Chemistry

Sulfonamides with varying physical, chemical, pharmacologic, and antibacterial properties are produced
by attaching substituents to the amido group ( ⎯ SO2 ⎯ NH ⎯ R) or the amino group ( ⎯ NH2) of the
sulfanilamide nucleus. Sulfonamides tend to be much more soluble at alkaline than at acid pH. Most can
be prepared as sodium salts, which are used for intravenous administration.

Mechanism of Action
Sulfonamide-susceptible organisms, unlike mammals, cannot use exogenous folate but must synthesize it
from PABA. This pathway is thus essential for production of purines and nucleic acid synthesis. As
structural analogs of PABA, sulfonamides inhibit dihydropteroate synthase and folate production.
Sulfonamides inhibit both Gram-positive bacteria, such as Staphylococcus sp and Gram-negative enteric
bacteria such as Escherichia coli, Klebsiella pneumoniae, Salmonella, Shigella, and Enterobacter sp, as
well as Nocardia sp, Chlamydia trachomatis, and some protozoa. Rickettsiae are not inhibited by
sulfonamides but are instead stimulated in their growth. Activity is poor against anaerobes.
Pseudomonas aeruginosa is intrinsically resistant to sulfonamide antibiotics.

Clinical Uses
Sulfonamides are infrequently used as single agents. Many strains of formerly susceptible species,
including meningococci, pneumococci, streptococci, staphylococci, and gonococci, are now resistant. The
fixed-drug combination of trimethoprim- sulfamethoxazole is the drug of choice for infections such as
Pneumocystis jiroveci pneumonia, toxoplasmosis, and nocardiosis.

Types
A. Oral Absorbable Agents

Sulfamethoxazole is a commonly used absorbable agent. Typical dosing and indications are discussed
below.

Administration of sulfadiazine with pyrimethamine is firstline therapy for treatment of acute

toxoplasmosis. Using sulfadiazine plus pyrimethamine, a potent inhibitor of dihydrofolate reductase, is
synergistic because these drugs block sequential steps in the folate synthesis pathway. Sulfadoxine is a
long-acting sulfonamide that is coformulated with pyrimethamine (Fansidar). This combination is no
longer commercially available in the USA but may be found in other parts of the world where it is used
as a second-line treatment for malaria.
B. Oral Nonabsorbable Agents

Sulfasalazine (salicylazosulfapyridine) is widely used in ulcerative colitis, enteritis, and other

inflammatory bowel disease.

C. Topical Agents

Sodium sulfacetamide ophthalmic solution or ointment is effective in the treatment of bacterial

conjunctivitis and as adjunctive therapy for trachoma. Another sulfonamide, mafenide acetate, is used
topically but can be absorbed from burn sites. The drug and its primary metabolite inhibit carbonic
anhydrase and can cause metabolic acidosis, a side effect that limits its usefulness. Silver sulfadiazine is a
less toxic topical sulfonamide and is preferred to mafenide for prevention of infection of burn wounds.

Adverse Reactions
Historically, drugs containing a sulfonamide moiety, including antimicrobial sulfas, diuretics, diazoxide,
and the sulfonylurea hypoglycemic agents, were considered to be cross-allergenic. However, more recent
evidence suggests cross-reactivity is uncommon and many patients who are allergic to nonantibiotic
sulfonamides tolerate sulfonamide antibiotics. The most common adverse effects are fever, skin rashes,
exfoliative dermatitis, photosensitivity, urticaria, nausea, vomiting, diarrhea, and difficulties referable
to the urinary tract (see below). Stevens-Johnson syndrome, although relatively uncommon (<1% of
treatment courses), is a particularly serious and potentially fatal type of skin and mucous membrane
eruption associated with sulfonamide use. Other unwanted effects include stomatitis, conjunctivitis,
arthritis, hematopoietic disturbances (see below), hepatitis, and, rarely, polyarteritis nodosa and
psychosis.

A. Urinary Tract Disturbances

Sulfonamides may precipitate in urine, especially at neutral or acid pH, producing crystalluria, hematuria,
or even obstruction. This is rarely a problem with the more soluble sulfonamides (eg, sulfisoxazole).
Sulfadiazine and sulfamethoxazole are relatively insoluble in acidic urine and can cause crystalluria,
particularly when given in large doses or if fluid intake is poor. Crystalluria is treated by administration of
sodium bicarbonate to alkalinize the urine and fluids to increase urine flow. Sulfonamides have also been
implicated in various types of nephrosis and in allergic nephritis.

B. Hematopoietic Disturbances

Sulfonamides can cause hemolytic or aplastic anemia, granulocytopenia, thrombocytopenia, or

leukemoid reactions. Sulfonamides may provoke hemolytic reactions in patients with glucose-6-
phosphate dehydrogenase deficiency. Sulfonamides taken near the end of pregnancy increase the risk of
kernicterus in newborns.