2. SULFONAMIDES
Sulfonamides were the first antimicrobial agents
(AMAs) effective against pyogenic bacterial infections.
Sulfonamido-chrysoidine (Prontosil Red) was one of
the dyes included by Domagk to treat experimental
streptococcal infection in mice and found it to be highly
effective.
A large number of sulfonamides were produced and
used extensively in the subsequent years, but because
of rapid emergence of bacterial resistance and the
availability of many safer and more effective
antibiotics, their current utility is limited, except in
combination with trimethoprim (as cotrimoxazole) or
pyrimethamine (for malaria).
4. ANTIBACTERIAL SPECTRUM
Sulfonamides are primarily bacteriostatic against many
gram-positive and gram-negative bacteria.
Those still sensitive are: many Strepto. pyogenes,
Haemophilus influenzae, H. ducreyi,
Calymmatobacterium granulomatis, Vibrio cholerae.
Only a few Staph. aureus, gonococci, meningococci,
pneumococci, Escherichia coli, and Shigella respond,
but majority are resistant.
SULFONAMIDES
5. Mechanism of action
Many bacteria synthesize their own folic acid (FA) of
which p-aminobenzoic acid (PABA) is a constituent,
and is taken up from the medium.
Woods and Fildes (1940) proposed the hypothesis
that sulfonamides, being structural analogues of
PABA, inhibit bacterial folate synthase → FA is not
formed and a number of essential metabolic
reactions suffer.
Sulfonamides competitively inhibit the union of PABA
with pteridine residue to form dihydropteroic acid
which conjugates with glutamic acid to produce
dihydrofolic acid.
Also, being chemically similar to PABA, the
sulfonamide may itself get incorporated to form an
altered folate which is metabolically injurious.
SULFONAMIDES
7. Resistance to sulfonamides
Most bacteria are capable of developing
resistance to sulfonamides. Prominent among
these are gonococci, pneumococci, Staph.
aureus, meningococci, E. coli, Shigella and
some Strep. pyogenes, Strep. viridans and
anaerobes.
The resistant mutants either:
(a) produce increased amounts of PABA, or
(b) their folate synthase enzyme has low affinity for
sulfonamides, or
(c) adopt an alternative pathway in folate metabolism.
Development of resistance has markedly limited
the clinical usefulness of this class of
SULFONAMIDES
8. Sulfadiazine
It is the prototype of the general purpose
sulfonamides that is rapidly absorbed orally
and rapidly excreted in urine.
Plasma protein binding is 50%, and it is
20–40% acetylated. The acetylated
derivative is less soluble in urine,
crystalluria is likely.
It has good penetrability in brain and
CSF—was the preferred compound for
meningitis.
SULFONAMIDES
9. Sulfamethoxazole
It has slower oral absorption and urinary
excretion resulting in intermediate duration
of action; t½ in adults averages 10 hours.
It is the preferred compound for combining
with trimethoprim because the t½ of both is
similar.
However, a high fraction is acetylated, which
is relatively insoluble—crystalluria can occur
SULFONAMIDES
10. Silver sulfadiazine
Used topically as 1% cream, it is active
against a large number of bacteria and fungi,
even those resistant to other sulfonamides,
e.g. Pseudomonas.
It slowly releases silver ions which appear to
be largely responsible for the antimicrobial
action.
It is considered to be one of the most effective
drugs for preventing infection of burnt surfaces
and chronic ulcers and is well tolerated.
SULFONAMIDES
11. ADVERSE EFFECTS
Adverse effects to sulfonamides are relatively
common.
These are: • Nausea, vomiting and epigastric pain. •
Crystalluria is dose related, but infrequent now.
Hypersensitivity reactions occur in 2–5% patients.
These are mostly in the form of rashes, urticaria and
drug fever. Photosensitization is reported.
Hepatitis, unrelated to dose, occurs in 0.1% patients.
Topical use of sulfonamides is not allowed, because
of risk of contact sensitization. However, ocular use
is permitted.
Kernicterus may be precipitated in the newborn,
especially premature, whose blood-brain barrier is
more permeable, by displacement of bilirubin from
plasma protein binding sites.
SULFONAMIDES
12. USES
Systemic use of sulfonamides alone (not combined with
trimethoprim or pyrimethamine) is rare now. .
Combined with trimethoprim (as cotrimoxazole)
sulfamethoxazole is used for many bacterial infections,
P. jiroveci and nocardiosis .
Along with pyrimethamine, certain sulfonamides are
used for malaria and toxoplasmosis.
Ocular sulfacetamide sod. is a cheap alternative in
trachoma/inclusion conjunctivitis.
Topical silver sulfadiazine or mafenide are used for
preventing infection on burn surfaces.
SULFONAMIDES
13. COTRIMOXAZOLE
The fixed dose combination of trimethoprim
and sulfamethoxazole is called cotrimoxazole.
Trimethoprim is related to the antimalarial drug
pyrimethamine which selectively inhibits
bacterial dihydrofolate reductase (DHFRase).
Cotrimoxazole introduced in 1969 causes
sequential block of folate metabolism
14. COTRIMOXAZOLE
Sulfamethoxazole was selected for combining with
trimethoprim because both have nearly the same t½ (~ 10
hr).
Optimal synergy in case of most organisms is exhibited at a
concentration ratio of sulfamethoxazole 20 : trimethoprim 1,
the MIC of each component may be reduced by 3–6 times.
Spectrum of action - Antibacterial spectra of trimethoprim
and sulfonamides overlap considerably.
Additional organisms covered by the combination are—
Salmonella typhi, Serratia, Klebsiella, Enterobacter, Yersinia
enterocolitica, Pneumocystis jiroveci and many sulfonamide-
resistant strains of Staph. aureus, Strep. pyogenes, Shigella,
enteropathogenic E. coli, H.influenzae, gonococci and
meningococci.
15. Adverse effects
All adverse effects seen with sulfonamides can be produced by
cotrimoxazole.
• Nausea, vomiting, stomatitis, headache and rashes are the usual
manifestations.
• Folate deficiency (megaloblastic anaemia) is infrequent, occurs only
in patients with marginal folate levels.
• Blood dyscrasias occur rarely. Cotrimoxazole should not be given
during pregnancy.
• Patients with renal disease may develop uremia. Dose should be
reduced in moderately severe renal impairment.
• A high incidence (upto 50%) of fever, rash and bone marrow
hypoplasia has been reported among AIDS patients with
Pneumocystis jiroveci infection when treated with high dose
cotrimoxazole.
• The elderly are also at greater risk of bone marrow toxicity from
cotrimoxazole.
• Diuretics given with cotrimoxazole have produced a higher
incidence of thrombocytopenia.
COTRIMOXAZOLE
16. Uses
1. Urinary tract infections- Most acute uncomplicated infections
respond rapidly.
2. Respiratory tract infections - Both upper and lower respiratory
tract infections, including chronic bronchitis and facio-maxillary
infections, otitis media caused by gram positive cocci and H.
influenzae respond well.
3. Bacterial diarrhoeas and dysentery Cotrimoxazole may be used
for severe and invasive infections by E. coli, Shigella, nontyphoid
Salmonella, and Y. enterocolitica.
4. Pneumocystis jiroveci causes severe pneumonia in neutropenic
and AIDS patients.
5. Chancroid Cotrimoxazole (800 + 160 mg) BD for 14 days is a 3rd
choice
6. Typhoid Initially cotrimoxazole was an effective alternative to
chloramphenicol.
7. Cotrimoxazole is an alternative to penicillin for protecting
agranulocytosis patients and for treating respiratory or other
infections in them.
COTRIMOXAZOLE
