Tuberculosis

ByAbhinav Sawhney

M. Pharmacy (Pharmacology)Amity Institute of Pharmacy

Amity University Noida.M. tuberculosis

TB TransmissionWhat is TB?TB is a disease caused by infection with a

bacteria called Mycobacterium tuberculosis.

How Are TB Germs Spread?

TB TransmissionHow 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.

How Are TB Germs Spread?TB germs are passed through the air when a

person who is sick with TB disease coughs, sings, sneezes, or laughs

To become infected with TB germs, a person usually needs to share air space with someone sick with TB disease (e.g., live, work, or play together)

The amount of time, the environment, and how sick the person is all contribute to whether or not you get infected

In most cases, your body is able to fight off the germs

TB Infection vs. TB DiseaseThere is a difference between TB “infection” and

TB “disease”

TB infection: TB germs stay in your lungs, but they do not multiply or make you sickYou cannot pass TB germs to others

TB disease: TB germs stay in your lungs or move to other parts of your body, multiply, and make you sickYou can pass the TB germs to other people

Tuberculosis in Humans- Reservoir: Humans- Transmission: Airborne disease (aerosol

transmission) - Symptoms:

Latent TB infection: Active TB infection:No symptoms Bad cough *Cannot spread TB Coughing up blood/sputum

Chest pain Loss of appetite Weight loss

Fever Chills Night sweats Swollen glands *Contagious Extra-pulmonary TB: Symptoms depend on location of infection

General symptoms: fatigue, fever, loss of appetite, weight loss.

TB of lymph nodes: swelling of lymph nodesTB meningitis: neurological symptoms including headacheSpinal TB: Mobility impairments, pain

Mycobacterium TuberculosisGeneral Characteristics- Family – Myobacteria- Gram-positive aerobic rod-shaped bacilli- “Acid fast” bacteria- Lack of spore formation and toxin production- No capsule, flagellum (non-motile)- Generation time of 18- 24 hours but requires

3-4 weeks for visual colonies

Pathological Features- Principle cause of Human Tuberculosis- Intracellular pathogen (alveolar

macrophages)- Waxy, thick, complex cellular envelope - Cell envelope components ex) sulfolipids - Produces tubercles, localized lesions of M.

tuberculosis

SEM of M. tuberculosis

M. Tuberculosis (stained in purple)

Mycobacterial Cellular EnvelopeGeneral Features- Thick, waxy and complex- Higher fluidity in more external

regions than internal regions- Relatively impermeable to

hydrophilic solutes- Contain porins (selective cationic

channels)

Main Components- Peptidoglycan

contains N-glycolylmuramic acid instead of N-acetylmuramic acid

- Arabinogalactan- Mycolic Acids (60% of cellular

envelope)- Lipoarabinomannan (LAM)

Mycobacterial Cellular Envelope

Contribution of Mycobacterial Cellular Envelope to PathogenesisResistance to Drying and Other Environmental Factors- Thick, waxy nature of cellular envelope protects M. tuberculosis

from drying, alkali conditions, and chemical disinfectants- Hinders entrance of antimicrobial agents

Entry into Host Cells- Lipoarabinomannan (LAM) binds to mannose

receptors on alveolar macropages leading to entry into the cell

Interference of Host Immune Response- Glycolipids and sulfolipids decrease the effects of oxidative

cytotoxic mechanism- Inhibition of phagosome and lysosome fusion inside

macrophage- Waxy cellular envelope prevents acidification of the bacteria

inside the phagosome

Factors Affecting PathogenicityActive Infection- Only individuals with an active infection

can transmit the disease

Transmission- Aerosolized droplets need to be <10μm

in order to evade the ciliated epithelium of the lung to establish infection in the terminal alveoli

Growth & Structure- Only require a very few number of

bacteria to establish an infection (1-10 bacteria)

- Slow generation time

M. Tuberculosis in sputum

(stained in red)

Common Symptoms of TB DiseaseCough (2-3 weeks or more)Coughing up bloodChest painsFeverNight sweatsFeeling weak and tiredLosing weight without trying Decreased or no appetiteIf you have TB outside the lungs, you may

have other symptoms

Diagnosis of Latent & Active TBTools for Diagnosing TB Infection

Mantoux skin test (PPD)Chest x-raySputum cultures

Diagnosis for Latent & Active TB Tools for Diagnosing TB Infection Mantoux Skin Test(PPD)

Mantoux tuberculin skin test (PPD) is a skin test for identifying exposure to the TB bacteria, Mycobacterium tuberculosis (latent infection)

The Mantoux test is recommended because it provides the most consistent and reliable result.

The Mantoux test is read 48-72 hours after administration. Induration or “knot-like” swelling at the test site is significant and the reaction is measured in millimeter units. Redness at the test site is not measured.

Diagnosis for Latent & Active TBTools for Diagnosing TB InfectionSputum

A sputum specimen is necessary to confirm that the TB bacteria is present in the lung.

The sputum specimens should: -come from deep within the lungs; -be obtained from the first coughed

up sputum of the day, for 3 consecutive days

-may be obtained through special respiratory therapy procedures.

Treatment for TB DiseaseTB disease is treated with medicine to kill the

TB germs

Usually, the treatment will last for 6-9 months

TB disease can be cured if the medicine is taken as prescribed, even after you no longer feel sick

TreatmentAntibacterial chemotherapy:

- Combination of first and second line drugs for the first 2 months which could include:- Isoniazid- Rifampicin- Pyrazinamide- Streptomycin or Ethambutol

- Next 4 months, combination of:- Isoniazid- Rifampicin

- Early resistance to isoniazid: other first-line drugs such as ethambutol, streptomycin, pyrazinamide and fluoroquinolones can be added to drug arsenal (treatment period also extended).

- These drugs are relatively effective in killing the bacteria, however, they also produce a wide variety of side effects.

Treatment

First line drugs:- Bactericidal agents: kill active bacteria, important in the

early stages of infection.

Second line drugs:- Bacteriostatic: hinder bacterial growth.

- Strengthen treatment in the case of resistant bacteria.- Less efficient and generally more toxic than first line

drugs.

Inappropriate chemotherapy:- Monotherapy (single drug treatment)- Decreased treatment period- Low absorption of drugs

Drug Bactericidal orBacteriostatic

Mechanism of Action Mutation Rate

Side Effects

Isoniazid Bactericidal to rapidly dividing bacteria and bacteriostatic to slowly dividing bacteria

Pro-drug: activated by a bacterial catalase.Inhibits enoyl-ACP reductase (key enzyme in fatty acid synthesis, different than equivalent mammalian enzymes)

1 in 105 - 106 Rash, abnormal liver function, anemia, peripheral neuropathy, mild CNS effects

Rifampicin Bactericidal Inhibits transcription by RNA polymerase

1 in 108 Fever, immune reactions, GI irritation, liver damage, can cause tears and urine to turn red/orange

Streptomycin Bactericidal Inhibits initiation of protein synthesis

1 in 108 - 109

Damage to the ears, nausea, rash, vomiting, vertigo

Ethambutol Bacteriostatic

Prevents formation of the cell wall

1 in 107 Decrease in visual acuity, colourblindness and other visual defects, joint pain, nausea, vomiting, fever, malaise, headache, dizziness

Fluoroquinolones

Bactericidal Act manly on DNA gyrase (DNA gyrase: introduces negative supercoils into DNA)

Tendon damage, heart problems, swelling of face and throat, shortness of breath, rash, loss of consciouness

Pyrazinamide Bacteriostatic, Bactericidal

Accumuates causing cellular damage

Joint pain, nauseau, vomiting, rash, malaise, fever, photosentivity

Treatment

Drug Resistance and Tuberculosis- M. tuberculosis: naturally resistant to

certain antibiotics due to presence of:- Drug-modifying enzymes- Drug-efflux systems- Hydrophobic cell wall

- Mycobacteria undergo natural mutations which can lead to development of drug resistance.- TB is treated by administration of

combination chemotherapy: decreases probability of development of drug resistance.

- Development of increasingly resistant strains mainly due to: Patient non-compliance

MDR and XDR Tuberculosis MDR: Multidrug-resistant strains:- Strains of tuberculosis resistant at least to rifampicin and

isoniazid.- Mortality rate: 40-60%- Estimated that 50 million people are infected with MDR-TB.- MDR-TB is approximately 125 times more expensive to treat than

drug susceptible TB.

XDR: Extensively-drug resistant strains:- Strains of tuberculosis resistant to rifampicin,

isoniazid and at least three of the following classes of second-line drugs: aminoglycosides, polypetides, fluoroquinolones, thioamides, cycloserine and para-aminosalicylic acid.

MDR and XDR Tuberculosis- Emergence due to lack of patient compliance during TB

treatment and inappropriate administration of TB drugs.- Results in more aggressive forms of TB.- Drug resistance does not increase infectiousness. - MDR and XDR-TB: uncommon in developing nations lacking

TB drugs (high drug-susceptible TB rates)- MDR and XDR-TB rates are higher in developed nations with

access to anti-TB drugs.

- HIV pandemic has reversed much of the progress made in the past few decades in combating TB.

- People with latent TB have a 10-20% of developing active TB in their lifetime. People with HIV and latent TB are 100 times more likely to develop active TB.

- HIV/AIDS leads to a compromised immune system:- HIV infects CD4+ T cells, macrophages, dendritic cells.- Result: decreased CD4+ T cells due to apoptosis of infected cells, CD8+

T cell mediated killing of infected cells- The numbers of CD4+ T cells progressively decline (loss of cell-

mediated immunity) and the body is much more susceptible to infection

Tuberculosis and HIV/AIDS

T cell

- A person with HIV/AIDS will have a harder time fighting off the M. tuberculosis infection due to a compromised immune system.

- HIV infection can cause latent M. tuberculosis infection to become reactivated.

- TB is the leading cause of death for people with HIV/AIDS: mean survival rate is 430 days.

- MDR and XDR-TB and HIV/AIDS:- Additional symptoms: excessive weight

loss, respiratory problems (including the formation of lesions in the lungs).

- Mean survival rate: 45 days.

Tuberculosis and HIV/AIDS

Directly Observed TreatmentWhy? Many patients don’t take medicines regularly,

even if excellent health education provided Who? All patients... impossible to predict which

patient will take medicine (1/3 not adherent) What? Observer watches and helps patient swallow

tablets Where? Anywhere! (home, clinic, work, school, etc) Who does it? HCW, community liaisons, teachers,

Direct observation ensures treatment for entire course with the right drugs, in the right doses, at the right intervals

DOT is necessary even whendrug supply ensured

88%

61%

0%

20%

40%

60%

80%

100%

Chaulk CP. JAMA 1998;279:943-8

Treatment Success

DOT No DOT