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Sulfonamides (see Table 18: Bacteria and Antibacterial Drugs: Sulfonamides ) are synthetic bacteriostatic antibiotics that competitively inhibit conversion of p-aminobenzoic acid to dihydropteroate, which bacteria need for folate synthesis and ultimately purine and DNA synthesis. Humans do not synthesize folate but acquire it in their diet, so their DNA synthesis is less affected.
Two sulfonamides, sulfisoxazole and sulfamethizole, are available as single drugs for oral use. Sulfamethoxazole may be combined with trimethoprim (TMP/SMX—see see Bacteria and Antibacterial Drugs: Trimethoprim and Sulfamethoxazole). Sulfadoxine plus pyrimethamine is available (but not in the US) as an oral, fixed combination for malaria due to chloroquine-resistant Plasmodium falciparum.
Sulfonamides available for topical use include silver sulfadiazine, vaginal cream and suppositories containing sulfanilamide, and ophthalmic sulfacetamide.
Pharmacology
Most sulfonamides are readily absorbed orally and, when applied to burns, topically. Sulfonamides are distributed throughout the body. They are metabolized mainly by the liver and excreted by the kidneys. Sulfonamides compete for bilirubin-binding sites on albumin.
Indications
Sulfonamides are active against
However, resistance is widespread, and resistance to one sulfonamide indicates resistance to all.
Sulfasalazine can be used orally for inflammatory bowel disease. Sulfonamides are most commonly used with other drugs (eg, for nocardiosis, UTI, and chloroquine-resistant falciparum malaria).
Topical sulfonamides can be used to treat the following:
Contraindications
Sulfonamides are contraindicated in patients who have had an allergic reaction to them or who have porphyria. Sulfonamides do not eradicate group A streptococci in patients with pharyngitis and should not be used to treat group A streptococcal pharyngitis.
Use During Pregnancy and Breastfeeding
Most sulfonamides are in pregnancy category B (animal studies show no risk and human evidence is incomplete, or animal studies show risk but human studies do not). However, use near term and in breastfeeding mothers is contraindicated, as is use in patients < 2 mo (except as adjunctive therapy with pyrimethamine to treat congenital toxoplasmosis). If used during pregnancy or in neonates, these drugs increase blood levels of unconjugated bilirubin and increase risk of kernicterus in the fetus or neonate.
Sulfonamides enter breast milk.
Adverse Effects
Adverse effects can result from oral and sometimes topical sulfonamides; effects include
Hypothyroidism, hepatitis, and activation of quiescent SLE may occur in patients taking sulfonamides. These drugs can exacerbate porphyrias.
Incidence of adverse effects is different for the various sulfonamides, but cross-sensitivity is common.
Sulfasalazine can reduce intestinal absorption of folate (folic acid). Thus, use of this drug may trigger folate deficiency in patients with inflammatory bowel disease, which also reduces absorption, especially if dietary intake is also inadequate.
Mafenide may cause metabolic acidosis by inhibiting carbonic anhydrase.
Dosing Considerations
To avoid crystalluria, clinicians should hydrate patients well (eg, to produce a urinary output of 1200 to 1500 mL/day). Sulfonamides can be used in patients with renal insufficiency, but peak plasma levels should be measured and sulfamethoxazole levels should not exceed 120 μg/mL. Sulfonamides can potentiate sulfonylureas (with consequent hypoglycemia), phenytoin (with increased adverse effects), and coumarin anticoagulants.
Trimethoprim and Sulfamethoxazole
Trimethoprim is available as a single drug or in combination with sulfamethoxazole. The drugs act synergistically to block sequential steps in bacterial folate metabolism. Trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate, and sulfamethoxazole inhibits conversion of p-aminobenzoic acid to dihydropteroate. This synergy results in maximal antibacterial activity, which is often bactericidal.
Trimethoprim/sulfamethoxazole (TMP/SMX) is available as a fixed combination consisting of a 1:5 ratio (80 mg TMP plus 400 mg SMX or a double-strength tablet of 160 mg TMP plus 800 mg SMX).
Pharmacology
Both drugs are well absorbed orally and are excreted in the urine. They have a serum half-life of about 11 h in plasma and penetrate well into tissues and body fluids, including CSF. TMP is concentrated in prostatic tissue.
Indications
TMP and TMP/SMX (see Bacteria and Antibacterial Drugs: Some Indications for TMP/SMX) are active against
The combination is inactive against anaerobes, Treponema pallidum, Mycobacterium tuberculosis, Mycoplasma sp, and Pseudomonas aeruginosa. Enterococci, many Enterobacteriaceae, and Streptococcus pneumoniae strains are resistant. TMP/SMX is not clinically effective for group A streptococcal pharyngitis.
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Table 19
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| Some Indications for TMP/SMX |
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Indication
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Comments
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Chronic bacterial prostatitis
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One of the few effective drugs, but cures < 1/2 of patients, even after 12 wk
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Uncomplicated cystitis in women
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As effective as fluoroquinolones for empiric short-course (3-day) therapy if the rate of TMP/SMX resistance is < 15%
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Prophylaxis for recurrent UTI in women and children
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Use of 1/2 to 1 double-strength tablet every night or every other night or, for women with previous recurrences after coitus, after coitus
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Treatment of Pneumocystis jirovecii pneumonia and prophylaxis of this infection in patients with AIDS or cancer
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Drug of choice
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Intestinal infections due to various bacteria (eg, Shigella sp, Vibrio sp, Escherichia coli)
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Usefulness limited by increasing prevalence of resistance
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Nocardia and Listeria monocytogenes infections
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—
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Acute exacerbations of chronic bronchitis
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—
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Methicillin-resistant Staphylococcus aureus infections
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Used if patients cannot tolerate vancomycin
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TMP/SMX = trimethoprim/sulfamethoxazole.
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TMP alone is especially useful for chronic bacterial prostatitis and for prophylaxis and treatment of UTI in patients allergic to sulfonamides.
Contraindications
TMP/SMX is contraindicated in patients who have had an allergic reaction to either drug. Relative contraindications include folate deficiency, liver dysfunction, and renal insufficiency.
Use During Pregnancy and Breastfeeding
TMP/SMX is in pregnancy category C (animal studies show some risk, evidence in human studies is inadequate, but clinical benefit sometimes outweighs risk). However, use near term is contraindicated; if used during pregnancy or in neonates, TMP/SMX increases blood levels of unconjugated bilirubin and increases risk of kernicterus in the fetus or neonate.
Sulfonamides enter breast milk and use during breastfeeding is usually discouraged.
Adverse Effects
Adverse effects include
Renal failure in patients with underlying renal insufficiency is probably secondary to interstitial nephritis or tubular necrosis. Also, TMP competitively inhibits renal tubular creatinine secretion and may cause an artificial increase in serum creatinine, although GFR remains unchanged. Increases in serum creatinine are more likely in patients with preexisting renal insufficiency and especially in those with diabetes mellitus.
Most adverse effects are the same as for sulfonamides. TMP has adverse effects identical to those of SMX, but they are less common. Nausea, vomiting, and rash occur most often. AIDS patients have a high incidence of adverse effects, especially fever, rash, and neutropenia.
Folate deficiency (resulting in macrocytic anemia) can also occur. Use of folinic acid can prevent or treat macrocytic anemia, leukopenia, and thrombocytopenia, which sometimes occur with prolonged TMP/SMX use.
Rarely, severe hepatic necrosis occurs. The drug may also cause a syndrome resembling aseptic meningitis.
Dosing Considerations
TMP/SMX may increase warfarin activity and levels of phenytoin, methotrexate, and rifampin. SMX can increase the hypoglycemic effects of sulfonylureas.
Last full review/revision July 2009 by Matthew E. Levison, MD
Content last modified February 2012
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