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Drugs Used in Management of

Tuberculosis
04 February 2014

Introduction
• Used to be called phthisis, Greek work for wasting (a clinical
presentation of weight loss, cough, fevers, and hemoptysis)

• Mycobacterium Tuberculosis identified in 1882 by Robert Koch

• Modern era of TB treatment began in 1944 after discovery of

streptomycin and then para-aminosalicylic acid

• Isoniazid was discovered in 1952 and rifampicin was discovered

in the 1960’s

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Introduction
• Mycobacterium Tuberculosis is an aerobic, non-spore forming
bacilli that resists decolourization by acid alcohol after staining
with basis fuchsin
• Replicates slowly once every 24 hours, thrives in the apices of the
lung, renal parenchyma, and growing ends of the bone
• Transmitted through the air by aerolised droplet nuclei, each
droplet contains 1-3 mycobacteria tuberculosis organisms
• Latent Infection: droplet nuclei containing mycobacterium
tuberculosis settle into the bronchioles of alveoli of the lungs
• Active Infection

Anti-TB’s
• 1st line drugs
Isoniazid, Rifampicin
Ethambutol, Pyrazinamide
Streptomycin

• 2nd line drugs

Amikacin, Clofazimine
Aminosalicylic acid, Cycloserine
Capreomycin, Ethionamide, Rifapentine
Ciprofloxacin, Levofloxacin, Rifabutin

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Isoniazid
• a small molecule (MW137) that is freely soluble in water

• Bactericidal against actively growing tubercle bacilli, penetrates

into macrophages and is active against intra and extracellular
organisms

• Inhibits synthesis of mycolic acids which are essential

components of mycobacterial cell walls

Isoniazid
• Activated by KatG a mycobacterial catalase peroxidase
• Activated form of INH forms a covalent complex with an acyl
carrier protein (ACPM) and KasA a beta-ketoacyl carrier protein
synthetase that blocks mycolic acids synthesis and kills the cell
• Mutations resulting in InhA overexpression which results in
mutation or deletion of KatG gene
• KatG mutants express high level INH resistance but no cross
resistance with Ethionamide
• Peak plasma concentrations achieved with 1-2 hours, diffuses
readily into body fluid and tissues

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Isoniazid
• Genetic polymorphism exists in the metabolism of INH, it
undergoes acetylation by liver N-acetyltransferase
• Rapid acetylators do not have clinical significance
• Drug metabolizing enzyme inhibitor (reduces metablosim of
phenytoin)
• Dose: 5mg/kg/day for children
-300mg/day for adults
-pyridoxine 25-50mg/day for predisposing neuropathy
• For latent TB 300mg/day (5mg/kg/day) or 900mg twice a week
for 9 months

Isoniazid
• Adverse Drug Effects
Immunologic reactions (fever and skin rashes)
Drug induced Systemic Lupus Erythematosus (SLE)
Drug induced hepatotoxicity (loss of appetite, nausea, vomiting,
jaundice, right upper quadrant pain) risk increases with age
Peripheral neuropathy (INH promotes excretion of pyridoxine)
Memory loss, psychosis, seizures
Tinnitus, GIT disturbances

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Rifampicin
• A semi synthetic derivative of rifamycin (antibiotic produced by
Streptomyces mediterranei)
• Has in vitro activity against gram negative and positive cocci,
enteric bacteria, mycobacteria, and chlamydiae
• Cross resistance occurs with rifamycin derivatives Rifabutin and
rifapentine
• Binds to the β-subunit of bacterial DNA-dependent RNA
polymerase and thus inhibiting RNA synthesis
• Resistance occurs with mutations to the rpoβ gene that codes for
the β-subunit of RNA polymerase

Rifampicin
• Bactericidal for mycobacteria, penetrates most tissues and
phagocytic cells
• Undergoes enterohepatic recirculation
• Widely distributes in body fluids and tissues, is highly protein
bound and CNS concns found if patient has meningeal
infection
• Dose: 600mg/day in adults for 6 months

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Rifampicin
Adverse Drug Effects
Orange colour discolouration of urine, sweat and tears
Rash
Thrombocytopenia
Nephritis
Cholestatic jaundice
Hepatitis
Light chain proteinuria
Acute tubular necrosis
Induces P450 isoforms (1A2, 2C9, 2C19, 2D6, 3A4)

Ethambutol
• A synthetic water soluble, heat stable compound
• In vitro inhibition of suspected mycobacteria tuberculosis and
other mycobacteria at 1-5mcg/ml
• Inhibits mycobacterial arabinosyl transferase encoded by
embCAB operon
• arabinosyl transferase are involved in polymerization reaction
of arabinoglycan an essential component of mycobacterial
cell wall
• Resistance is due to mutations resulting in overexpression of
emb gen products or within embB structural gene

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Ethambutol
• Blood level peaks of 205mcg/ml achieved in 2-4 hours after
oral intake
• 20% excreted in feces unchanged and 50% in urine
unchanged
• Accumulates in renal failure and dose should be decreased
by 50% if creatinine clearance is <10mL/min
• Crosses the BBB if meninges are inflamed
• Dose: 15-25mg/kg/day

Ethambutol
Adverse Drug Effects

Hypersensitivity (though rare)

Retrobulbar neuritis resulting in loss of visual acuity and red-

green color blindness (contraindicated in children)

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Pyrazinamide
• A relative of Nicotinamide, that is stable and slightly soluble in
water
• Inactive at neutral pH, at pH 5.5 it inhibits tubercle bacilli at
20mcg/ml
• Taken up by macrophages and exerts its activity against
mycobacteria residing within acidic environment of lysosomes
• Converted to pyrazinoic acid (active form of PZA) by mycobacterial
pyrazinamidase encoded by pncA
• Disrupts mycobacterial cell membrane metabolism and transport
functions (bacteriostatic)

Pyrazinamide
• Resistance due to impaired uptake of PZA or mutations in
pncA that impair conversion of PZA to its active form
• Serum concns of 30-50mcg/mL at 1-2 hours after oral
administration at 25mg/kg/day
• T1/2 is 8-11 hours, well absorbed orally and widely
distributed body tissues and enter meninges if inflamed

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Pyrazinamide
Adverse Drug Effects
Hepatotoxicity
Nausea
Vomiting
Drug fever
Hyperuricemia (may provoke acute gouty arthritis)

Streptomycin
• Water soluble, stable in solution, and more active at alkaline
pH than acidic pH
• Irreversible inhibitors of protein synthesis, bactericidal activity
mechanism unknown
• Initially passive diffusion via porin channels across outer
membranes
• Bind to 30S-subunit ribosomal proteins and then cause
protein synthesis interruption by
Interfering with the initiation complex of peptide formation
Misreading m-RNA causing incorporation of incorrect amino acids
into the peptide resulting in non-functional or toxic proteins
Breakup of polysomes into non-functional monosomes

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Streptomycin
• Resistance occurs by 3 mechanisms
Production of a transferase enzyme or enzymes that
inactivate the aminoglycoside by adenylylation, acetylation,
or phosphorylation
Impaired entry of aminoglycoside into cell due to
mutation or deletion of a porin protein or proteins
involved in transport and maintance of electrochemical
gradient
Receptor protein on 30S ribosomal subunit may be
deleted or altered due to mutations

Streptomycin
• Poor absorption after oral administration
• Entire dose excreted in fecal matter
• After i.m injection peak concns in blood occur in 30-
90minutes
• Highlypolar and does not readily enter cells rapidly
• Concentration dependent killing and postantibiotic effect
• Synergistic killing of certain bacteria of given with
vancomycin and β-lactam antibiotic
• Dose: 0.5g-1g/kg/day in adults, and 7.5-15mg/kg/day in
children

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Streptomycin
Adverse Drug Effects (time and concentration dependent)
Ototoxicity
Nephrotoxicity
Fever, skin rashes
Allergic manifestations
Pain at injection site
Vertigo and loss of balance
Contraindicated in pregnancy

Ethionamide
• Chemically related to isoniazid (INH) and blocks synthesis of
mycolic acid
• Poor water solubility, available in oral form and metabolized
by the liver
• Inhibits tubercle bacilli
• Initial dose of 250mg once a day increasing to 1g/day
• Causes intense gastric irritation and neurologic symptoms
• Hepatotoxic
• Neurologic symptoms alleviated by pyridoxine

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Capreomycin
• A peptide protein synthesis inhibitor
• Dose: 1g/day intravenous
• 15mg/kg/day for drug resistant mycobacterium tuberculosis
• Adverse drug effects
Nephrotoxicity
Ototoxicity
Tinnitus
Deafness
Vestibular disturbances
Local pain at injection site and sterile abscesses

Cycloserine
• Inhibits cell wall synthesis
• Dose: 0.5g-1g/day in two divided oral doses
• Renal clearance occurs
• Reduce dose by half if creatinine clearance is <50mL/min
• Adverse drug effects
Peripheral neuropathy
CNS dysfunction (depression and psychosis)
Pyridoxine 150mg/d to reduce neurologic toxicity

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Para-aminosalicylic Acid
• Folate synthesis antagonist active against mycobacterium
tuberculosis
• 8-12g/day for adults and 300mg/kg/day for children
• Widely distributes into tissue except CSF fluid
• Adverse drug effects
GIT discomfort
Peptic ulceration
Hemorrhage
hypersensitivity

Fluoroquinolones
• Inhibits strains of mycobacterium tuberculosis
• Moxifloxacin is the most active
• Levofloxacin is more active than ciprofloxacin
Ciprofloxacin 750mg twice a day
Levofloxacin 500-75omg/day
Moxifloxacin 400mg/day

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Linezolid
• Inhibits strains of mycobacterium tuberculosis
• Causes bone marrow suppression
• Irreversible peripheral and optic neuropathy
• 600mg/day for adults
• Uses as a last resort

Rifabutin
• Derived from rifamycin and related to rifampicin
• Has significant activity against mycobacterium tuberculosis
• Strong inducer of cytochrome P450 enzymes though less
potent than rifampicin
• Dose of 300mg/day

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Rifapentine
• An analogue of rifampicin
• Bacterial RNA polymerase inhibitor with cross resistance
between rifampicin
• Potent inducer of cytochrome P450 enzymes
• Has a microbiologocally active metabolite 25-
desacetylrifapentine
• Dose of 600mg (10mg/kg) once a week

Category 1 TB Treatment
• Intensive phase
2 months of INH, RIF, PZA, and ETH
• Continuation Phase
4 months of INH and RIF or 6 months of INH and ETH for patients
in NVP containing ART regimen

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Category 2 – TB Treatment
• Any retreatment of any form of TB
• Adults: Intensive Phase-2 months SHRZE + 1 month HRZE
Continuation phase – 5 months HRE

• Children: Intensive Phase- months HRZ

Continuation phase – 5 months HR

TB Prevention
• BCG vaccination at birth, non healing ulcers from the
injection site should be treated with INH 10mg/kg/day for 2
months
• Secondary Prevention: if parents are sputum positive INH
10mg/kg/day for 6 months

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References
• Katzung: Basic and Clinical Pharmacology 12th Edition

• Pharmacotherapy: A Pathophysiologic Approach 9th Edition

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