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"Pharmacology

Antimicrobial Drugs
Lecture 4
‫ﺣﯿﺪر ﻣﮭﺪي‬.‫د‬
 Antimicrobial Drugs

Chemotherapy for tuberculosis:

 Mycobacteria are slender, rod shaped
bacteria with lipid rich cell wall.
 Mycobacterial infections are intracellular.
Mycobacterium tuberculosis can lead to
serious infections. It is currently estimated
that about 1/3 of the world is infected with
M.tuberculosis. Treating tuberculosis (TB)
presents therapeutic problems. The organism
grows slowly & resistant organisms readily
emerge. Therefore, multi drug therapy is
employed when treating TB in an effort to
delay or prevent the emergence of resistant
strains.
 Isoniazid, rifampin, ethambutol, streptomycin & pyrazinamide are the
principle or so called 1 st line drugs because of their efficacy & acceptable
degree of toxicity. Although treatment regimens vary in duration & in the
agent employed, they always include a minimum of 2 drugs, preferably with
both being bactericidal. For example the short course chemotherapy for TB
include isoniazid, rifampin, pyrazinamide & ethambutol or streptomycin for
2 months (the intensive phase) & then isoniazid & rifampin for the next 4
months (the continuation phase).Before susceptibility data are available ,
more drugs may be added to the first-line ones for patients who have
previously had TB or those in whom multidrug resistant TB is suspected.
Once susceptibility data are available, the drug regimen can be individually
tailored to the patient. One successful strategy for achieving better
treatment completion rates is (directly observed therapy) also known as
DOT,in which patients take their medication while being supervised and
observed.

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 Antimicrobial Drugs

Isoniazid
Isoniazid, often referred to as INH, the hydrazide of isonicotinic acid, is a synthetic
analog of pyridoxine. It’s the most potent of the antitubercular drugs.

Mechanism of action:
INH is a prodrug that is activated by a mycobacterial catalase peroxidase (KatG).
There are at least 2 different target enzymes for INH within the unique type II
fatty acid synthase system involved in the production of mycolic acids. The
activated drug covalently binds to & inhibits these enzymes, which are essential
for the synthesis of mycolic acid. Mycolic acid is a β-hyroxylated fatty acid found in
the mycobacterial cell walls.

Antimicrobial spectrum:
For bacilli in the stationary phase, INH is bacteriostatic, but for rapidly dividing
organisms, it is bactericidal. It is effective against intracellular bacteria. Isoniazid
is specific for treatment of M.tuberculosis (mycobacterium kansasi may be
susceptible at higher drug levels).

Resistance:
This is associated with several chromosomal mutations. When it is used
alone,resistant organisms rapidly emerge.

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 Antimicrobial Drugs

Pharmacokinetics:
Orally administrated INH is readily absorbed. Absorption is impaired if INH is
taken with food. The drug diffuses into all body fluids, cells & caseous material.
INH undergoes N-acetyaltion & hydrolysis ,resulting in inactive products.
Acetylation is genetically regulated ,with the fast acetylator trait being
autosomally dominant. A bimodal distribution of fast & slow acetylators exists.
Slow acetylators excrete more of the parent compound.

Adverse effects:
1. Peripheral neuritis: peripheral neuritis (manifesting as parasthesia), which is
the most common adverse effect, appears to be due to a relative pyridoxine
(vitamin B6) deficiency.
2. Hepatitis & idiosyncratic hepatotoxicity: potential fatal hepatitis is the most
severe side effect of INH. It is caused by a toxic metabolite during the
metabolism of INH.
3. Drug interactions: because INH inhibits metabolism of phenytoin, INH can
potentiate the adverse effect of that drug (e.g. nystagmus, ataxia)
4. Other adverse effects: mental abnormalities, convulsions, optic neuritis &
hyper sensitivity reactions have been observed.

Rifampin
Rifampin has a broader antimicrobial activity than INH & has found application in
the treatment of a number of different bacterial infections.

Mechanism of action: Rifampin blocks transcription by interacting with β-

subunit of bacterial but not human DNA dependant RNA polymerase. Rifampin
inhibits RNA synthesis by suppressing the initiation step.

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 Antimicrobial Drugs

Antimicrobial spectrum: Rifampin is bactericidal for both intracellular &

extracellular mycobacteria including M.tuberculosis & atypical mycobacteria(e.g
M.kansasii). It is effective against many gram –ve & gram +ve organisms and is
frequently used prophylactically for individuals exposed to meningitis caused by
meningococci or H.influenza. Rifampin is the most active antileprosy drug present.
It is usually given in combination with other drugs. .Rifabutin, an analog of
rifampin,has some activity against
Mycobacterium avium-intracellulare complex, but
[Type sideba r content. A sideba r is a
it is less active against TB. s tandalone supplement to the main
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Resistance: resistance to rifampin can be caused ri ght of the page, or loca ted a t the top or
bottom. Use the Text Box Tools tab to change
by mutation in the affinity of the bacterial DNA- the forma tting of the sideba r text box.
dependant RNA polymerase for the drug or by Type sideba r content. A sideba r is a
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document. It is often aligned on the left or
ri ght of the page, or loca ted a t the top or
Pharmacokinetics: absorption is adequate bottom. Use the Text Box Tools tab to change
after oral administration & distribution occurs to the forma tting of the sideba r text box.]

all body fluids. Adequate levels are attained in the

CSF even in the absence of inflammation. The drug
is taken up by the liver and undergoes
enterohepatic cycling. Rifampin itself can induce the hepatic mixed function
oxidases, leading to a shortened t1/2. Elimination of metabolites & the parent
drug is via the bile into the feces or via the urine (urine,feces and other secretions
have orange-red color).

Drug interaction: because rifampin can induce a number of cytochrome p450

enzymes, it can decrease the t1/2 of the other drugs that are coadministered &
metabolized by this system. Rifabutin, an analog of rifampin, doesn’t increase the
metabolism of other drugs.

Adverse effects: GIT upset, rashes, fever ,hepatitis, and a flu-like syndrome

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 Antimicrobial Drugs

Pyrazinamide
 Pyrazinamide is a synthetic, orally effective, bactericidal, antitubercular
agent used in combination with isoniazid & rifampin. Pyrazinamide must be
enzymatically hydrolyzed to pyrazinoic acid, which is the active form of the
drug. Some resistant strains lack the pyrazinamidase. Pyrazinamide is active
against tubercle bacilli in the acidic environment of lysosomes as well as in
macrophages.
 Pyrazinamide distributes throughout the body, penetrating the CSF. About
1-5% of patients taking isoniazid, rifampin & pyrazinamide may experience
liver dysfunction. Urate retention can also occur & may precipitate a gouty
attack.

Ethambutol
 Ethambutol is bacteriostatic and specific for most strains of M.tuberculosis
and M.kansasii. It inhibits arabinosyl transferase-an enzyme that is
important for the synthesis of mycobacterial arabinogalactan cell wall.
Ethambutol can be used in combination with pyrazinamide, isoniazid &
rifampin to treat TB.
 Absorbed on oral administration, ethambutol is well distributed.
Penetration into the CSF is therapeutically adequate in tuberculous
meningitis. Both parent drug & metabolites are excreted by glomerular
filtration & tubular secretion.
 The most important adverse effect is optic neuritis, which results in
diminished visual activity & loss of ability to discriminate between red &
green.Visual acuity should be periodically examined. Discontinuation of the
drug results in reversal of the toxic symptoms. In addition, urate excretion is
decreased by the drug; thus gout may be exacerbated.

Therapeutic margin of 1st line drugs

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 Antimicrobial Drugs

As with any drug, antitubercular drugs have a therapeutic margin-that is the

difference between the minimum drug concentration required to inhibit the
growth of M.tuberculosis & the maximum concentration that can be given without
provoking drug toxicity. The therapeutic margin is large for isoniazid & rifampin
but narrow for pyrazinamide, ethambutol & streptomycin.

Alternate 2nd line drugs

A number of drugs are considered to be second-line drugs, either because they’re
no more effective than the 1 st line agents & their toxicities are often more serious
or they’re particularly active against atypical strains of mycobacteria.

a) Aminosalicyclic acid: It is bacteriostatic agent that acts as a competitive

inhibitor for P-amonobenzoic acid (PABA) in folate biosynthesis.
b) Capreomycin: It is a peptide that inhibits protein synthesis. Capreomycin
is primarily reserved for the treatment of multi drug resistant tuberculosis.It
is administered pareterally.
c) Cycloserine: It is tuberculostatic agent that antagonizes bacterial cell wall
synthesis. It distributes well throughout body fluids, including the CSF.
Adverse effects involve CNS disturbances,exacerbation of epileptic seizures
& peripheral neuropathies.
d) Ethionamide: It is a structural analog of isoniazid. It’s widely distributed
throughout the body fluids, including the CSF. Adverse effects include
gastric irritation, hepatotoxicity, peripheral neuropathies & optic neuritis.

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e) Fluoroquinolones: They have an important role in the treatment of

multi-drug resistant tuberculosis. An example is moxifloxacin & levofloxacin.
f) Macrolide: Macrolides such as azithromycin & clarithromycin are part of
the regimen that includes ethambutol & rifabutin used for the treatment of
infections by M.avium-intracellular complex. Azithromycin is preferred for
HIV-infected patients, because it’s least likely to interfere with the
metabolism of antiviral drugs.
g) Streptomycin : Its action is directed against extracellular
organisms .Infections due to streptomycin-resistant organisms may be
treated with kanamycin or amikacin,to which these bacilli remain sensitive.

This lecture was printed and prepared by Mohammed Khalid Al-Askari©

El-7amdellah 3al salama abo 7aider menterna
el 3azeez

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