History of TB

TB has affected humans for millennia Historically known by a variety of names, including:
Consumption Wasting disease White plague

TB was a death sentence for many

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History of TB
Scientific Discoveries in 1800s Until mid-1800s, many believed TB was hereditary
1865 Jean Antoine-Villemin proved TB was contagious 1882 Robert Koch discovered M. tuberculosis, the bacterium that causes TB

History of TB
Sanatoriums Before TB antibiotics, many patients were sent to sanatoriums
Patients followed a regimen of bed rest, open air, and sunshine TB patients who could not afford sanatoriums often died at home
Sanatorium patients resting outside

Breakthrough in the Fight Against TB

Drugs that could kill TB bacteria were discovered in 1940s and 1950s
Streptomycin (SM) discovered in 1943 Isoniazid (INH) and p-aminosalicylic acid (PAS) discovered between 1943 and 1952
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TB Resurgence
Increase in TB in mid 1980s
Contributing factors:
Inadequate funding for TB control programs HIV epidemic Increased immigration from countries where TB is common Spread in homeless shelters and correctional facilities Increase and spread of multidrugresistant TB
March 16, 1992 Newsweek Magazine Cover

TB History Timeline
1993: TB cases decline due to increased funding and enhanced TB control efforts

1865: Jean-Antoine Villemin proved TB is contagious

1884: First TB sanatorium established in U.S.

1943: Streptomycin (SM) a drug used to treat TB is discovered

Mid-1970s: Most TB sanatoriums in U.S. closed

1840

1860

1880

1900

1920

1940

1960

1980

2000

1882: Robert Koch discovers M. tuberculosis

1943-1952: Two more drugs are discovered to treat TB: INH and PAS

Mid-1980s: Unexpected rise in TB cases

TB Transmission
Types of Mycobacteria
M. tuberculosis causes most TB cases Mycobacteria that cause TB:
M. tuberculosis M. bovis M. africanum M. microti M. canetti
M. tuberculosis

Mycobacteria that do not cause TB

e.g., M. avium complex

ETIOLOGY
The tubercle bacillus (M.Tuberculosis) is A aerobic, non-motile, non-spore-forming, high in lipid content, and acid and alcoholfast bacteria. It grows slowly . It cant tolerate heat, but It can live in humid or dry or cold surroundings

TB Transmission
TB is spread person to person through the air via droplet nuclei M. tuberculosis may be expelled when an infectious person:
Coughs Sneezes Speaks Sings

Transmission occurs when another person inhales droplet nuclei

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TB Transmission

Dots in air represent droplet nuclei containing M. tuberculosis

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TB Transmission
Probability that TB will be transmitted depends on:
Infectiousness of person with TB disease

Environment in which exposure occurred

Length of exposure Virulence (strength) of the tubercle bacilli

The best way to stop transmission is to:

Isolate infectious persons Provide effective treatment to infectious persons as soon as possible
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TB Pathogenesis

Pathogenesis is defined as how an infection or disease develops in the body.

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TB Pathogenesis
Latent TB Infection (LTBI) Occurs when tubercle bacilli are in the body, but the immune system is keeping them under control
Detected by the Mantoux tuberculin skin test (TST) or by blood tests such as interferon-gamma release assays (IGRAs) which include:
QuantiFERON-TB Gold test (QFT-G) QuantiFERON-TB Gold In-Tube (QFT-GIT) T-Spot.TB test (T-SPOT)

People with LTBI are NOT infectious

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TB Pathogenesis
TB Disease Develops when immune system cannot keep tubercle bacilli under control
May develop very soon after infection or many years after infection About 10% of all people with normal immune systems who have LTBI will develop TB disease at some point in their lives People with TB disease are often infectious
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TB Pathogenesis

Droplet nuclei containing tubercle bacilli are inhaled, enter the lungs, and travel to small air sacs (alveoli)
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TB Pathogenesis
2
bronchiole blood vessel tubercle bacilli

alveoli

Tubercle bacilli multiply in alveoli, where infection begins

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TB Pathogenesis
3
brain bone lung

kidney

A small number of tubercle bacilli enter bloodstream and spread throughout body

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TB Pathogenesis
LTBI

special immune cells form a barrier shell (in this example, bacilli are in the lungs)

Within 2 to 8 weeks the immune system produces special immune cells called macrophages that surround the tubercle bacilli These cells form a barrier shell that keeps the bacilli contained and under control (LTBI)
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TB Pathogenesis
TB Disease

shell breaks down and tubercle bacilli escape and multiply (in this example, TB disease develops in the lungs)

If the immune system CANNOT keep tubercle bacilli under control, bacilli begin to multiply rapidly and cause TB disease This process can occur in different places in the body
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LTBI vs. TB Disease

Latent TB Infection (LTBI) TB Disease (in the lungs)
Inactive, contained tubercle bacilli Active, multiplying tubercle bacilli in the body in the body TST or blood test results usually positive Chest x-ray usually normal Sputum smears and cultures negative No symptoms Not infectious Not a case of TB TST or blood test results usually positive Chest x-ray usually abnormal Sputum smears and cultures may be positive Symptoms such as cough, fever, weight loss Often infectious before treatment A case of TB
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Natural History of TB Infection

Exposure to TB

No infection (70-90%) Latent TB (90%)

Never develop Active disease Die within 2 years

Infection (10-30%)

Active TB (10%)

Untreated
Survive

Treated Die Cured

Sites of TB Disease
Bacilli may reach any part of the body, but common sites include:
Brain Larynx Bone Kidney Lymph node Pleura Lung Spine

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Sites of TB Disease
Location Pulmonary TB
Lungs

Frequency
Most TB cases are pulmonary Found more often in:

Extrapulmonary TB Places other than

lungs such as: Larynx Lymph nodes Pleura Brain Kidneys Bones and joints

HIV-infected or other immunosuppressed persons

Young children Rare

Miliary TB

Carried to all parts of body, through bloodstream

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Laboratory and physical examinations

Chest radiography Sputum examination Tuberculin testing PCR test to detect TB bronchoscopy

Classification
First line drugs these have high anti tubercular and low toxicity and are used routinely. Second line drugs either low anti tubercular efficacy or high toxicity or both and are used as reserve drugs.

First line drugs

Isoniazid Rifampin(rifampicin) Pyrazinamide Ethambutol Streptomycin

Second line drugs

Kanamycin Flouroquinolones Ethionamide Cycloserine Para amino salicylic acidrifabutin

Isoniazid
Trade Name: Isonex 100mg,300,isokin100mg Drug Class: Antimycobacterial (anti-tuberculosis) Mechanism of Action:
Inhibits biosynthesis of mycolic acids which are important for mycobacterial cell wall synthesis; bactericidal in dividing cells Bacteriostatic in resting cells

Indications:
Along with Rifampin, Isoniazid is considered one of the best anti-TB drugs available It should be included in all treatment regimens unless the organism is resistant It is relatively inexpensive, and only ~5% of patients exhibit adverse effects

Contraindications:
isoniazid drug hypersensitivity including drug -induced hepatitis; previous isoniazid-associated hepatic injury.

 Side Effects:
Isoniazid induced hepatic toxicity is the most frequent major toxic effect Peripheral neuropathy can occur in 10-20% of patients, but this side effect is minimized by daily prophylactic administration of vitamin B6 - pyridoxine Isoniazid can also induce hemolytic anemia in patients with G-6-P dehydrogenase deficiency

Pharmacokinetics:
Well absorbed orally. Widely distributed in various tissues. Metabolized in liver-acetylation, renal excretion Plasma half-life in fast acetylators is 70 min and in slow acetylators is 2-5 hr

Rifampin
Trade Names: Rifadin, Rimactane.rifampicin,Rcinex Drug Class: Antimycobacterial Mechanism of Action:
Inhibits RNA synthesis by inhibiting DNA dependent RNA polymerase Bactericidal

Indications:
Rifampin is considered one of the most important & potent anti-TB drugs It is administered along with isoniazid, pyrazinamide, ethambutol (e.g. RIPE drug combination) or another anti-TB drug to prevent the emergence of drugresistant myocbacteria Also used to treat infections by Gram+ and Gram-cocci, Methicillin resistant Staph; Gram- organisms- Legionella, H. influenzae. It is also considered the most active agent for the treatment of leprosy.
It reduces the number of viable M. leprae bacilli in patient's tissues faster than any other available agent.

 It must be combined with other antileprosy agents to prevent resistance (e.g. RDC - Rifampin, Dapsone, Clofazamine).

Side Effects:
Orange-red colored urine, sweat, tears and feces (harmless, but patients should be warned)
Can stain contact lenses

Flu-like symptoms Rash Hepatitis (rare)

Pharmacokinetics:
Well absorbed orally Widely distributed Enterohepatic circulation, deacetylation, biliary excretion

 Drug Interactions:
Rifampin is a strong inducer of P-450 enzymes, which increases the elimination of other drugs including:
Anticoagulants Anticonvulsants (some) HIV-1 protease inhibitors, nevirapine (NNRTI) Contraceptives Methadone Antirejection medications (tacrolimus, cycosporine) Cardiac medications

Note:
Rifabutin is an alternative (2nd choice) drug for treating M. tuberculosis.

Pyrizinamide
Trade Names: pyzina , rizap 0.75mg,1mg Drug Class: Antimyocobacterial Mechanism of Action:
A derivative of nicotinic acid Exact mode of action not known - it is believed to inhibit electron transport in mycobacteria The mycobacterial fatty acid synthase I gene involved in mycolic acid biosynthesis may also be a target Bactericidal Especially effective against the intracellular form of M. tuberculosis

Indications:
Used in combinationg with isoniazid and rifampin for short course (e.g. 2 month) regimens, as a sterilizing agent against residual intracellular organisms that may cause a relapse of infection by tubercle bacilli

 Side Effects:
Hepatotoxicity (1-5%) Nausea, vomiting Hyperuricemia

Pharmacokinetics:
Well absorbed orally Distributed widely Hydrolyzed to pyrazinoic acid Renal excretion

Ethambutol
Trade Names: Myambutol , combutol Drug Class: Antimycobacterial Mechanism of Action:
Inhibits synthesis of arabinogalactan, an essential component of mycobacterial cell wall Bacteriostatic Enhances the activity of lipophilic drugs such as rifampin

Indications:
Administered along with isoniazid or rifampin to inhibit the growth of M. tuberculosis and other susceptable mycobacteria

Side Effects:
Optic neuritis resulting in decrease of visual acuity and loss of ability to differentiate red from green.
The risk depends upon the dose and duration of therapy. Patients should be tested for visual acuity and red-green color discrimination at baseline & whenever there is a subjective change in vision.

Pharmacokinetics:
Well absorbed orally Metabolized partially to a dicarboxylic acid derivative 75% excreted unchanged in urine

Streptomycin
Drug Class: Aminoglycoside antimicrobial Indications:
Streptomycin was the first clinically available drug for the treatment of tuberculosis (TB) Streptomycin is now considered the least-used first-line supplemental drug for TB because of its toxicity (e.g. ototoxicity, nephrotoxicity), difficulty to achieve adequate CSF levels & the inconvenience of parenteral administration. It is typically used in patients who are resistant to another first line drugs used to treat TB
In this case streptomycin is added as a 4th drug in a regimen that includes rifampin, isoniazid, &pyrazinamide (RIPS) for the initial treatment of TB

It is also indicated for treatment of TB when there is a contraindication to the use of isoniazid, rifampin or pyrazinamide due to toxicity or intolerance

Treatment guidelines
Preventive Therapy Prophylaxis in Patients with negative TB skin test Isoniazid for 3 months
Preventive Therapy in Patients with Positive Skin Test Isoniazid for 9 months Rifampin for 4 months Give pyridoxine (Vit B6)

Subclinical Infection Isoniazid for 1 year

Active Tuberculosis
Conventional Therapy for susceptible organisms 1st 2 months: Rifampin + Isoniazid + Pyrazinamide Next 4 months: Rifampin + Isoniazid Possibly Resistant Organisms or Patients with HIV Rifampin + Isoniazid + Pyrazinamide Ethambutol or Streptomycin Tuberculosis resistant to Isoniazid Rifampin + Ethambutol for 12 months Pyrazinamide Multi-Drug Resistant Organisms Combination of at least 3 drugs to which organisms are susceptible Pyrazinamide is used for short term (~2 month) therapy as a sterilizing agent against residual intracellular organisms that may cause a relapse of infection by tubercle bacilli. Once the intracellular form has been killed after ~ 2 months of therapy, it no longer needs to be included in the drug combination. It produces hepatoxicity,

MINOR SIDE EFFECTS SIDE EFFECT Decreased appetite, nausea, abdominal pain Joint pains DRUG RIFAMPICIN, PYRIZIAMIDE MANAGEMENT Give tablets with small meals or last thing at night Aspirin

pyrazinamide

Burning sensation in the feet

Orange/red urine

isoniazid

Pyridoxine 100 mg daily

Reassurance; symptom is harmless

rifampicin

SIDE EFFECT Deafness

DRUG streptomycin

MANAGEMENT Refer to higher health facility where TB treatment is available

Dizziness (vertigo, imbalance and loss of balance) Yellowish discoloration of the eye (hepatitis) Vomiting and confusion Visual impairment

streptomycin

-DO-

most anti-TB drugs

-DO-

most anti-TB drugs ethambutol

-DO-DO-

Shock, skin rash and decreased urine output

rifampicin

-DO-

Classification of Patients in Categories for Standardized Treatment Regimen of DOTS

Category Type of Patient Regimen Duration in months

Category I

New Sputum Positive 2 (HRZE)3, Seriously ill sputum negative, 4 (HR)3 Seriously ill extra pulmonary,

Color of box: RED Category II Color of box: BLUE Sputum Positive relapse Sputum Positive failure Sputum Positive treatment after default 2 HRZES)3, 1 (HRZE)3 5 (HRE)3 8

Contd.
Category Type of Patient Regimen Duration in months 2 (HRZ)3, 4 (HR)3 6

Category III

Sputum Negative, extra pulmonary not Seriously ill

Color of box: GREEN

DOTS-Plus Vision
By 2010 DOTS-Plus services available in all states By 2012, universal access under RNTCP to laboratory based quality assured MDR-TB diagnosis for all retreatment TB cases and new cases who have failed treatment By 2012, free and quality assured treatment to all MDR-TB cases diagnosed under RNTCP (~30,000 annually) By 2015, universal access to MDR diagnosis and treatment for all smear positive TB cases under RNTCP

3/23/2014

Dr. KANUPRIYA CHATURVEDI