Anti Tuberculous Drugs And Patient Counseling

Dr. Yamini D. ShahAssociate Professor

L.M.College Of Pharmacy, Ahmedabademail id: ydslmcp@gmail.com

TUBERCULOSIS ?• Chronic granulomatous disease caused

by Mycobacterium tuberculosis.

• Tuberculosis typically attacks the lungs,

but can also affect other parts of the

body.

• It is spread through the air when people

who have an active TB infection cough,

sneeze, or otherwise transmit respiratory

fluids through the air.

TUBERCULOSIS AND GLOBAL CHALLENGESTuberculosis (TB) persists as a global public health problem of serious magnitude

requiring urgent attention. Current global efforts to control TB have three distinct but

overlapping dimensions: humanitarian, public health, and economic.

MAGNITUDE OF THE PROBLEM

Source: WHO Geneva; WHO Report 2013: Global Tuberculosis Control; Surveillance, Planning and Financing

Global annual incidence = 9.1 million

India annual incidence = 1.9 million

India is 17th among 22 High Burden

Countries (in terms of TB incidence rate)

PROBLEM OF TB IN INDIA

ESTIMATED INCIDENCE OF TB IN INDIA*

National 75 North Zone 95East Zone 75**West Zone 80South Zone 75**

North

West East

South** For programme monitoring purpose estimated cases in East & South zones have been kept at the national level of 75 and this is within the upper limit of CI or ARTI in these zones

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

SOCIAL AND ECONOMIC BURDEN OF TB IN INDIA

Estimated burden per year

• Indirect costs to society $3 billion

• Direct costs to society $300 million

• Productive work days lost due to TB illness 100 million

• Productive work days lost due to TB deaths 1.3 billion

• School drop-outs due to parental TB 300,000

• Women rejected by families due to TB 100,000

TRC, Socio-economic impact of TB on patients and family in India, Int J Tub Lung Dis 1999 3: 869-877

PHYSIOLOGY & STRUCTURE Gram +ve , aerobic acid fast bacilli.

Resistant to disinfectant ,detergent.

Capable of intracellular growth.

Human are the only natural reservoir.

TUBERCULOSIS DIAGNOSIS

Clinical (presenting symptomsTB)

Diagnostic Imaging(X-Rays)

Bacteriology (smears, cultures)

Pathology of biopsy specimens

Epidemiological Factors

Medical History

• HIV status

• Symptoms of disease

• History of TB exposure, infection, or disease

• Past TB treatment and Demographic risk factors for TB

• Other medical conditions that increase risk for TB disease

EVALUATION TEST FOR TB

Emerging Rapid Methods Fast Plaque TB uses phage amplification technology.

ELISA(QuantiFERON–TB)

Enzyme-Linked immuno spot (ELISPOT). ELISPOT proved highly

useful to detect active tuberculosis in Adults and children.

Microscopic Observation Drug Susceptibility Assay. ( MODS ) A new method gained importance in several reviews.

Use a tissue culture plate based assay with use of Middle Brook

7HG. Needs a inverted light microscope.

Even the drug resistance can be tested with Rifampicin, and

Isoniazid.

Non Specific Tests: Tuberculin Test ( Mantoux Test )

Test to be interpreted in relation to clinical evaluation.

Even the induration of 5 mm to be considered positive when tested on HIV

patients. Lacks specificity.

Specimen Collection Procedure

Obtain 3 sputum specimens for smear examination and culture

Spot, first morning, spot. Follow infection control precautions during specimen

collection

Sputum Smear Examination

Always aim for three specimens at each exam

Always store at a cool temperature and away from sunlight to preserve the

quality of specimens. 3 respiratory specimens will detect 90% of smear-positive

cases

AFB Smear-microscopy Acid Fast Smear Showing Tb Bacilli

Chest Radiograph Diagnosis of PTB solely on basis of

CXR not encouraged

May have unusual appearance in HIV-

positive persons

CXR is helpful in HIV+, smear -

negative patients

Cannot confirm diagnosis of TB Arrow points to cavity in patient's right upper lobe.

SEROLOGY IN TUBERCULOSIS.

• Several serological methods were evaluated.

• But never gained the acceptance of the majority of the clinicians.

• Serological tests are low sensitivity.

• Many physicians depend on serology in extra pulmonary tuberculosis.

HIV/AIDS - TUBERCULOSIS

• Consider the HIV status

• Identify the severity of Tuberculosis.

• Early use of chest radiography.

• Maximal number of sputum smear examinations.

• Sputum concentration methods to be encouraged even by smaller laboratories.

• Explore the use of Florescent Microscopy.

• All smear negative specimens should be cultured.

EXTRA PULMONARY TUBERCULOSIS

• Optimal specimen collection a priority,

• Molecular Methods are growing need.

• Clinicians start drug regimes on empirical basis.

• Several serological tests for antibody determinations are evaluated.

PULMONARY TB

•Productive, prolonged cough (duration of 2-3 weeks)

•Chest pain and Hemoptysis (bloody sputum)

•Signs may vary based on HIV status

ATYPICAL MYCOBACTERIUM

• Needs different drug regimes, unlike typical Mycobacterium isolates.

• Now a gowning concern in the era of AIDS.

FUTURE PERCEPTIONS

• It is highly essential to explore and discover rapid, simple, and accurate

tuberculosis diagnostic tools.

• A massive investment, greater scientific interest, political commitment a

top priority,

• Man power development, Human resource utilization a greater concern.

• Microscopy and Florescent Microscopy utilization should be immediate

concern, and strengthening of treatment initiation protocols.

• Effective methods in diagnosing smear negative patients a growing

priority.

ANTI-TUBERCULOSIS TREATMENT

• ISONIAZIDE (INH), [H]

• RIFAMPIN [R]

• PYRAZINAMIDE [Z]

• ETHAMBUTOL[E]

• STREPTOMYCIN [S]

• AMIKACIN

• AMINOSALICYCLIC ACID

• CAPREOMYCIN

• CIPROFLOXACIN

• CLOFAZIMINE

• CYCLOSERINE

• ETHIONAMIDE

• LEVOFLOXACIN

• RIFABUTIN

• RIFAPENTINE

FIRST LINE DRUGS SECOND LINE DRUGS

Standard Regimen And Dosing Frequency For TB Patients

Recommended Doses Of First-line Anti-tuberculosis Drugs For Adults

Mechanism of action

The activated form of isoniazid - forms a covalent complex with an inh-A (Acyl carrier protein -AcpM) and KasA, a ß-ketoacyl carrier protein synthetase, which blocks mycolic acid synthesis and kills the cell.

Absorption Rapid and complete; rate can be slowed with food. Peak Plasma Time: 1-2 hr

Distribution All body tissues and fluids including CSF; crosses placenta; enters breast milk Protein Bound: 10-15%

Metabolism Hepatic ( fast, slow acetylators)

Elimination From 50 to 70 percent of a dose of isoniazid is excreted in the urine within 24 hours

Half life Fast acetylators: 0.5 to 1.6 hours. Slow acetylators: 2 to 5 hours.Adverse effects Peripheral neuritis

Hepatitis PsychosisSeizuresAnorexia GIT discomfortFever

ISONIAZID

Mechanism of action

Rifampin binds to the β subunit of bacterial DNA–dependent RNA polymerase and thereby inhibits RNA synthesis. Resistance results from any one of several possible point mutations in repoB, the gene for the β subunit of RNA polymerase.

Absorption PO well absorbed; food may delay absorptionPeak plasma time: 2-4 hr

Distribution Highly lipophilic; crosses blood-brain barrier well, with or without inflammationProtein bound: 80%

Metabolism Metabolized by liver; undergoes enterohepatic recirculation

Elimination Feces (60-65%) and urine (~30%) as unchanged drug

Half life 3-4 hr (prolonged in hepatic impairment); in end-stage renal disease, 1.8-11 hr

Adverse effects HepatotoxicityGIT disturbancesFlu-like syndromeCNS symptoms – drowsiness, ataxia, confusion, peripheral neuropathy Hypersensitivity reactionsStaining of secretions

RIFAMPICIN

Mechanism of action

Susceptible strains  release pyrazinamidase, which converts PZA to pyrazinoic acid (POA).  POA decreases the pH below that which retards the growth of M. tuberculosis and inhibiting the fatty acid synthesis .

Absorption well absorbed

Distribution Protein binding: 50%.widely into body tissues and fluids including liver, lung, and CSF. Relative diffusion from blood into CSF: adequate with or without inflammation . CSF: blood level ratio: inflamed meninges: 100%

Metabolism hepatic

Elimination urine (4% as unchanged drug)

Half life 9-10 hr

Adverse effects Malaise, Nausea, Vomiting , Anorexia, Arthralgia, Myalgia, Fever, Rash, Itching, Acne, Photosensitivity, Gout, Dysuria, Porphyria, Thrombocytopenia, Hepatotoxicity, Interstitial nephritis.

Pyrazinamide

Mechanism of action

Ethambutol inhibits mycobacterial arabinosyl transferases. Arabinosyl transferases are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall.

Absorption Bioavailability: ~80%Peak Plasma Time: 2-4 hr

Distribution Widely throughout body; concentrated in kidneys, lungs, saliva, and red blood cells CSF: blood level ratio: 0% (normal meninges); 25% (inflamed meninges) Protein binding: 20-30%

Metabolism Hepatic (20%) to inactive metabolite

Elimination ~50% urine; ~50% feces as unchanged drug.

Half life 2.5-3.6 hr; 7-15 hr (end-stage renal disease)Adverse effects Acute gout or hyperuricemia, Abdominal pain, Anaphylaxis,

Confusion, disorientation, Fever, Headache, LFT abnormalities, Malaise, NauseaOptic neuritis; symptoms may include decreased acuity, color blindness or visual defects (usually reversible with discontinuation)Peripheral neuritisRash

Ethambutol

Mechanism of action

Irreversibly inhibits bacterial protein synthesis. Protein synthesis is inhibited in at least three ways: 1. Interference with the initiation complex of peptide formation.2. Misreading of mRNA, which causes incorporation of incorrect

aminoacids into the peptide, resulting in a nonfunctional or toxic protein.

3. Breakup of polysomes into nonfunctional monosomes.

Absorption well absorbed; not absorbed from gut

Distribution To extracellular fluid including serum, abscesses, ascitic, pericardial, pleural, synovial, lymphatic, & peritoneal fluids; crosses placenta; small amounts enter breast milk

Metabolism Protein Bound: 34%

Elimination urine (90% as unchanged drug); feces, saliva, sweat, & tears (<1%)

Half life newborns: 4-10 hr; adults: 2-4.7 hr, prolonged with renal impairmentAdverse effects Hypotension, Neurotoxicity, Drowsiness, Drug fever, Skin rash,

Nausea, Vomiting, Eosinophilia , Arthralgia, Tremor, Ototoxicity (auditory, vestibular), Nephrotoxicity.

Streptomycin

Mechanism of action

Aminosalicylic acid is a folate synthesis antagonist that is active almost exclusively against mycobacterium tuberculosis.It is structurally similar to p-amino benzoic acid(PABA) and the sulfonamides.

Absorption T max is about 6 h

Distribution About 50% to 60% is protein bound.

Elimination 80% is excreted in the urine with at least 50% excreted in acetylated form.

Half life The t 1/2 of free aminosalicylic acid is 26.4 min.

Adverse effects Nausea; vomiting; diarrhea; abdominal pain, Goiter with or without myxedema., Hypersensitivity (eg, fever, skin eruptions, leukopenia, thrombocytopenia, hemolytic anemia, jaundice, hepatitis, encephalopathy, Loffler syndrome, vasculitis).

PARA AMINO SALICYLIC ACID

Mechanism of action

Ethionamide, like pyrazinamide, is a nicotinic acid derivative related to isoniazid. It is thought that ethionamide undergoes intracellular modification and acts in a similar fashion to isoniazid.

Absorption Completely absorbed following oral administration. Bioavailability approximately 100%.

Distribution Volume of distribution 93.5 L. Approximately 30% bound to proteins.

Metabolism Metabolism: Hepatic . Metabolized to the active metabolite sulfoxide, and several inactive metabolites. The sulfoxide metabolite has been demonstrated to have antimicrobial activity against Mycobacterium tuberculosis.

Elimination Less than 1% of the oral dose is excreted as ethionamide in urine.

Half life 2 to 3 hoursAdverse effects Disorder of gastrointestinal tract (50%)

Postural hypotensionDizzinessDrowsinessHeadachePeripheral neuropathyPsychosis

ETHIONAMIDE

Mechanism of action

It inhibits the incorporation of D- alanine into peptidoglycan pentapeptide by inhibiting alanine racemase, which converts L-alanine to D- alanine, and D- alanyl-D –alanine ligase (finally inhibits mycobacterial cell wall synthesis). Cycloserine used exclusively to treat tuberculosis caused by mycobacterium tuberculosis resistant to first line agents

Absorption Rapidly and almost completely absorbed (70 to 90%) from the gastrointestinal tract following oral administration.

Distribution CSF concentration equal to that in plasma

Metabolism liver

Elimination urine

Half life with normal renal function is 10 hours, and is prolonged in patients with impaired renal function.

Adverse effects ConfusionDizzinessHeadacheSeizurePsychosis

CYCLOSERINE

Mechanism of action

Bacteriostatic- inhibits cyclopropanaton of cell wall mycolic acids.

Half life 12 hrs

Adverse effects hepatitis, exfoliative dermatitis, SJS, bone marrow depression rarelyCommon: Abdominal discomfort, loose motions, rashes, mild anemia, anorexia.

THIOACETAZONE

Mechanism of action

Bactericidal and believed to inhibit protein synthesis by binding to 30 S ribosomal subunit.

Elimination urine

Adverse effects Agranulocytosis, Anorexia, Diarrhea, Dyspnea, Elevated BUN, Enterocolitis, Headache, Incr salivation, Muscle cramps, Nausea, Nephrotoxicity, Neurotoxicity, Ototoxicity, Pruritus.

KANAMYCIN

Mechanism of action

Binds to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest; does not affect nucleic acid synthesis

Absorption Rapidly absorbedBioavailability: 37%; variable effect with foodPeak plasma time: 2.3-4 hr

Distribution Extensively distributed into skin, lungs, sputum, tonsils, and cervix; penetrates cerebrospinal fluid (CSF) poorly

Metabolism Metabolized in liver

Elimination Immediate release, ~70 hr; extended release, 59 hr

Half life Excretion: Feces (50% as unchanged drug), urine (5-12%)

Adverse effects Diarrhea ,Nausea ,Abdominal pain ,Loose

stool ,Cramping ,Vaginitis ,Dyspepsia ,Flatulence ,Vomiting ,Malaise,Ag

itation, Allergic reaction, Anemia, Anorexia, Candidiasis, Chest pain,

Conjunctivitis, Constipation, Dermatitis (fungal), Dizziness, Eczema

AZITHROMYCIN

Mechanism of action

Semisynthetic macrolide antibiotic that reversibly binds to P site of 50S ribosomal subunit of susceptible organisms and may inhibit RNA-dependent protein synthesis by stimulating dissociation of peptidyl t-RNA from ribosomes, thereby inhibiting bacterial growth

Absorption Highly stable in presence of gastric acid (unlike erythromycin); food delays but does not affect extent of absorption

Distribution Distributed widely into most body tissues except central nervous system (CNS)Protein bound: 42-50%

Metabolism Partially metabolized by CYP3A4Metabolites: 14-OH clarithromycin (active)

Elimination Approximates normal glomerular filtration rate (GFR)Excretion: Urine (30-55%)

Half life Immediate release, 3-7 hr; active metabolite, 5-9 hr

Adverse effects Gastrointestinal effects, general, Abnormal taste, Diarrhea, Nausea, Vomiting, Abdominal pain, Rash, Dyspepsia, Headache, Elevated prothrombin time,Anaphylaxis, Anxiety, Clostridium difficile colitis, Dizziness, Dyspnea, Elevated liver function tests

CLARITHROMYCIN

Mechanism of action

Irreversibly binds to 30S subunit of bacterial ribosomes; blocks recognition step in protein synthesis; causes growth inhibition. For gram-negative bacterial coverage of infections resistant to gentamicin and tobramycin

Absorption IM: May be delayed in bedridden patient

Distribution 0.25-0.4 L/kg, primarily into extracellular fluid (highly hydrophilic); penetrates blood-brain barrier when meninges inflamed; crosses placenta.

Elimination urine (94-98%)

Half life 2-3 hr

Adverse effects Neurotoxicity, Nephrotoxicity (if trough >10 mg/L), Ototoxicity, Hypotension, Headache, Drug fever, Rash, Nausea, Vomiting, Eosinophilia, Tremor, Arthralgia

AMIKACIN

Mechanism of action

Inhibits DNA-dependent RNA polymerase

Absorption readily, 53%

Distribution body tissues including the lungs, liver, spleen, eyes, & kidneysVd: 9.32 L/kgProtein Bound: 85%Bioavailability: absolute: HIV: 20%

Metabolism hepatic CYP3A4 to active and inactive metabolites

Elimination Urine: 10% as unchanged drug, 53% as metabolitesFeces: 10% as unchanged drug, 30% as metabolites

Half life 45 hr (range: 16-69 hr)

Adverse effects Discoloration of urine, Neutropenia, Leukopenia, Rash , Thrombocytopenia, Abdominal pain, Diarrhea , Eructation , Headache, Nausea/vomiting, Anorexia, Flatulence

RIFABUTIN

Mechanism of action

They inhibit bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA Gyrase) and topoisomerase IV.Inhibition of DNA Gyrase prevents the relaxation of supercoiled DNA that is required for normal transcription and replication.Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the daughter cells during cell division.

Absorption Rapidly absorbed orally- but food delays absorption,

Distribution High tissue penetration: lungs, sputum, muscle, prostate but low in CSF

Elimination Excreted primarily in urine, urinary and biliary concentrations are 10-50 times more than plasma

Half life 3-8hrs,

Adverse effects Nausea, vomiting,diarrhoea(most common). Headache, dizziness, insomnia, skin rash, photosensitivity. Damage growing cartilage and cause an arthropathy. Tendinitis, tendon rupture.

FLUOROQUINOLONES

Determining Drug Completion

1) Within 3 months for initial phase

2) Within 6 months for 4-month continuation phase

Consider therapy interrupted if target doses not met within

specified time period

Management of Initial Phase Treatment Interruptions

• If lapse > 14 days, start from beginning

• If lapse < 14 days, continue treatment to complete total doses

warranted (if can be completed within 3 months)

• If received > 80% continuation-phase doses and:

1) sputum AFB smear negative on initial presentation, further

therapy not necessary

2) sputum AFB smear positive on initial presentation, continue

to complete full course

• If received < 80% continuation-phase doses and:

1) lapse < 3 months duration, continue to complete full course

(as long as all doses can be completed within 6 months)

2) lapse was 3 months or greater, then start initial phase 4-drug

regimen from the beginning

COMMON ADVERSE REACTIONS TO DRUG TREATMENT Caused by Adverse Reaction Signs and Symptoms

Ethambutol Eye damage Blurred or changed vision, Changed color visionRifamycins• Rifabutin• Rifapentine• Rifampin

Thrombocytopenia

GIT intoleranceDrug interactions

Easy bruisingSlow blood clotting Upset stomachInterferes with certain medications, such as birth control pills, birth control implants, and methadone treatment

Isoniazid,Pyrazinamide,orRifampin

Hepatitis Abdominal pain, Abnormal liver function test FatigueLack of appetiteNausea, VomitingYellowish skin or eyes, Dark urine

Isoniazid Peripheral neuropathy Tingling sensation in hands and feetPyrazinamide GIT intolerance

ArthralgiaArthritis

Upset stomach, vomiting, lack of appetiteJoint achesGout (rare)

Streptomycin Ear damage

Kidney damage

Balance problemsHearing loss, Ringing in the earsAbnormal kidney function test results

DRUG INTERACTIONS

Relatively few drug interactions substantially change concentrations of

antituberculosis drugs

Antituberculosis drugs sometimes change concentrations of other drugs

Rifamycins can decrease serum concentrations of many drugs, (e.g., most

of the HIV-1 protease inhibitors), to subtherapeutic levels

Isoniazid increases concentrations of some drugs (e.g., phenytoin) to

toxic levels

RELAPSE

A patient’s cultures become and remain negative while receiving

antituberculosis drugs, but at some point after completion of therapy:

patient develops culture-positive TB disease again, or

patient experiences clinical or radiographic deterioration consistent

with active TB disease

Most relapses occur within the first 12 months after completion of therapy

Patients with cavitation on initial chest radiograph and a positive culture at

completion of 2 months of therapy are at increased risk of relapse with

standard 6-month regimens

Patients with relapse are at increased risk for acquired drug resistance,

especially if the therapy was not directly observed

TREATMENT FAILURE

Defined as positive cultures after 4 months of treatment in patients for

whom medication ingestion was ensured

Single new drug should never be added to a failing regimen; it may

lead to acquired resistance to the added drug

Add at least three new drugs (e.g., fluoroquinolone, ethionamide, and

an injectable drug: SM, amikacin, kanamycin, or capreomycin) to the

existing regimen being cognizant of the possibility of drug resistance

DRUG RESISTANCE

Established only by drug-susceptibility testing

Treatment of TB caused by drug-resistant organisms should be done in

close consultation with an expert

Patients not on DOT in the past or who had irregular treatment are at

risk of drug resistance

Consider the following expanded regimen for drug resistance:

INH, RIF, PZA, EMB plus three additional agents based on

probability of in vitro susceptibility (e.g., fluoroquinolone,

ethionamide, or an injectable drug: SM, amikacin, kanamycin, or

capreomycin)

SPECIAL TREATMENT SITUATIONS HIV/AIDS

Treatment for HIV-positive patients same as for HIV-negative

patients, except

Once-weekly INH-rifapentine in continuation phase is

contraindicated in HIV-positive patients

Twice-weekly INH-RIF or INH-rifabutin should not be used

in patients with CD4+ T-lymphocyte counts less than 100/l

Every effort should be made to use a rifamycin-based regimen for

the entire course of therapy

SPECIAL TREATMENT SITUATIONS (CHILDREN)*

Thrice-weekly therapy not recommended

Recommended duration of treatment is 6 months (absence of factors

associated with increased risk of relapse)

Use DOT

Treat young children (<5 years old) with three (rather than four) drugs in

initial phase (i.e., INH, RIF, and PZA)

EMB not recommended unless increased likelihood of INH resistance or

diagnosis of adult-like TB**

* Defined as persons <15 years old** Defined as upper-lobe infiltration and cavitation associated with sputum

production

TREATMENT SITUATIONS EXTRAPULMONARY TB

Similar treatment regimen for pulmonary TB*

6- to 9-month regimens that include INH and RIF are effective

Corticosteroids used as adjunctive therapy for patients with TB

meningitis and pericarditis

If PZA cannot be used in the initial phase, continuation phase must

be increased to 7 months

* Except for central nervous system (CNS) TB, including meningitis; length of therapy is 9-12 months

TREATMENT SITUATIONS PREGNANCY - BREASTFEEDING

Untreated TB represents greater hazard to a woman and her child than

treatment of disease

Treatment of pregnant woman with suspected TB should be started if

probability of TB is moderate to high

Initial phase treatment regimen should consist of INH, RIF, and EMB

SM should not be substituted for EMB because of possible teratogenic

effects

PZA not generally recommended for pregnant women in the United

States

TREATMENT SITUATIONS RENAL INSUFFICIENCY-

END-STAGE RENAL DISEASE Renal insufficiency complicates management of TB because some

antituberculosis medications are cleared by the kidneys

Dosage should not be decreased because peak serum concentrations may be

too low; smaller doses may decrease drug efficacy

Dosing interval of antituberculosis drugs should be increased

Most drugs can be given 3 times weekly after hemodialysis; for some drugs,

dose must be adjusted

SPECIAL TREATMENT SITUATIONS HEPATIC DISEASE

Must consider regimens with fewer hepatotoxic agents for patients with

liver disease

Recommended regimens:

1) Treatment without PZA Initial phase (2 months): INH, RIF, and

EMB Continuation phase (7 months): INH and RIF

2) Treatment without INH Initial phase (2 months): RIF, PZA, and

EMB Continuation phase (4 months): RIF, EMB, and PZA

REFERENCES1. Continuing education credit will be awarded through: CDC’s Public Health

Training Network (PHTN) http://phppo.cdc.gov/phtnonline

2. MMWR at http://www.cdc.gov/mmwr

3. CDC’s Morbidity and Mortality Weekly Report:http://www.cdc.gov/mmwr

4. American Thoracic Society:

http://www.thoracic.org/adobe/statements/treattb.pdf

5. Recent Advances in Multi-Drug-Resistant Tuberculosis and RNTCP

Gagandeep Singh Grover and Jaspreet TakkarIndian J Community Med.

2008 October; 33(4): 219–223.

6. DOTS-Plus Guidelines-Central TB Division, Directorate General of Health

Services, Ministry of Health & Family Welfare, Nirman Bhavan, New Delhi

– 110011