Synthetic Antibacterial Agents

Synthetic Antibacterial Agents

I. Sulfonamides
II. Trimethoprim
III. Quinolones
IV. Metronidazole
V. Nitrofurans
I. Classification and chemistry
II. Mechanism of action
III. Antimicrobial effects
IV. Resistance
V. Pharmacokinetics
VI. Clinical uses
VII. Adverse effects
SULPHONAMIDES
History
 The antibacterial activity of sulphonamides was first
discovered by Domagk in 1935 who demonstrated that
Prontosil an azo dye is effective against streptococcal
infection in mice.
 Noble prize in medicine for 1938
 The antibacterial activity of Prontosil is due to release of an
active metabolite the Sulphanilamide
 Sulphanilamide was synthesized and introduced in market
as the first sulphonamide for antibacterial use
 Many sulphonamides developed for use in human and
veterinary medicines.
SULPHONAMIDES
Structure. The sulfonamides are derivatives of p-
aminobenzene sulfonic acid and are structurally
similar to p-aminobenzoic acid (PABA), an
intermediate in the bacterial synthesis of folic acid.
Characteristics. The sulfonamides behave as weak
organic acids, which are poorly water-soluble unless
prepared as sodium salts.
a. Concentrated solutions of the sodium salts of
most sulfonamides are alkaline (pH 9-10) and may
be corrosive.
c. Sulphas have low water solubility and in body
they are more or less acetylated & become
more or less soluble in water, but acetyl
sulphadiazine is more insoluble and form
crystalluria.
d. Highly soluble Sulphas are retained in lumen
of GIT for prolonged periods & are called “gut
active Sulphas”
e. Sulphas are white crystalline powders,
insoluble in water, form salts with strong acids
or base.
Chemistry of Sulfonamides
Sulphonamide nucleus possesses two amino groups
(N1, N4).
Members differ in N1 substitution for solubility,
potency and pharmacokinetics
Presence of para-amino group(N4) is essential for
antibacterial activity
Chemistry of Sulfonamides

4
Classification of Sulfonamides
1. Oral, absorbable;
① Short-acting ( ＜ 12 hours)
sulfisoxazole (SIZ).
② Medium-acting (12 ～ 24 hours)
sulfamethoxazole (SMZ);
sulfadiazine (SDZ).
③ Long-acting ( ＞ 24 hours)
sulfadoxine,
Classification of Sulfonamides
2. Oral, nonabsorbable;
Sulfasalazine,
3. Topical;
Sodium sulfacetamide ophthalmic
solution or ointment,
Mafenide acetate,
Silver sulfadiazine, SD-Ag;
CLASSIFICATION
Into several types, based mainly on indications and
duration of action in body: (Generic Names)
A. Rapidly Absorbed & Rapidly Excreted Sulphas:
 Sulphadiazine, Sulphapyridine, Sulphathiazole,
Sulphamerazine, Sulphamethazine,
Sulphamethoxazole
B. Rapidly Absorbed & Slowly Excreted Sulphas:
 Sulphamethoxypyridazine Sulphadimethoxine,
Sulphamethoxydiazine, Sulphaethoxypyridazine
C. Poorly Absorbed (Enteric) Sulphas:
 Sulphaguinidine
 Succinylsulphathiazole
D. Special Purpose Sulphas
Sulphaisoxazole (Urinary infection)
Sulphacetamide (Eye infection)
E. Potentiated Sulphas:
Sulphas are used in combination with pyrimethamine
to treat protozoal diseases like Leishmaniasis &
Toxoplasmosis e.g
Sulphamethoxazole+TMP= Septran
Sulphadiazine+TMP= Tribrissen

TMP= Trimethoprim
Depending on their type and duration
I. Systemically acting sulphonamides.
1. Short acting (Duration less than 12 hours)
2. Intermediate acting ( Duration 12-24 Hours)
3. Long acting (Duration 24-48 hours)
4. Ultra long acting (Duration more than 48 hours)
II. Locally acting Sulphonamides.
1. Gut-acting (Sulphaguinidine, Succinylsulphathiazole, Sulphasalazine)
2. Topically acting (Sulphacetamide, Mafenide, SD-Ag)
Mechanism of action

Sulfonamides are structural analogs of

PABA that competitively inhibit
dihydropteroate synthase. Drugs inhibit
growth by reversibly blocking folic acid
synthesis.
Inhibition of tetrahydrofolate synthesis by
sulfonamides and trimethoprim.
 Antimicrobial effects
① Broad spectrum
Both G+ & G- bacteria, nocardia,
chlamydia trachomatis, some
protozoa, some enteric bacteria (E
coli, klebsiella, salmonella, shigella, &
enterobacter)
Sulfonamides stimulate rickettsiae in
their growth.
 Antimicrobial Spectrum:
Against G+ and G- bacteria
Broad Spectrum
Sensitive organisms are:
Streptococci
Staphylococci
Corynebacterium
E. coli
Salmonella
Klebsiella
Pasteurella etc.
 Resistant Strains:
Mycobacterium tuberculosis, typhoid and
paratyphoid bacilli etc.
Resistance can be avoided by:
Stopping unjustified use
Initiate therapy early
Establish and maintain bacteriostatic conc. of drug in
host.
Resistance to Sulfonamides
① Over-production of PABA;
② Produce dihydropteroate synthase
with low sulfonamide affinity;
③ Loss permeability to the
sulfonamide;
④ Use exogenous sources of folate;
By mutations or encoded on a
plasmid, cross-resistances,
Pharmacokinetics
① Oral administration, absorbed well,
② Distributed widely to tissues and
body fluids, including CNS and
cerebrospinal fluid, placenta, and
fetus; 20-90% protein binding rate;
③ Acetylated or glucuronidated in the
liver,
Pharmacokinetics
④ Sulfonamides and inactive
metabolites are excreted into the
urine, they are more soluble at
alkaline than at acid pH. In renal
failure patient, drug dose must be
reduced.
 PHARMACOKINETICS
Absorption: PO, IV, IP, IM, IU or topically.
Distribution: throughout body tissues.
Biotransformation: extensively metabolized. The
acetylated, hydroxylated & conjugated forms have
a little antibacterial activity.
Acetylation reduces the solubility of most Sulphas.
Hydroxylated & conjugated forms are less likely to
precipitate in urine.
Excretion: Excreted in urine, bile, feces, milk, sweat
etc.
Administration and fate of the sulfonamides
 Clinical uses of Sulfonamides
① SMZ+TMP (Co-trimoxazole)
a. Treatment of urinary tract infections
b. Respiratory tract infections, sinusitis,
bronchitis, pneumonia, otitis media, and
dysentery,
② SDZ+TMP (Tribrissen)
First-line therapy for treatment of acute
toxoplasmosis
sulfamethoxazole (SMZ)
sulfadiazine (SDZ).
 Clinical uses of Sulfonamides
3. Sulfadoxine+TMP (Trivertin)
Used as a second-line agent in treatment for malaria.
4. Sulfasalazine
widely used in ulcerative colitis, enteritis, and other
inflammatory bowel disease.
Sulfapyridine (antibacterial)
Sulfasalazine is split by intestinal microflora

5-aminosalicylate (5-ASA)
(anti-inflammatory)
Clinical uses of Sulfonamides
5. Sodium sulfacetamide (SA-Na)
Bacterial conjunctivitis
6. Mafenide acetate
Prevent bacterial colonization and infection of burn
wounds,
7. Silver sulfadiazine
For prevention of infection of burn wounds
Adverse effects of Sulfonamides
1. Allergenic reactions
All sulfonamides and their
derivatives, including carbonic
anhydrase inhibitors, thiazides,
furosemide, torsemide ,bumetanide,
diazoxide, and the sulfonylurea
hypoglycemic agents are cross-
allergnic.
 Adverse effects of Sulfonamides
The most common adverse effects are
fever, skin rashes, exfoliative dermatitis
or cutaneous eruption , photosensitivity,
urticaria, nausea, vomiting, diarrhea.
Stevens-Johnson syndrome, is a
particularly serious and potentially fatal
type of skin and mucous membrane
eruption associated with sulfonamide
use.
 Sulfonamides
2. Urinary tract disturbances
Sulfonamides may precipitate in urine, especially at
neutral or acid pH, producing crystalluria, hemturia, or
even obstruction.
SD & SMZ, when in large doses, fluid intake is poor, can
cause crystalluria.
Sodium bicarbonate to alkalinize the urine, adequate
fluids,
Sulfonamides
3. Hematopoietic disturbances
Hemolytic or aplastic anemia,
granulocytopenia, thrombocytopenia,
or leukemoid reactions.
Provoke hemolytic reactions in patients
whose red cells are deficient in glucose-
6-phosphate dehydrogenase.
 SIDE EFFECTS
Hypersensitivity or direct
toxic effects.

Hypersensitivity includes
urticaria, anaphylaxis, skin
rashes, drug fever, hemolytic
anemia etc.
Some adverse reactions to sulfonamides.
 DRUG INTERACTIONS!
Antacids tend to inhibit GI absorption of Sulphas
Alkalization (sodium lactate, sodium
bicarbonate and sodium citrate) of urine
promotes Sulphas excretion and urinary
acidification increases risk of crystalluria.
Renal Toxicity:
 Sulphanilamide and Sulphathiazole, precipitation of
crystals in collecting tubules of kidney and pelvis
 Obstruction of urine flow
 Injury to tubular epithelium or epithelial lining

Precipitation occurs due to

1. Solubility of drug in urine is low
2. pH of urine is low
3. Concentration of drug in urine is high
As weak organic acids, sulphas are more soluble in
alkaline than acidic solutions

Urinary precipitation of sulphas can be checked by

Use drugs of high urine solubility
Increase pH of urine (Sodium lactate, sodium
bicarbonate or sodium citrate)

In general,carnivores and omnivores(acid urine) are

more prone to renal toxicity than herbivores.
Contraindication for sulfonamide
treatment.
Formation of formaldehyde from methenamine at
acid pH.
Sulphonamide react with formaldehyde,and must not
be used concomitantly with methenamine.
POTENTIATED SULPHAS
 Group of Diaminopyrimidines (Trimethoprim,
Methoprim, Ormetoprim, Aditoprim, Pyrimethamine
etc.)
 Inhibit dihydrofolate reductase in bacteria and
protozoa
 Bactericidal activity with sulphas
 Basic drugs, accumulate in acidic media as urine, milk
Examples of Potentiated sulphas:

1. Sulphadiazine+TMP
2. Sulphamethoxazole+TMP
3. Sulphadoxine+TMP
4. Sulphadimethoxine+Ormetoprim
Combination of Sulphas with Trimethoprim (TMP)
 Effectiveness of Sulphas can be improved by
combining them with inhibitors of bacterial
dihydrofolate reductase like trimethoprim (TMP).
 TRIMETHOPRIM (TMP)
1. Decreases amount of sulpha
2. Increases therapeutic index
3. Widens antibacterial spectrum
Synergism between trimethoprim and sulfamethoxazole on the inhibition
of growth of Escherichia coli.
The action of combinations is bactericidal and are
effective against
Actinomyces, Bacillus anthracis, Brucella, Clostridium,
Corynebacterium, E. coli, Haemophilus, Klebsiella,
Proteus, Salmonella, Staph, Strepto, Vibrio etc.
Administration and fate of the cotrimoxazole.
Mechanism of Action of Trimethoprim
Dihydrofolic acid reductases inhibitor

Dihydrofolic acid reductases convert

dihydrofolic acid to tetrahydrofolic
acid, a step leading to the synthesis
of purines and ultimately to DNA.
Trimethoprim
It Inhibits bacterial dihydrofolic acid
reductase about 50000 times more
efficiently than the same enzyme of
mammalian cells. Pyrimethamine,
inhibits the activity of dihydrofolic acid
reductase of protozoa more than that
of mammalian cells.
Sulfonamides & Trimethoprim
They produce sequential blocking in
this metabolic sequence, resulting in
marked enhancement of the activity of
both drugs. The combination often is
bactericidal, compared to the
bacteriostatic activity of a sulfonamide
alone.
Inhibition of tetrahydrofolate synthesis by
sulfonamides and trimethoprim.
Resistance to tri metho prim

Resistance to trimethoprim
 Reduced cell permeability
 Overproduction of dihydrofolate
reductase,
 Production of an altered reductase
with reduced drug binding
By mutation, plasmid-encoded,
 Pharmacokinetics of Trimethoprim
Given orally, absorbed well.
Distributed widely in body fluids and tissues, including
cerebrospinal fluid, 65-70% protein-bound.
TMP 50-60% excreted in the urine within 24 hours.
TMP concentrates in prostatic fluid and in vaginal fluid, it
has more effects than many other drugs.
TMP∶SMZ=1∶5, they have similar half-life
Clinical uses of Trimethoprim
Oral TMP
alone in acute urinary tract infections
Oral TMP+SMZ
① Pneumocystis carinii
pneumonia (PCP), shigellosis,
systemic salmonella infections
caused by ampicillin- or
chloramphenicol-resistant bacteria,
② Complicated urinary tract infections, prostatitis, some
nontuberculous mycobacterial infections
③ Many respiratory tract pathogens

TMP+SMZ (IV)
④ The agent of choice for moderately severe to severe
pneumocystis pneumonia, such as in AIDS patients
② Used for G- bacterial sepsis, including
that caused by some multiple-drug-
resistant species such as
enterobacter and serratia, shigellosis,
typhoid fever, or urinary tract
infection.
Typical therapeutic applications of co-trimoxazole
(sulfamethoxazole plus trimethoprim).
Oral Pyrimethamine + SN

① Leishmaniasis
② Toxoplasmosis
③ Falciparum malaria
Adverse effects of Trimethoprim
① Hematologic toxicity
Megaloblastic anemia,
leukopenia, and
granulocytopenia
② Nausea and vomiting, drug fever,
vasculitis, renal damage, and CNS
disturbances
Some adverse reactions to cotrimoxazole.
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