treated 1H1H33RR33ZZ33EE33

(Cat II)(Cat II)

CHEMOPROPHYLAXISCHEMOPROPHYLAXIS

Chemoprophylaxis of TB:Chemoprophylaxis of TB:Prevention of active disease from latent inf.& It is indicated by +ve Mantuox test+ve Mantuox test.Mantuox test / Tuberculin testMantuox 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 induration of > 5 mm & in immunocompromised Pts >10 >10

mm indurationmm induration is considered positive after giving 5 units of PPD .5 units of PPD . Subjects require prophylaxis are –- PPD +ve pts but no active disease- PPD +ve pts but no active disease- -ve PPD but in close contact with TB Pts - -ve PPD but in close contact with TB Pts -Immunocompromised Pts ( having leukemia ,HIV, taking corticosteroid) with-Immunocompromised Pts ( having leukemia ,HIV, taking corticosteroid) with +ve MT+ve MT- HIV inf. Pts . exposed to MDR TB cases- HIV inf. Pts . exposed to MDR TB cases

ChemoprophylaxisChemoprophylaxis

Standard drug is INH daily for 6-12 months.Standard drug is INH daily for 6-12 months.OR: INH + Rifampin daily for 6 months.OR: INH + Rifampin daily for 6 months.

If INH can not be used: Rifampin (4 months)/R+Z (2 months).If INH can not be used: Rifampin (4 months)/R+Z (2 months).MDR: E+Z + FQ.MDR: E+Z + FQ.

THE DEVELOPMENT PIPELINE THE DEVELOPMENT PIPELINE FOR NEW DRUGS, 2010FOR NEW DRUGS, 2010

• Rifaximin Rifaximin : Newer non systemic rifamycin

approved for :

- Traveler's diarrhea, Traveler's diarrhea,

- Hepatic encephalopathyHepatic encephalopathy

- Irritable bowel syndromeIrritable bowel syndrome,

- Small intestinal bacterial overgrowthSmall intestinal bacterial overgrowth &

- Clostridium difficile infection 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 regimensCure all forms of TBCompatible 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 agentsAnti- Leprotic agents

• Also known as Hansen’sHansen’s disease• It is a chronic granulomatous infection caused by Mycobacterium lepraeMycobacterium 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 ArmedillonArmedillon.)


• 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 Anti- Leprotic drugs :Classification-Classification--Sulfone-Sulfone- Dapsone (DDS)-Phenazine derivatives-Phenazine derivatives- Clofazimine-Antitubercular drugs-Antitubercular drugs- Rifampicin Ethionamide-Other Antibiotics Other Antibiotics - Ofloxacin , Minocycline & Clarithromycin


Sulfones -Sulfones -

Derivative of 4-4’ diamino diphenyl sulfone

(DDS)

Dapsone:

-Bacteriostatic

-High risk of resistance if used alone


Mechanism:Mechanism:Similar to sulfonamide i.e. ↓ of dihydrofolatesynthase enzyme.( Anti-inflammatory effect occurs via ↓ ofAnti-inflammatory effect occurs via ↓ oftissue damage by neutrophils by ↓ neutrophil myeloperoxidase activitytissue damage by neutrophils by ↓ neutrophil myeloperoxidase activity,↓activity of neutrophil lysosomal enzyme , free radical scavanger ,↓ of,↓activity of neutrophil lysosomal enzyme , free radical scavanger ,↓ of migration of neutrophils to the inflammatory sites migration of neutrophils to the inflammatory sites )

ADRs:ADRs:-Nausea , vomiting , anorexia-Allergic reaction-Hemolysis in pts with G6PD deficiency-Methemoglobinaemia


• Neurotoxicity & PsychosisSulphone Syndrome:After 5/6 wks of Tt. in malnourished patientsthere may be exacerbation of Lepromatousexacerbation of LepromatousLeprosy Leprosy similar to Jerisch Hexheimerreaction (seen with Penicillin ) ,characterizedby fever, malaise , exfoliative dermatitis ,lymphadenopathy, Jaundice etc.


Indication –Indication –

-Leprosy

-Resistant Malaria ( with pyrimethamine)

-Toxoplasma encephalitis in AIDS

-Pneumocystis jirovecii in AIDS


Clofazimine :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 reactionLepra reaction.

-used for common skin ulcers & MACS/ES/E- Red discolouration of skin - Eosinophilic enteritis


Rifampicin :Rifampicin :- Important antiTb drug also bactericidal tobactericidal to M. Leprae.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)

EthionamideEthionamide - Has significant antileproticantileprotic

activity but is hepatotoxicactivity but is hepatotoxic . It can be used

as an alternative to Clofazimine but other

substitutes are preferred.


Other Antibiotics:-FluoroquinolonesFluoroquinolones : Ofloxacin , Pefloxacin, Gatifloxacin are highly active against M. leprae ( but not Ciprofloxacin but not Ciprofloxacin )-MinocyclineMinocycline: due to high lipophilicity, it is active against M. leprae. , antibacterial activity is less than Rifampicin but more than that of Clarithromycin .


ClarithromycinClarithromycin :

Only macrolide antibiotic having significant activity against M. leprae . It is being included in alternative MDT regimensincluded in alternative MDT regimens.


Diagnosis of Leprosy: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 LeprosyTreatment of Leprosy

• Leprosy primarily affect skin , mucous membranes & nerves

• Prevalent in poors ( low socioeconomic

strata ) .

• National Leprosy Control Programme National Leprosy Control Programme launched in 1955 launched in 1955

• It was changed to National Leprosy National Leprosy

Eradication Programme ( NLEP) in 1982Eradication Programme ( NLEP) in 1982


• India achieved elimination of Leprosy as

a public health problem .

• Incidence is less than 1 case/ 10,000

population .


Classification:Classification:1. Indeterminate2. Tuberculoid3. Borderline4. Lepromatous5. Pure neuritis ( no skin lesion )Tuberculoid:Tuberculoid: Well defined skin lesion


-anesthetic patches

-Organism may or may not be found in skin

lesions.

-Lepromine test is positive Lepromine test is positive (diagnostic fordiagnostic for

Leprosy. It evaluate the immune system ofLeprosy. It evaluate the immune system of

the patient & classify the type of diseasethe patient & classify the type of disease.)

-prolonged remission occurs


Lepromatous: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 Lepromine test is –ve ( as cell mediatedas cell mediated immunity is absentimmunity is absent )-Smear is +ve for organism Smear is +ve for organism .For treatment purpose –leprosy is classifiedas- Multibacillary Multibacillary - It includes lepromatous, borderline cases with +ve skin smear test Tt- Rifampicin - 600 mg / month supervised600 mg / month supervised


Dapsone-100 mg / day self administration100 mg / day self administration

Clofazimine – 300 mg/ month supervised300 mg/ month supervised

+ 50 mg/ day self administration+ 50 mg/ day self administration X 2 years- relapse – repeatX 2 years- relapse – repeat

PaucibacillaryPaucibacillary : ( small no. of organism)- It includes indeterminate & tuberculoidTt- Rifampicin – 600 mg / month supervised600 mg / month supervised

Dapsone – 100 mg / day self administration100 mg / day self administration

X minimum for 6 months-repeat if relapseX minimum for 6 months-repeat if relapse


Single lesion paucibacillarySingle lesion paucibacillary –single dosesingle dose

ROM- Rifampicin-600 mg + Ofloxacin - 400mg + ROM- Rifampicin-600 mg + Ofloxacin - 400mg + Minocycline-100 mgMinocycline-100 mg

(MDT was introduced by the WHO in 1981& was implemented under the NLEPNLEP ( National Leprosy Eradication ProgrammeNational Leprosy Eradication Programme). It includes Dapsone , Rifampicin & Clofazimine Dapsone , Rifampicin & Clofazimine . The WHO in 1994 recommended a fixed duration therapy( FDT) of 2 years for MBL 2 years for MBL & 6 6 months for PBL months for PBL . WHO expert committee On Leprosy in 1995 recommended shortening of MDT in MBL to 12 months shortening of MDT in MBL to 12 months & this was implemented in our country since 1999 implemented in our country since 1999 . The purpose of this is to render the Pts noncontiguous & therefore cut down transmission 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 isin case of Rifampicin resistance or when MDT is

not advisable not advisable e.g.- ClofazimineClofazimine + any two of Ofloxacin / Minocycline/ ClarithromycinOfloxacin / Minocycline/ Clarithromycin

for 6 months followed by Clofazimine + Clofazimine + any one of any one of Ofloxacin /Ofloxacin /

Minocycline 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 single dose of Rifampicin -600 mg + Ofloxacin-Ofloxacin-400 mg

+ MinocyclineMinocycline -100 mg. This has been recommended by the This has been recommended by the WHO for WHO for solitary lesion of PBLsolitary lesion of PBL.).)


Two types of reactional state may occur

with therapy1.1. Type IType I : Lepra reaction Lepra reaction (reversal reaction) In borderline leprosyborderline leprosy due to increased in host immunity- skin lesion & nerves become swollen & tender without systemic manifestation – Tt. – PrednisolonePrednisolone (Thalidomide not effectiveThalidomide not effective)


Type IIType II :Lepra reaction ( erythema nodosum leprosum) –observed in lepromatous lepromatous

leprosyleprosy – there is skin & nerve manifestation with fever & systemic involvement.

Tt.- by analgesic /antipyretic for mild cases, in severe cases-PrednisolonePrednisolone or Thalidomide.Thalidomide. -ChloroquineChloroquine & cytotoxic drugs are also effective.


-ClofazimineClofazimine require 3-4 wks so not suitable

for acute cases, but useful in chronic but useful in chronic cases & prevention of this reaction cases & prevention of this reaction .

- No need to stop the antileprotic drugs .

MCQsMCQs• 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)

•

MCQsMCQs• 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)•

MCQsMCQs• 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 )

MCQsMCQs• 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)

MCQsMCQs• 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 )•

MCQsMCQs

• 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 )•

BibliographyBibliography

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)