Pharmacotherapy of TUBERCULOSIS

PHARMACOTHERAPY

OF

TUBERCULOSIS

By – Mr. Rahul P Kshirsagar M.Pharm (Ph.D)

Assistant Professor

Dept. of Pharmacology

School of Pharmacy, Anurag Group of Institutions

WHAT IS TB?

TB is a disease caused by

infection with a bacteria called

Mycobacterium tuberculosis.

HOW CAN YOU CATCH TB?

TB is spread through tiny drops

sprayed into the air when an infected

person coughs, sneezes, or speaks,

or another person breathes the air

into their lungs containing the TB

bacteria.

TUBERCULOSIS – THE FACTS

• 7. position of leading causes of deaths

• 1/3 of the world's population could be

infected

• > 80% can be cured

• prevention can be > 90% effective

Global tuberculosis control: WHO report 2011

TUBERCULOSIS – THE FACTS

• 1.45 million people died in 2010 due to TB

• equally to 3800 deaths per day

• 8.8 million new cases of TB in 2010

• Global incidence rate of 128/100 000

• Most cases occurred in

• Asia (59%) and

• Africa (26%)

WHO report 2011

ESTIMATED TB INCIDENCE RATES 2010

WHO report 2011

THE GLOBAL BURDEN OF TB IN 2010

IN RELATION TO HIV CO-INFECTION

Estimated number

of cases

Estimated number of

deaths

All forms of TB 8.8 Mio

(8.5–9.2 Mio)

1.45 Mio

(1.2–1.5 Mio)

HIV-associated TB 1.1 Mio (13%)*

(1.0–1.3 Mio)

0.35 Mio

(0.32–0.39 Mio)

WHO report 2011

*82% of TB cases among people livingwith HIV originate from the African region

ESTIMATED HIV PREVALENCE

IN NEW TB CASES 2010

WHO report 2011

TRENDS IN TB INCIDENCE RATES

Lawn and Zumla (2011) Lancet 378: 57

• M. tuberculosis causes most TB cases in U.S.

• Mycobacteria that cause TB:

• M. tuberculosis

• M. bovis

• M. africanum

• M. microti

• M. canetti

• Mycobacteria that do not cause TB

• e.g., M. avium complex

M. tuberculosis

ETIOLOGY - TYPES OF MYCOBACTERIA

CHARACTERISTICS OF M. TUBERCULOSIS

• Slightly curved, rod shaped

bacilli

• 0.2 - 0.5 microns in

diameter; 2 - 4 microns in

length

• Acid fast - resists

decolorization with

acid/alcohol

• Multiplies slowly (every 18

- 24 hrs)

• Thick lipid cell wall

• Can remain dormant

for decades

• Aerobic

• Non-motile

HOW IS TB TRANSMITTED?

• Person-to-person through

the air by a person with

TB disease of the lungs

Less frequently transmitted by:

• Ingestion of Mycobacterium bovis found in unpasteurized milk products

• Laboratory accident

TRANSMISSION OF M. TUBERCULOSIS

• One cough can

release 3,000 droplet

nuclei

• One sneeze can

release tens of

thousands of droplet

nuclei

• Millions of tubercle bacilli in lungs

(mainly in cavities)

• Coughing projects droplet nuclei

into the air that contain tubercle

bacilli

FATE OF M. TB AEROSOLS

• Large droplets settle to

the ground quickly

• Smaller droplets form

“droplet nuclei” of 1–5

µ in diameter

• Droplet nuclei can

remain airborne

PATHOGENESIS

TB PATHOGENESIS• Bacterial entry

• T Lymphocytes.

• Macrophages.

• Epitheloid cells.

• Proliferation.

• Central Necrosis.

• Giant cell formation.

• Fibrosis.

MORPHOLOGY OF GRANULOMA

1. Rounded tight collection of chronic inflammatory cells.

2. Central Caseous necrosis.

3. Active macrophages - epithelioid cells.

4. Outer layer of lymphocytes & fibroblasts.

5. Langhans giant cells – joined epithelioid cells.

TUBERCULOUS GRANULOMA

TB TRANSMISSION AND

PATHOGENESIS

Not everyone who is exposed to TB will become infected

No infection (70%)

Adequate Immunity

Non-specific immunity

Inadequate Immunity

Infection (30%)

EXPOSURE

THE CHANCE OF INFECTION INCREASES…

• When the concentration of TB bacteria circulating in the air

is greater

• Coughing; smear +;

• Exposure occurs indoors

–Poor air circulation and ventilation; small, enclosed

space

–Poor or no access to sunlight (UV light)

THE CHANCE OF INFECTION INCREASES…(2)

• The greater the time spent with the infectious person or

breathing in air with infectious particles

TB GERMS CANNOT BE SPREAD BY:• Sharing dishes and utensils

• Using towels and linens

• Handling food

• Sharing cell phones

• Touching computer keyboard

SPREAD OF TB TO OTHER PARTS OF THE

BODY1. Lungs (85% all cases)

2. Pleura

3. Central nervous system(e.g., brain, meninges)

4. Lymph nodes

5. Genitourinary system

6. Bones and joints

7. Disseminated (e.g., miliary)

© ITECH, 2006

TB CAN AFFECT ANY PART OF YOUR BODY: EXTRA PULMONARY TB

Pleura

Lymph Node

Brain

Spine

CELL-MEDIATED IMMUNE RESPONSE

Special immune cells

form a hard shell (in

this example, bacilli are

in the lungs)

Source: CDC, 2001

Latent TB Infection (LTBI)

Person:

• Not ill

• Not contagious

• Normal chest x-ray

• Usually the tuberculin skin test is

positive

Germs:

• Sleeping but still alive

• Surrounded (walled off) by body’s

immune system

TB TRANSMISSION AND PATHOGENESIS

(2)

Immunologic defenses

No infection (70%)

Adequate Immunity


Inadequate Immunity

Infection (30%)

Inadequate Defenses

Early Progression

(5%)

Adequate Defenses

Containment(95%)

EXPOSURE

REACTIVATION

Hard shell breaks down

and tubercle bacilli

escape and multiply

(in this example, TB

disease develops in the

lungs)

Source: CDC, 2001

ACTIVE TB DISEASE

Granuloma breaks down and tubercle escape and multiply

TBGerms:

• Awake and multiplying

• Cause damage to the lungs

Person:

• Most often feels sick

• Contagious (before TB treatment started)

• Usually have a positive tuberculin skin

test

• Chest X-ray is often abnormal (with

pulmonary TB)

TB TRANSMISSION AND PATHOGENESIS (3)


Continued

containment

(90%)

Adequate Defenses


No infection (70%)

Adequate Immunity


Inadequate Immunity

Infection (30%)

Inadequate Defenses

Early Progression

(5%)

Adequate Defenses

Containment(95%)

EXPOSURE

Inadequate Defenses

Late progression (5%)

TB INFECTION & DISEASETHERE ARE 2 CATEGORIES OF TB: LATENT & ACTIVE

TB infection of the lungs can fall into 2 categories of disease: Latent TB or Active TB.

Latent TB means a person is infected by TB bacteria, but cannot infect others, and is not coughing or appearing sick.

Latent TB means the body’s immune system has contained the infection.

TB - INFECTION & DISEASE CATEGORIES OF TB - LATENT

Persons with latent TB are

identified by a positive skin test

(PPD).

Persons who are not infected

with Mycobacterium

tuberculosis have a negative

skin test (PPD).

TB - INFECTION & DISEASECATEGORIES OF TB - LATENT

• When a person with a previously negative PPD, converts to a

positive PPD, the conversion indicates recent infection with

M. tuberculosis.

TB - INFECTION & DISEASECATEGORIES OF TB - ACTIVE

Active pulmonary and laryngeal TB means a person infected

with the TB bacteria is sick and can infect others unless they

are taking medicine prescribed by their physician to treat TB.

TB - INFECTION & DISEASECATEGORIES OF TB - ACTIVE

Persons with active TB disease

usually have some of the following

symptoms: cough ( 3 weeks or

more), feel weak, have a fever, lose

weight, experience night sweats,

cough up blood, or have chest pain

when coughing.

TB - INFECTION & DISEASE CATEGORIES OF TB - ACTIVE

Persons with active TB need to take their

medications as prescribed in order to treat

the disease and prevent the spread to

others.

DIAGNOSIS OF TB

• Clinical features are not confirmatory.

• Zeil Nielson Stain

• Adenosine deaminase test

• Culture most sensitive and specific test.

• Conventional Lowenstein Jensen media 3-6 wks.

• Automated techniques within 9-16 days

• PCR is available, but should only be performed by

experienced laboratories

• Mantoux test

AFB - ZEIL-NIELSON STAIN

COLONY MORPHOLOGY – LJ SLANT

MANTOUX TEST

• Infection with mycobacterium tuberculosis leads delayed

hypersensitivity reaction which can be detected by Mantoux

test

• About 2 to 4 weeks after infection, intracutaneous injection of

purified protein derivative (PPD) of M.tuberculosis induces a

visible and palpable induration that peaks in 48 to 72 hours

PPD TUBERCULIN TESTING

• Sub cutaneous

• Weal formation

• Itching – no scratch.

• Read after 72 hours.

• Induration size.

• 5-10-15mm

• (i) Induration less than 5 mm – no exposure to tubercular

bacilli.

• (ii) Induration between 5-9 mm – this can be due to atypical

mycobacteria or BCG vaccination. It may suggest infection in

immunocompromised children such as HIV infection or other

immunosupression;

• (iii) Induation 10 mm or more – an induration of 10 mm or

more at 48-72 hours in a child with symptoms of tuberculosis

should be interpreted as tubercular disease

PPD RESULT AFTER – 72 HOURS.

TREATMENT FOR LATENT TBWHY DO YOU NEED TREATMENT FOR LATENT TB IF YOU DO NOT HAVE

THE DISEASE?

Medication is given to prevent

the Latent TB from becoming

Active TB disease.

Preventive treatment reduces

the risk of getting active TB by

more then 90%.

TREATMENT OF T.B.

• Divided into chemoprophylaxis and treatment of active

disease.

• Careful diagnostic studies must always precede therapy.

CHEMOPROPHYLAXIS

• To prevent clinically active disease in people already

infected.

• Given only to those who will derive the greatest benefit

and the least risk.

CHEMOPROPHYLAXIS

• 300 mg Isoniazid once daily for 6-12 months.

TREATMENT OF ACTIVE T.B.

• First line drugs (used in the initial treatment of

T.B.) : Isoniazid, Rifampin, Streptomycin,

Ethambutol And Pyrazinamide.


• Secondary agents: PAS, Ethionamide, Amikacin,

Kanamycin, Capreomycin, Cycloserine,

Ciprofloxacin, Levofloxacin And Clofazimine.

MECHANISM OF ACTION OF

ANTITUBERCULOSIS AGENTS

• Drugs which interfere with mycolic acid synthesis

• Drugs which inhibit nucleic acid synthesis

• Drugs inhibiting protein synthesis

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Peptidoglycan

Porin

Arabinogalactan

Mycolic Acid

Lipid of intermediate lengthLipid with C14-C18 acids

MYCOBACTERIAL CELL WALL

ISONIAZID-MECHANISM OF ACTION

• Interferes with biosynthesis of cell wall mycolic acids.

• Mycolate depleted cell walls are structurally weak.

Isoniazid

(Prodrug)

Active

Form

Catalase/Peroxidase

katG

INH MECHANISM OF ACTION

• InhA gene encodes an enoyl-ACP reductase of fatty acidsynthase II which converts 2 -unsaturated to saturated fattyacids on the pathway to mycolic acid biosynthesis.

• Activated INH inhibits this enzyme.

Peptidoglycan

Porin

Arabinogalactan

Mycolic Acid


Mycobacterial Cell Wall

INH

RESISTANCE

• Mutations in the katG gene can lead to loss of catalase-

peroxidase activity.

• Resistance also maps to mutations in four other genes

including inhA

RESISTANCE

• Overall incidence of resistance is higher in certain ethnic

groups such as African Americans, Mexican Americans

and Indochinese refugees.

ETHAMBUTOL-MECHANISM OF

ACTION

• It is not bactericidal.

• Inhibits synthesis of the mycobacterial cell wall.

MECHANISM OF ACTION

• It is an inhibitor of mycobacterial arabinosyl transferases

(encoded by the embAB genes).

• Arabinoglycan an essential component of the cell wall.

Peptidoglycan

Porin

Arabinogalactan

Mycolic Acid


MYCOBACTERIAL CELL WALL

Ethambutol

RESISTANCE

• Mutations in the emb genes.

PYRAZINAMIDE-MECHANISM OF

ACTION

• PZA POA (pyrazinoic acid)pyrazinamidase

Occurs mostly in the liver.

MECHANISM OF ACTION

• Inhibits fatty acid synthetase I of Mycobacterium

tuberculosis.

Short chain fatty acid precursors

Pyrazinamide

RESISTANCE

• Mutations in the pncA gene which results in impairment in

the conversion of PZA to its active form.

DRUGS INHIBITING NUCLEIC ACID

SYNTHESIS

• Rifampin

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RESISTANCE

• Results from an alteration in the polymerase enzyme (mutation

in the rpoB gene).

STREPTOMYCIN-ANTI TB ACTIVITY

• Most strains of M.Tuberculosis are sensitive.

• Bactericidal only against the extracellular tuberculosis

bacilli.

• Overall only suppressive.

RESISTANCE

• Major problem with streptomycin use in T.B.

• Combination therapy will delay or prevent resistance.

THERAPEUTIC USES IN T.B.

• It is used in drug resistant disease.

• More serious forms of T.B. (disseminated T.B. or

meningitis).

ANTITUBERCULAR ACTIVITY

• Bactericidal vs actively growing tubercle bacilli .

• Also bactericidal vs intracellular bacteria.

• Poor activity against atypical organisms.


• Therapy requires at least two effective drugs

concurrently.


• If the treatment is appropriate improvement is usually

seen within 2 weeks.

• Continue treatment for at least 3-6 months after the

sputum becomes negative.


• Never use 1 drug and never add a single drug to

a failing regimen.


• Minimum length of therapy is 6-9 months.


• Initiation phase of 2 months.

• Continuation phase of 4-7 months.


• Initial therapy is a 4 drug regimen of INH, rifampin,

pyrazinamide and ethambutol.

• For patients with drug-susceptible disease the

pyrazinamide can be discontinued after 2 months.

• Ethambutol can also be discontinued.


• Combining daily therapy with intermittent therapy.

INTERMITTENT THERAPY

• Daily therapy for 2 weeks (INH, rifampin, pyrazinamide

and streptomycin) followed by therapy 2 times a week for

six weeks. Then INH + Rifampin 2x weekly for 16 weeks.

Directly Observed Therapy (“DOT”) –

DOT is especially critical for patients with drug-

resistant TB, HIV-infected patients, and those on intermittent

treatment regimens (i.e., 2 or 3 times weekly).

What is DOT?

DOT means that a trained health care worker or other

designated individual (excluding a family member) provides

the prescribed TB drugs and watches the patient swallow

every dose.

Why use DOT?

• We cannot predict who will take medications as directed, and

who will not. People from all social classes, educational

backgrounds, ages, genders, and ethnicities can have

problems taking medications correctly.

• Studies show that 86-90% of patients receiving DOT complete

therapy, compared to 61% for those on self-administered

therapy.

• DOT helps patients to finish TB therapy as quickly as possible,

without unnecessary gaps.

• DOT helps to prevent TB from spreading to others.

• DOT decreases the risk of drug-resistance resulting from

erratic or incomplete treatment.

• DOT decreases the chances of treatment failure and relapse.

HIV COUNSELING

All persons with suspected and confirmed TB disease

should be offered HIV counseling and blood testing, in

addition to treatment.

This is because TB is more likely to occur among HIV

positive individuals.

HIV COUNSELING

Treatment recommendations may differ for HIV infected

persons.

It is best to offer HIV counseling and testing in the health care

facility.

Follow up testing and counseling is essential.

FUNDAMENTALS OF TB

INFECTION CONTROL PRACTICES

Identify persons with active TB early.

Initiate effective and appropriate isolation of known or suspected TB cases.

Initiate effective anti-TB treatment promptly.

FUNDAMENTALS OF TB


Employees should use N95 respirators for any contact with

patients suspected of having TB.

Screen persons at high risk for TB and provide preventative

therapy if infected.

FUNDAMENTALS OF TB


Identify and evaluate persons and

health care workers exposed to

infectious TB.

Screen health care workers for

skin test conversions.

Conduct surveillance for TB

cases among patients and

healthcare workers.

INITIATE

AIRBORNE PRECAUTIONS WHEN:

A patient is suspected of having TB.

A patient has a rule-out diagnosis of TB.

A patient has a positive AFB smear.

A patient has a significant skin test reaction.

A patient is at high risk for TB, and has pneumonia, a cough

or bloody sputum.

ISOLATION ROOMS

Isolation rooms are necessary to prevent the spread of TB.

Isolation rooms should have at least 6 total air exchanges per

hour.

Isolation rooms must have air that flows from the hallway into

the isolation room (negative pressure).

ISOLATION ROOMS

Doors to isolation rooms must remain closed at all times to

maintain the negative pressure.

The number of healthcare workers entering an isolation room

should be limited.

ISOLATION ROOMS

When isolation rooms are in use, the air flow must be

checked daily.

P1

P2

WHAT FACTORS CONTRIBUTE TO TB OUTBREAKS IN

HEALTHCARE FACILITIES?

Lack of compliance with infection

control practices to control the

transmission of TB.

Healthcare facilities which are

providing services to increased

numbers of people with TB and HIV

infection.

WHAT FACTORS CONTRIBUTE TO TB OUTBREAKS IN

HEALTHCARE FACILITIES?

Multi-drug resistant TB cases are on the rise.

Lack of using a respirator mask when taking care of patients

with active TB.

Lack of suspicion that some patients are at risk for TB.

AS A HEALTHCARE WORKER, HOW CAN I PROTECT

MYSELF FROM BEING EXPOSED?

Have your skin test performed at least once a year to determine your TB status.

Always wear personal protective equipment (N95) when taking care of patients with active or suspected TB. Personal protective equipment includes a respirator (N95) and may include a gown and gloves.



Instruct your patients to cover their mouth when coughing and

do not transport patients with TB throughout the hospital

unless they are wearing a mask.



Protect yourself in the community by being more aware

of the disease and its transmission.

Patients with active TB or suspected of having TB should

be placed in an isolation room until it is determined that

this is no longer necessary.

OCCUPATIONAL HEALTH & SAFETY

PROTOCOLS FOR MONITORING TB

All applicants are screened for TB.

All employees are screened annually for TB, or more

frequently if necessary.

Employees exposed to patients with active TB will be

identified and followed through Employee Health.

FIT TESTING FOR N95 RESPIRATORSWHAT IS FIT TESTING AND WHY MUST IT BE DONE?

Fit testing determines whether a healthcare worker can

achieve an adequate facial seal with a particular respirator.

(N95)

An appropriately fitted respirator (mask) will prevent the

transmission of TB to the healthcare worker.

FIT TESTINGWHAT IS FIT TESTING AND WHY MUST IT BE DONE?

Fit testing must be done prior to the initial use of a respirator

mask.

Each time a respirator is worn the healthcare worker should

ensure it fits tightly over the nose and mouth.

PATIENT EDUCATION

Patient education is an essential component to prevent the

spread of TB.

TB patients should be taught to use tissues to cover coughs

and sneezes.

Tissues should be disposed appropriately and not left on

counter tops.

PATIENT EDUCATION

A surgical mask must be worn by a TB patient

whenever they leave the isolation room.

Visitors of a TB patient must wear a respirator

but are not required to be tested.

EVEN IF A SKIN TEST IS NEGATIVE…..

Chiclls

FFeverTHINK TB !

Chills

Fatigue

Difficulty

in

Breathing

Anorexia

Loss

of Appetite

Night sweats

Coughing

up Blood

Pharmacotherapy of TUBERCULOSIS

Education

Transcript of Pharmacotherapy of TUBERCULOSIS