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Artificial Synthetic
Antimicrobial Drugs
linrong
Department of pharmacology
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Synthesized Antimicrobial Agents
J Sulfonamides
J Trimethoprim
J Quinolones
L Nitrofurans
L Nitroimidazole
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Synthesized Antimicrobial Agents
J Sulfonamides
J Trimethoprim
J Quinolones
History
Classification of Sulfonamides: 3 groups
Clinical pharmacokinetics
Spectrum of activity: broad-spectrum
Mechanisms of action:affect the synthesis
of dihydrofolic acid
Clinical Uses
bacteriostatic drug
Sulfonamides and trimethoprim:
Combination therapy
Adverse effects
Roughly be classified into 4 generations
Mechanisms of Action
Fluoroquinolones: Pharmacokinetics
Spectrum of activity
Clinical uses
Adverse effect
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History
Classification of Sulfonamides: 3 groups
Clinical pharmacokinetics
Spectrum of activity: broad-spectrum
Mechanisms of action:affect the
synthesis of dihydrofolic acid
Clinical Uses
Sulfonamides
Sulfonamides
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History
! 1932 Gerhard Domagk
Discovered protective aspects of Prontosil
(azo dye).
! 1933 Prontosil given to 10 month old girl who
survived
! 1935 Sulfa first used in US unsuccessfully
! Late 1930"s sulfanilamide derivatives
synthesized
Increase efficacy and decrease side effects
! 1968 Sulfa combined with Trimethoprim
Sulfonamides
Sulfonamides
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v Found in1930!s. these drugs have been
used in clinical therapy for about 70 years.
v The first chemotherapeutic agent effectively
used to treat general infections.
v Also called sulfa drugs. bacteriostatic.
v At present, most sulfonamides have been
substituted by other new antimicrobial
drugs.
Sulfonamides
Sulfonamides
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! Prontosil breaks down to form sulfanilamide.
! Sulfanilamide is similar in shape to PABA.
(para-aminobenzoic acid)
! PABA is part of folic acid.
! Sulfanilamide is a competitive inhibitor of
enzyme that incorporates PABA into folic acid.
! Result: folic acid synthesis stops
" Sulfonamides are synthetic derivatives of
sulfanilamide.
Chemistry-Sulfonamides
Chemistry-Sulfonamides
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Spectrum of activity: broad-spectrum
v G+ bacteria: group A Streptococcus
pyogenes and Streptococcus pneumoniae.
v G- bacteria: meningococcus, gonococcus
Escherichia coli, shigella, etc.
v Others: bacillus anthracis, Nocardia
actinomyces, Chlamydia trachomatis, and
some protozoa.
Antimicrobial Activity
-Sulfonamides
Antimicrobial Activity
-Sulfonamides
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Mechanisms of action
!Sulfonamides could compete for dihydrofolic
acid synthetase with PABA (para aminobenzoic acid)
and affect the synthesis of dihydrofolic acid.
Susceptible bacteria need PABA because
they are incapable of using folic acid directly.
!Human cells use exogenous folic acid
exclusively and thus a lack of PABA does not
affect them.
"bacteriostatic drugs
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Sulphonamides: inhibitors of folate synthesis
Pteridine + PABA
dihydrofolic acid
synthetase
sulphonamides
dihydrofolic acid
tetrahydrofolic acid
trimethoprim
dihydrofolic acid
reductase
Purine and pyrimidine synthesis
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Clinical pharmacokinetics
! Most sulfonamides are well absorbed orally
and they are widely distributed including to the
CNS.
" The concentrations in the kidney are the
highest. So they are suitable for treating
urinary tract infections.
# lower solubility in the urine, most sulfonamides
and their metabolites easily cause crystalluria,
bloody urine, and kidney damage.
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Clinical Uses - Classification of Sulfonamides
According to administration ways and absorbed degree
in intestinal tract, be divided into 3 groups:
!oral, absorbable: well absorbed in intestinal tract and
mainly used to treat general infections. On the basis of
their half-lives, also be classified as short-, medium-,
or long-acting ones such as sulfisoxazole,
sulfamethoxazole and sulfadoxine;
"oral, nonabsorbable: poorly absorbed in intestinal tract
and mainly used to treat intestinal tract infections;
such as sulfasalazine.
#topical use: such as SD-Ag and sulfamylone. external
application
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Clinical Uses
v Many strains of formerly susceptible species,
are now resistant.
v Sulfonamides are rarely used alone today.
Formerly drugs of choice for infections have
been largely supplanted by the fixed drug
combination of trimethoprim-sulfamethoxazole.
v Nevertheless, sulfonamides can be useful for
treatment of urinary tract infections due to
susceptible
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! The affinity of PABA with dihydrofolic acid
synthetase is 5000-15000 times more strongly
than that of sulfonamides,
" Sulfonamide resistance may occur as a result
of mutations that cause overproduction of
PABA, cause production of a folic acid-
synthesizing enzyme that has low affinity for
sulfonamides, or cause a loss of permeability
to the sulfonamide.
Drug resistance
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# Urinary Tract Disturbances
Sulfonamides may precipitate in urine producing
crystalluria, hematuria or even obstruction.
Crystalluria is treated by administration of sodium
bicarbonate to alkalinize the urine.
Hematopoidtic Disturbances
Sulfonamides can cause hemolytic or aplastic anemia.
On the other hand, Sulfonamides may provoke
hemolytic reactions in patients whose red cells are
deficient in glucose-6-phosphate dehydrogenase.
Adverse Reactions
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History
Classification of Sulfonamides: 3 groups
Clinical pharmacokinetics
Spectrum of activity: broad-spectrum
Mechanisms of action:affect the
synthesis of dihydrofolic acid
Clinical Uses
Sulfonamides
Sulfonamides
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bacteriostatic drug
Sulfonamides and trimethoprim:
Combination therapy
l Adverse effects
Trimethoprim (TMP)
Trimethoprim (TMP)
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Trimethoprim (TMP)
! Trimethoprim is a bacteriostatic drug,
synergist of sulfonamide.
" Its antimicrobial spectrum is similar to
that of sulfonamide, but the antimicrobial
action is stronger.
# Trimethoprim is a highly selective
inhibitor of the dihydrofolate reductase of
lower organisms.
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Clinical Use- TMP
! Oral Trimethoprim
Trimethoprimcan be give alone in acute urinary
infections.
"Oral Trimethoprim- Sulfonamides
A combination of Trimethoprim- Sulfonamides is
effective treatment for P jiroveci pneumonia,
shigellosis et al.
.
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Why are the Sulfonamides and
trimethoprim used?
n Combination therapy - The sulfonamides
are used in combination with trimethoprim;
this combination blocks two distinct steps
in folic acid metabolism and prevents the
emergence of resistant strains.
n Trimethoprim is not chemically related but
is considered here because their modes of
action are complementary.
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Adverse effects
# Sensitizations: exfoliative dermatitis, skin
rashes, urticaria, drug fever. etc.
Crystalluria. sulfonamides poor solubility
in the urine, especially in the acidic urine.
Prevent: during the treatment, drink a great
deal of water or alkalinize the urine.
! Blood dyscrasias: hemolytic or aplastic
anemia, granulocytopenia, or leukemoid
reactions.
" Gastrointestinal upsets and kernicterus
in newborns.
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bacteriostatic drug
Sulfonamides and trimethoprim:
Combination therapy
l Adverse effects
Trimethoprim (TMP)
Trimethoprim (TMP)
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Synthesized Antimicrobial Agents
J Sulfonamides
J Trimethoprim
J Quinolones
L Nitrofurans
L Nitroimidazole
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Roughly be classified into 4 generations
Mechanisms of Action
Fluoroquinolones: Pharmacokinetics
Spectrum of activity
Clinical uses
Adverse effects
Quinolones
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Roughly be classified into 4 generations
F First generation
" nalidixic acid
F Second generation
" Pipemidic acid
F Third generation(fluoroquinolones,FQs)
" norfloxacin, ciprofloxacin, ofloxacin, enoxacin.
F Fourth generation
" Lomefloxacin
Quinolones
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Fluoroquinolones
Novel group of synthetic antibiotics developed
in response to growing resistance
Agents available today are all structural
derivatives of nalidixic acid
The fluorinated quinolones (FQs) represent a
major therapeutic advance:
Broad spectrum of activity
Improved PK properties ! excellent bioavailability,
tissue penetration, prolonged half-lives
Overall safety
Disadvantages: resistance, expensive
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Mechanisms of Action
Inhibiting bacterial topoisomerase (DNA gyrase)
and topoisomerase IV, block bacterial DNA
synthesis and put bacteria to death.
" Inhibition of DNA gyrase prevents the relaxation of
positively supercoiled DNA that is required for
normal transcription and replication.
" Inhibition of topoisomerase IV probably interferes
with separation of replicated chromosomal DNA
into the respective daughter cells during cell
division
Quinolones are rapidly bactericidal drugs
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Fluoroquinolones
Mechanisms of Resistance
Altered target sites ! chromosomal
mutations in genes that code for DNA
gyrase or topoisomerase IV
most important and most common
Altered cell wall permeability !
decreased porin expression
Expression of active efflux ! transfers
FQs out of cell
Cross-resistance occurs between FQs
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Fluoroquinolones: Pharmacokinetics
v Ofloxacin, enoxacin and lomefloxacin are
almost completely absorbed orally; norfloxacin is
35-45%; ciprofloxacin is 67% orally absorbed.
v The FQs are widely distributed in body fluids
and tissues , The concentrations in prostate,
kidney, neutrophils, and macrophages exceed
serum concentrations, but in the cerebrospinal
fluid are low.
v Most FQs are elimiated by renal mechanisms;
therefore the dosage must be adjusted
according to renal function.
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! FQs have excellent activity against G
-
microorganisms: neisseria gonorrhea, H.
influenzae, moraxella catarrhalis, etc.
" They are also effective against G
+
cocci:
S.pneumoniae, staphylococci and streptococci.
# Several newer agents are active against
anaerobes, atypical pneumonia (e.g.
mycoplasmas and chlamydiae), and
intracellular pathogens (e.g. legionella species
and some mycobacteria, including
Mycobacterium tuberculosis and M avium
complex).
Fluoroquinolones: Spectrum of activity
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$ Norfloxacin is the least active of FQs against
both gram-negative and gram-positive
organisms.
% Ciprofloxacin is the most active agent against
gram-negatives, P.aeruginosa in particular.
& Levofloxacin, the L-isomer of ofloxacin and
twice as potent, has superior activity against
gram-positive organisms, including S.
pneumoniae.
Fluoroquinolones: Spectrum of activity
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' Methicillin-susceptible strains of S.
aureus are generally susceptible to FQs,
but methicillin-resistant strains of
staphylococci are often resistant.
( Pneumococci and streptococci of group
are resistant to enoxacin.
) In general, Penicillins and
cephalosporins are more active than FQs
against streptococci and staphylococci.
Fluoroquinolones: Spectrum of activity
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FQs are extremely useful agents, relatively
nontoxic, well tolerated, broad-spectrum.
1. Urinary tract infections:
FQs are effective for uncomplicated and
complicated urinary tract infections even when
caused by multidrug-resistant bacteria.
Ciprofloxacin and ofloxacin are effective for
gonococcal infection; Ofloxacin is effective for
chlamydial urethritis or cervicitis.
Fluoroquinolones: Clinical uses
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Fluoroquinolones: Clinical uses
2. Intestinal tract infections:
These agents are also effective for intra-
abdominal infections and bacterial diarrhea
caused by shigella, salmonella, E. coli, or
campylobacter.
3. prostatitis
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4. Respiratory tract infections:
Not been routinely recommended for treatment of
pneumonia and other upper respiratory tract infections.
These infections, predominantly caused by pneumococci
and streptococci, are usually well treated with beta-
lactams or macrolides.
However, levofloxacin, sparfloxacin, and newer FQs with
enhanced G+ activity and activity against atypical
pneumonia pathogens (e.g. chlamydia, mycoplasma, and
legionella) are likely to be effective and used increasingly
for treatment of upper and lower respiratory tract infections.
Fluoroquinolones: Clinical uses
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5. Infections of the bones, joints, skin and soft
tissues:
Including those caused by multidrug-resistant
organisms such as pseudomonas and
enterobacter.
6. Others:
Ciprofloxacin or ofloxacin is occasionally used
for treatment of tuberculosis and atypical
mycobacterial infections.
Ciprofloxacin is also a second-line agent for
legionellosis.
Fluoroquinolones: Clinical uses
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! Gastrointestinal upsets (the most
common)
F Nausea, vomiting, diarrhea, dyspepsia
" Allergy and anaphylaxis
# Central Nervous System (1~7%)
F Headache, agitation, insomnia, dizziness, rarely,
F hallucinations and seizures (rarely)
Fluoroquinolones: Adverse effects
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$ Possibly damage to growing cartilage: NOT
recommended for patients younger than 14
years old, pregnant or nursing women.
% Concomitant administration of theophylline and
quinolones can lead to elevated levels of
theophylline with the risk of toxic effect,
especially seizure.
Fluoroquinolones: Adverse effects
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Roughly be classified into 4 generations
Mechanisms of Action
Fluoroquinolones: Pharmacokinetics
Spectrum of activity
Clinical uses
Adverse effects
Quinolones
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Synthesized Antimicrobial Agents
J Sulfonamides
J Trimethoprim
J Quinolones
History
Classification of Sulfonamides: 3 groups
Clinical pharmacokinetics
Spectrum of activity: broad-spectrum
Mechanisms of action:affect the synthesis
of dihydrofolic acid
Clinical Uses
bacteriostatic drug
Sulfonamides and trimethoprim:
Combination therapy
Adverse effects
Roughly be classified into 4 generations
Mechanisms of Action
Fluoroquinolones: Pharmacokinetics
Spectrum of activity
Clinical uses
Adverse effect
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