Tuberculosis-a brief outlookBY- VISHNU.R.NAIR3RD YEAR PHARM DNATIONAL COLLEGE OF PHARMACYKERALA UNIVERSITY OF HEALTH SCIENCES (KUHS).

A. GENERAL INTRODUCTION:

Defined as “slowly spreading,chronic,granulomatous bacterial infection, characterized by gradual weight loss and PULMONARY and or EXTRAPULMONARY manifestations”.

Primarily affects lung parenchyma Caused mainly by the bacterium “MYCOBACTERIUM TUBERCULOSIS” May spread to any part of the body, including MENINGES, KIDNEY, BONES

and LYMPH NODES One of the most prevalent infections in human beings Spread by inhaling tiny droplets of saliva from coughs/ sneezes of an infected

person.

B. TYPES OF TB:

1. PULMONARY TB

2. AVIAN TB:

-Caused in birds

-Caused by M.avium

3.BOVINE TB:

-Caused in cattle

-Caused by M.bovis

Continued…………….

4. MILIARY TB:

-Also known as “Disseminated TB”

-Characterized by:

a.Wide dissemination into human body

b. Tiny size of lesions (1-5 mm).

C. ETIOLOGY AND MODE OF TRANSMISSION:

1. DIRECTLY, FROM M.TUBERCULOSIS

2. VIA DROPLET NUCLEI:

-Coughing

-Sneezing

-Laughing

3. TB EXPOSURE

D. EPIDEMIOLOGY:

-With increased incidence of AIDS

TB poses a major threat to the world

-Almost one third of the world’s population is infected with TB

-Global Emergency TB kills 5000 people a day

-2.3 million die each year

-30% cases are observed in Asians

-Age specific risk is high in persons aged more than 65 years…………………

e. Incubation period of m.tuberculosis:

2-12 weeks

F. RISK FACTORS FOR TB:

Close contact with someone who has active TB In immuno-compromised patients Elderly Cancer patients Intravenous drug abusers Alcoholism People, lacking adequate health care Diabetes mellitus Chronic renal failure

CONTINUED……………..

Immigrants from countries, with increased incidence for TB Institutionalization (long term care facilities) Living in substandard conditions Occupational (health care workers) Immunosuppressant use TNF-Alpha antagonists Gastrectomy Decreased body weight Smoking Age greater than 5 years

CONTINUED………………………..

Genetic factors:

-The following genes are associated with TB risk:

1. NRAMP 1

2. SP 110

3. CISH

4. IRGM

5. IFNG

6. IFNGR 1

7. TIRAP

8. CD 209

CONTINUED………………………………..

The following factors are used to determine whether a TB infection is likely to be transmitted:

1. No. of organisms expelled

2. Organisms concentration

3. Length of exposure time to concentrated air

4. Immune status of the exposed individual…………………………………………………….

G. PATHOPHYSIOLOGY OF TB: There are 2 major factors that result in bacterial susceptibility:

1. PREDISPOSING FACTORS:- Age: Children below 14 years, or elders above 65 years of age- Native Americans, Eskimos, Asians, Blacks

2. PRECIPITATING FACTORS:

-Immunocompromised person- Malnourishment- Economically disadvantaged\homeless\poor housing- Living in over crowded areas- Alcohol dependence\abuse- Poor hygiene- Lack of health care access

CONTINUED……………….Both pre-disposing and precipitating factors

Cause inhalation of droplet infected with M.Tuberculosis

Initially, it is trapped in the upper airways

Primary defenses are activated (Mucus secreting Goblet cells , cilia)

Defense becomes unsuccessful

CONTINUED………………………………

Bacteria reaches and deposits itself in the lung periphery( lower part of upper lobe \ upper part of lower lobe , especially in alveoli)

Bacteria is quickly surrounded by POLYMORPHONUCLEAR LEUCOCYTES (PML)

Engulfed by alveolar macrophages

CONTINUED………………………………

Some mycobacterial organisms are carried off by lymphatics to hilar lymph nodes

Now known as “GHON COMPLEX” , (Rarely results in spread to other body organs)

As macrophages (epithelial cells) engulf bacteria , these cells join and form into giant cells that encircle the foreign cells

Hypersensitivity to the organism

CONTINUED………………………………..

Results in giant cells “caseous necrosis” (granular cheesy appearance)

T-lymphocytes assimilate in the surrounding of the central core of caseous necrosis

Lesions occur

Ageing of lesions

CONTINUED………………………………… Fibrosis and calcification

Granuloma formation (tubercle)

Collagenous scar tissue encapsulates tubercle to separate organism from body

As the process progresses, bacteria may\may not be killed

Growth continuation

CONTINUED……………………………… Results in cell mediated immunity (detected through PPD – Purified protein

derivative test \ Mantoux test)

PULMONARY TUBERCULOSIS

- For poorly immunocompromised individuals,

- Pulmonary TB causes liquefaction of necrotic tissue

- Fibrous walls loose their structural integrity

CONTINUED…………………………………. Semi-liquid necrotic material formed

Drained into bronchus\ nearby blood vessel, leaving an air-filled cavity at the original site………………

- If drainage occurs into bronchus:

a. Purulent discharge occurs

b. Can affect other people through transmission- If drainage occurs into blood vessel:

Necrotic material can enter blood stream or lymphatic system, leading to formation of new caseous granulomas, and finally EXTRAPULMONARY TB……………………………..

H. SIGNS N SYMPTOMS :1. FOR PULMONARY TB:- Cough (non- productive)- Dyspnea- Non-resolving bronchopneumonia- Chest tightness- Mucopurulent sputum- Hemoptysis- Chest pain- Weight loss- Anorexia- Fatigue- Fever- Night sweats

Continued……………………………….2. TUBERCULOUS MENINGITIS:- Headache (for 2-3 weeks)- Changes in mental status- Coma- Low grade fever

3. SKELETAL TB:- Back pain- Tuberculous arthritis (in knee, ankles , elbow etc)- Lower extremity paralysis

4. GENITOURINARY TB:

-Flank pain- Dysuria- Frequent urination- In men : Painful scrotal mass, prostatitis, orchitis, epididymitis- In females : Symptoms resemble pelvic inflammatory disease

Continued…………………………….5. GI TB:- Non healing ulcers of mouth or anus- Difficulty in swallowing- Abdominal pain- Malabsorption- Pain- Diarrhea- Hematochezia

6. EXTRAPULMONARY TB :- Confusion- Coma- Neurologic deficit- Chorioretinitis- Lymphadenopathy- Cutaneous lesions- Inflammation…………………………..

I. DIAGNOSIS:1. PATIENT HISTORY DETAILS COLLECTION

2. PHYSICAL EXAMINATION:- Clubbing of fingers or toes (in people with advanced disease)- Swollen or tender lymph nodes in neck or other areas- Pleural effusion (Fluid around a lung)- Unusual breath sounds (Crackles)

If its MILIARY TB, a physical exam. may show :- Swollen liver- Swollen lymph nodes- Swollen spleen

3. DIAGNOSTIC TESTS:- Biopsy of affected tissue- Bronchoscopy- Chest CT Scan- Chest X-ray

Continued………………………….- Interferon gamma blood test (QFT Gold Test)- Sputum examination and cultures- Thoracentesis- Tuberculin skin test (PPD test)

QUANTIFERON GOLD TEST (QFT):

Measures Interferon gamma in testee’s blood after incubating it with specific antigens from M.tuberculosis proteins.

TUBERCULIN SKIN TEST:

Take 0.1 ml PPD

CONTINUED……………….............

Inject in forearm (s.c)

Wait for 48-72 hours

Check for induration presence at the site of injection

If Induration >= 10 mm ,the patient tests POSITIVE for TB…………….

J. COMPLICATIONS OF TB: Lung function damage Bone pain (in spine, ribs, and joints) Meningitis Kidney damage Liver damage Cardiac tamponade Visual disturbances Pleural effusions TB pneumonia………………………………….

MANAGEMENT OF TB:INCLUDES:

1. GOALS OF THERAPY

2. GENERAL PRINCIPLES OF THERAPY

3. PHARMACOTHERAPY

4. NON-PHARMACOTHERAPY

5. TB PREVENTION

1. Goals of therapy:- Rapid identification of new TB cases- Isolation of patient (with active disease) to prevent spread- Collection of appropriate samples for smears and cultures- Prompt resolution of signs and symptoms after disease treatment initiation- Non-infectious state achievement, leading to isolation- Medication adherence- To cure as quickly as possible (within 6 months of treatment)- To reduce pain and distress- To avoid precipitation of complications and associated morbidity and mortality- To improve QOL (Quality of Life )……………………….

2. GENERAL PRINCIPLES OF THERAPY: Drug treatment is the cornerstone of TB management

Minimum of 2 drugs (generally 3-4 drugs) must be used simultaneously Drug treatment should be continued for at least 6 months ( and up to 2-3 years for some cases of

MDR –MULTIDRUG RESISTANT TB) Measures to observe medication adherence, such as DOTS therapy, are important Patients with active disease should be isolated to prevent disease spread Public health departments are responsible to prevent TB spread Such departments are duty-bound to find where TB has already spread , using contact

investigation…………………………..

3. PHARMACOTHERAPY:A. FIRST LINE ANTI-TB DRUGS:- Effective - Possess acceptable degree of toxicity- Include:

i. STREPTOMYCIN : 15 mg/kgii. INH (ISONIAZID) : 5 mg/kg (max. 300 mg/day)iii. RIFAMPIN : 10 mg\kgiv. PYRAZINAMIDE : 15-30 mg\kgv. ETHAMBUTOL : 15-25 mg\kg daily for 8 weeks (continue for 4-7 months)

B. SECOND LINE ANTI-TB DRUGS:- Mainly used for microbial resistance or patient related factors- Include:

i. CAPREOMYCIN: 12-15 mg/kgii. ETHIONAMIDE: 15 mg/kgiii. PARA AMINO SALICYLIC ACID SODIUM : 200- 300 mg/kgiv. CYCLOSERINE: 15 mg\kg

Continued…………………………..C. THIRD LINE ANTI-TB DRUGS:- May be useful- Not on the WHO list of medications for TB therapy- Include:

i. RIFABUTINii. MACROLIDES : CLARITHROMYCIN (CLR)iii. LINEZOLID (LZD)iv. THIOACETAZONE (T)v. THIORIDAZINEvi. ARGININE………………………..

CONTINUED…………………………………D. TREATMENT DIVERSITY PLANS:

1. For Latent Infection:- Initiate chemoprophylaxis in patients to reduce risk of progression to active disease- INH (300 mg daily) is generally given for 9 months- Non-compliant individuals are given 15 mg\kg (max. 900 mg) twice weekly with observation- Give RIF (RIFAMPIN) 600 mg daily for 4 months in cases like :

a. Suspected INH resistance

b. INH intolerance- Substitute RIFABUTIN 300 mg daily for RIF in patients at risk of severe drug interactions- For pregnant women, alcoholics and malnutritioned ones : Administer PYRIDOXINE (VIT.B)

10-50 mg daily ,to decrease risk of peripheral neuropathies (especially with INH)

CONTINUED………………………..2. For active infection:- Anti-TB regimen includes:

a. INH, RIF, Pyrazinamide and Ethambutol (for 2 months)

Continue therapy with INH and RIF for 4 months

-Before initiating therapy, focus on appropriate microbial culture sensitivity and susceptibility tests, to determine initial drug selection for patient.- If patient is being evaluated for re-treatment of TB, make note on what drugs were used previously and for how

long- Patient should complete at least 6 months of more of therapy- Treat patients for at least 9 months under the following criteria:

a. Slow response to therapy

b. Culture positivity for at least 2 months of treatment

c. HIV- positive patients

-For patients, who cant tolerate INH and RIF, extend therapy to 2 years or more. (regardless of immune status).

CONTINUED……………………………..3. For Drug resistant TB:

-If organism is drug resistant

Introduce 2 or more active agents that the patient has not received previously.- For MULTIDRUG RESISTANT (MDR) TB, no standard regimen can be proposed- Drug resistance should be suspected in the following conditions:

a. Patients, who have received prior therapy for TB

b. Patients, from areas with increased rates of resistance (NEW YORK CITY, MEXICO, SOUTH EAST ASIA, MEXICO,etc)

c. Patients, who are homeless, institutionalized, i.v drug abusers or HIV infected

d. Patients, who still have acid fast bacilli positive sputum smears , even on 2 months of therapy

e. Patients, who still have positive cultures after 2-4 months of therapy

f. Patients , who fail therapy / relapse after treatment

g. Patients known to be exposed to MDR-TB………………….

CONTINUED………………………………4. For special populations:

I. TUBERCULOUS MENINGITIS AND EXTRAPULMONARY DISEASE:- INH, Pyrazinamide, ethionamide and cycloserine penetrate CSF- Patients with CNS TB are treated for 9-12 months- TB of bone is treated for 9 months, mostly with drugs + surgery

II. CHILDREN:- Prefer 9 months treatment, with drug regimen similar as that advised for “active disease”- Pediatric doses should be opted

III. PREGNANT WOMEN:- Use INH , RIF and Ethambutol for 9 months- For women with TB, exercise caution about being pregnant , since the disease risks fetus and

mother.- Vit.B supplementation is important.

CONTINUED……………………………….- RIF may cause:

a. Limb reduction

b. CNS lesions- Ethionamide can cause:

a. Premature delivery

b. Congenital deformities

c. Down’s syndrome- Streptomycin: Can cause hearing loss in newborn- Cycloserine: Not recommended in pregnancy……….

IV. FOR RENAL FAILURE:- INH and RIF do not require dose modifications- Pyrazinamide and Ethambutol require dose reduction from daily to thrice

weekly…………………………

CONTINUED………………………E. DRUG DETAILS:

I. INH (LANIAZID):a. Mechanism of action:

Drug >> enters body in prodrug form >> enters mycobacterial cell >> undergoes oxidation reaction catalyzed by CATALASE PEROXIDASE>> Forms activated INH>> Acylates enzyme system found in bacteria, which is required for mycolic acid production>> Mycolic acid synthesis inhibited>> Disruption of bacterial cell wall

b. ADR (Adverse drug reactions):- Peripheral neuritis- Optic neuritis

c. Drug interaction:

-Food, antacids+ INH= Decreased effect of INH (due to decreased absorption)>> Thus take drug on empty stomach…..

CONTINUED………………………….II. PYRAZINAMIDE (PYZID):- Bio-isomer of nicotinic acid- MOA:

Drug>>enters body>>enters bacterial cell>> converted to PYRAZINOIC ACID, by the organism, in presence of enzyme PYRAZINE AMIDASE>> Acid lowers pH of surrounding bacteria>>organism cant grow in the high lowered environment

-ADR:

a. Hepatotoxicity

b. Jaundice

- Essential component of combination therapy……………..

CONTINUED…………………………….III. ETHAMBUTOL HYDROCHLORIDE (MYCOBUTOL):- Positive enantiomer is 200-500 times more active than negative one- MOA:

Drug>> inhibits mycobacterial arabinosyl transferase (involved in polymerization of D- arabino furanose to arabino glycan , which is an essential cell wall component) >>decreased synthesis of arabino glycan>> cell wall synthesis inhibition.- ADR:

a. Decrease in visual acuity

b. Green red color blindness

- Should not use in children below 5 years

- Used in patients who are resistant to INH\ Streptomycin……………………

Continued……………………….IV. RIFAMPIN ( LS RIF):- MOA:

Drug>> aromatic naphthalene ring in drug binds to bacterial DNA-dependent RNA polymerase (DDRP) >> Inhibits DDRP>> Blocks chain formation of RNA synthesis- ADR;

a. GI disturbances

b. Skin reactions

c. Eosinophilia

d. Hepatotoxicity

e. TTP (Thrombotic thrombocytopenic purpura)

- Not recommended for use in HIV patients>> drug decreases activity of protease inhibitors……..

CONTINUED…………………………E. PARA-AMINO SALICYLIC ACID (PAS-SODIUM):- MOA:

Drug>>interferes with incorporation of PABA(Para amino butyric acid) into folic acid>> DNA synthesis inhibited

- Mainly, this drug acts as an anti-metabolite- ADR:

a. Nausea

b. Vomiting

c. GI irritation

d. Thyroid goiter

- Mainly bacteriostatic in nature, so used in combination with other drugs……………

CONTINUED…………………………..F. ETHIONAMIDE (ETHIDE):- Primary drug for treatment of Mycobacterium Tuberculosis- Most effective- ADR:

a. Anorexia

b. Excessive salivation

c. Metallic taste- Drug>> more toxic than INH>> Avoid general use- Use only when combination for (INH+Streptomycin+PAS) is ineffective or

intolerated…………………………

CONTINUED……………………………….VII. CYCLOSERINE (CYCLORINE):- Antibiotic, obtained from Streptomyces species- MOA:

In M.Tuberculosis>> L-alanine is converted to D-alanine by the enzyme D-alanine racemase>> D-alanine is incorporated into peptidoglycan portion by D-alanine ligase

D-alanine is an important component of peptidoglycan portion of mycobacterial cell wall

Drug>> forms D-cycloserine, which is an analogue of D-alanine>> Competitively inhibits both enzymes

-ADR:

a. Headache

b. Dizziness

c. Anxiety- Uses:

a. Resistance to other drugs

b. As combination therapy

- Avoid in pregnancy………………….

CONTINUED……………………………… VIII. STREPTOMYCIN (ISOS):-MOA:

Drug>> binds to 30S ribosomal subunits>> interferes with normal bacterial protein synthesis

-ADR:

a. Giddiness

b. Vertigo

c. Tinnitus

d. Ataxia

e. Hypersensitivity

- Used in combination with PAS and RIF……………………

CONTINUED…………………….F. DOTS THERAPY:- Also known as DIRECTLY OBSERVED TREATMENT SHORTCOURSE- Mainly used by WHO as part of TB control strategy- Uses a combination of different drugs to prevent drug resistance and infection spread- Supervision by medical and non-medical professionals to ensure medication adherence is

recommended- DOTS is mainly useful to the following people:

a. Drug resistant TB

b. HIV patients

c. Those on intermittent treatment regimes (twice\thrice weekly)

CONTINUED…………………………..- DOTS Therapy involves 5 components:

1. Government commitment:

Includes:

i. Political will and support at all levels

ii. Establishing centralized and prioritized system of TB monitoring , recording and training

2. Case detection: By sputum smear microscopy

3. Standardized Treatment Regimen:

a. Directly observed by health care or community health workers for at least the first 2 months

4. Regular Drug Supply

5. Standardized Recording and Reporting System: Allows assessment of treatment results……………

CONTINUED………………………….G. MULTI DRUG THERAPY:- Involves taking different anti-TB drugs at the same time- Standard treatment is to take INH, RIF, Ethambutol and Pyrazinamide for 2 months- Treatment is then considered for at least 4 months, with fewer

medications……………………………..

4. NON-PHARMACOTHERAPY:1. Advise patients about the severity of disease and need for medication adherence

2. Encourage rest

3. Avoid exertion

4. Administer and teach self-administration of medications ordered

5. Encourage increased fluid intake

6. Make patient aware that TB can be transmitted via respiratory droplets

7. Instruct about the best position to facilitate drainage

8. Educate patient to cover nose and mouth while coughing and sneezing to control infection spread

9. Patient isolation

10. Instruct about risk of drug resistance, if the drug regimen is not strictly and continuously followed

11. Carefully monitor vital signs

12. Observe for temperature changes

13. Explain importance of eating nutritious diet to promote healing and defense against infection

CONTINUED……………………..

14. Provide small frequent meals

15. Monitor patient weight

16. Give vitamin supplements as ordered

17. Educate patient about etiology, transmission, effects and TB complications

18. Educate patient about ADRs of drug therapy (example red colored urine associated with INH administration, etc.)

19. Explain to patient that TB is a communicable disease , and that taking medications is the most effective way to prevent transmission

20. Instruct about medications schedule………………..

5. PREVENTION OF TB:

A. ISOLATION

B. ROOM VENTILATION

C. COVER MOUTH

D. WEAR MASK

E. FINISH ENTIRE COURSE OF MEDICATION

F. VACCINATIONS……………………………………

THANK YOU!!!!