TUBERCULOSIS

CLINICAL CLERK TANYA MARIE P. FERNANDEZ

 CONTENTS

01 WHAT IS
TUBERCULOSIS 03 PATHOPHYSIOLOGY
AND PATHO GENESIS
05 SCREENING AND
DIAGNOSTIC
MODALITIES

02 EPIDEMIOLOGY
04 CLINICAL
MANIFESTATIONS 06 TREATMENT
 01
WHAT IS
TUBERCULOSIS?
TUBERCULOSIS (TB)
-is caused by bacteria of the
Mycobacterium Tuberculosis
complex, is one of the oldest diseases
known to affect humans and the top
cause of infectious death worldwide
- most often affects the lungs
-transmitted through airborne spread
of droplent nuclei produced by
patients with infectious pulmonary TB
 MYCOBACTERIUM
TUBERCULOSIS
- belong to the family
Mycobacteriaceae and the order
Actinomycetales
- M. tuberculosis is a rod-
shaped, non-spore-forming, thin
aerobic bacterium, measuring
0.5 um by 3 um.
 MYCOBACTERIUM
TUBERCULOSIS
- often neutral on Gram staining, but
once stained, the bacilli cannot be
decolorized by acid alcohol thus it is
classified as acid-fast bacilli.

- Acid fastness is due mainly to the

organisms’ high content of mycolic
acid, long-chain cross-linked fatty
acids, and other cell wall lipids.
 MYCOBACTERIUM
TUBERCULOSIS
- In the mycobacterial cell wall, lipids are
linked to underlying arabinogalactan and
peptidoglycan – results in low
permeability of the cell wall – reducing
effectiveness of most antibiotics

- lipoarabinomannan, another molecule

in the bacterial cell wall, is involved in the
pathogen-host interaction and facilitates
the survival of M. tuberculosis within the
macrophage
 02
EPIDEMIOLOGY
In 2016,
6.3 million new cases
of TB (both pulmonary and extrapulmonary) were
reported to the World Health Organization (WHO) by
its member states; 95% of cases were reported
from developing countries.
PHILIPPINES
In 2019, the Philippines had the highest TB incidence in
Asia with 554 cases per 100,000 people, according to a
World Health Organization (WHO) report. Approximately,
74 Filipinos die of TB every day and is among the top 10
causes of death in the country.

Source: DOH
 03
PATHOPHYSIOLOGY
PATHOGENESIS
PATHOGENESIS
 04
CLINICAL
MANIFESTATIONS
 TUBERCULOSIS (TB)
- is classified as pulmonary or extrapulmonary, or
both, depending on several factors linked to
different populations and bacterial strains
- extrapulmonary tb may occur in 10-40% of patients
- up to 2/3 of HIV-infected patients with TB have both
pulmonary and extrapulmonary tb or
extrapulmonary tb alone
Cardinal signs and symptoms that
are lasting for ≥2 weeks:
• Cough
• Unexplained fever
• Unexplained weight loss
• Night sweats
If any of the above signs/symptoms are present for at least 2
weeks, identify as presumptive TB.
PRIMARY
POSTPRIMARY
(ADULT-TYPE)

EXTRAPULMONARY
PRIMARY DISEASE
-Primary pulmonary tuberculosis
occurs soon after initial infection
with tubercle bacilli.

- It can be asymptomatic or may

present with fever and occasionally
pleuritic chest pain.

- In areas of high TB transmission,

this form o f disease is often seen in
children.
POSTPRIMARY
(ADULT TYPE) DISEASE
- also referred to as reactivation
or secondary TB

- postprimary TB is probably
most accurately termed adult-
type TB because it may result
from endogenous reactivation of
distant LTBI or recent infection
(primary infection or reinfection).
EXTRAPULMONARY
DISEASE
- In order of frequency, the extrapulmonary sites
most commonly involved in TB are lymph nodes,
pleura, genitourinary tract, bones and joints,
meninges, peritoneum, and pericardium.

- Virtually, all organ systems may be affected.

-As a result of hematogenous dissemination in

HIV-infected individuals, extrapulmonary TB is
more common today
 05
SCREENING
Systematic screening for pulmonary TB in adults ≥ 15 years old with
unknown HIV infection status in health facilities
Systematic screening for the diagnosis of active PTB
disease in PLHIV
Screening for PTB in targeted community, workplace
and congregate settings
 05
DIAGNOSIS
 DIAGNOSIS

01 AFB
MICROSCOPY
03 MYCOBACTERIAL
CULTURE
05 RADIOGRAPHIC
PROCEDURES

02 NUCLEIC ACID
AMPLIFICATION
TECHNOLOGY
04
DRUG
SUSCEPTIBILITY
TESTING
06 TUBERCULIN
SKIN TEST
Collection and transport of
sputum specimens
• The only contraindication to collecting sputum for bacteriological
diagnosis of TB is massive hemoptysis, which is expectoration of
large volumes of blood from the respiratory tract.
• Blood-streaked sputum can still be examined.
• Prepare a sputum cup or 50 ml conical tube and accomplish
Form. Laboratory Request and Result Form.
Collection and transport of
sputum specimens
• Instruct patient to expectorate one sputum sample on the
spot for diagnostic testing with Xpert (if not available, SM or
TB.)
• If the child cannot expectorate (especially < 5 years old),
nasopharyngeal aspirate or gastric lavage may be
performed in facilities where trained staff, supply and
equipment are available.
Xpert MTB/RIF
• A rapid diagnostic test (RDT)
• Primary diagnostic test for PTB
and EPTB in adults and children
• An automated diagnostic test
that can identify Mycobacterium
tuberculosis (MTB) DNA and
resistance to rifampicin (RIF)
• High specificity and sensitivity
 Extrapulmonary specimens that may be submitted for
Xpert MTB/RIF test and corresponding volume required
XPERT MTB/RIF results and interpretation
SMEAR MICROSCOPY
• SM (Smear Microscopy) may be performed using either
brightfield microscopy (Ziehl-Neelsen technique) or
fluorescence microscopy (FM).
• Smear microscopy (whether brightfield or fluorescence
microscopy) or loop mediated isothermal amplification
(TB LAMP) shall be the alternative diagnostic test if Xpert is
not accessible.
• TB LAMP is utilized to process large sample loads.
Interpretation of results for both brightfield and
fluorescence microscopy

• Positive = at least one sputum smear is positive for AFB (+n, 1+, 2+, 3+)
• Negative = both sputum smears are negative for AFB.
MYCOBACTERIAL CULTURE
• Definitive diagnosis depends on the isolation and
identification of M. tuberculosis from a clinical specimen or
the identification of specific DNA sequences in a nucleic acid
amplification test.
• Mycobacterial growth indicator tube (MGIT) system are
recommended by the WHO as the reference standard for
culture.
• MGIT cultures usually become positive after 10 days to 2-3
weeks.
DRUG SUSCEPTIBILITY TESTING
• Universal DST is considered by the WHO as the current
standard of care for all TB patients and should consist in
DST to at least rifampin for all initial isolates of M.
tuberculosis – rifampin resistance is an excellent proxy for
MDR-TB.
• Important if one or more risk factors for drug resistance are
identified or if the patient fails to respond to initial therapy
or has relapse after the completion of treatment.
TUBERCULIN SKIN TEST
• Tuberculin skin test (TST), also known as purified protein
derivative (PPD) test or Mantoux test
• Shall be used only as an adjuvant when there is doubt in making a
clinical diagnosis of TB in children.
• Can be used to identify identification of individuals with Latent TB
infection.
• (+) TST reaction:
o At least 10 mm induration regardless of BCG vaccination
status or 5 mm in immunocompromised children
Approach to diagnosis
of TB in children (< 15
years old)
Chest X-ray findings strongly suggestive
of PTB in children and adolescents
 06
TREATMENT
TB Disease Registration Group
- refers to the classification of TB cases based on history of previous treatment.
 TREATMENT
Aims of TB treatment:
(1) to prevent morbidity and death by
curing TB while preventing the
emergence of drug resistance
(2) to interrupt transmission by
rendering patients noninfectious
TREATMENT
ISONIAZID

• Isoniazid is the most active drug for the

treatment of tuberculosis caused by susceptible
strains.
• It is a small molecule (MW 137) that is freely
soluble in water. The structural similarity to
pyridoxine.
ISONIAZID

• Mechanism of Action: Isoniazid inhibits synthesis of mycolic acids,

which are essential components of mycobacterial cell walls. Isoniazid is
a prodrug that is activated by KatG, the mycobacterial catalase-
peroxidase.
• Resistance:
o associated with mutations resulting in overexpression of inhA -
encodes an NADH-dependent acyl carrier protein reductase
omautation or deletion of the katG gene;
o promoter mutations resulting in overexpression of ahpC - a
putative virulence gene involved in protection of the cell from
oxidative stress
o mutations in kasA
ISONIAZID

• Pharmacokinetic: Metabolism of isoniazid, especially acetylation

by liver N-acetyltransferase, is genetically determined.
• Clinical Uses: The typical dosage of isoniazid is 5 mg/kg/d; a
typical adult dose is 300 mg given once daily. Up to 10 mg/kg/d may
be used for serious infections or if malabsorption is a problem.
Isoniazid as a single agent is also indicated for treatment of latent
tuberculosis.
ISONIAZID
• Adverse Reactions: The incidence and severity of untoward reactions to
isoniazid are related to dosage and duration of administration.
• Immunologic Reactions: Fever and skin rashes are occasionally seen.
Drug-induced systemic lupus erythematous has been reported.
• Direct Toxicity: Isoniazid-induced hepatitis is the most common major
toxic effect. This is distinct from the minor increases in liver
aminotransferases (up to three or four times normal), which do not require
cessation of the drug and which are seen in 10–20% of patients, who
usually are asymptomatic.
• Neuropathy is due to a relative pyridoxine deficiency.
RIFAMPIN

• Rifampin is a semisynthetic derivative of rifamycin, an

antibiotic produced by Streptomyces mediterranei.
RIFAMPIN

• Mechanism of Action: Rifampin binds to the β subunit of bacterial DNA-

dependent RNA polymerase and thereby inhibits RNA synthesis.
• Resistance: Results from any one of several possible point mutations in
rpoB, the gene for the β subunit of RNA polymerase. These mutations
result in reduced binding of rifampin to RNA polymerase.
• Pharmacokinetics: Rifampin is bactericidal for mycobacteria. It readily
penetrates most tissues and penetrates into phagocytic cells. It can kill
organisms that are poorly accessible to many other drugs, such as
intracellular organisms and those sequestered in abscesses and lung
cavities.
RIFAMPIN

• Clinical Use: Rifampin, usually 600 mg/d (10 mg/kg/d) orally,

must be administered with isoniazid or other antituberculous
drugs to patients with active tuberculosis to prevent emergence
of drug-resistant mycobacteria.
• Adverse Reactions: Rifampin imparts a harmless orange color
to urine, sweat, and tears (soft contact lenses may be
permanently stained). Occasional adverse effects include rashes,
thrombocytopenia, and nephritis. Rifampin may cause cholestatic
jaundice and occasionally hepatitis, and it commonly causes
light-chain proteinuria.
ETHAMBUTOL

• Ethambutol is a synthetic, water-soluble, heat-stable

compound; dispensed as the dihydrochloride salt.
ETHAMBUTOL
• Mechanism of Action & Clinical Use: Ethambutol inhibits
mycobacterial arabinosyl transferases, which are encoded by
the embCAB operon. Arabinosyl transferases are involved in the
polymerization reaction of arabinoglycan, an essential
component of the mycobacterial cell wall.
• Resistance: is due to mutations resulting in overexpression of
emb gene products or within the embB structural gene.
• Adverse Reactions: Hypersensitivity is rare. The most common
serious adverse event is retrobulbar neuritis, resulting in loss of
visual acuity and red-green color blindness.
PYRAZINAMIDE
• Pyrazinamide (PZA) is a relative of nicotinamide. It is stable and
slightly soluble in water.
• It is inactive at neutral pH, but at pH 5.5 it inhibits tubercle
bacilli at concentrations of approximately 20 mcg/mL.
• The drug is taken up by macrophages and exerts its activity
against mycobacteria residing within the acidic environment of
lysosomes.
PYRAZINAMIDE

• The specific drug target is unknown, but pyrazinoic acid

disrupts mycobacterial cell membrane metabolism and
transport functions.
• Resistance: may be due to impaired uptake of pyrazinamide
or mutations in pncA that impair conversion of pyrazinamide to
its active form.
• Adverse Reactions: Major adverse effects of pyrazinamide
include hepatotoxicity (in 1–5% of patients), nausea, vomiting,
drug fever, and hyperuricemia.
STREPTOMYCIN
• Prevents bacterial protein synthesis by binding to the S12
ribosomal subunit
• Resistance: is due to a point mutation in either the rpsL gene
encoding the S12 ribosomal protein gene or the rrs gene encoding
16S ribosomal rRNA, which alters the ribosomal binding site.
STREPTOMYCIN
• Streptomycin penetrates into cells poorly and is active mainly
against extracellular tubercle bacilli. Streptomycin crosses the
blood-brain barrier and achieves therapeutic concentrations
with inflamed meninges.
• Streptomycin sulfate is used when an injectable drug is needed or
desirable and in the treatment of infections resistant to other
drugs.
• Adverse Reactions: Streptomycin is ototoxic and nephrotoxic.
Vertigo and hearing loss are the most common adverse effects
and may be permanent.
Treatment Regimens for DS-TB
Standard regimens for DS-TB: dosing
for adults
Management of
adverse drug
reactions
(first-line TB drugs)
Schedule of sputum follow-up examinations
for PTB on DS-TB regimen
MANAGEMENT OF CASES WHO HAVE
INTERRUPTED TREATMENT
TREATMENT OUTCOMES FOR DS-TB
DRUG-RESISTANT
TUBERCULOSIS
MDR-TB and RR-TB treatment regimens
• Strains of M. tuberculosis resistant to individual drugs arise by
spontaneous point mutations in the mycobacterial genome that
occur at low but predictable rates.
• There is no cross-resistance among the commonly used drugs.
• MDR-TB and RR-TB treatment shall be started within seven days
from diagnosis.
• Standard treatment regimens for MDR-TB and RR-TB shall be given
based on patient eligibility and exclusion criteria.
• Individualized treatment shall be given to patients who are not
eligible for any of the standard regimens.
2nd LINE DRUGS
• in case of resistance to first-line agents
• in case of failure of clinical response to conventional therapy
• in case of serious treatment-limiting adverse drug reactions
 LATENT
TUBERCULOSIS
 SOURCES:
● Harrison’s Principles of Internal Medicine 20th ed.
● National Tuberculosis Control Program Manual of
Procedures 6th edition Copyright 2020 Department of
Health.
● Katzung, et al., Basic & Clinical Pharmacology