PULMONARY TUBERCULOSIS

Presented By:

Anindya Banerjee

Pharmacovigilance Associate

Dept of Pharmacology

NRS Medical College, Kolkata

INTRODUCTION

Tuberculosis is a chronic Infectious disease • caused by M.tuberculosis/M.bovis• mainly affecting the lung causing Pulmonary TB• also affect other parts causing Extra Pulmonary TB

Characterized by

•Cough lasting > 3 wks and not respond to usual antibiotic.•Production of purulent, sometimes blood- stained sputum

•Evening rise of temp.•Night sweats•Weight loss

CHARECTERISTICS OF M. TUBERCULOSIS

gram +ve bacilli Non motile, non sporing,&

noncapsulated Strict aerobes Branching filamentous forms ≈

fungal mycelium =>MYCOBACTERIUM

A.F.B => when stained by Carbol Fuschin by

Z-N Stain they resist decolorisation by 25% H2S04 &Abs.alcohol

Cell wall is lipid rich with mycolic acid which is essential & unique component

CAUSES:The primary cause of TB, Mycobacterium tuberculosis , is a small  aerobic  non-motile  bacillus.

The M. tuberculosis complex includes four other TB-causing  mycobacteria: M. bovis, M. africanum, M. canetti  and M. microti. M. africanum is not widespread, but in parts of Africa it is a significant cause of tuberculosis.

The high lipid content of this pathogen accounts for many of its unique clinical characteristics.

 M. microti is mostly seen in immunodeficient people, although it is possible that the prevalence of this pathogen has been underestimated.

RISK FACTORS OF TUBERCULOSIS

Signs and symptoms:When the disease becomes active, 75% of the cases are pulmonary TB, that is, TB in the lungs. Symptoms include  chest pain, coughing up blood, and a productive, prolonged cough for more than three weeks. Systemic symptoms include  fever, chills, night sweats, appetite loss, weight loss, pallor, and often a tendency to  fatigue very easily.

In the other 25% of active cases, the infection moves from the lungs, causing other kinds of TB, collectively denoted extrapulmonary tuberculosis. This occurs more commonly in immunosuppressed persons and young children. Extrapulmonary infection sites include the  pleura in tuberculosis pleurisy, the central nervous system in  meningitis, the lymphatic system in  scrofula of the neck, the genitourinary system in urogenital tuberculosis, and bones and joints in Pott's disease of the spine.

Transmission of the disease Pulmonary tuberculosis is a disease of

respiratory transmission, Patients with the active disease (bacilli) expel them into the air by:– coughing, – sneezing, – shouting,– or any other way that will expel bacilli into

the air Transmission is dependent on closeness and

time of contact Once inhaled by a tuberculin free person, the

bacilli multiply 4 -6 weeks and spreads throughout the body. The bacilli implant in areas of high partial pressure of oxygen:

lung renal cortex reticuloendothelial system

EPIDEMIOLOGY:It is currently estimated that 1/2 of the world's population (3.1 billion) is infected with Mycobacterium tuberculosis. Mycobacterium avium complex is associated with AIDS related TB.

 The proportion of people who become sick with tuberculosis each year is stable or falling worldwide but, because of population growth, the absolute number of new cases is still increasing.

 In 2007 there were an estimated 13.7 million chronic active cases, 9.3 million new cases, and 1.8 million deaths, mostly in  developing countries.

The distribution of tuberculosis is not uniform across the globe; about 80% of the population in many Asian and African countries test positive in tuberculin tests, while only 5-10% of the US population test positive.

Most TB cases were in India and China

10 000 - 99 999

100 000 - 999 999

< 1 000

1 000 - 9 999

No estimate

Number of cases

1 000 000 or more

Asia59%Africa

21%

Problem of TB in India• Estimated incidence

– 1.96 million new cases annually– 0.8 million new smear positive cases annually– 75 new smear positive PTB cases/1lakh population per year

• Estimated prevalence of TB disease– 3.8 million bacillary cases in 2000 – 1.7 million new smear positive cases in 2000

• Estimated mortality– 330,000 deaths due to TB each year– Over 1000 deaths a day– 2 deaths every 3 minutes

Gopi P et al (TRC), IJMR, Sep 2005

Problem of TB in India (contd)

• Prevalence of TB infection – 40% (~400m) infected with M. tuberculosis (with a 10% lifetime risk

of TB disease in the absence of HIV)

• Estimated Multi-drug resistant TB– < 3% in new cases– 12% in re-treatment cases

• TB-HIV– ~2.31 million people living with HIV (PLWHA)– 10-15% annual risk (60% lifetime risk) of developing active

TB disease in PLWHA– Estimated ~ 5% of TB patients are HIV infected

India is the highest TB burden country accounting for more than one-fifth of the global incidence

Indonesia6%

Nigeria5%

Other countries20%

Other 13 HBCs16% China

14%

South Africa5%

Bangladesh4%

Ethiopia3%

Pakistan3%

Phillipines3%

India21%

Source: WHO Geneva; WHO Report 2009: Global Tuberculosis Control; Surveillance, Planning and Financing

Global annual incidence = 9.4 million

India annual incidence = 1.96 million

India is 17th among 22 High Burden Countries (in terms of TB incidence rate)

PATHOGENESIS OF TUBERCULOSIS

Pathogenesis in a previously

unexposed ,immunocompetent person depends

on the development of anti-mycobacterial cell

mediated immunity,which confers resistance to

bacteria and development of hypersensitivity to

mycobacterial antigens.

Pathologic manifestation of tuberculosis like

caseating granuloma and cavitation are result

of hypersensitivity that develops in concert

with the protective host immune response.

Macrophages are the primary cells infected

by M.tuberculosis.

Diagnosis of Pulmonary TB Routine investigations- Hb, TLC,

DLC (lymphocytosis), ESR.

Chest x-ray-

• Abnormalities often seen in apical

or posterior segments of upper lobe

or superior segments of lower lobe.

• May have unusual appearance in

HIV-positive persons.

• Cannot confirm diagnosis of TB.

15

Arrow points to cavity inpatient's right upper lobe.

TUBERCULIN (MONTOUX )TEST

The Mantoux skin test consists of an intradermal injection of 5 IU PPD is extensor aspect of forearm tuberculin.

The size of induration is measured 48–72 hours later. Erythema (redness) should not be measured.

Mantoux test injection site in a subject without chronic conditions or in a high risk group clinically diagnosed as negative at 50 hours.

SPUTUM EXAMINATION – Sputum examination are essential to confirm TBBest collected in morning before any meal.Sputum examination on 3 days increase chances of detection.Sputum can be collected from laryngeal swab or bronchial washing.In small children, gastric lavage can be examined.Smear should be prepared from thick dirty part of sputum & stained with Ziehl-Neelson technique.

Culture - Use to confirm diagnosis of Tuberculosis.

Conventional cultures take up to 10 weeks.

Culture all specimens, even if smear report is negative.

Culture is done in Lowenstein Jansen media.

Susceptibility testing is essential.

Result in 4-14 days when liquid medium system is used.

For example- BACTEC can confirm TB growth within one week by indirectly

measuring TB bacilli growth in special bottles and medium.

Difficult to treat:

1. Most antibiotics are effective against rapidly growing organism in contrast to M.tb slow growing

2. Mycobacterium Cell can be dormant, thus completely resistant to many antibiotics or killed very slowly by few drugs

3. The lipid rich mycobacterium Cell wall is impermeable to many drugs.

4. A substantial proportion are intracellular &chemotherapeutic agents penetrate poorly

5. Mycobacterium =>develop resistance to any single drug

6. Caseation &fibrosis block the b.v. supplying necrotic area thus penetration of antitubercular drug difficult

TREATING TB DISEASE(GENERAL PRINCIPLES)

Always treat with multiple drugs.

Never add a single drug to a failing regimen.

DOTS (Directly Observed Treatment Shortcourse) is given.

Treatment course depends on the categories of the patient.

Usually 6 months, sometimes 9 months.

Four drugs for two months.

Isoniazid – Rifampicin – Ethambutol - Pyrazinamide

Two drugs for four or seven months.

Isoniazid - Rifampicin

19

Classification of AntitubercularDrugs

First line Drug(Essential AntiTB) High Anti TB effect Acceptable degree of toxicity Used routinely

- ISONIAZID(H) -RIFAMPICIN(R) -PYRAZINAMIDE(Z) - ETHAMBUTOL(E) - STREPTOMYCIN(S)

Contd.• SECOND LINE DRUG (RESERVE ANTI TB DRUG)

-low anti tb effect - high toxicity -or both -used in special circumstances only

1. Fluroquinolone- Ciprofloxacin, Ofloxacin, Levofloxacin, Moxifloxacin2. Amikacin3. Capreomycin4. Ethionamide5. Para Amino salicylic Acid (PAS)6. Cycloserine7. Thiacetazone

Newer Drugs: a) Linezolidb) R-207910 (also known as TMC 2007)

ISONIAZID(INH) Salient features: 1) Most active antitb drug 2)Important assets are -potency -infrequent toxicity -low cost 3)Bactericidal for rapid growers 4)Useful for tb meningitis 5)Effective for both extra cellular & intracellular tb 6)If combined with other drug it has good

resistance preventing action

Mechanism of Action ISONIAZID Kat G(catalase peroxidase in mycobacteria) Active INH

AcpM & Kas AcpM-Acyl Carrier protein KasA( ßketoAcyl Carrier protein synthetase)

Block Mycolic Acid Synthesis

Pharmacokinetics Absorption: complete orally. Oral dose=Parenteral dose

Distribution: penetrate all body tissue Placenta Meninges Caseous tb lesion

Metabolism: In liver by N- Acetyltransferase, to acetylisoniazid. Generic variation has been observed in its rate of N- Acetylation which is inherited as autosomal recessive trait.

• Indians are rapid acetylators while egyptians are slow acetylators.

• Excretion: 75-95% excreted in urine

-Dose adjustment is not required in Renal Failure

-INH & Acetyl Hydrazine are not bound to P.P, thus dialyzable

Contra Indication: - KNOWN HYPERSENSITIVITY

-ACUTE HEPATIC DISEASE

Drug interaction

• Inhibit metabolism of Warfarin,Diazepam,Disulfiram

• Abs.impaired by Al(OH)3

• PAS inhibits the metabolism of INH

Adverse Effect:-I. Rash

II. Peripheral Neuropathy

III. Hepatitis

IV. Transient loss of Memory

V. Seizure

HEPATOTOXICITY -Acetyl Hydrazine cause the damage -↑in Serum Transaminase -Can be fatal if not withdrawn promptly

Clinical Use Therapeutic: Essential component of all AntiTB Regimen Prophylactic: -Transmission to close contact -Baby born to inf.mother -Development of active TB in immunodeficient individuals

Doses of INHI. 5mg/kg/dayII. 10mg/kg/A.DIII. 10mg/kg/day –in serious infection -If malabsorbtion is a problem

IV. Prophylactic: 5mg/kg/day

RIFAMPIN(R)Semisynth. deri of Rifamycin B-from St.meditarraneiBactericidal ,affect all subpopulation of

M.tb.acts best on Spurters &slow growingActs both extra &intracellularlyGood sterilising property &resistance preventing

actionBactericidal efficacy ≈ INH

&>any other 1st line drugAnalogue of RIFAMPIN isRIFABUTIN

obtained from Rifamycin S

Bactericidal EfficacyInhibits - Gm+ve -Gm-ve -Mycobact.inf -M.tb,M.leprae,M.kansassi Important ones are -H.influenzae -N.meningitis -Legionella -Brucella -M.R.S.A

M.O.A Of RifampicinNormal synthesis of RNA from DNA by DNA dependent RNA polymerase (DDRP)

D.N.A DNA dependent R.N.A.polymerase R.N.A Protein Syn. Cell multiplication Rifampicin bind to β S.U of DDRP Drug –Enz Complex Suppression of chain initiation

Pharmacokinetics

Abs: -Well absorbed from g.i tract -PAS interferes with abs. -Food also interferes with abs.Dist: -wide. Penetration to

•Cavities •Meninges •Caseous Mass •PlacentaRifampicin causes an orange red coloration of

body secretion due to various aspect of Rifampin metabolism

P/K Contd.Metabolism

Following abs. from G.I. Tract Eliminated rapidly in the bile&undergoes Enterohepatic Circulation Rifampin is progressively deacetylated This metabolite is bactericidal

T1/2 varies from 1.5-5 hrs

EXCRETION: Urine-30% Faeces 60-65% Recycling through liver by excretion in bile, reabsorption from intestines

into portal circulation, passage back into liver, and re-excretion in bile.

Doses of Rifampin

Doses- 10mg/kg/day

10mg/kg/Alt.dayC/I –k/c/o history of h/s to Rifamycin

-Hepatic DysfunctionPrecaution –Careful monitoring of L.F.T.

-In elderly

- In alcoholics

-Pts. having hepatic disease

Side Effects:

1)Hepatitis2)Exfoliative Dermatitis in H.I.V +ve3)Fever, Thrombocytopenia, Haemolytic anemia4)Flu like Syndrome

Adverse Effects:

Orange – Red Colour urine.

Drug Interactions of RIFAMPIN

Strongly induces CYTP450 isoforms

Oral Contraceptive PillOral anticoagulantAntiretroviral drugs –PI & NNRTI except EFAVIRENZAntifungal Drugs –Ketoconazole

USES OF RIFAMPIN

1)Mycobacterial infection

☻M.tb

☻M.leprae

☻Atypical mycobacteria

-M.kansassi

-M.intracellulare

-M.marinum

2)Other indications

a)meningococcal meningitis-carrier state 600mg B.D for 2 daysb)H.influenzae meningitis –close contact 20mg/kg/dayfor 4daysc)Legionella infection -Along wiyh Erythromycind) Serious staphylococcal infection like - osteomylitis -prosthetic Valve Surgerye)Brucellosis –Along with Doxycyclinef)MRSA g)T/t of meningitis caused by highly penicillin resistant strain

PYRAZINAMIDE(Z)Synthetic analogue of NicotinamideThough weakly tuberculocidal More active in acidic mediumHighly effective during 1st 2monthsMore effective against Slow GrowingActive both intra&extracellularly Including Z in combination tharapy -duration of t/t is ↓ -It has potent sterilising action -Risk of relapse is reduced

MOA Of Pyrazinamide Pyrazinamide

Mycobacterial Pyrazinamidase

Pyrazinoic Acid

Inhibits Mycolic Acid Synthesis

Resistance due to mutation of gene pncA, A few pyrazinamidase resistant strains with mutations in the rpsA gene have also been identified.

Pharmacokinetics

Absorption: Well absorbed from g.i.tract Distribution: good penetration to all body tissue &

CSF Metabolism: Pyrazinamide

Pyrazinoic Acid

5-OH pyrazinoic Acid T1/2 6-10hrs Dose: 25mg/kg/day once Daily 35mg/kg/day thrice in a week.

Adverse Effects:1)Hepatotoxicity: Most hepatotoxic SGOT &SGPT Serum Bilirubin C/I-Not to be given with any degree of hepatic dysfn2)Inhibits the excren of ureates Hyperuracemia Acute episodes of Gout3)Joint pain ,Arthralgia

ETHAMBUTOL(E)

Tuberculostatic ,active against

M.tb

M.A.C

M.intracellularaeRapid Growers are more susceptibleHastens the rate of sputum conversionPrevent the emergence of Resistant bacilli

M.O.A of Ethambutol

Ethambutol Mycobact. Arabinosyl Transferase Polymerisation reaction of Arabinoglycan Essential component of

Mycobacterial Cell wall

Ethambutol inhibits the enzyme Mycobacterial Arabinosyl Transferase, which is required for polymerisation reaction of Arabinoglycan

Pharmacokinetics

Abssorption: Well absorbed from g.i.t. Distribution: Wide,penetrates the meninges Metabolism: Hepatic T1/2 ~ 4hrs

Excretion :-unchanged in urine(3/4th)

-Excreted by G.F& T.S

-Dose to be reduced in Renal failure C/I ; Cr. Clearance <50ml/min

Doses of Ethambutol : usual daily dose - 15mg/kg/day

30mg/kg/day can be given thrice in a week orally.

Adverse Effects: 1)RETROBULBAR NEURITIS :causing

-Loss of Visual Acuity - Red Green Color blindness

Early recognition &stoppage of drug-

visual toxicities is largely reversible

Contra-indication ;In children <6yrs

a) they are unable to report early.

b) may not permit the assessment of Vascular Acuity

& red green color blindness discrimination

2) Renal uric acid excretion

Hyperuricemia

3)Pruritus, Joint Pain

First-line Supplement Drug

Aminoglycoside from Str.griseus 1st clinically active against Mycobact. Limitation of its use i)dose related toxicity ii)devlopment of resistant org. iii)pt compliance is poor due to i.m Present status: -Least used 1st line A.T.D

-More active against extracellular bacilli -Inactive against intracellular bacilii

STREPTOMYCIN(S)

1.Streptomycin2.Rifabutin3.Rifapentine

Mechanism of Action of Streptomycin

Streptomycin is a protein synthesis inhibitor. It binds to the small 16S rRNA of the 30S subunit of the bacterial ribosome, interfering with the binding of formyl-methionyl-tRNA to the 30S subunit.

-Protein Syn . Is hampered *Interferes with chain initiation *Induce misreading of mRNA * Incorporation of incorrect Amino Acid into peptide Formation of Nonfunctional /toxic protein *Cause break up of polysomes into monosomes IRREVERSIBLE &LETHAL FOR CELL

This results in an unstable ribosomal-mRNA complex, leading to a frameshift mutation and defective protein synthesis; leading to cell death.

Pharmacokinetics

Neither absorbed / destroyed in G.I.Tract. Absorption from inj site is rapid (30-60min) Distributed to Extracellular TB cavities. Not metabolized, Excreted unchanged in urine

Adverse Effects:i)OTOTOXICITY-drugs get conc. In labrynthine fluid, both vestibular &

cochlear damage

ii)NEPHROTOXICITY

iii)Neuro Muscular PARALYSIS -Ach release,

sensitivity of post.syn. receptors.

iv)Sterile abscess at the inj. site

Contra Indication:

- Not to be given in pregnancy

-Avoid use with other ototoxic drug eg;High ceiling diuretics,Minocycline,Cisplatin

-Avoid use of other nephrotoxic drug eg;Amphotericin B, Vancomycin,Cyclosporin,Cisplatin

-Pts with renal disease.

-Cautious use with muscle relaxant.

Uses Sensitive to M.tb Mycobacterium Avium Complex M.kansassi It is as an important drug when inj. form is needed- -especially with severe & life threatening

condition. -TB meningitis -Miliary TB

Dose:15mg/kg/D 15mg/kg/A.D

Rationale behind Combination Therapy

To prevent emergence of resistant bacilliDrugs like H & R act synergistically & Z is more active during the inflammatory statesDuration of treatment is reducedTo act simultaneously with all subpopulation of

Mycobacterium tuberculosis

Aminoglycosides: least effective and more toxic Capreomycin - Viomycin – KanamycinAdverse effects:These drugs are: Nephrotoxic will cause

Proteinuria, Hematuria, Nitrogen metabolism, and Electrolyte disturbances However effect is reversible when drug is stopped

Capreomycin has replaced viomycin because of less toxic effects, but all three drugs have the same effects.

Second line drugs:

Can cause CNS disturbances Therapeutic States :

Cycloserine should be used when re-treatment is necessary or when the micro-organism is resistant to the other drugs.

It must be given in combination with other anti-tuberculosis drugs.

Mechanism of Action : An analog of D- alanine synthetase, will block

bacterial cell wall synthesis.

Cycloserine:

cys absorbed orally, diffuses all over.

About 1/3 of a dose is metabolised the rest is excreted unchanged by kidney.

Toxicity: Most common in the CNS: Headache, Tremor,

Vertigo, Confusion, Nervousness,

Pharmacokinetics:

These are first anti tubercular drugs.It is a tuberculostatic drug.Low efficacy drug.Side effects: hepatitis, optic neuritis, mental disturbences impotence

Thioacetazone & Ethionamide:

PAS is a tuberculostatic and one of least active drugs.

It inhibits denovo folate synthesis.PAS is completely absorbed by oral route and

distributed all over .T1/2 is 1hr.Patient acceptability of PAS is poor.Adverse effects ; Rashes, fever, liver dysfunction

Para-amino salicylic acid:

ChemotherapyDOTS (Directly Observed Treatment Shortcourse) :

To control tuberculosis requires: Effective, inexpensive, simple and standardised technology.The success of the DOTS strategy depends on: Government commitment to a national tuberculosis

programme. Case detection –finding by smear microscopy examination

of TB susceptible in general health services. Regular uninterrupted supply of essential anti-TB drugs. Monitoring system for programme supervised and

evaluation.

Short Course Chemotherapy:

These are regimens of 6-9 month duration.

All regimens have an initial intensive phase lasting 2-3 months to kill the TB bacilli and afford symptomatic relief.

This is followed by continuation phase for 4-6 months so that relapse does not occur.

Type of patient Duration of treatment Regimen

Category-11.New sputum positive2.Seriously ill, sputum negative, Pulmonary3.Seriously ill

Intensive phase(2months)

Continuation phase(4months)

INH+RMP+ETB+PZA

INH+RMP

Category-2Retreatment group1.Relapse2.Treatment failure

Intensive phase(3months)

Continuation phase(5months)

INH+RMP+ETB+PZA

INH+RMP+ETB

Category-31.New smear negative pulmonary2.extrapulmonary

Intensive phase(2months)

Continuation phase(4months)

INH+RMP+PZA

INH+RMP

REGIMENS :

Resistance to both Isoniazid and Rifampin and number of other anti-TB drugs . MDR-TB has a more rapid course ,(some die in 4-16 weeks).

Treatment is difficult as  second line drugs are less efficacious, less convenient, more expensive and

toxic. Therapy depends on drugs used in earlier regimen, dosage and

regularity with which they have been taken. In India>200,000patients have been treated under DOTS by

early 2001 with cure rate of 75-80%. In other countries 80-93%cure rates have been obtained.

Multiple Drug Resistance(MDR):

Extensively Drug Resistant TB (XDR TB) is a form of TB caused by bacteria resistant to all the most effective Drug [i.e., MDR-TB plus resistance to any Fluroquinolone (FQ) and any of the second line anti TB injectable drugs: Amikacin, Kanamycin, Capreomycin

Extensively Drug Resistant TB (XDR- TB)

MDR/XDR Treatment Strategies: WHO

Three approaches to treatment: Standardized regimens Empiric regimens Individualized treatment regimens

(based on DST results)

The choice among these should be based on: Availability of second-line drugs Local drug-resistance patterns, and the history of use of

second-line drugs Drug susceptibility testing of first- and second-line drugs

Use any available

One of these

One of these

First-line drugs Fluoroquinolones Injectable

agents

Pyrazinamide

Ethambutol

Levofloxacin

Moxifloxacin

Ofloxacin

Amikacin

Capreomycin

Streptomycin

Kanamycin

Building a Regimen for MDR-TB STEP 1

Begin with any first-line agents to which the isolate is susceptible

Add a fluoroquinolone and an injectable drug based on susceptibilities

PLUS PLUS

Pick one or more of these

Oral second-line drugs

CycloserineEthionamidePAS

Building a Regimen for MDR-TB STEP 2

If 4 drugs are not identified in Step 1:Add second-line drugs until you have four to six drugs to which the isolate is susceptible (and preferably which have not been used to treat the patient previously)

Consider use of these

Third-line drugs

Clofazimine

Linezolid

Amoxicillin/Clavulanate

Imipenem

Clarithromycin

STEP 3

Building a Regimen for MDR-TB

If there are not four to six drugs available in the abovecategories, consider third-line drugs in consultation with an expert.

Building a Regimen for XDR-TB STEP 1

Begin with any first-line agents to which the isolate is susceptible

Add a fluoroquinolone and an injectable drug based on susceptibilities

Use any available

One of these

One of these

First-line drugs Fluoroquinolones Injectable

agents

Pyrazinamide

Ethambutol

Levofloxacin

Moxifloxacin

Ofloxacin

Amikacin ?

Capreomycin ?

Streptomycin ?

Kanamycin ?

Commonly not susceptible

By definition there is fluoroquinolone resistance

Select agent based on historyand susceptibility testing

PLUS PLUS

STEP 2

Building a Regimen for XDR-TB

Add second-line drugs until you have four to six drugs to which the isolate is susceptible (and preferably which have not been used to treat the patient previously)

Pick one or more of these

Oral second-line drugs

CycloserineEthionamidePAS

With XDR-TB, often all three of these agents are necessary

STEP 3

Building a Regimen for XDR-TB

If there are not four–six drugs available in the above categories, consider third-line drugs in consultation with an expert.

Consider use of these

Third-line drugs

Clofazimine

Linezolid

Amoxicillin/Clavulanate

Imipenem

Clarithromycin

• Ensure laboratory services for hematology, biochemistry and audiometry are available

• Establish a clinical and laboratory baseline before starting the regimen

• Initiate treatment gradually when using drugs that cause gastro-intestinal intolerance

• Ensure availability of ancillary drugs to manage adverse effects

• Use DOT for all doses

Initiating Treatment: WHO

• Isolate until three consecutive sputum AFB smears (or documented culture conversion) are negative and there has been a good clinical response to treatment

• Initiate MDR-TB treatment under close supervision to provide patient education and monitoring and to treat drug toxicity

• Tailor toxicity monitoring to specific drugs employed

• Seek consultation with an expert as soon as drug resistance is known

MDR/XDR-TB: Management Principles

• Use daily patient-centered DOT throughout entire treatment course

• Record drugs given, bacteriological results, chest radiographic findings, and the occurrence of toxicities

• Optimize management of underlying medical conditions (example: diabetes) and nutritional status

MDR/XDR-TB: Management Principles

MDR/XDR-TB: Monitoring

• Collect sputum specimens for smear and culture periodically during treatment once culture negative

• Obtain end-of-treatment sputum specimen for smear and culture

• Perform chest radiograph periodically during treatment and at end of treatment

• Resources permitting, monitor minimum of two years following treatment (quarterly during first year, every six months during second year)

RNTCP

Evolution of TB Control in India

• 1950s-60s Important TB research at TRC and NTI• 1962 National TB Programme (NTP)• 1992 Programme Review

• only 30% of patients diagnosed; • of these, only 30% treated successfully

• 1993 RNTCP pilot began• 1998 RNTCP scale-up • 2001 450 million population covered• 2004 >80% of country covered • 2006 Entire country covered by RNTCP

Objectives of RNTCP

• To achieve and maintain a cure rate of at least 85% among newly detected infectious (new sputum smear positive) cases

• To achieve and maintain detection of at least 70% of such cases in the population

RNTCP Organization structure: State levelHealth Minister

Health Secretary

MD NRHM Director Health Services

Additional / Deputy / Joint Director(State TB Officer)

State TB CellDeputy STO, MO, Accountant, IEC Officer, SA, DEO, TB HIV Coordinator etc.,

State Training and Demonstration Center (TB)Director, IRL Microbiologist, MO, Epidemiologist/statistician, IRL LTs etc.,

One/ 100,000

(50,000 in hilly/ difficult/

tribal area)

One/ 500,000 (250,000 in hilly/ difficult/ tribal area)

TB Health Visitors (TBHV), DOT Provider (MPW, NGO, PP, ASHA,Community Volunteers)

Medical Officer, paramedical staff And Laboratory Technician (20-50%)

Medical officer-TB Control,Senior Treatment supervisor(STS), Senior TB Laboratory Supervisor(STLS)

District Health Services

District TB Centre

Tuberculosis Unit

Microscopy Centre

DOT Centre

Nodal point for TB control

Structure of RNTCP at district levels

Chief Medical Officer and other supporting staff

District Administration District Magistrate/District Collector

DTO, MO-DTC (15%), LT, DEO, Driver, Urban TB Coordinators, TBHVs, Communication Facilitators

Unique features of RNTCP

• District TB Control Society

• Modular training

• Patient wise boxes

• Sub-district level supervisory staff (STS, STLS)

for treatment & microscopy

• Robust reporting and recording system

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

110%

120%

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Annualised New S+ve CDR Success rate

•Population projected from 2001 census•Estimated no. of NSP cases - 75/100,000 population per year (based on recent ARTI report)

Annualized New Smear-Positive Case Detection Rate and Treatment Success Rate in DOTS Areas, India, 2000-2009*

Impact of RNTCP• Cure rate more than doubled compared with earlier NTP,

85% global target consistently achieved 2003 onwards

• Case detection rate is more than 70%

• Case fatality reduced from 29% to 4% in NSP cases, and deaths due to TB from 500,000 to <330,000 a year

• Over 11 million patients initiated on DOTS, and over 2 million additional lives saved