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ANTI-MYCOBACTERIALS
DIAGNOSIS OF TB
The recognition of an active TB case:
Symptomatic due to lesions caused by
Mycobacterium tuberculosis.
Confirmed by microbiologic studies to harbor
M.tuberculosis
Classification of TB Cases
WHO Case Definitions:
Latent TB
Active TB
Pulmonary
Smear (-)
Smear (+)
Extra Pulmonary
Smear (-)
Smear (+)
TB Symptomatic
TB Symptomatic : work up
TB Symptomatic : work up
Chest radiography (CXR)
Tuberculin Skin Testing (PPD)
Sputum TB culture and
Drug Susceptibility Testing
Blood or serum tests
Classification of TB
based on
Location & Sputum Smear
Location
Pulmonary
TB
Smear
Definition of Terms
(+)
(-)
A patient with at least 3 sputum specimens () for AFB with CXR abnormalities consistent
with active TB, and there has been no
response to a course of antibiotics and/or
symptomatic medications, and the Medical
Officer decides treatment with anti-TB drugs.
Location
ExtraPulmonary
TB
Definition of Terms
1. A patient w/ at least 1 mycobacterial
smear / culture (+) from an extrapulmonary site (organs other than the
lungs: pleura, lymph nodes, genitourinary tract, skin, joints and bones,
meninges, intestines, peritoneum and
pericardium, among others), or
1. A patient with histiological and / or
clinical evidence consistent with active TB
and there is a decision by a Medical
Officer to treat the patient with anti-TB
drugs.
Category
Definition
New
Relapse
Return to
treatment
after default
Category
Definition
Failure
Transfer-in
Treatment
Drug Therapy aims to:
Cure
Prevent death
Prevent relapse
Prevent drug resistance
Decrease transmission
Treatment
Therapeutic Principles
Treatment of disease must contain
multiple drugs to which organisms are
susceptible.
Drugs must be taken regularly.
Therapy must continue for a sufficient
length of time.
Treatment
2 Phases of Treatment
Intensive Phase
kills actively replicating bacilli
Continuation Phase
kills slowly dividing bacilli
Intensive phase: initial, consisting of more than 2 drugs promotes
efficient killing of actively dividing organisms and leads to the rapid
reduction of large bacillary populations; provides relief of symptoms,
terminates transmission and prevents the emergence of drug resistance.
Continuation phase: uses fewer drugs, kills slowly or irregularly dividing
bacilli, sterilizes lesions, prevents relapse
Treatment Regimens
TB Patient To Be Given Tx
Drugs /TxDuration
II
Failure cases
Relapse cases
Return after default smear(+)
Others smear (+)
III
2HRZES/1HREZ/
5HRE
Outcomes of Treatment
Cure
Treatment Completed
Died
Treatment Failure
Defaulter Failure
Transfer Out
Cure: sputum smear (+) patient who has completed tx and is sputum
smear (-) in the last month of tx and on at least one previous occasion.
Treatment completed: a patient who has completed tx but does not meet
the criteria to be classified as cure or failure. This group includes:
(1)a sputum smear-positive patient initially who has completed treatment
without follow-up sputum examinations during the treatment, or with only
one negative smear during the treatment, or without sputum in the last
month of treatment; and
(2)a sputum smear (-) patient who has completed treatment
Died - A patient who dies for any reason during the course of treatment
Failure: A patient who is smear(+)at five months or later during treatment
or a sputum smear (-) patient initially before starting tx and becomes
smear (+) during the treatment.
A defaulter is one whose treatment was interrupted for 2 consecutive
months or more
Transfer out: A patient who has been transferred to another facility with
proper referral/transfer slips for continuation of treatment.
Spectrum of TB
TB exposure: child in close contact with a
source case
(-) Signs & symptoms presumptive of TB
(-) Tuberculin Skin Test (TST)
TB infection: child is found to have
(-) Signs & symptoms presumptive of TB
(+)Tuberculin Skin Test
(-) radiologic/laboratory evidence
suggestive of TB
Spectrum of TB
TB disease:
(+) signs & symptoms presumptive of TB
(+) Tuberculin Skin Test and/or
(+) radiologic/laboratory evidence suggestive
of TB
Diagnosis of TB in Children
GOLD STANDARD
a positive culture with or without
a positive AFB smear for
Mycobacterium tuberculosis
Diagnosis of TB in Children
The occurrence of asymptomatic infection
(latent TB infection) and early disease in
childhood.
The poor bacteriologic yield.
The difficulty of collecting specimen in the
young.
Diagnosis of TB in Children
Demonstration of acidfast bacilli on microscopy
and histologic changes on biopsy can only
provide presumptive diagnosis in the absence of
a positive culture.
Radiologic evidence is often equivocal: it
requires consensus among radiologists.
The Tuberculin Skin Test has logistic limitations
on top of high false negative findings even under
ideal settings.
Diagnosis of TB in Children
In the absence of bacteriologic evidence,
a child is presumed to have active TB if
3 or more of the following criteria are
present:
Epidemiologic
Clinical
Immunologic
Radiologic
Laboratory
Epidemiologic
Exposure to an adult/adolescent with active
TB disease
Clinical: TB symptomatic
cough or wheezing of >2wks
Immunologic
(+) Tuberculin Skin Test
>5mm induration
Hx: close contact with known or
suspected case of TB
Clinical findings suggestive of TB
Chest X-ray suggestive of TB
Immunocompromised condition
>10mm induration
Radiologic
No pathognomonic radiologic findings
Most suggestive of PTB:
hilar/paratracheal adenopathy
parenchymal changes
Laboratory
Laboratory findings suggestive of TB
Histologic
Cytologic
Biochemical
Immunologic
Molecular
Classification:
TB Disease in Children
Pulmonary TB
Latent Infection
Primary TB
Progressive Primary TB
Extra-Pulmonary TB
The First-Line
INH
Rifampicin
Pyrazinamide
Ethambutol
Streptomycin
Anti-TB Drugs
INH
MOA
Bactericidal for actively growing bacilli
Acts on extra/intracellular populations
Inhibit biosynthesis of mycolic acid (cell
wall component)
The INH prodrug is activated by KatG,
mycobacterial catalase peroxidase. Once
activated, forms a covalent complex that
blocks mycolic acid synthesis.
INH
Pharmacokinetics
Absorption Readily absorbed fr GIT
Distribution Diffuses to all body fluids
and tissues
CSF concn 20-100% of serum
Metabolism genetically determined
Rapid acetylators T/2 1hr; achieves
subtherapeutic levels if given once/wk
Slow acetylators T/2 3hrs
INH
Adverse Reactions
Hepatotoxicity INH induced hepatitis
most frequent major toxic effect
d/c INH if (+) sx or if transaminases increase
>3.5 x upper limits of normal
Rifampicin
Bactericidal / acts on extra and intracellular
bacillary populations
MOA: binds strongly to subunit of bacterial DNAdependent RNA polymerase inhibits RNA
synthesis.
Pharmacokinetics
Well absorbed orally, enterohepatic circulation
Well distributed in tissues, body fluids with
therapeutic levels in CSF
Rifampicin
Pharmacokinetics
Metabolism even deacetylated form
(metabolized form) has antibacterial activity
Excreted mainly through liver into bile and
urine (deacylated form)
Drug interactions:
Potentiate microsomal Cytochrome P450
mediated enzymatic activities causing increased
metabolism of digoxin, phenytoin,
chloramphenicol,coumadin, ketoconazole,
prednisone, theophyline
Rifampicin
Adverse Effects
GI intolerance may be severe
Produce reddish coloration of body fluids urine, tears, saliva
Cholestatic jaundice/hepatitis
Hypersensitivity: flushing, fever, pruritus,
flu-like sx
Increases risk of hepatotoxicity if used with
INH (adjust doses)
Rifampicin
Other clinical uses
Leprosy in combination with other drugs
For chemoprophylaxis- household contacts
of meningococcal and H.flu dis.
MRSA
In combination with Vancomycin or
Ceftriaxone for meningitis
Pyrazinamide
Weakly bactericidal but with potent sterilizing activity
within macrophages and areas of acute inflammation,
vs residual intracellular organisms that may cause
relapse.
MOA
Converted to active pyrazinoic acid (unknown drug
target and MOA)
Pharmacokinetics
Well absorbed from GIT
Widely distributed to body tissues and inflammed
meninges
T/2 8-11hrs
Pyrazinamide
Adverse Effects
Most hepatotoxic of all TB agents
GI sx
Photosensitivity and rash
Hyperuricemia due to decreased urate
excretion
Arthralgia, esp of shoulders
If patient is diabetic: monitor glucose levels
Protect from light.
Ethambutol
Bacteriostatic in macrophages, but with some
cidal action at higher doses.
Acts on extra and intracellular bacillary
populations, active vs bacilli in cavities.
MOA
Inhibitor of mycobacterial arabinosyl transferases
leading to inhibition of polymerization of
arabinoglycan, an essential component of the
mycobacterial cell wall.
Ethambutol
Pharmacokinetics
Well absorbed from the gut
CSF concn increases with inflammed
meninges = 4-64% of serum levels
50% of dose is excreted in the urine
unchanged
20% excreted in feces
Reduce dose by half if Cr clearance is
<10mL/min
Ethambutol
Adverse Effects
Retrobulbar neuritis
Reduced visual acuity
contraction of visual fields
green-red color blindness
Not usually seen at recommended doses
Hypersensitivity reactions rare
Should not be given to children <6yrs or where
visual acuity and color discrimination cannot be
monitored.
Streptomycin
Bactericidal aminoglycoside vs M.tb in vitro
but inactive vs intracellular bacilli limited
activity to suppression, activity limited to
extracellular bacteria.
MOA
Binds to 30S ribosomal subunit and
interferes with initiation of protein
synthesis by fixing the 30S-50S ribosomal
complex at the start codon (AUG) of
mRNA.
Streptomycin
Pharmacokinetics
Poorly absorbed orally
Must be given parenterally
Poor CSF penetration, unless meninges
inflammed
Elimination renal
reduce dose if with decreased UO or if (+)
casts/albumin in urine
Streptomycin
Adverse Effects
Ototoxicity
Nephrotoxicity
Vertigo and hearing loss most common
side effects
Sterile abscess
Lupoid reactions rare
Do not give with other nephrotoxic and
ototoxic drugs
Adverse Reactions
What are the recommendations in case the
patient develops these adverse drug
reactions?
GI intolerance
Mild skin reactions
Orange-red colored urine
Pain at the injection site
Burning sensation in the feet (periph neuropathy)
Arthralgia due to hyperuricemia
Flu-like sx
Side Effects
Drug
Responsible
GI intolerance Rifampicin
Mild skin
reactions
Any kind
Orange-red Rifampicin
colored urine
What to Do
Give
medication at
bedtime
Give antihistamines
Reassure the
patient
Side Effects
Drug
Responsible
What to Do
Burning
sensation
feet
Arthralgia
hyperuricemia
Flu-like sx
INH
Give vit B6
PZA
Give NSAID
Rifampicin
Give antipyretics
Side Effects
Drug
Responsible
What to Do
severe rash
d/c anti TB
drugs, refer to
MD
hypersensitivity
Jaundice -
acuity/color
vision-optic
neuritis
d/c anti TB
refer, resume tx
if sx gone
d/c etham,
refer to ophtha
Side Effects
Drug
Responsible
What to Do
Hearing
impairmnt,
tinnitus CN8
Streptomycin
d/c anti-TB
drugs and refer
to MD
Oliguria/albumi Streptomycin
nuria
Rifampicin
Renal dis.
Psychosis and
convulsion
INH
Clinical Form
Intensive
Phase
TB Exposure
< 5 yrs
5 yrs
3H
to be modified based
on follow up TST
result
Latent TB
9H
PPD conversion
within past 1-2 yrs ()Cxray
Latent TB
9H
PPD(+) with stable
healed lesion
(-) previous Tx
Continuation
Phase
Clinical Form
Intensive
Phase
Latent TB
PPD(+),stable/healed
lesion, previous tx(+)
At risk for reactivation
due to
measles/pertussis
Latent TB
PPD(+),stable/healed
lesion, previous tx(+)
At risk for reactivation
due to
immunosuppression
1-2 H
H for the
duration
immunosuppression
Continuation
Phase
Clinical Form
Intensive
Phase
Continuation
Phase
Active TB disease
New, smear(-)
pulmonary TB
2HRZ
4HR or 6HE
Active TB disease
Less severe form
extrapulmonary TB
2HRZ
4HR or 6HE
Active TB disease
New, smear(+)
pulmonary TB
2HRZE(S)
4HR or 6HE
Clinical Form
Intensive
Phase
Continuation
Phase
Active TB Disease
New smear (-)
pulmonary TB
with extensive
parenchymal
involvement
Active TB Disease
Severe forms of
extrapulmonary TB
(other than TB
meningitis)
2HRZE(S)
4HR or 6HE
2HRZE(S)
4HR or 6HE
Clinical Form
Intensive
Phase
Continuation
Phase
Active TB Disease
TB Meningitis
2HRZS
4HR
Active TB Disease
Miliary TB
Bone & Joint TB
2HRZS
7-10HR
Active TB Disease
previously treated
smear(+)Pulmo TB,
Relapse tx after
interruption tx failure
2HRZES/
1HRZE
5HRE
TB & Pregnancy
TB in pregnancy should be treated
without delay.
H,R,Z,E have no known teratogenic
effects
2HRZE then 4HR
Pyridoxine 25mg/day
Streptomycin - contraindicated
TB and Breastfeeding
Lactating women being treated for TB with the
first-line anti-TB drugs may continue to breastfeed.
The small concentrations of anti-TB drugs in breast
milk do not produce toxicity in nursing newborns.
Drugs in breast milk should not be considered as
an effective treatment for active TB or latent TB
infection in a nursing infant. Drug levels in breast
milk are not sufficient for Treatment of TB in the
infant.
Review
Mechanisms of Action of first line & second
line anti-TB drugs
Pharmacokinetics
Adverse Drug Reactions