Pathogenesis: <3 weeks

• Breathe in the
droplets
• Bacteria into their
lungs
• Engulfed by the
alveolar
macrophages
• Hilar lymph nodes
• Beginning of
primary
tuberculosis
• Middle or lower
lobes of the lungs
• May be Atutubo, Cosette
Pathogenesis: 2-3 Weeks
• hypersensitivity immune
response
• Macrophages present bacterial
peptide
• Class II (MHC) to CD4 T cells.
• IF gamma activates the
macrophages reactive nitrogen
intermediates
• Kill mycobacteria
Atutubo, Cosette
Pathogenesis: 2-3 Weeks

Kills mycobacterium

Atutubo, Cosette
 Pathogenesis: 2-3 Weeks
• formation of the epithelioid
granulomas

• epithelioid cells merge

multinucleated Langhans giant
cells.

Atutubo, Cosette
 Pathogenesis: 2-3 Weeks
• Macrophage lysis mechanism

• CD8+ T cells
• granule-dependent mechanism
• death of the mycobacteria.

• CD4-CD8- T cells cause

• Fas-dependent mechanism
• does not kill the organisms
• epithelioid granulomacaseous
granuloma
Atutubo, Cosette
 Pathogenesis: 2-3 Weeks
• initial parenchymal granuloma-
Ghon focus
• Ghon complex - Ghon focus +
caseated hilar lymph nodes that
drain the area
• Ranke complex – calcified

• Mycobacteria can survive for years

within this complex as latent
Atutubo, Cosette
tuberculosis
 Secondary PTB
• Reinfection or
reactivation
• High Oxygen
requirement
• Apex of lung
• Granuloma erosion 
cavitation
– Airways
– Airways + BV
• parenchyma-
localized spread
Atutubo, Cosette
• Body’s attempt to
repair 
permanent
damage
• Repaired by fibrous
deposits
– Pockets
– Thick scars
• HIV infection has
greatest risk of
developing
secondary TBAtutubo, Cosette
Atutubo, Cosette
PATHOLOGY
Primary tuberculosis

• Ghon’s complex

• Peripheral
parenchymal
granuloma often in the
lower lobes

•Prominent mediastinal
lymph node
Primary tuberculosis

• Caseous granuloma

• Epitheloid marcrophages,
Langhan’s giant cells,
lymphocytes,
and peripheral fibrous tissu
 Secondary tuberculosis
• pattern of disease that arises in a
previously sensitized host
• reactivation of dormant primary
lesions many decades after initial
infection
• exogenous reinfection
 Secondary tuberculosis
• localized to the apex of the upper
lobes of one or both lungs

• Cavitary formation
 Gross Morphology

Upper parts of both lungs are riddled with gray-white areas of

caseation and multiple areas of softening and cavitation

Source: Robin’s Pathologic Basis of Disease, 7th ed

• Scattered tan granulomas

• Central caseation

• Irregularly sized rounded nodules

that are firm and tan

• Nodules may have central necrosis

• Granulomatous disease of the lung

• Pattern of smaller nodules which

have a propensity for upper lobe
involvement (granulomatous process
• Granulomas have areas of caseous
necrosis

• Multiple caseating granulomas primarily

in the upper lobes
Cavitation in the upper lobes
Histologic characteristics

Central caseation surrounded by

epitheloid and multinucleated
giant cells

Source: Robin’s Pathologic Basis of Disease, 7th ed

•Necrotizing granulomas are
prominent

•Giant cells of the Langerhans type

•Adjacent air spaces filled with blood

• Well-defined granulomas
(epithelioid cells,
lymphocytes
PMN's, plasma cells,
fibroblasts)

• Langhans giant cells

• Multiple granulomas
• Caseous material

• Epithelioid cells, lymphocytes,

and fibroblasts

• Langhan’s Giant cell

PHARMACOTHERAPY
 THERAPEUTIC GOALS
• Symptom relief

• Treat infection

• Prevent recurrence

• Prevent relapse and emergence of

resistance
 PLAN OF THERAPY
• Give Antibiotics
• Monitor liver enzymes for possible
adverse effects of the drugs
• Give healthy foods
• Vitamin supplement for
enhancement of immune system
• Surgical treatment if needed
 FIRST-LINE DRUGS
• Isoniazid

• Rifampin

• Pyrazinamide

• Ethambutol

• Streptomycin
 ISONIAZID
• MOA:Inhibits mycolic acid synthesis by forming covalent
complex with an acyl carrier protein (AcpM) and KasA
• Activated by KatG: mycobacterial catalase-peroxidase
• Resistance:mutations or deletion of inhA,KatG,ahpC and
KasA
• Penetrates phagocytic cells and active against both
intracellular and extracellular organisms
• Rapidly absorbed in the GI and will peak w/in 1-2hrs; mainly
excreted in urine
• Metabolized in the liver by acetylation
• Dose: 300mg oral
• Adverse effects: SLE like reactions, hepatotoxicity and
neuropathy, reduces metabolism of phenytoin: Inc toxicity
 RIFAMPIN
• MOA: Binds to beta-subunit of DNA dependent RNA
polymerase thereby inhibits RNA synthesis; bactericidal
• Resistance: mutation of rpoB
• Penetrates tissues and phagocytic cells; active against
intacellular organisms, abscess and lung cavities
• Well absorbed orally and excreted thru liver into the bile
(deacylated in stool and some in urine)
• High protein bound, wide volume of distribution
• Crosses BBB if inflamed
• Dose: 600mg oral
• Adverse effects: orange color to body fluids, hepatotoxicity,
thrombocytopenia, nephritis, induces cytochrome P450
isoforms
 ETHAMBUTOL
• MOA: Inhibits mycobacterial arabinosyl
transferase (embCAB operon) involved in
polymerization of arabinoglycan (component of
mycobacterial cell wall)
• Resistance: mutations of emb gene
• Well absorbed orally and peaks within 2-4hrs
• Excreted in feces and 50% unchanged in urine
• Accumulates in renal cases: reduced dose
• Crosses BBB if inflamed
• Dose: 15-25mg/kg oral
• Adverse effects: retroulbar neuritis, red-green
color blindness, loss of visual acuity
 PYRAZINAMIDE
• Converted to pyrazinoic acid by
mycobacterial pyrazinamidase (pncA);
Unknown MOA
• Resistance: mutation of pncA
• Well absorbed orally, wide distribution and
will peak w/in 1-2hrs, crosses BBB when
inflamed
• “sterilizing agent” in conjunction with RIF
and INH
• Dose: 50-70mg/kg oral
• Adverse effects: hepatotoxicity,
 STREPTOMYCIN
• MOA: Binds to 30S-subunit S12 ribosomal
protein (interfere with initiation,
misreading of mRNA and breakup of
polysomes) thereby inhibits protein
synthesis
• Resistance: mutarion of rpsL and rrs
• Active against extarcellular tubercle bacilli
• Crosses BBB when inflamed
• Dose: 15mg/kg/d IM or 20-40/mg/kg/d IV
• Adverse effects; ototoxicity and
nephrotoxicity. Most common is vertigo
 SECOND-LINE DRUGS
• Ethionamide
• Capreomycin
• Cycloserine
• Aminosalicylic acid (PAS)
• Kanamycin
• Amikacin
• Ciprofloxacin
• Levofloxacin
• Ethionamide: chemically related to INH and
blocks mycolic acid synthesis. Causes intense GI
irritation and neurologic symptoms. Dose (250mg
once daily)

• Capreomycin: a peptide protein synthesis

inhibitor. It is nephrotoxic and ototoxic. Dose (1g
IM 2-3 times weekly and 15mg/kg for drug
resistant tubercle)

• Cycloserine: inhibits cell wall synthesis. Causes

neuropathy and CNS dysfunctions. Dose (0.5-1g/d
in 2 divided doses)

• PAS: folate synthesis antagonist and is related to

PABA. Causes GI symptoms and hypersensitivity
reactions. Dose (8-12g/d orally)
• Kanamycin and Amikacin: inhibits
protein synthesis. Used for
streptomycin resistant strains and
atypical mycobacteria. Dose
(15mg/kg/day IV or IM for 5 days for
2 months)

• Ciprofloxacin and Levofloxacin:

b;ocks DNA synthesis thru inhibition
of DNA gyrase and topoisomerase IV.
Also effective against atypical
mycobacteria
 Pharmacotherapy
THE STANDARD REGIMEN

Multiple drugs are used for the treatment of

tuberculosis to prevent the development of
resistance.

Short course regimens are divided into two

phases:
a. Initial or bactericidal phase (2 months)
b. Continuation or sterilizing phase (4 months)
 Pharmacotherapy
2 months initial phase (4 drugs)
- isoniazid
- rifampin
- ethambutol
- pyrazinamide

4 months continuation phase (2 drugs)

- isonoazid
- rifampin
 Pharmacotherapy

RECOMMENDED DOSAGE for the initial treatment of tuberculosis

Drug Daily dose Thrice-weekly dose

Isoniazid 5mg/kg, max 300 mg 15mg/kg, max 900 mg
Rifampin 10 mg/kg, max 600 mg 10mg /kg, max 600 mg
Pyrazinamide 20-25 mg/kg, max 2 g 30-40 mg/kg, max 3 g
Ethambutol 15-20 mg/kg 25-30 mg/kg
 Pharmacotherapy
Monitoring treatment

 Bacteriologic evaluation
- patients should have their sputum
examined every month until culture becomes
negative

- at the end of the third month, patients

should have negative sputum culture
 AFB Smear
 Pharmacotherapy

Patients with delayed sputum conversion after 3

months should have their treatment extended by
3 months with a total course of 9 months.

For patients with culture negative, their

treatment can be reduced to 4 months.
 Pharmacotherapy
Non-compliance

 Treatment failure

 Relapse

 Drug resistance
 Pharmacotherapy
Non-pharmacologic treatment

 stop smoking and alcohol drinking

 Vitamin D supplementation

 nutrition