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Tuberculosis
Definition
Tuberculosis (TB) is a chronic granulomatous bacterial
infectious disease usually caused by Mycobacterium
tuberculosis and occasionally by Mycobacterium bovis
and Mycobacterium africanum
Epidemiology
 TB is the second leading infectious disease that causes most deaths
in the world
 It is estimated that about two billion people i.e. one third of the
world’s population are infected with M.Tuberculosis
 Each year more than eight million new cases are reported and
nearly three million people die due to mismanagement of the
disease
 Management of TB is worsening due to the spread of drug-
resistant organisms and also due to rapid spread of HIV infection.
Types of Tuberculosis
Primary tuberculosis:
The infection of an individual with tubercle bacilli who has
not been previously infected or immunized is called primary
tuberculosis
Secondary tuberculosis:
The infection of an individual who has been previously
infected or sensitized is called secondary or post-primary or
reinfection.

The causes for secondary tuberculosis may be,
 Treatment failure during primary infection
 May be the patient is immunocompromised
Depending upon the organ involved, tuberculosis is
classified into,
Pulmonary tuberculosis
 The organ involved is lung and is the most common
type of tuberculosis.
Extra pulmonary tuberculosis (Milliary TB)
 Tuberculosis of skin, bone, kidney, intestine, liver,
spinal chord, eyes, male genital tuberculosis, female
genital tuberculosis and tubercular meningitis of brain.
 Tuberculosis in this type spreads from lung to other
organs through haematogenous route and forms millets
on the organs hence it is also called as milliary TB.
Etiology
Acid fast bacilli or tubercle bacilli,
Mycobacterium tuberculosis
Mycobacterium bovis
Mycobacterium africanum
Mycobacterium avium complex
Spread of infection
 Air borne disease
 Infected patients coughs, sneezes, splits expels germs
which remain suspended in air
 Healthy person inhales infected air and get infected
Pathogenesis
Aerobic bacterium- grows successfully in tissues
having highest oxygen tension (lung apices)
Infected droplets get lodged in the terminal alveoli
Multiplication of bacilli
Formation of granuloma
Pathogenesis . . .
After 4-6 weeks- development of immune response
Progression of disease, signs and symptoms
May spread to other organs through blood leading to
extra pulmonary TB
 AIDS- progressive weakening of immune system-
more chances of primary infection, reinfection and
reactivation of disease
Laboratory detection
Tuberculin test (Mantoux test)
 Intradermal tween-80 stabilized PPD injection
 Evaluated after 48-72 hours
 Diameter of induration determines interpretation
Laboratory detection
Microbiological test
 Ziehl neelsen staining
 Sample-early morning sputum
 Acid fast bacilli found under microscope
Laboratory detection….
Chest X-ray
Management
Goals:
 To cure the infection and relieve the signs and
symptoms
 To prevent the individual from death due to active TB or
its late effects
 To prevent TB relapse
 To prevent the transmission of infection to others
Treatment categorization
TB
PATIENTS CHARACTERISTICS
TREATMENT
CATEGORY
Category 1
New sputum smear-positive pulmonary TB
Category 2
Newly diagnosed seriously ill patients with severe forms of
TB
Relapse
Treatment failure
Return after default (interrupted treatment)
Category 3
Category 4
Sputum smear-negative pulmonary TB with limited
parenchymal involvement
Extra pulmonary TB (less severe forms)
Chronic cases
The essential anti TB drugs
RECOMMENDED DOSE (mG/KG)
ESSENTIAL ANTITB DRUG
MODE OF
ACTION
POTENCY DAILY
INTERMITTENT
Isoniazid (H)
Bactericidal
High
5
10
15
Rifampacin (R)
Bactericidal
High
10
10
10
Pyrazinamide (Z)
Bactericidal
Low
25
35
50
Streptomycin (S)
Bactericidal
Low
15
15
15
Etambutol (E)
Bacteriostatic
Low
15
30
45
Thiacetazone (T)
Bacteriostatic
Low
03
3x/wk
2x/wk
NOTAPPLICABLE
Principal activity and site of action of major anti-TB
agents
AGENT
Isoniazid
ACTIVITY
Bactericidal
SITE OF ACTION
Intracellular bacilli
extracellular bacilli
bacilli in caseous lesions
Rifampacin
Bactericidal
Intracellular bacilli
extracellular bacilli
bacilli in caseous lesions
Pyrazinamide
Streptomycin
Etambutol
Bactericidal
Bactericidal
Bacteriostatic
Intracellular bacilli
Extracellular bacilli
Intracellular
Extracellular
Recommended treatment regimens
TB
Treatment
category
1
2
3
TB patient
TB Treatment regimens
Initial Phase
New smear-positive PTB and
2 SHRZ (EHRZ)
seriously ill extra pulmonary or
2 SHRZ (EHRZ)
smear negative pulmonary (severe
2 SHRZ (EHRZ)
TB)
2 E3H3R3Z3
2 SHRZE/ 1 HRZE
Sputum smear-positive: relapse,
treatment failure and return after
2 SHRZE/ 1 HRZE
default
2 S3H3R3Z3E3/ 1 H3R3Z3E3
Smear-negative PTB and Extra
2 HRZ or 2 H3R3Z3
pulmonary TB (Less severe)
2 HRZ or 2 H3R3Z3
2 HRZ or 2 H3R3Z3
4
Continuation Phase
6 HE
4 HR
4 H3R3
4 H3R3
5 H3R3E3
5 HRE
5 H3R3E3
6 HE
2 HR/4 H
2 H3R3/ 4 H
2 H3R3Z3
4 H3R3
Chronic case (still sputum-positive NOT APPLICABLE
after supervised re-treatment)
(REFER TO SPECIAL CENTRE IF SECONDLINE DRUGS AVAILABLE)
Isoniazid
 It is a potent bactericidal agent
 Kills 90% of the total population of bacilli
 Most effective against the metabolically active,
continuously growing bacilli
 MOA- impairs the cell-wall mycolic acid synthesis and
mycobacterial DNA synthesis
 Due to good tissue penetration activity, it distributes
into the CNS, tuberculous abscesses and intracellular
sites
Drug interactions
Isoniazid....
 INH increases serum concentration of phenytoin,
Carbamazepine, primidone and barbiturates
 INH decreases serum levels of ketoconazole
 Prednisolone decreases serum concentration of INH
Counseling points
Isoniazid....
 Ask patient to take this medication on empty stomach
 About ADRs-
Common: peripheral neuropathy
Rare: convulsions, pellagra, joint pains, agranulocytosis,
lupoid reactions, skin rash, optic neuritis, personality
changes, Rheumatic syndromes, fever.
Rifampicin
 It is a bactericidal agent, kills the semi-dormant bacilli
which Isoniazid is unable to kill
 It acts by inhibiting DNA-dependent RNA polymerase
 As it is a fat soluble molecule, achieves excellent tissue
penetration including CNS
Drug interactions
Rifampicin….
Rifampicin decreases the serum concentration of
Warfarin, oral contraceptives, cyclosporine,
Glucocorticoids, Itraconazole, Ketoconazole,
Theophylline, Quinidine, Digitoxin, Verapamil,
Nifedipine and Methadone.
Counseling points
Rifampicin….
• Ask the patient to take this medication on empty stomach
• Inform the patient that this drug may cause orange
discoloration of urine, sweat, tears and saliva
• Counsel the patient to adopt alternate methods of
contraception if they are on oral contraceptives as this
drug may decrease the effect of oral contraceptives
• Advice the patients on Rifampicin to avoid using contact
lenses and encourage them to use spectacles
Counseling points…
Rifampicin….
 About ADRs-
Common- Anorexia, nausea, vomiting, abdominal
pain, hepatitis, orange discoloration of urine, sweat,
tears and saliva.
Rare-Fever, rash, eosinophilia, thrombocytopenia,
leucopenia, hemolytic anemia, acute renal failure.
Pyrazinamide
 It is a bactericidal agent, kills bacilli in an acid
environment inside cells (ex: macrophages)
 It is well absorbed from the gastrointestinal tract
 Widely distributed in body tissues and fluids
including CSF
Counseling points
Pyrazinamide….
 Ask the patient to take this medication on empty
stomach
 About ADRs
Common- joint pains, hepatitis
Rare- skin rashes, sideroblastic anaemia
Ethambutol
 It is a Bacteriostatic agent
 Acts by impairing incorporation of mycolic acids into
the cell wall
 It also suppresses mycobacterial multiplication by
interfering with RNA synthesis
 It has tissue penetration property including those of
CNS especially when the meninges are inflamed
Drug interactions
Ethambutol….
 Aluminium containing antacids decreases the
absorption of Ethambutol
Counseling points
Ethambutol….
 Patient must be told to avoid concurrent administration
of aluminium containing antacids for at least 4 hours
following Etambutol
 Drug may be taken with food as absorption is not
affected
 Patient should be instructed to report any changes in
visual acuity and seek medical attention immediately if
changes do occur
Counseling points….
Ethambutol….
 About ADRs
Retro bulbar neuritis (decreased visual acuity, loss
of red-green color vision, central scotomata)
Hypersensitivity reactions, neuritis, GI Intolerance,
headache, hyperuricemia.
Streptomycin
 It is an aminoglycoside bactericidal antibiotic
 It act by inhibiting protein synthesis by binding
directly to the 30 S ribosomal subunit causing faulty
peptide sequence to form in the protein chain.
Drug interactions
Streptomycin….
 Use of Amphotericin B or loop diuretics along with
streptomycin increases the risk of Nephrotoxicity
Counseling points
Streptomycin….
 Patient should be informed to avoid high pitch sounds
 About ADRs-
Ototoxicity, Nephrotoxicity, skin rashes, nausea,
vomiting, headache, drowsiness, difficulty in
breathing
Contraindication:
Pregnancy
Treatment of Tuberculosis in Special Population
Children
Dosage in Children
DRUGS
THERAPY PER DOSE (THRICE A WEEK)
Isoniazid
10-15 mg/kg
Rifampicin
10 mg/kg
Pyrazinamide
35 mg/kg
Streptomycin
15 mg/kg
Ethambutol
30 mg/kg
Pregnancy
 pregnant women infected with TB should be treated
with anti TB drugs similarly as that of a non-pregnant
woman
 Use of streptomycin in pregnancy is contraindicated as
it can cause permanent deafness in the baby
Renal failure
 Based on creatinine clearance, Isoniazid,
Pyrazinamide and streptomycin requires dosage
adjustment
 Rifampicin found to be safe in renal impairment.
Hepatic disease
 Most of the anti TB drugs can cause liver damage
 If the patient develops clinical signs of liver damage,
all antitubercular drugs should be stopped as it is not
possible to identify the agent responsible for liver
damage
 The antitubercular drugs should then be reintroduced
one at a time, each drug being given for about a week
before another is added
Hepatic disease . . .
 This should be accompanied by regular monitoring of
LFTs and close clinical supervision, so that the drug
responsible may be identified by a recurrence in
symptoms
 The offending drug could be then omitted from the
regimen or replaced by Streptomycin
 Jaundiced patients who develop TB should receive
treatment with 2 SHE/ 6 HE
 Pyrazinamide should be avoided in patients with liver
disease
Elderly
 In elderly population as their renal and hepatic
functions are compromised
 Anti TB drugs such as Isoniazid, Pyrazinamide and
streptomycin requires dosage adjustment based on
their individual creatinine clearance and extent of
hepatic impairment
HIV patients with TB
 HIV infected individual who do not require
antiretroviral therapy can receive standard anti TB
regimen
 If the individual with HIV who is co infected with TB
and also receiving antiretroviral drugs the
management of TB becomes complicated due to
interactions between antiretroviral and anti TB drugs
HIV patients with TB ....
 There are two options available
 In first, Rifabutin, Isoniazid, Pyrazinamide and
Ethambutol are administered daily for either 2 weeks or
8 weeks to complete the induction phase and therapy is
completed by administering Rifabutin and Isoniazid
daily or twice a week for 4 months
HIV patients with TB ....
 The usual Rifabutin dose of 300 mg should be reduced
to 150 mg during daily therapy in patients who are also
receiving Indinavir, Nelfinavir or amprenavir
 Dosage reduction for Rifabutin is not necessary during
twice weekly Rifabutin therapy.
HIV patients with TB . . .
 The second option is usually reserved for HIV patients
who cannot receive Rifabutin
 It consists of Isoniazid, Streptomycin, Pyrazinamide
and Ethambutol administered daily for either 2 weeks
or 8 weeks and then twice a week for 6 weeks to
complete the induction phase
 The therapy is completed by administration of
Isoniazid, Streptomycin and Pyrazinamide two or
three times a week for 7 months
Drug resistant cases
Multi-drug resistant tuberculosis (MDR-TB) is defined as
“resistance to Isoniazid and Rifampicin whether there
is resistance to other drugs or not”
Extremely drug resistant TB (XDR-TB) is
“The condition in which the bacilli show resistance to
Isoniazid and Rifampicin plus resistance to any
Fluroquinolones and any one of the second line
injectable drug”
Factors related to the development of drug
resistance include
 Inadequate or inefficient administration of effective
treatment
 Poor case handling
 Use of substandard drugs
 Inadequate or irregular drug supply
 Ignorance of health care workers in the treatment and
control of TB
Factors related to the development of drug resistance
include...
 Interruption of chemotherapy due to side effects
 Non adherence of patients to the prescribed
regimen
 Availability of anti TB drugs without prescription
 Illiteracy
Factors related to the development of drug resistance
include...
 Low socio economic status patients
 Massive bacillary load
 Laboratory delay in identification and susceptibility testing
of Mycobacterium tuberculosis isolates
 Lack of use of uniform laboratory methodology and quality
control measures
Prevention of drug resistance
 Directly Observed Therapy (DOT)
 Monitoring the patient taking Anti-TB drugs by HCP
 WHO believes that personal monitoring will reduce
the relapse and increases therapeutic outcome
Treatment for MDR-TB
 Should be based on sensitivity testing
 Patient with suspected MDR-TB should be started on SHREZ
 Based on known sensitivities, five drugs should be choosen
in the following order:
An Aminoglycoside (Amikacin, Kanamycin) or polypeptide
antibiotic (capreomycin)
Pyrazinamide
Ethambutol
A Fluroquinolone (Moxifloxacin, Ofloxacin)
Treatment for MDR-TB....
Rifabutin
Cycloserine
A Thioamide (Prothionamide or Ethionamide)
Paraamino salicylic acid
A Macrolide (Clarithromycin)
Linezolid
High dose INH (if low level resistance)
Interferon alpha
Thioridazine
In XDR-TB, surgery is the last choice
ADRs of essential anti-TB drugs
Drug
Isoniazid
Rifampicin
Pyrazinamide
Ethambutol
Common effects
Peripheral neuropathy
Skin rash
Hepatitis
Sleepiness and lethargy
Abdominal pain
Nausea, vomiting,
Hepatitis, Generalized cutaneous reactions,
Thrombocytopenic purpura
Rare effects
Convulsions
Psychosis
Arthralgia
Anemia
Osteomalacia
Pseudomembranous colitis
Pseudo adrenal crisis
Acute renal failure
Hemolytic anemia
Arthralgia, Hepatitis, abdominal pain, nausea and
Cutaneous reactions
Sideroblastic anemia
vomiting
Generalized cutaneous reactions
Retro bulbar neuritis
Arthralgia
Peripheral neuropathy
Hepatitis (very rare)
Streptomycin
Vestibular and auditory nerve damage
Nephrotoxicity
Injection site cutaneous hypersensitivity
Thiacetazone
Skin rash, sometimes with mucosal involvement
pain, rash, induration and
numbness around the mouth
and tingling soon after the
injection
ADRs of reserve anti-TB drugs
Drug
Common effects
Rare effects
Aminoglycosides Vestibular (vertigo) and Auditory nerve Cutaneous hypersensitivity
Clinical renal failure
damage
Nephrotoxicity
Ethionamide
Anorexia, nausea, diarrhoea,
abdominal pain, hepatotoxicity
Convulsions, Mental
symptoms
Impotence, Gynaecomastia
Fluroquinolones
Anorexia, nausea,
Vomiting
Dizziness, headache,
convulsions,
Rupture of Achilles tendon
Cycloserine
Dizziness, Headache, Depression,
Hepatitis,
Psychosis, Convulsion
Suicide
Generalized hypersensitivity
Hepatitis
Para amino
salicylic acid
Anorexia, nausea, vomiting
Hypersensitivity reactions like fever,
rash, pruritus
Hypothyroidism
Hematological reactions
Grading and Management of Adverse Drug Reactions
Grade
Adverse reaction
Management
Abnormal but requiring no immediate
intervention
Reassurance, occasionally symptomatic
therapy, continue ATT
Sufficiently abnormal requires evaluation to
assess the causality and requires mild
therapeutic intervention but may not require
immediate changes in drug
Symptomatic treatment and
continuation of ATT
III
Sufficiently severe to require evaluation and
treatment, including at least temporary
suspension of the responsible drug
Symptomatic treatment.
If needed to reduce the dosage of drug
responsible or
temporary with-holding of the drug
IV
Life threatening severity, require an immediate
evaluation, treatment and hospitalization.
Study drug must be stopped immediately and
drug should not be restarted until the
abnormality is clearly felt to be caused by some
other mechanism than the study drug
Termination of the drug responsible/
change of treatment regimen
I
II