SULFONAMIDES

Sulfonamides - first antimicrobial agents (AMAs)

effective

against pyogenic bacterial infections.

Sulfonamide-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.
By 1937 it became clear that Prontosil was broken down

in the body to release sulfanilamide which was the

active antibacterial agent.

A large number of sulfonamides were produced and

used extensively in the subsequent years, but because of

resistance their current utility is limited.

Classification

Short acting (4-8 hr): sulfadiazine

Intermediate acting (8-12 hr): sulfamethoxazole

Long acting (~ 7 days): Sulfadoxine,

Sulfamethopyrazine

Special purpose sulfonamides: Sulfacetamide, sod.

Mafenide, Silver sulfadiazine,

Sulfasalazine
ANTIBACTERIAL SPECTRUM
- Primarily bacteriostatic against many gram-positive and
gram-negative bacteria.
- However bactericidal concentrations may be attained in
urine.
Those still sensitive are
- Many strepto. Pyogens, H. influenza, H. ducreyi, C.
granulomatis, V. cholera.

Only a few Staph. Aureus, gonococci, meningococci,

pneumococci, E. coli and shigella.

- Trachoma, LGV, inclusion conjunctivitis, Actinomyces,

Nocardia and toxoplasma are sensitive.
Mechanism of action
Many bacteria synthesize their own folic acid (FA) of
which p-aminbenzoic acid (PABA) is a constituent, and
is taken up from the medium.
 
PABA

folic acid synthase X Sulfonamides

Dihydrofolic acid
Woods and fildes (1940) proposed the hypothesis that

sulfonamides, being structural analogues of PABA, inhibit

bacterial folate synthase → FA is not formed and number

of metabolic reactions suffer.

Sulfonamides competitively inhibit the union of PABA

with pteridine residue to form dihydropteroic acid which

conjugate 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.

Human cells also require FA, but they utilize preformed

FA supplied in diet and are unaffected by sulfonamides.

Evidence in favour of this mechanism of action of
sulfonamides are:

- PABA, in small quantities, antagonizes the antibacterial

action of sulfonamides

- Only those microbes which cannot synthesize their own

FA, and cannot take it from the medium are susceptible to
sulfonamides.

- Pus is rich in PABA.

Resistance to sulfonamides
Most bacteria are resistant

- Produce increased amount of PABA or

- Their folate synthase enzyme has low affinity for

sulfonamides or

- Adopt an alternative pathway in folate metabolism.

 
Pharmacokinetics
- Sulfonamides rapidly and completely absorbed from GIT,

- PPB differs considerably among different members.

- Widely distributed in the body- enters serous cavities

easily.

- They cross placenta freely.

- Less soluble in acidic urine → precipitate and cause

crystalluria.
SULFADIAZINE: PPB- 50%, good penetration in brain
& CSF- was the preferred compound for meningitis.
 
Sulfamethoxazole

- Slow oral absorption and urinary excretion.

- It is preferred compound for combining with

trimethoprim because half life of both is similar.

- Crystalluria can occur.

 
 
Sulfadoxine, Sulfamethopyrazine
Ultralong acting compound with action lasting > 1 week

because of high PPB and slow renal excretion. (t½ 5-9

days).

Uses
- In combination with pyrimethamine in the treatment of
malaria (esply. chloroquine resistant falciparum malaria)

- Pneumocystis jiroveci pneumonia in AIDS patients

- Toxoplasmosis.
Sulfacetamide sod.

- Attains high concentrations in anterior segment and

aqueous humour after topical instillation.

- Used topically for ocular infections due to susceptible

bacteria and Chlamydia, including ophthalmia neonatarum.
Mafenide
- Used only topically in infection caused by gram positive
and gram negative bacteria.

- It is active in the presence of pus and against

pseudomonas and clostridia.

- Mainly employed for burn dressing to prevent infection,

but not to treat already infected cases.

S.E: burning sensation and severe pain when applied to raw

surface.
Silver sulfadiazine

- Effective against large number of bacteria, fungi and

pseudomonas.

- It slowly releases silver ions which is responsible for the

antimicrobial action.

- considered to be one of the most effective drugs for

preventing infection of burnt surfaces and chronic ulcers.

- However it is not good for treating established infection.

SE: Local- burning sensation and itch.

Sulfasalazine
- Used in ulcerative colitis and rheumatoid arthritis

Adverse effects
Nausea, vomiting and epigastric pain

Crystalluria- Precipitation in urine can be minimized by

taking plenty of fluids and by alkalinizing the urine.

Hypersensitivity reaction: rashes, urticaria, drug fever,

photosensitization, stevens-Johnson syndrome and
exfoliative dermatitis

Hepatitis,
Topical- Contact sensitization

Haemolysis:G-6-PD deficient individual with high doses of

sulfonamide
Kernicterus may be precipitated in the newborn

USES

- Systemic use of sulfonamide is rare now

- Combined with trimethoprim (as cotrimoxazole)

sulfamethoxazole is used for many bacterial infections, P.
jiroveci, and nocardiasis
- 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.
 COTRIMOXAZOLE
The fixed dose combination of trimethoprim and

sulfamethoxazole is called cotrimoxazole.

Trimethoprim related to the antimalarial drug

pyrimethamine which selectively inhibits bacterial

dihydrofolate reductase (DHFRase).

Cotrimoxazole causes sequential block of folate metabolism.

Trimethoprim is > 50,000 times more active against
bacterial DHFRase than against mammalian enzyme.

Thus human folate metabolism is not interfered at

antibacterial concentrations of trimethoprim.

Individually, both are bacteriostatic, but the

combination becomes cidal.

trimethoprim because
- both have nearly same t½ (~ 10 hr)

- Optimal synergy is exhibited at a concentration ratio of

sulfamethoxazole 20: trimethoprim 1

- Given in a dose ratio of 5:1, because trimethoprim enters

many tissues, has a larger volume of distribution and attains

lower plasma conc.

Antibacterial spectra of trimethoprim and sulfonamides
overlap considerably.

Additional organisms covered by the combination are

S. typhi, Serratia, Klebsiella, Enterobacter, Yersinia

enterocolitica, P. jiroveci and

many sulfonamide-resistant strains of Staph. Aureus, Strep.

Pyogenes, Shigella, Enteropathogenic E. coli, H. influenza,

Resistance

Adverse effects
Nausea, vomiting, stomatitis, headache, rashes, blood
dyscrasias rarely
Should not be given during pregnancy, being antifolate →
teratogenic risk.
Neonatal haemolysis and methaemoglobinaemia (if given at
term)
Pts with renal disease → uraemia

AIDS pts with P. jiroveci treated with cotrimoxazole: High

incidence of fever, rash and bone marrow hypoplasia.
Preparations
80 mg + 400 mg tab: 2 BD for 2 days then 1 BD
80 mg + 800 mg tab: double strength (DS): 1 BD
40 mg + 200 mg per 5 ml susp

USES
1. Urinary tract infections:
Acute cystitis- SD of 4 tab of cotrimoxazole
Lower and upper UTI- 3-10 days therapy
Prostatitis- because trimethoprim concentrated in
prostate
2. Respiratory tract infections
Both URTI, LRTI, chronic bronchitis, facio-maxillary
infections, otitis media caused by gram positive cocci and
H. influenza.

3. Bacterial diarrhoeas and dysentery

Severe and invasive infection caused by E.coli, shigella,
non-typhoid salmonella, and Y. enterocollitica
4. Pneumocystis jeroveci
Cotrimoxazole has prophylactic as well as therapeutic value

DS tab 4-6 times/day for 2-3 weeks may be curative.

DS tab daily used for prophylaxis and is better tolerated

5. Chancroid

DS tab BD for 14 days is a 3rd choice, but less expensive

alternative to Ceftriaxone, Azithromycin or Ciprofloxacin