ANTI MYCOBACTERIAL

AGENTS

Dr. B.Madhu Harika

Vikas Institute of
Pharmaceutical Sciences
 Mycobacteria
• Mycobacteria are a class of gram positive acid fast bacilli.
• Mycobacteria are intrinsically resistant to most antibiotics.
• Because they grow slowly compared with other bacteria,
antibiotics that are most active against growing cells are
relatively ineffective.
• Mycobacterial cells can also be dormant and thus completely
resistant to many drugs or killed only very slowly.
• The lipid-rich mycobacterial cell wall is impermeable to many
agents.
• Mycobacterial species are intracellular pathogens, and
organisms residing within macrophages are inaccessible to
drugs that penetrate these cells poorly.
Mycobacteria (cont.)
• Mycobacteria are notorious for their ability to
develop resistance.
• Combinations of two or more drugs are required to
overcome these obstacles and to prevent emergence
of resistance during the course of therapy.
• The response of mycobacterial infections to
chemotherapy is slow, and treatment must be
administered for months to years, depending on
which drugs are used.
Comparison between cell envelopes of mycobacteria and other bacteria
Types of Mycobacterial infections
• Tuberculosis
• Leprosy
• MAC – Mycobacterium Avium Intracellulaire complex
Tuberculosis
• Tuberculosis (TB) is a potentially fatal contagious
disease that can affect almost any part of the body
but is mainly an infection of the lungs.
• Neo-latin word : -
– Tubercle : Round nodule/ Swelling
– Osis : - Condition
Causative agent:
Mycobacterium tuberculosis – in humans
Mycobacterium bovine – in animals
pathogenesis
Clinical Manifestations
• Primary TB
• Most individuals (~75%) are asymptomatic or have
flu-like symptoms along with fever and chest pain
• Around 3 weeks after infection, they become PPD+
(tuberculin skin test)
• For most, the lesions eventually heal with fibrosis and
calcification
• Dormant lesions that still contain bugs may reactivate
to yield secondary TB
• Progressive Primary TB
• Some individuals (5-15%) don’t contain the primary
infection and develop a progressive disease that resembles
a necrotizing bacterial pneumonia
• This presents with fever, productive cough, and chest pain
• Coughing aerosolizes secretions and distributes them
throughout the lung
• There are expanding areas of caseating necrosis with
irregular cavity formation along with erosion of blood
vessels resulting in hemoptysis
• Lesions will usually heal by fibrosis with adequate
treatment
• Secondary TB
• Pattern of disease that arises in a previously infected
and sensitized patient
• The lesions typically localize to the apex of the upper
lobes
• There is rapid tissue response (Th1) because of
previous sensitization
• Cavitary formation is very likely
• Symptoms include low grade fever, night sweats, and
weight loss
• Without therapy, miliary TB may develop
• Miliary TB
• This refers to the uncontrolled hematogenous
dissemination of M. tuberculosis
• Infection may involve any organ and the course is
usually rapid when it occurs with primary or
secondary progressive disease
• Multiorgan failure, septic shock, and respiratory
distress, followed by death, may occur
First line drugs:
• High efficacy and low toxicity
• Kill active bacteria, important in the early stages of
infection.
• Routinely used

streptomycin
 Isoniazid
• Isoniazid is the most active drug for the treatment of
tuberculosis caused by susceptible strains.
• It is small (MW 137) and freely soluble in water.
• It has structural similarity to pyridoxine.
• It is bactericidal for actively growing tuberculosis
bacilli.
• It is less effective against atypical mycobacterial
species.
• Isoniazid penetrates into macrophages and is active
against both extracellular and intracellular
organisms.
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.
• The activated form of isoniazid forms a covalent complex
with an acyl carrier protein (AcpM) and a beta-ketoacyl
carrier protein synthetase (KasA), which blocks mycolic
acid synthesis and kills the cell.
• Isoniazid may be bacteriostatic or bactericidal in action,
depending on the concentration of the drug attained at
the site of infection and the susceptibility of the infecting
organism.
• The drug is active against susceptible bacteria only
during bacterial cell division.
Isoniazid – Adverse reactions
• Isoniazid-induced hepatitis is the most common
major toxic effect.
• Peripheral neuropathy is observed in 10-20% of
patients given dosages greater than 5 mg/kg/d but is
infrequently seen with the standard 300 mg adult
dose.
• Central nervous system toxicity, which is less
common, includes memory loss, psychosis, and
seizures. These may respond to pyridoxine.
Isoniazid – clinical uses
• In combination with rifampicin or a second line drug
isoniazid is used for the treatment of severe
infections with mycobacterium tuberculosis.
• As a single agent indicated for the prevention and
treatment of active tuberculosis in early stages.
• Rifampicin is a • Ethambutol inhibits
semisynthetic derivative mycobacterial
of rifamycin, an
antibiotic produced by arabinosyl transferases,
Streptomyces which are involved in
mediterranei. the polymerization
• Rifampin binds to the reaction of
beta subunit of arabinoglycan, an
bacterial DNA-
dependent RNA essential component of
polymerase and thereby the mycobacterial cell
inhibits RNA synthesis. wall.
• Pyrazinamide is a • Streptomycin causes a
relative of nicotinamide structural change which
• The drug is taken up by interferes with the
macrophages and exerts recognition site of
its activity against codon – anticodon
mycobacteria residing interaction resulting in
within the acidic misreading of the
environment of genetic message carried
lysosomes.
by m RNA
• The drug target and
mechanism of action are • Inhibition of protein
unknown. synthesis.
•
• Isoniazid and rifampin are the two most active drugs.
• An isoniazid-rifampin combination administered for 9 months will cure 95-
98% of cases of tuberculosis caused by susceptible strains.
• The addition of pyrazinamide to an isoniazid-rifampin combination for the
first 2 months allows the total duration of therapy to be reduced to 6
months without loss of efficacy.
• In practice, therapy is initiated with a four-drug regimen of isoniazid,
rifampin, pyrazinamide, and ethambutol until susceptibility of the clinical
isolate has been determined.
• Ethambutol (and streptomycin) only provide additional coverage if the
isolate proves to be resistant to isoniazid, rifampin, or both.
• The prevalence of isoniazid resistance among US clinical isolates is
approximately 10%.
• Prevalence of resistance to both isoniazid and rifampin (ie, multiple drug
resistance) is about 3%.
Second line drugs
• Less efficient and generally more toxic than first line
drugs.
• Hinder mycobacterial growth.
• Strengthen treatment in case of resistant bacteria.
• Always used in combination with a first line drug.
PAS – Para amino salicylic acid
• It is a synthetic second line agent used in case of
resistance, retreatment, or intolerance to first line
drugs.
• It is a bacteriostatic agent.
• Always used in combination with isoniazid and
rifampicin.
PAS – Mechanism of action
PAS – Adverse effects
• Bulky and unpleasant taste.
• GI disturbances – anorexia, nausea, vomiting,
abdominal discomfort.
• Hypothyroidism, goitre.
• Hepatic dysfunction.
• Hypersensitivity reaction.
(Rarely used in first line therapy today)