Tuberculosis

TUBERCULOSIS

CONTENTS: •INTRODUCTION•EPIDEMIOLOGY•CAUSES•PATHOGENESIS•DIAGNOSIS•TREATMENT

Tuberculosis or TB  is a common and often deadly infectious disease caused by mycobacteria, usually Mycobacterium tuberculosis in humans.

Tuberculosis usually attacks the lungs but can also affect other parts of the body. 

The classic symptoms are a chronic cough with blood-tinged

sputum, fever, night sweats, and weight loss.

The primary cause of TB, Mycobacterium tuberculosis , is a small  aerobic  non-motile  bacillus.

The M. tuberculosis complex includes four other TB-causing  mycobacteria: M. bovis, M. africanum, M. canetti  and M. microti. 

M. africanum is not widespread, but in parts of Africa it is a significant cause of tuberculosis.

CAUSES:

It is currently estimated that 1/2 of the world's population (3.1 billion) is infected with Mycobacterium tuberculosis. Mycobacterium avium complex is associated with AIDS related TB.

 The proportion of people who become sick with tuberculosis each year is stable or falling worldwide but, because of population growth, the absolute number of new cases is still increasing.

EPIDEMIOLOGY:

 In 2007 there were an estimated 13.7 million chronic active cases, 9.3 million new cases, and 1.8 million deaths, mostly in  developing countries.

The distribution of tuberculosis is not uniform across the globe; about 80% of the population in many Asian and African countries test positive in tuberculin tests, while only 5-10% of the US population test positive.

Per 1,000,00

10 - 24< 10

25 - 4950 - 99

100 - 299300 or moreNo estimate Highest

estimated TB rates per

capita were in Africa

Pulmonary tuberculosis is a disease of respiratory transmission, Patients with the active disease (bacilli) expel them into the air by:coughing, sneezing, shouting,or any other way that will

expel bacilli into the air Transmission is dependent on closeness and time of contact

Transmission:

Once inhaled by a tuberculin free person, the bacilli multiply 4 -6 weeks and spreads throughout the body. The bacilli implant in areas of high partial pressure of oxygen:

lung renal cortex reticuloendothelial system

When the disease becomes active, 75% of the cases are pulmonary TB, that is, TB in the lungs.

 Symptoms include  chest pain, coughing up blood, and a productive, prolonged cough for more than three weeks.

Systemic symptoms include  fever, chills, night sweats, appetite loss, weight loss, pallor, and often a tendency to  fatigue very easily.

Signs and symptoms:

In the other 25% of active cases, the infection moves from the lungs, causing other kinds of TB, collectively denoted extrapulmonary tuberculosis. This occurs more commonly in immunosuppressed persons and young children.

Extrapulmonary infection sites include the  pleura in tuberculosis pleurisy, the central nervous system in  meningitis, the lymphatic system in  scrofula of the neck, the genitourinary system in urogenital tuberculosis, and bones and joints in Pott's disease of the spine.

Signs and symptoms:

Infection via inhalation of droplet nuclei.↓

Transport of bacilli to terminal alveoli (especially lower segments of lungs)

↓Ingestion of organisms by macrophages followed by multiplication within macrophages

↓Transport of organisms to regional lymph nodes by infected macrophages with continue multiplication and minimal inflammatory response

Pathophysiology

↓

Extension of organisms( within 4-6 weeks after inhalation) into the bloodstream from the regional nodes

↓Cell mediated immunity / hypersensitivity reaction

↓Development of clinical infection

Diagnosis by X-ray:

Chest x-rays: Multi nodular infiltrate above or behind the clavicle with or without pleural effusion unilaterally or bilaterally.

Diagnosis sputum investigation:• Cultures will reveal the

presence of mycobacterium tuberculosis

• Patients stay infectious for as long as the bacilli are excreted in the sputum

Diagnosis by tuberculin test:

Skin test. PPD (purified protein derivative) antigens are injected intradermally. A positive reaction is a helpful adjunct in diagnosis.

Tuberculin test positivity indicated hypersentivity to bacterial protein

According to their clinical utility the drugs are:

First line drugs : High antitubercular efficacy and low toxicity which are used routinely.

Second line drugs: Either low antitubercular efficacy or high toxicity or both, used in special circumstances only.

Classification of drugs:

First line drugs include: -ISONIAZIDE - PYRAZINAMIDE

- ETHAMBUTOL -RIFAMPICIN -STREPTOMYCIN

HIGH EFFICACY AND LOW TOXICITY

Second line drugs include:

-THIACETAZONE -CAPREOMYCIN -P-AMINOSALICYLIC

ACID -ETHIONAMIDE -CYCLOSERINE -KANAMYCIN -AMIKACIN

LOW EFFICACY AND HIGH TOXICITY

NEWER SECOND LINE DRUGS:

Flouroquinolones are active against M.tuberculosis.

Ciproflaxacin, Oflaxacin, Newer macrolides and some rifampin congeners

are the recent additions. Clarithromycin, Azithromycin, Rifabutin.

Considered the drug of choice for the chemotherapy of TB. discovered in 1945 a hydrazide of isonicotonic acid

bacteriostatic for resting bacilli,

bactericidal for growing bacilli.

ISONIAZIDE[H]:

Most active anti-tb drug. Dose:5mg/kg dailyIt inhibits cell wall sythesis or mycolic acid synthesis. Important assets are -potency -infrequent toxicity -low cost

Useful for tb meningitis. Effective for both extra cellular & intracellular tb. If combined with other drug it has good resistance preventing action.

ISONIAZIDE[H]:

ISONIAZID Kat G( catalase peroxidase in mycobacteria) Active INH

AcpM & Kas AcpM- Acyl Carrier protein KasA ( ß ketoAcyl Carrier protein

synthetase)

Block Mycolic Acid Synthesis

MOA of H:

I. RashII. Peripheral NeuropathyIII. HepatitisIV. Transient loss of MemoryV. SeizureVI. Pleural effusion

VII. Arthralgia

Adverse Effects:

Semisynth. deri of Rifamycin B-from St.meditarranei.

Acts both extra & intracellularly.Bactericidal efficacy ≈ INH &>any other 1st line drugAnalogue of RIFAMPIN is RIFABUTIN. obtained from Rifamycin S.Dose: 10mg/kg daily or 2-3 times weekly

RIFAMPIN[R]:

D.N.A RIFAMPIN DNA dependent R.N.A.polymerase R.N.A Protein Syn. Cell multiplication Rifampin bind to β S.U of D.D.R.P Drug –Enz Complex Supression of chain initiation

MOA OF RIFAMPIN:

Hepatitis, a major adverse effect.Respiratory syndrome: breathlessness.Purpura, haemolysis, shock and renal failure.Cutaneous syndrome : flushing, pruritis +

rash.Flu like syndrome : fever, headache, bone

pain.

Adverse effects:

Synthetic analogue of Nicotinamide.Though weakly tuberculocidal More active in acidic medium.Highly effective during 1st 2months.More effective against Slow Growing.Active both intra & extracellularly.

Dose : 20-25mg/kg daily

PYRAZINAMIDE[z]:

Pyrazinamide

Mycobacterial Pyrazinamidase

Pyrazinoic Acid

Inhibits Mycolic Acid Synthesis

MOA OF PYRAZINAMIDE:

Adverse effects:ArthralgiaFlushingRashesFeverloss of diabetes controlHepatotoxicity

Rapid Growers are more susceptible.Prevent the emergence of Resistant bacilli.C/I ; Cr. Clearance <50ml/min Doses of Ethambutol : 15mg/kg/day

ETHAMBUTOL[E]:

Mycobact. Arabinosyl Transferase ETHAMBUTOL Polymerisation reaction of Arabinoglycan Essential component of Myco.Cellwall

MOA OF E:

Loss of visual acuity Color blindness Field DefectEarly recognition &stoppage of drug-

visual toxicities is largely reversibleContra-indication ;In children <6yrs a) they are unable to report early. b) may not permit the assessment of red green color blindness discrimination Renal uric acid excretion Hyperuricemia Joint Pain

Side effects:

First drug used for the treatment of TB.It is aminoglycoside antibiotic.It is tuberculocidal .It acts only on extracelluluar bacilli.Limitation of its use i)dose related toxicity ii)development of resistant org. iii)pt compliance is poor due to i.

m

STREPTOMYCIN

acts by protein synthesis inhibitor and decreases the fidelity mRNA and garbles the message, leads to nonsense proteins.

Streptomycin only binds to the 30s subunit.Dose: 15mg/kg 3 times weekly for first 2-3

months for severe disease

H1 receptor blockers cause ototoxicity, with other aminoglycosides, diuretics and vancomycin

MOA:

INT:

SIDE EFFECTS:OTOTOXICITY-drugs get conc. In labrynthine fluid,

both vestibular & cochlear damageNEPHROTOXICITY PARALYSIS Sterile abscess at the inj. site

Aminoglycosides: least effective and more toxic

Capreomycin - Viomycin – KanamycinAdverse effects:These drugs are: Nephrotoxic will cause

Proteinuria, Hematuria, Nitrogen metabolism, and Electrolyte disturbances However effect is reversible when drug is stopped

Capreomycin has replaced viomycin because of less toxic effects, but all three drugs have the same effects.

Second line drugs:

Can cause CNS disturbances Therapeutic States :

Cycloserine should be used when re-treatment is necessary or when the micro-organism is resistant to the other drugs.

It must be given in combination with other anti-tuberculosis drugs.

Dose: 500 mg to 1g per day

Mechanism of Action : An analog of D- alanine synthetase, will block bacterial cell wall synthesis.

Cycloserine:

These are first anti tubercular drugs.It is a tuberculostatic drug.Low efficacy drug.Side effects: hepatitis, optic neuritis, mental disturbences impotenceDose: 150mg per day

Thioacetazone & Ethionamide:

PAS is a tuberculostatic and one of least active drugs.

It inhibits denovo folate synthesis.PAS is completely absorbed by oral route and

distributed all over .Dose : 150 mg/kg/dayPatient acceptability of PAS is poor.Adverse effects ; Rashes, fever, liver dysfunction

Para-amino salicylic acid:

ChemotherapyDOTS:

To control tuberculosis requires:Effective, inexpensive, simple and standardised

technology.

The success of the DOTS strategy depends on:Government commitment to a national tuberculosis

programme.Case  detection –finding by smear microscopy

examination of TB susceptible in general health services.

Regular uninterrupted supply of essential anti-TB drugs.

Monitoring system for programme supervised and evaluation.

Short Course Chemotherapy:

These are regimens of 6-9 month duration.

All regimens have an initial intensive phase lasting 2-3 months to kill the TB bacilli and afford symptomatic relief.

This is followed by continuation phase for 4-6 months so that relapse does not occur.

Type of patient Duration of treatment

Regimen

Category-11.New sputum positive2.Seriously ill, sputum negative, Pulmonary3.Seriously ill

Intensive phase(2months)

Continuation phase(4months)

INH+RMP+ETB+PZA

INH+RMP

Category-2Retreatment group1.Relapse2.Treatment failure

Intensive phase(3months)

Continuation phase(5months)

INH+RMP+ETB+PZA

INH+RMP+ETB

Category-31.New smear negative pulmonary2.extrapulmonary

Intensive phase(2months)

Continuation phase(4months)

INH+RMP+PZA

INH+RMP

REGIMENS :

Multiple Drug Resistance(MDR):Resistance to both Isoniazid and Rifampin and number

of other anti-TB drugs . MDR-TB has a more rapid course ,(some die in 4-16 weeks).

Treatment is difficult as  second line drugs are less efficacious, less convenient, more expensive

and toxic.Therapy depends on drugs used in earlier regimen,

dosage and regularity with which they have been taken.

In India>200,000patients have been treated under DOTS by early 2001 with cure rate of 75-80%.

In other countries 80-93%cure rates have been obtained.

Chemotherapy

Treatment of TB is categorised by:Site of disease (pulmonary or extra

pulmonary), its severity: the bacillary load and acute threat to life are taken into consideration.

Sputum smear positivity/negativity :positive cases are infectious.

History of previous treatment: risk of drug resistance is more in irregularly treated patients.

WORLD TUBERCULOSIS DAY MARCH24

MARCH24

Thank u

For your Attention..