Antituberculosis Drugs

Dr Mazhar Ul Haq
 Animal Tuberculosis
• Bovine tuberculosis (TB)
• Bovine TB is infection in Bovids & Bisons with any of disease
causing mycobacterial species within the Mycobacterium
tuberculosis complex
✔ Mycobacterium bovis
✔ Mycobacterium caprae
• Mycobacterium bovis closely related to human and poultry
tuberculosis
• TB - an important disease of animals and of zoonotic
importance
• Zoonotic importance has raised public health concern as
well
 Continued ……
• In developing countries human and animal TB
infection is endemic
• 10-20% of total deaths in people caused by TB
had an animal origin
• http://dx.doi.org/10.1016/j.rvsc.2014.09.003
International standards for
tuberculosis care 2016
 Chemotherapy
• Mycobacteria are acid
fast bacteria have lipid
rich cell walls
• Mycobacterial infections
are intracellular
• Treatment is difficult as
they grow slow
• Standard Antituberculosis
therapy requires use of
multiple drugs for certain
periods
 Mechanisms of action of anti-tuberculosis drugs.

Ioana Diana Olaru et al. Eur Respir J 2015;45:1119-1131

©2015 by European Respiratory Society

 Isoniazid
• Synthetic analog of Pyridoxine
• Low MW, H2O soluble bactericidal drug
• Most potent among the antitubercular drugs
• Has revolutionized the treatment of tuberculosis
• Always administered in combination with other
drugs
• Has been used for the treatment of Actinomycosis
and Johne’s disease in cattle
• Not approved for use in food animals in some
countries
 Mechanism of Action
• Isoniazid often reffered as INH, a prodrug
• Activated by mycobacterial catalase-peroxidase
(KatG)
• Has targets within Type II fatty acid synthase
system involved in production of mycolic acids
• Activated drugs covalantly bind with some carrier
proteins (InhA, KasA) and inhibit them
• Decreased mycolic acid synthesis results in the
loss of acid fastness of bacteria
 Mechanism of resistance
• Chromosomal mutations in target proteins
• KatG, InhA, KasA
• Cross resistance does not occur
 Adverse effects
• Fairly low adverse effects
except hypersensitivity
• Usually related to dosage
and duration
• Peripheral neuritis due to
relative deficiency of
pyridoxine
• Idiosyncratic
hepatotoxicity
• Slow acetylators are
particularly at risk
 Rifampin
• Most important synthetically modified
member of Rifamycins
• Highly active first line oral drug in TB
• Has a broader antimicrobial activity than
Isoniazid
• Always used in combination with other drugs
to the development of resistance
 Mechanism of action
• Rifampin inhibits DNA dependent RNA
polymerase in bacteria more specifically
• Inhibits RNA synthesis by suppressing the
initiation step
• High degree of lipid solubility makes it
effective against both intracellular and
extracellular pathogens
 Continued …
• Bacteriostatic, time-dependent antibacterial activity
with long PAEs
• Rapidly absorbed after oral administration with low F
value in horses
• Due to very lipophilic nature highly penetrates tissues
and fluids like milk
• It induces the hepatic enzymes CYP3A12 in many
species
• Equine @10mg/Kg BID PO
• Not recommended to be used by IM, SQ but only IV
 Toxicity and Adverse effects
• Well tolerated in horses
• Minor problems are reported in other species
• Rifampin is not approved to be used in food
producing animals in both USA and Canada
 Pyrazinamide
• Synthetic, bactericidal antitubercular drug
• Used in combo with Isoniazid and Rifampin
• Bactericidal to actively dividing bacteria
• Enzymatically metabolized to Pyrazinoic acid (POA)
which is active form of drug
• Highly active against bacteria in the acidic
environment of lysosomes and in macrophages
• A portion of POA exits the cell, get protonated and
re-enters as a protonated POA, ultimately helps to
disrupt the membrane potential of bacteria
• Inhibits fatty acid synthesis in bacteria
 Ethambutol
• Usually Bacteriostatic
• In most countries replaced by Streptomycin
• Fourth drug for empiric therapy in TB
• Should not be used alone
• Absorbed after PO, well distributed
throughout body
• Both parent drug and metabolites are
excreted through GF and tubular secretion
 Continued …
• Specifically effective against actively growing
microorganisms
• Indicated in dogs, cats and birds
• Dog @10-25mg/Kg PO SID with other drugs
 Mechanism of Action
• It interfers with the construction of
arabinogalactan layer of mycobacterial cell
wall (Arabionsyl tranferase) leads to an
increase in cell wall permeability
• Ultimately inhibits the transfer of mycolic
acids into the cell wall of tubercle bacillus
• It may also inhibit the synthesis of Spermidin,
this action is bactericidal
 Toxicity and Adverse effects
• Optic neuritis with
diminished visual acuity
and ability to discriminate
between red and green
• Discontinuation results in
reversal of symptoms of
toxicity
• Gout may be exacerbated
due to decrease in urate
excretion
 Streptomycin
• Streptomycin belongs to atypical
aminoglycosides
• Though many bacteria have gained resistance
against this molecule, has been replaced by
other drugs in many applications
• However, more recently it is renewed as its
application in treatment of MDR-TB
 Mechanism of action
• Its binding site is not identical but adjacent to
that of typical aminoglycosides
• Antibacterial effect is produced by interfering
with ribosomal proof reading which leads to
increased miscoding of newly sythesized
proteins
 Clinical Application
• In 1950s, Streptomycin was first successfully
used by inhaled route to treat childhood TB in
advanced state
• Only used in induction phase with others
• Long use is associated with typical
aminoglycoside toxicity