Download Mycobacterium tuberculosis

Chemotherapy of Tuberculosis
Tuberculosis
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Chronic granulomatous disease.
Usually affects the lungs, up to one third of
cases, other organs are involved.
Etiologic agent

Mycobacterium causes:

Tuberculosis
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Mycobacterium avium complex disease
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Leprosy
Mycobacterium tuberculosis
complex:
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Mycobacterium tuberculosis :
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M. bovis
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Rod shaped, non- pore-forming, thin aerobic
bacterium.
Important agent for human disease.
Important cause of tuberculosis for transmitted
by unpasteurised milk.
M . africanum
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West, central & east africa.
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Less virulent, rarely encountered organism.
M .microti
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M.tuberculosis transmitted from patient with
infectious pulmonary Tb to other persons
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By droplet nuclei,
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Aerosolised by coughing, sneezing or
speaking.
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As many as 3000 infectious nuclei per cough.
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Tiny droplets dry rapidly.
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Smallest droplets (<10 um in diameter)
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Suspended in the air for several hours ,
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May gain direct access to the terminal air
passages when inhaled.
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Risk factors for acquiring infection with
M.Tuberculosis:
Probability of contact with the case of Tb.
Intimacy and duration of that contact.
Degree of infectiousness of the case.
Shared environment of the contact.

Risk factor for developing disease after being
infected :
Individuals innate susceptibility to disease.
Level of function of cell mediated immunity.
Clinical manifestations
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Pulmonary Tb
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Primary
Secondary
Extra pulmonary Tb
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Lymph node Tb
Pleural Tb
Tb of upper airways
Genitourinary Tb
Skeletal Tb
Tuberculous meningitis
Gastrointestinal Tb
Pericardial Tb
Miliary / disseminated Tb
Primary Tuberculosis


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Results from initial
infection with tubercle
bacilli.
Children up to 4 yrs of
age.
Middle, lower lung
zone affected mainly.
Rapid progression to
illness in HIV patients.
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Pleural effusion:
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Lymphadenopathy:
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as enlarged lymph node compress bronchi.
Obstructive emphysema:
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due to spread of bacilli from lung parenchyma
through lymphatic vessel.
Obstruction & subsequent segmental collapse:
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due to penetration of bacilli into pleural space
from subsequent subpleural area.
due to partial obstruction.
Granulomatous lesions:

seen in severe cases as bacilli reach blood
stream from pulmonary lesion/lymph nodes
Secondary Tuberculosis


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Adult type.
Dormant bacilli, may persist for years before
reactivating to produce Secondary Tuberculosisoften infectious.
Localised to the apical & posterior segments of
the upper lobes , where high oxygen
concentration favours mycobacterial growth.
Secondary Tb.....
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Early symptoms: fever, night sweats, weight
loss, malaise, weakness.
Development of Cough : non productive
initially, production of purulent sputum.
Diagnosis of Tuberculosis
AFB (Acid Fast Bacilli) microscopy
Presumptive diagnosis.
Mycobacterial culture
Definitive diagnosis
Nucleic acid amplification
Use limited due to low sensitivity.
Drug susceptibility testing
To find out drug resistance.
Radiographic procedure
Based on abnormal chest radiographic
findings
Tuberculin skin testing
Lack of mycobacterial specificity limits
use
Cytokine release assay
Diagnosis of latent tuberculosis
infection.
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Treatment
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Aim of treating Tuberculosis:
To interrupt tuberculosis transmission by
rendering patients non-infectious.
To prevent morbidity & mortality by curing
patients with tuberculosis disease.
Antitubercular drugs

First line drugs :
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High efficacy & low toxicity.
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Isoniazid 5mg / kg /d , max of 300 mg / d
Rifampin 10 mg/kg/d, max of 600 mg / d
Pyrazinamide 20-25 mg/kg/d, max of 2g / d
Ethambutol 15 -20 mg / kg / d
Streptomycin 15 mg / kg / d

Second line agents
Either low efficacy or high toxicity or both Slide 76
Drugs
Doses
Amikacin
15 mg/kg/d
Aminosalicylic acid
8-12 g/d
Capreomycin
15 mg/kg/d
Ciprofloxacin
1500 mg/kg/d
Clofazimine
200 mg/d
Cycloserine
500-1000 mg/d
Ethionamide
500-750 mg/d
Levofloxacin
500 mg/d
Rifabutin
300 mg/d
Rifapentine
600 mg o.d weekly
Isoniazid

Bacteriostatic for resting bacilli but
bactericidal for rapidly dividing microorganisms.

Minimal effective conc.: 0.025-0.05 ug/ml.

Peak plasma conc. : 1-2 hrs.

Good oral & parenteral absorption.
Metabolism
via acetylation
(acetylisoniazid)
& via hydrolysis
(isonicotinic
acid).
N-acetyltransferase type 2 (NAT 2)
Fast acetylators
t½ of INH =1hr
Hepatic insufficiency
Dosage reduction
recommended
Slow acetylators
t½ of INH =2-5 hrs
In case of renal impairment,
may accumulate to toxic
concentration.
MECHANISM OF ACTION….INH
Resistance
1. Mutation in catalase peroxidase
 Decreases its activity
 Prevent conversion of prodrug to active
metabolite.
2. Mutation in inh A gene involved in mycolic
acid biosynthesis.
 Resulting in over expression of inh A.
Tuberculous cavity contains 109 microorganism.
1 in 106 bacilli genetically resistant to INH.
So, resistant mutants selected out in INH
monotherapy.
Adverse effects
 INH induced hepatotoxicity.
 Peripheral neuropathy.
 Neurotoxicity.
 Hematological reactions.
 Hypersensitivity reactions.
• INH induced hepatotoxicity.
• Multilobular necrosis – by liver biopsy.
• Risk factor :
• Older age & excessive alcohol intake.
• <20 years: Rare
• 35-49 years & >50 years: elevated serum transaminase
level.
• > 5 times serum transaminase level: DISCONTINUE
Drug.
Peripheral neuropathy:
• Due to interference with utilization of
pyridoxine and its increased excretion in
urine.
• Paresthesia of feet & hands.
• Pyridoxine 10 mg/d for treatment.
Neurotoxicity:
• Convulsion , in patients with seizure disorder.
• Optic neuropathy.
• Muscle twitching, stupor.
Hematological reaction:
• Agranulocytosis, eosinophilia,
thrombocytopenia.
• Sideroblastic anemia (presence of ring sideroblasts
in the bone marrow)
• Reversible .
• INH deprives ALAS2 (delta-aminolaevulinic acid synthase 2) of
pyridoxal phosphate therefore inhibits haem
synthesis.
• Overcome by concomitant administration of
pyridoxine(25 to 50 mg/d).
Hypersensitivity reaction:
• Fever, rashes, hepatitis , SLE.
INH overdose:
• Tonic - clonic seizure, metabolic acidosis,
coma in pregnant women.
• Pyridoxine – specific antidote.
• Management :
• GI decontamination with gastric lavage,
• Stabilization of vital signs with provision of
patent airway and IV sodium bicarbonate,
• Cardiovascular support with IV fluids and
vasopressors.
• IV pyridoxine – highly effective for INH
intoxication and should be administered to all
symptomatic patients.
Uses of INH
Latent Tb
Recent converters: who test positive within 2
years after a documented negative skin test.
Immunocompromised patients.
Prevention, in close contacts of active cases
of pulmonary Tb.
INH
ᵡ Phenytoin
• Effect :
• Increased serum phenytoin level.
• Slow acetylators – Phenytoin toxicity.
• Mode :
• INH – hepatic microsomal enzyme inhibitor.
• Monitoring:
• Need to monitor serum phenytoin level.
INH ᵡ Rifampin
• Effect:
• Hepatotoxicity.
• Mode:
• Altered INH metabolism by rifampin.
• Monitoring:
• If LFT alter, discontinue one or both agents.
Rifamycins
 Rifampin
 Rifabutin
 Rifapentine
Mechanism of action:
Bactericidal at 3-12 ng/ml for both
intracellular & extracellular microorganisms.
Kills organisms at poorly accessible sites like
abscess, lung cavities.
Binds to β subunit of bacterial DNA
dependent RNA polymerase.
Suppression of initiation of chain formation
but no chain elongation in RNA synthesis.
Inhibit RNA synthesis in mammalian
mitochondria, viral DNA dependent RNA
Polymerase, reverse transcriptase at high
concentration.
Mechanism of resistance
1. Mutation between codons 507 & 533 of
polymerase rpo B gene “for β subunit of
RNA polymerase.
 Prevent binding of rifampin to RNA polymerase.
2. Alterations in the target of drug:
 DNA dependent RNA polymerase.
Adverse effects
Hepatitis from rifampin rarely occurs in
patients with normal hepatic function.
Chronic liver disease, alcoholism, and old
age increase the risk of severe hepatitis
when rifampin is given alone or concurrently
with isoniazid.
< 5% of patients, serum level of
aminotransferase, phosphatase, bilirubin
increase slightly, but diminish spontaneously
despite continuation of treatment.
Rifampin may potentiate toxic effect of INH,
particularly in patients in whom INH is rapidly
inactivated.
Rifampin induces microsomal enzyme.
Facilitate conversion of monoacetylhydrazine,
a metabolite of acetylated INH into an
acylating agent that could cause hepatic
necrosis.
Light chain proteinuria.
Imparts a harmless orange colour to urine,
sweat, tears, and contact lenses (soft lenses
may be permanently stained)
GI disturbances –
(epigastric distress, nausea, vomiting,
abdominal cramps, diarrhea)
occasionally required drug discontinuation.
Thrombocytopenia, transient leukopenia,
and anaemia have occurred during therapy.
Rifampin × Anticoagulants
 EFFECT :
 Decreased anticoagulant effect.
 MECHANISM:
 Rifampin induces CYP2C9, CYP2C19, CYP2D6
 Increases elimination of other drug.
 MONITORING:
 Carefully monitor coagulation parameter.
Adjust anticoagulant dose.
Ethambutol
Inhibit mycobacterial arabinosyl transferases,
which is involved in polymerization reaction of
arabinoglycan …….essential component of
mycobacterial cell wall.
Adv. :

Retrobulbar neuritis causing loss of visual
acuity and red-green colour blindness.
(Serious).

Not recommended for children under 5
years of age because of concern about the
ability to test their visual acuity.
Pyrazinamide
PRODRUG
Pyrazinoic acid
pyrazinamidase
(ACTIVE FORM)
encoded by pnc A
BACTERICIDAL
Impaired mutation
of pnc A
RESISTANCE
Hepatotoxicity (in 1–5% of patients), nausea,
vomiting, drug fever, and hyperuricemia.
Hyperuricemia may provoke acute gouty
arthritis.
Streptomycin
 Binds with S12 ribosomal protein.
 Interfere with initiation of peptide formation.
 Misreading of mRNA.
 Breakup of polysomes into nonfunctional
monosomes.
 Irreversible inhibition of mycobacterial protein
synthesis.
 Ototoxic and nephrotoxic.(8th cranial nerve
involves).
 Vertigo and hearing loss -most common.
may be permanent.
Ethionamide
Inhibits mycobacterial growth by inhibiting the
activity of the enoyl-ACP reductase of fatty
acid synthase II.
Thus inhibit mycolic acid biosynthesis with
consequent impairment of cell-wall
synthesis.
Neurologic symptoms –
depression, drowsiness, and asthenia.
olfactory disturbances, blurred vision,
diplopia, dizziness, paresthesias, headache,
restlessness, and tremors.
Pyridoxine relieves.
Chemoprophylaxis
To prevent development of active TB in
patients who are at risk.
Tuberculin skin test
ȳ interferon test
Mantoux test
T-Spot.Tb
Heaf test
QuantiFeron Tb Gold
Tine test
Indications for chemoprophylaxis:
1. New born of a mother with active TB.
2. Young children (<6 yrs.) with positive TB.
3. Household contacts of patients with TB.
4. Patients with positive tuberculin test with
additional risk factors such as diabetes mellitus,
malignancy, AIDS.

Isoniazid prophylaxis, continued for 12
months. Pyridoxine co-administered.

HIV infected, exposed to MDRTb –
rifampin + pyrazinamide (with close
monitoring for hepatic toxicity) or high-dose
ethambutol +pyrazinamide, with or without a
fluoroquinolone.
FOUR drug regimen treatment for whom?
1. Known to exposed to drug resistant
organisms.
2. Recent immigrants.
3. Pts with extrapulmonary TB.
4. Pts with meningitis.
5. HIV pts.
Continued for atleast 6 months after three
negative cultures obtained.
MDT
Objectives:
1. To make patient non-infectious as early as
possible by rapidly killing the dividing bacilli by
using 3 to 4 bactericidal drugs.
2. To prevent the development of drug-resistant
bacilli.
3. To prevent relapse by killing the persisters
(dormant bacilli).
4. To reduce the total duration of effective therapy.
Recommended by WHO.
Choice of treatment regimen based on:
Their efficacy, effectiveness, availability of
financial recourses.
Long course regimens:
INH alone with one or two bacteriostatic
drugs for 18 months.
Poor patient compliance,
high failure rate.
Short course regimen:
6-9 months duration.
Highly effective.
Less toxic.
Intensive phase:
- 3-4 tuberculocidal drugs daily or thrice
weekly for a period of 2-3 months.
- To render the patient non-contagious.
INH 300mg + Rifampicin 600 mg +
Pyrazinamide 1500 mg + Ethambutol
1000 mg/Streptomycin 1000 mg +
Pyridoxine 10 mg daily for 2 months.
Continuous phase:
- 2-3 drugs usually INH & Rifampicin
daily or thrice weekly for a period of 4-6
months.
- Helps to eliminate persisters &
prevents relapse.
- INH 300mg +Pyridoxine 10 mg +
Rifampicin 600 mg daily for 4 months.
DOTS …. Backbone of RNTCP
RNTCP:
Revised National Tuberculosis Control
Programme, launched in 1997
DOTS:
Directly observed treatment short course.
Patient is administered drugs under the
supervision of a health worker to ensure that
drugs are actually consumed.
Supervised and monitored by bacteriological
examinations.
Aimed at ensuring patient compliance thus
preventing the emergence of drug resistant
tuberculosis.
WHO recommended treatment
regimen
Diagnostic
category
Type of patient
Intensive
phase
Continuation
phase
Total duration
(months)
Category 1
New sputum
positive,
seriously ill
sputum
negative,
seriously ill
extrapulmonary
Daily
2HRZE
Thrice weekly
2 (HRZE)3
4HR
6
4(HR)3
6
Sputum positive
relapse, sputum
positive
treatment
Daily
2HRZES
1HRZE
5 HRE
8
Thrice weekly
2(HRZES)3
1(HRZE)3
5(HRE)3
8
Category 2
Diagnostic
category
Type of patient
Intensive
phase
Continuation
phase
Total duration
(months)
Category 3
Sputum
negative, not
seriously ill,
extrapulmonary,
not seriously ill
Daily
2 HRT
4HR
6
Thrice weekly
2(HRZ)3
4(HR)3
6
Category 4
Chronic or
suspected
MDR-TB cases
Specially designed standardized or
individualized regimen
H=isoniazid, R=Rifampicin, Z=Pyrazinamide, E=Ethambutol,
S=Streptomycin
HRZ & E= orally ; S= i.m
Prefix= number of months, Subscript= doses per week.
DOTS plus :
- first WHO endorsed DOTS-Plus
programmes began in 2000
- To treat MDR-TB using second line
anti TB drugs.
- Recommended in areas where
DOTS is fully in place.
Five components of DOTS Plus
 Sustained political and administrative
commitment
 A well functioning DOTS programme.
 Long term investment of staff and resources.
 Coordination efforts between community, local
governments, and international agencies.
 Addressing the factors leading to the
emergence of MDR-TB
 Diagnosis of MDR-TB through qualityassured culture and drug susceptibility
testing.
 Proper triage of patients for Culture & testing
and management under DOTS-Plus.
 Co-ordination with National and Supra-National
Reference Laboratories
 Appropriate treatment strategies that utilize
second-line drugs under proper
management conditions
 Rational standardized treatment design (evidencebased)
 Directly observed therapy (DOT) ensuring long-term
adherence.
 Monitoring and management of adverse drug
reactions.
 Adequate human resources.
TB treatment in HIV patients:
Rifabutin preferred over rifampicin in
HIV patients on antiretroviral drugs
as it doesn’t interact with PI’s.
Role of glucocorticoids in tuberculosis
Tuberculosis is a relative CI for use of
glucocorticoids.
 TB of serum membrane like pleura,
peritonium, pericardium, meninges, to prevent
fibrous tissue formation.
 To treat hypersensitivity reactions to antiTB
drugs.
 Tuberculosis of eye, larynx, genitourinary tract
to prevent fibrosis & scar tissue formation.
Once patients general condition improves,
steroid is tapered to avoid HPA axis
suppression.