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Uses

Although at one time sulfonamides were widely used in the treatment and prophylaxis of infections, the development of resistance in formerly susceptible organisms has greatly limited the clinical usefulness of the drugs. Whenever possible, sulfonamide therapy should be justified by bacteriologic diagnosis.

Acute Otitis Media

Oral sulfonamides have been used for the treatment of acute otitis media (AOM). The fixed combination containing sulfisoxazole acetyl and erythromycin ethylsuccinate (see ) has been used for the treatment of AOM caused by susceptible Haemophilus influenzae. The fixed combination containing sulfamethoxazole and trimethoprim (co-trimoxazole) has been used for the treatment of AOM caused by susceptible H. influenzae or Streptococcus pneumoniae when the fixed combination offered some advantage over other anti-infectives usually used for the treatment of AOM. The manufacturers state that the fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) should not be used for prolonged periods or for prophylaxis in patients with AOM.

When anti-infective therapy is indicated for the treatment of AOM, the American Academy of Pediatrics (AAP) recommends high-dose amoxicillin or the fixed combination of amoxicillin and clavulanate potassium as the drugs of first choice for initial treatment and certain cephalosporins (cefdinir, cefpodoxime, cefuroxime, ceftriaxone) as alternatives for initial treatment in penicillin-allergic patients who do not have a history of severe and/or recent penicillin-allergic reactions. Because substantial resistance to the drugs has been reported in S. pneumoniae, AAP states that the fixed combination of sulfisoxazole acetyl and erythromycin ethylsuccinate and the fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) should not be used as alternatives in patients who do not respond to amoxicillin.

GI Infections

Cyclospora and Cystoisospora Infections

The fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) is considered the drug of choice for the treatment of GI infections caused by Cyclospora cayetanensis or Cystoisospora belli (formerly Isospora belli). The fixed combination also has been recommended for long-term suppressive or chronic maintenance therapy (secondary prophylaxis) to prevent recurrence of cystoisosporiasis in adults and adolescents with human immunodeficiency virus (HIV) infection who have CD4 T-cell counts less than 200/mm and in HIV-infected children with severe immunosuppression.

Shigella Infections

The fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) is used for the treatment of enteritis caused by susceptible Shigella flexneri or Sh. sonnei when anti-infective therapy is indicated. However, data from 2012 indicated that approximately 43% of Shigella isolates tested were resistant to the fixed combination.

Infections caused by Sh. sonnei usually are self-limited (48-72 hours), and mild cases may not require treatment with anti-infectives. Because there is some evidence that anti-infectives may shorten the duration of diarrhea and the period of fecal excretion of Shigella, anti-infective treatment generally is recommended in addition to fluid and electrolyte replacement in patients with severe shigellosis, dysentery, or underlying immunosuppression (e.g., HIV infection). An empiric treatment regimen can be used initially, but in vitro susceptibility testing of clinical isolates is indicated since resistance is common. A fluoroquinolone (e.g., ciprofloxacin, levofloxacin, moxifloxacin), ceftriaxone, or azithromycin (not recommended in those with bacteremia) are considered drugs of choice for the treatment of shigellosis when the susceptibility of the isolate is unknown or when ampicillin- or co-trimoxazole-resistant strains are involved.

Travelers' Diarrhea

Although the fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) has been used for the treatment of travelers' diarrhea caused by susceptible enterotoxigenic Escherichia coli, the fixed combination is no longer considered effective against enteric bacterial pathogens and is not recommended for empiric treatment of travelers' diarrhea.

The most common cause of travelers' diarrhea worldwide is noninvasive enterotoxigenic strains of E. coli (ETEC), but travelers' diarrhea also can be caused by various other bacteria, including enteroaggregative E. coli (EAEC), Campylobacter jejuni, Shigella, Salmonella, Aeromonas hydrophila, Plesiomonas shigelloides, Yersinia enterocolitica, V. parahaemolyticus, or non-O-group 1 V. cholerae. In some cases, travelers' diarrhea is caused by parasitic enteric pathogens (e.g., Giardia duodenalis [also known as G. lamblia or G. intestinalis], Cryptosporidium parvum, C. cayetanensis, Entamoeba histolytica, Dientamoeba fragilis) or viral enteric pathogens (e.g., rotavirus, norovirus, astrovirus).

Respiratory Infections

The fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) is used for the treatment of acute exacerbations of chronic bronchitis caused by susceptible S. pneumoniae or H. influenzae when the fixed combination offers some advantage over single-entity anti-infectives. Some clinicians consider co-trimoxazole the drug of choice for the treatment of upper respiratory tract infections and bronchitis caused by H. influenzae and an alternative for the treatment of infections caused by S. pneumoniae.

The fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) has been recommended as an alternative for the treatment of infections caused by Legionella.

Urinary Tract Infections

Sulfonamides have been used for the treatment of urinary tract infections (UTIs).

Oral sulfadiazine has been used for the treatment of pyelonephritis, pyelitis, and cystitis caused by susceptible E. coli, Klebsiella, Enterobacter, Staphylococcus aureus, Proteus mirabilis, or P. vulgaris. The fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) is used orally for the treatment of UTIs caused by susceptible E. coli, Klebsiella, Enterobacter, Morganella morganii, P. mirabilis, or P. vulgaris when the fixed combination offers some advantage over single-entity anti-infectives usually used for the treatment of UTIs. The fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) is used IV for the treatment of severe or complicated UTIs caused by susceptible E. coli, Klebsiella, Enterobacter, M. morganii, or Proteus when oral administration of the drug is not feasible and the causative organism is not susceptible to single-entity anti-infectives usually effective for the treatment of UTIs. Although some experts no longer recommend the fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) as a drug of first choice for the treatment of uncomplicated cystitis because of high rates of resistance to the drug, other experts suggest that the fixed combination may be a good choice for empiric treatment of acute, uncomplicated UTIs when the causative agent is known to be susceptible or when local in vitro susceptibility patterns for uropathogens indicate that the rate of resistance to the drug does not exceed 20%.

Chancroid

Oral sulfonamides (e.g., sulfadiazine) have been used for the treatment of chancroid (genital ulcers caused by Haemophilus ducreyi). However, sulfonamides are not included in US Centers for Disease Control and Prevention (CDC) recommendations for treatment of chancroid; these experts recommend azithromycin, ceftriaxone, ciprofloxacin, or erythromycin as the drugs of choice.

Chlamydial Infections

Oral sulfonamides (e.g., sulfadiazine) have been used for the treatment of infections caused by Chlamydia trachomatis (e.g., inclusion conjunctivitis, trachoma). However, other anti-infectives (e.g., azithromycin, erythromycin) usually are the drugs of choice for treatment of these infections.

Crohn's Disease and Ulcerative Colitis

Sulfasalazine is used in the treatment of mild to moderate ulcerative colitis, as adjunctive therapy in the treatment of severe ulcerative colitis, and for the prolongation of the remission period between acute attacks of ulcerative colitis.

Sulfasalazine also has been used for the management of mildly to moderately active Crohn's disease, but its role in the management of this condition is not as well defined as in the symptomatic treatment of ulcerative colitis.

Granuloma Inguinale (Donovanosis)

The fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) is used for the treatment of granuloma inguinale (donovanosis) caused by Calymmatobacterium granulomatis. CDC recommends that granuloma inguinale be treated with a regimen of azithromycin or, alternatively, a regimen of doxycycline, ciprofloxacin, erythromycin, or the fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole).

Neisseria meningitidis Infections

Oral sulfonamides (e.g., sulfadiazine) have been used for chemoprophylaxis in close contacts of individuals with invasive meningococcal disease caused by sulfonamide-susceptible Neisseria meningitidis serogroup A. However, strains of N. meningitidis resistant to sulfonamides are prevalent, and sulfonamides are no longer recommended. CDC and AAP recommend rifampin, ciprofloxacin, or ceftriaxone for chemoprophylaxis in close contacts of patients with invasive meningococcal disease.

Although sulfonamides have been used for the treatment of infections caused by susceptible N. meningitidis (including meningitis), other anti-infectives (e.g., ceftriaxone, cefotaxime, penicillin G, ampicillin, chloramphenicol, fluoroquinolones, aztreonam) are recommended for the treatment of these infections.

Nocardia Infections

Sulfonamides have been used for the treatment of nocardiosis caused by Nocardia.

The fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) usually is considered the drug of choice for the treatment of nocardiosis. Other sulfonamides (e.g., sulfadiazine, sulfamethoxazole [not commercially available as a single-entity preparation in the US]) also have been used; however, some experts suggest that sulfonamides that are less urine soluble (e.g., sulfadiazine) should be avoided. Multiple-drug regimens may be necessary in patients who are immunocompromised or have severe or disseminated infections. Other drugs that have been used alone or in multiple-drug regimens for the treatment of nocardiosis include amikacin, tetracyclines, cephalosporins (ceftriaxone), carbapenems (imipenem, meropenem), fixed combination of amoxicillin and clavulanate potassium, clarithromycin, cycloserine, or linezolid. In vitro susceptibility testing, if available, is recommended to guide selection of anti-infectives for the treatment of severe nocardiosis or for treatment in patients who cannot tolerate or failed to respond to sulfonamide treatment.

Plague

Sulfonamides (e.g., sulfadiazine, fixed combination of sulfamethoxazole and trimethoprim [co-trimoxazole]) have been used in the treatment of plague caused by Yersinia pestis, but appear to be less effective than other anti-infectives used for treatment of the disease (e.g., streptomycin, gentamicin, tetracycline, doxycycline, chloramphenicol). Because of lack of efficacy, some experts state that the fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) should not be used alone for the treatment of pneumonic or septicemic plague.

The fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) has been used for postexposure prophylaxis of plague, especially in infants and children younger than 8 years of age. However, because efficacy of the drug for prevention of plague is unknown, other anti-infectives (e.g., doxycycline, ciprofloxacin, chloramphenicol) are recommended for such prophylaxis.

Pneumocystis jirovecii Pneumonia

The fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) is used for the treatment of Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PCP) and for prevention of P. jirovecii infections.

Treatment of Pneumocystis jirovecii Pneumonia

The fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) is the drug of choice for the treatment of mild, moderate, or severe PCP, including PCP in HIV-infected adults, adolescents, and children.

CDC, National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) state that alternatives for treatment of moderate to severe PCP in HIV-infected adults and adolescents who cannot tolerate or have not responded to the fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) include IV pentamidine or a regimen of primaquine in conjunction with clindamycin. For the treatment of PCP in HIV-infected children who cannot tolerate or have not responded after 5-7 days of treatment with the fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole), CDC, NIH, IDSA, and AAP recommend IV pentamidine; these experts state that treatment in such children can be switched to an appropriate oral regimen (e.g., atovaquone) after an initial response is obtained with IV pentamidine.

Prevention of Pneumocystis jirovecii Infections

The fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) is the drug of choice for prevention of initial episodes (primary prophylaxis) of PCP in HIV-infected adults, adolescents, and children. CDC, NIH, and IDSA recommend that primary prophylaxis to prevent initial episodes of PCP be initiated in HIV-infected adults and adolescents with CD4 T-cell counts less than 200/mm or a history of oropharyngeal candidiasis. These experts state that primary PCP prophylaxis also should be considered in HIV-infected adults and adolescents with CD4 T-cell percentages less than 14% or a history of an AIDS-defining illness who would not otherwise qualify for prophylaxis and also should be considered in those with CD4 T-cell counts greater than 200/mm but less than 250/mm if frequent monitoring of CD4 T-cell counts (e.g., every 3 months) is not possible. CDC, NIH, IDSA, and AAP recommend that primary prophylaxis to prevent initial episodes of PCP be initiated in HIV-infected children 1 to less than 6 years of age with CD4 T-cell counts less than 500/mm or CD4 T-cell percentages less than 15% and in HIV-infected children 6 years of age or older with CD4 T-cell counts less than 200/mm or CD4 T-cell percentages less than 15%. These experts recommend that all HIV-infected infants younger than 1 year of age (regardless of CD4 T-cell count or percentage) receive primary PCP prophylaxis. In addition, infants born to HIV-infected mothers should be considered for primary PCP prophylaxis beginning at 4-6 weeks of age and those with indeterminate HIV status should continue to receive prophylaxis until they are determined to be non-HIV-infected or presumptively non-HIV-infected.

CDC, NIH, IDSA, and AAP also recommend that HIV-infected adults, adolescents, and children who have a history of PCP receive long-term suppressive or chronic maintenance therapy (secondary prophylaxis) to prevent recurrence. The fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) is the drug of choice for secondary PCP prophylaxis in HIV-infected adults, adolescents, and children.

CDC, NIH, IDSA, and AAP recommend that primary or secondary prophylaxis with the fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) be continued, if clinically feasible, in individuals who experience adverse reactions to the drug that are not life-threatening; however, prophylaxis with the fixed combination should be permanently discontinued and an alternative used in those with life-threatening adverse reactions to the drug.

For additional information on recommendations regarding treatment and prevention of PCP,

Rheumatoid Arthritis

Sulfasalazine is used in the management of rheumatoid arthritis in adults who have had an inadequate response to nonsteroidal anti-inflammatory agents (NSAIAs) and for the management of polyarticular course juvenile rheumatoid arthritis in pediatric patients who have had an inadequate response to NSAIAs.

Toxoplasmosis

Sulfonamides are used for the treatment and prevention of toxoplasmosis caused by Toxoplasmosis gondii.

Sulfadiazine is used in conjunction with pyrimethamine (and leucovorin) or, alternatively, in conjunction with atovaquone for the treatment of toxoplasmosis. The fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) is used for primary prophylaxis against toxoplasmosis in HIV-infected adults, adolescents, and children. In addition, sulfadiazine is used in conjunction with pyrimethamine (and leucovorin) for chronic maintenance therapy to prevent relapse of toxoplasmosis (secondary prophylaxis) in HIV-infected individuals.

Treatment of Toxoplasmosis

CDC, NIH, IDSA, AAP, and others state that a regimen of sulfadiazine in conjunction with pyrimethamine (and leucovorin) is the regimen of choice for initial treatment of toxoplasmosis, including toxoplasmosis in HIV-infected adults, adolescents, and children. These experts also recommend a regimen of sulfadiazine in conjunction with atovaquone or a regimen of the fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) as alternatives for the treatment of toxoplasmosis in HIV-infected adults and adolescents who are unable to tolerate or who failed to respond to or relapsed with the regimen of choice. When a parenteral regimen is required for initial treatment of toxoplasmosis in severely ill adults or adolescents, some experts suggest that parenteral co-trimoxazole can be used.

Sulfadiazine in conjunction with pyrimethamine (and leucovorin) also is the regimen of choice for treatment of acquired CNS, ocular, or systemic toxoplasmosis in HIV-infected children and for treatment of congenital toxoplasmosis. Empiric treatment of congenital toxoplasmosis should be strongly considered in infants born to HIV-infected women who had symptomatic or asymptomatic toxoplasmosis during pregnancy, regardless of whether the mother received toxoplasmosis treatment during the pregnancy.

Prevention of Toxoplasmosis

The fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) is the drug of choice for prevention of initial episodes (primary prophylaxis) of toxoplasmosis in HIV-infected adults, adolescents, and children. CDC, NIH, and IDSA recommend primary prophylaxis against T. gondii encephalitis in all HIV-infected adults and adolescents who are seropositive for Toxoplasma IgG antibody and have CD4 T-cell counts less than 100/mm. Although specific levels of immunosuppression that increase the risk for T. gondii encephalitis in HIV-infected children are less well defined, CDC, NIH, IDSA, and AAP recommend primary prophylaxis against Toxoplasma encephalitis in toxoplasma-seropositive children younger than 6 years of age who have CD4 T-cell percentages less than 15% and in HIV-infected children 6 years of age or older who have CD4 T-cell counts less than 100/mm.

CDC, NIH, IDSA, and AAP also recommend that HIV-infected adults, adolescents, and children who have completed initial treatment of T. gondii encephalitis receive chronic maintenance therapy (secondary prophylaxis) to prevent relapse. A regimen of sulfadiazine in conjunction with pyrimethamine (and leucovorin) usually is the regimen of choice for secondary prophylaxis of toxoplasmosis in HIV-infected adults, adolescents, and children since it provides coverage against both toxoplasmosis and PCP. Limited data indicate that the fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) may be an effective alternative for secondary toxoplasmosis prophylaxis in HIV-infected individuals, but is recommended in children only when pyrimethamine regimens are not tolerated.

For additional information on recommendations regarding treatment and prevention of toxoplasmosis,

Prevention of Rheumatic Fever Recurrence

Sulfadiazine is used as an alternative for prevention of recurrent attacks of rheumatic fever (secondary prophylaxis). IM penicillin G benzathine generally is considered the drug of choice for secondary prophylaxis of rheumatic fever; alternatives include oral penicillin V potassium, oral sulfadiazine, and oral sulfisoxazole (only available in the US in fixed combination with erythromycin ethylsuccinate). A sulfonamide is recommended when hypersensitivity precludes the use of a penicillin; however, a macrolide (azithromycin, clarithromycin, erythromycin) should be used in patients allergic to penicillins and sulfonamides.

The American Heart Association (AHA) and AAP recommend long-term (continuous) secondary prophylaxis in patients who have been treated for documented acute rheumatic fever (even if manifested solely by Sydenham chorea) and in those with documented rheumatic heart disease (even after prosthetic valve replacement).

Sulfonamides, including sulfadiazine and the fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole), should not be used for the treatment of S. pyogenes (group A β-hemolytic streptococci, GAS) infections (e.g., pharyngitis and tonsillitis) because the drugs will not eradicate S. pyogenes and, therefore, will not prevent sequelae such as rheumatic fever and glomerulonephritis.

Dosage and Administration

Administration

Sulfonamides are administered orally.

Dosage

Sulfonamide dosage should be adjusted individually according to the severity of the infection, the pharmacokinetics of the individual sulfonamide being used, and the response and tolerance of the patient. The short-acting sulfonamides must usually be given at 4- to 6-hour intervals; an initial loading dose usually is recommended.

Cautions

Adverse effects of the sulfonamides are numerous and may involve nearly all organ systems. Although serious, in some cases fatal, reactions have been reported, they occur infrequently.

Sensitivity Reactions

Many of the adverse effects that have been attributed to the sulfonamides appear to be hypersensitivity reactions. The incidence of hypersensitivity reactions appears to increase with increased sulfonamide dosage. Although cross-sensitization has been reported to occur between the various anti-infective sulfonamides, some diuretics such as acetazolamide and the thiazides, some goitrogens, and sulfonylurea antidiabetic agents, the association between hypersensitivity to sulfonamide anti-infectives and subsequent sensitivity reactions to non-anti-infective sulfonamides (e.g., thiazides, sulfonylurea antidiabetic agents, furosemide, dapsone, probenecid) appears to result from a predisposition to allergic reactions in general rather than to cross-sensitivity to the sulfa moiety per se. The mechanism of sulfonamide sensitivity is poorly understood, and the contribution of allergens, haptens, and/or other immune mechanisms remains to be established. For additional information on cross-sensitivity, .

Various dermatologic reactions, including rash, pruritus, urticaria, erythema nodosum, erythema multiforme (Stevens-Johnson syndrome), Lyell's syndrome (may be associated with corneal damage), Behcet's syndrome, toxic epidermal necrolysis, and exfoliative dermatitis, have been reported in patients receiving sulfonamides. Because photosensitivity may also occur, patients should be cautioned against exposure to UV light or prolonged exposure to sunlight. A relatively high proportion of fatalities has occurred as a result of the Stevens-Johnson syndrome, especially in children. Although long-acting sulfonamides (no longer commercially available in the US) have been associated most often with the Stevens-Johnson syndrome, other sulfonamides also have been reported to cause this reaction. Clinicians should be alert to the signs, including high fever, severe headache, stomatitis, conjunctivitis, rhinitis, urethritis, and balanitis, which may precede the onset of the cutaneous lesions of the Stevens-Johnson syndrome. If a rash develops during sulfonamide therapy, the sulfonamide should be discontinued at once. In rare instances, a skin rash may precede a more serious reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis, and/or serious blood disorders.

Fever, which may develop 7-10 days after the initial sulfonamide dose, is a common adverse effect of sulfonamide therapy. Serum sickness syndrome or serum sickness-like reactions (e.g., fever, chills, rigors, flushing, joint pain, urticarial eruptions, conjunctivitis, bronchospasm, leukopenia), have been reported; rarely, anaphylactoid reactions and anaphylaxis may occur. Lupus erythematosus-like syndrome, disseminated lupus erythematosus, angioedema, vasculitis, vascular lesions including periarteritis nodosa and arteritis, cough, shortness of breath, chills, pulmonary infiltrates, pneumonitis (which may be associated with eosinophilia), fibrosing alveolitis, pleuritis, pericarditis with or without tamponade, allergic myocarditis, hepatitis, hepatic necrosis with or without immune complexes, parapsoriasis varioliformis acuta, alopecia, conjunctival and scleral injection, periorbital edema, and arthralgia have also been reported.

If a hypersensitivity reaction occurs during sulfonamide therapy, the drug should be discontinued immediately. Desensitization to sulfasalazine has been used when reinstitution of therapy with the drug was considered necessary in patients with inflammatory bowel disease who had hypersensitivity reactions to the drug. Desensitization to sulfadiazine has also been used in several patients with acquired immunodeficiency syndrome (AIDS) when use of sulfadiazine for the treatment of toxoplasmosis was considered necessary in patients who had hypersensitivity reactions to the drug. Specialized references should be consulted for specific information on desensitization procedures and dosage.

Hematologic Effects

Adverse hematologic effects, including methemoglobinemia, sulfhemoglobinemia, granulocytopenia, leukopenia, congenital neutropenia, eosinophilia, hemolytic anemia, agranulocytosis, aplastic anemia, purpura, clotting disorder, thrombocytopenia, myelodysplastic syndrome, hypofibrinogenemia, and hypoprothrombinemia, rarely resulting in death, have been associated with sulfonamide therapy. Acute hemolytic anemia may occur during the first week of therapy as a result of sensitization or glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. This reaction may also occur in the fetus or premature infant in whom G-6-PD is normally deficient. Mild, chronic hemolytic anemia may occur during prolonged sulfonamide therapy. Agranulocytosis may rarely occur 10-14 days after initiation of therapy. Complete blood cell counts should be performed regularly in patients receiving sulfonamides for longer than 2 weeks. If signs of adverse hematologic effects such as sore throat, fever, pallor, purpura, jaundice, or weakness occur, sulfonamide therapy should be discontinued until the possibility of a blood disorder is eliminated.

Hepatic Effects

Functional and morphologic hepatic changes, possibly causing jaundice, may appear within 3-5 days after initiation of sulfonamide therapy. Focal or diffuse necrosis of the liver has been reported rarely.

Renal Effects

Renal damage, manifested by renal colic, nephritis, urolithiasis, toxic nephrosis with anuria and oliguria, hematuria, proteinuria, kidney stone formation, and elevation of BUN and creatinine concentrations, is usually a result of crystalluria caused by precipitation of the sulfonamide and/or its N-acetyl derivative in the urinary tract. The occurrence of crystalluria is related to the urinary concentration and the solubility characteristics of the sulfonamide and its metabolites. The risk of crystalluria may be decreased by maintaining an adequate urinary output and by increasing urinary pH. Unless the urine is highly acidic and/or the drug is relatively insoluble, alkalinization of the urine is usually not necessary if the urinary output is maintained at a minimum of 1500 mL daily. Urinary alkalinization may be achieved by administering 2.5-4 g of sodium bicarbonate orally every 4 hours. Urinalysis and kidney function tests should be performed weekly to detect any renal complications. If persistent, heavy crystalluria, hematuria, or oliguria occurs, sulfonamide therapy should be discontinued and alkali therapy maintained. Nephritis and hemolytic-uremic syndrome also have been reported.

GI Effects

Nausea and vomiting occur frequently in patients receiving sulfonamides. Abdominal pain, anorexia, glossitis, stomatitis, pancreatitis, gastroenteritis, diarrhea, neutropenic enterocolitis, GI hemorrhage, melena, flatulence, and salivary gland enlargement also have been reported.

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile.C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) have been reported with nearly all anti-infectives, including the fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole), and may range in severity from mild diarrhea to fatal colitis.C. difficile produces toxins A and B, which contribute to the development of CDAD; hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.(See Cautions: Precautions and Contraindications.)

Nervous System Effects

Headache occurs frequently in patients receiving sulfonamides. Dizziness, vertigo, peripheral neuritis, ataxia, mental depression, hallucinations, disorientation, confusion, seizures, intracranial hypertension, tinnitus, hearing loss, anxiety, apathy, and acute psychosis, occur less frequently. Peripheral neuropathy, paresthesia, weakness, fatigue, drowsiness, lassitude, restlessness, insomnia, meningitis, cauda equina syndrome, and Guillain-Barre syndrome also have been reported.

Other Adverse Effects

Other reported adverse effects of sulfonamides include goiter production, hypothyroidism, hypoglycemia, diuresis, pharyngitis, arthralgia, acidosis, and cyanosis. The nonabsorbable sulfonamides reportedly decrease bacterial synthesis of vitamin K1, which may result in hypoprothrombinemia and hemorrhage; these sulfonamides may also reduce fecal output of thiamine.

Precautions and Contraindications

Sulfonamides are contraindicated in patients with a history of hypersensitivity to sulfonamides or other chemically related drugs (e.g., sulfonylureas, thiazides). The drugs are also contraindicated in patients with marked renal or hepatic impairment. Sulfonamides are contraindicated in patients with porphyria, since the drugs may precipitate an acute attack. Sulfasalazine (but not other sulfonamides) is contraindicated in patients hypersensitive to salicylates and in patients with intestinal or urinary obstruction.

Sulfonamides should be used with caution and in reduced dosage in patients with impaired hepatic function, impaired renal function, or urinary obstruction, since excessive accumulation of the drugs may occur in these patients. The drugs should also be administered with caution in patients with blood dyscrasia, severe allergies or asthma, or G-6-PD deficiency. The development of sore throat, fever, rash, pallor, arthralgia, cough, shortness of breath, purpura, or jaundice during sulfonamide therapy may be an early sign of a serious adverse reaction. Renal function tests and complete blood cell counts should be performed frequently during sulfonamide therapy, especially during prolonged therapy with the drugs. Microscopic urinalyses should be done weekly when patients are treated with a sulfonamide for longer than 2 weeks.

Because CDAD has been reported with the use of nearly all anti-infectives, including the fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole), it should be considered in the differential diagnosis in patients who develop diarrhea during or after sulfonamide therapy. Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued. If CDAD is suspected or confirmed, anti-infective therapy not directed against C. difficile should be discontinued whenever possible. Patients should be managed with appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated. Other causes of colitis also should be considered. Patients should be advised that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued; however, it is important to contact a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.

The frequency of resistant organisms limits the usefulness of sulfonamides as sole therapy in the treatment of urinary tract infections, especially for recurrent and complicated urinary tract infections. Since sulfonamides are bacteriostatic and not bactericidal, a complete course of therapy is needed to prevent immediate regrowth and the development of resistant urinary pathogens.

Pediatric Precautions

Kernicterus, caused by displacement of bilirubin from protein-binding sites, has occurred in neonates treated with sulfonamides. Unless indicated for the treatment of congenital toxoplasmosis, sulfonamides are generally contraindicated in children younger than 2 months of age.

Pregnancy and Lactation

Pregnancy

Safe use of sulfonamides during pregnancy has not been established. The teratogenic potential of most sulfonamides has not been adequately studied in humans or animals; however, an increase in the incidence of cleft palate and other bony abnormalities has been reported when some sulfonamides were administered orally in doses 7-25 times the usual human dose to pregnant rats and mice. Sulfonamides are contraindicated in pregnant women at term or whenever the possibility of premature birth exists, since the drugs cross the placenta and may cause kernicterus.

Lactation

Because sulfonamides are distributed into milk, and because of the potential for serious adverse reactions from the drugs in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the woman. Because of the risk of kernicterus in infants younger than 2 months of age, use of sulfonamides is contraindicated in lactating women who are nursing such infants.

Drug Interactions

Folic Acid Antagonists

Because pyrimethamine and trimethoprim also interfere with folic acid synthesis in susceptible organisms, but at different stages, these drugs act synergistically with sulfonamides against some organisms. This synergism is used to therapeutic advantage in the treatment of toxoplasmosis and malaria.

Sulfonamides may increase concentrations and potentiate the effects of methotrexate by displacing methotrexate from its protein-binding sites or inhibiting renal transport of the antineoplastic agent. Sulfonamides should be administered with caution to patients receiving methotrexate.

p-Aminobenzoic Acid and its Derivatives

Because the antibacterial activity of sulfonamides involves competitive inhibition of p-aminobenzoic acid (PABA), the concomitant use of PABA or local anesthetics which are derivatives of PABA (e.g., chloroprocaine, procaine [no longer commercially available in the US], propoxycaine [no longer commercially available in the US], tetracaine) reportedly may antagonize the antibacterial activity of sulfonamides. Although the clinical importance of this effect is unclear, PABA and local anesthetics derived from PABA probably should not be used in patients receiving a sulfonamide.

Anticoagulants

Sulfonamides may potentiate the effects of warfarin by displacing the anticoagulant from protein-binding sites. Patients receiving a sulfonamide and warfarin concomitantly should be monitored closely.

Antidiabetic Agents

Sulfonamides may potentiate the hypoglycemic effects of oral hypoglycemic agents, including sulfonylurea hypoglycemic agents. The fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole) potentiates the effects of oral antidiabetic agents metabolized by cytochrome P-450 (CYP) 2C8 (e.g., pioglitazone, repaglinide, rosiglitazone), metabolized by CYP2C9 (e.g., glipizide, glyburide), or eliminated renally via organic cation transporter (OCT) 2 (e.g., metformin). Increased glucose monitoring may be warranted in patients receiving a sulfonamide and oral antidiabetic agent concomitantly.

Digoxin

Increased serum digoxin concentrations can occur in patients receiving the fixed combination of sulfamethoxazole and trimethoprim (co-trimoxazole), especially in elderly patients. Sulfasalazine reportedly may reduce GI absorption of digoxin. Serum digoxin concentrations should be monitored in patients receiving sulfonamides.

Methenamine

Since methenamine requires acidic urine for its antibacterial effect, the drug should not be used concomitantly with less soluble sulfonamides (e.g., sulfadiazine, sulfapyridine [no longer commercially available in the US]) which may crystallize in acidic urine. In addition, an insoluble precipitate forms between formaldehyde and sulfamethizole (no longer commercially available in the US) in acidic urine.

Nonsteroidal Anti-inflammatory Agents

Since salicylates and other nonsteroidal anti-inflammatory agents (e.g., fenoprofen, indomethacin, meclofenamate) are highly protein bound, these drugs theoretically could be displaced from binding sites by sulfonamides, or could displace sulfonamides from binding sites. Patients receiving sulfonamides concomitantly with nonsteroidal anti-inflammatory agents should be observed for adverse effects.

Pharmacokinetics

Absorption

Individual sulfonamides differ markedly in their absorption, distribution, and elimination. With the exception of sulfapyridine (no longer commercially available in the US) and sulfasalazine, which are only slightly absorbed, sulfonamides are generally well absorbed from the GI tract. Approximately 70-90% of an oral dose of the absorbable sulfonamides is reportedly absorbed from the small intestine; small amounts may also be absorbed from the stomach. Sulfamethizole (no longer commercially available in the US) and sulfisoxazole (commercially available in the US only in fixed combination with erythromycin ethylsuccinate) are absorbed rapidly; peak blood concentrations are usually obtained within 2-4 hours. Sulfadiazine and sulfapyridine are absorbed at a slower rate with peak blood concentrations occurring within 3-7 hours. Administration of oral sulfonamides with food appears to delay, but not reduce, absorption of the drugs.

Absorption of sulfonamides from the vagina, respiratory tract, or abraded skin is variable and unreliable; however, enough drug may be absorbed to induce sensitization or toxicity.

Although only free (unmetabolized and unbound) sulfonamides are microbiologically active, blood concentrations are often determined on the basis of total sulfonamide concentration. Generally, sulfonamide plasma concentrations are approximately twice the blood concentrations. Wide variations in blood concentrations have been reported in different individuals receiving identical doses of the same sulfonamide. Blood total sulfonamide concentrations of 12-15 mg/dL have been reported to be optimal; blood concentrations greater than 20 mg/dL have been associated with an increased incidence of adverse reactions.

Distribution

Absorbable sulfonamides are widely distributed in the body. Although most sulfonamides appear to cross cell membranes, sulfisoxazole appears to be distributed only in extracellular fluid. Sulfonamides may appear in pleural, peritoneal, synovial, amniotic, prostatic, and seminal vesicular fluid, and aqueous humor. Concentrations of some sulfonamides in the CSF may reach 35-80% of blood concentrations. Small amounts of sulfonamides are also distributed into sweat, tears, saliva, and bile.

Sulfonamides readily cross the placenta; fetal plasma concentrations may exceed 50% of maternal plasma concentrations. Sulfonamides are distributed into milk.

Sulfonamides are bound in varying degrees to plasma proteins. Sulfadiazine and sulfapyridine (no longer commercially available in the US) are reportedly 32-70% bound to plasma proteins and sulfamethizole and sulfisoxazole are reportedly 85-90% bound to plasma proteins. All sulfonamides are loosely bound, mainly to albumin, but small amounts of the drugs may be bound by serum globulin. Protein-bound sulfonamides do not have antibacterial activity and there is evidence that the concentration of sulfonamide in tissues is related to the concentration of unbound sulfonamide in serum.

Elimination

Sulfonamides are generally classified as short-acting, intermediate-acting, or long-acting depending on the rate at which they are absorbed and eliminated. Sulfamethizole (no longer commercially available in the US), sulfasalazine, and sulfisoxazole (commercially available in the US only in fixed combination with erythromycin ethylsuccinate) are considered to be short-acting sulfonamides and have plasma half-lives of about 4-8 hours. Sulfadiazine, sulfamethoxazole (commercially available in the US only in fixed combination with trimethoprim [co-trimoxazole]), and sulfapyridine (no longer commercially available in the US) are considered to be intermediate-acting sulfonamides and have plasma half-lives of about 7-17 hours.

Although the liver is the major site of metabolism, sulfonamides may also be metabolized in other body tissues. Most sulfonamides are metabolized mainly by N-acetylation. The degree of acetylation, which is a function of time, varies from less than 5% for sulfamethizole to up to 40% for sulfadiazine. The N-acetyl metabolites, which do not possess antibacterial activity, have greater affinity for plasma albumin than does the nonacetylated drug and are usually less soluble than the parent sulfonamide, particularly in acidic urine. Like acetyl derivatives, glucuronide derivatives do not possess antibacterial activity; however, glucuronide derivatives are water soluble, appear to resemble the nonacetylated sulfonamide in plasma binding capacity, and have not been associated with adverse effects.

Sulfonamides and their metabolites are excreted mainly by the kidneys via glomerular filtration, but the drugs vary widely in their rates of excretion and solubility characteristics at various urinary pH values. Although alkalinization of urine generally increases the solubility of sulfonamides and their metabolites, alkalinization decreases tubular reabsorption, resulting in increases renal excretion of the drugs and decreased sulfonamide blood concentrations. The metabolites do not appear to be reabsorbed by the tubules and their concentration in urine is greater than in blood. Protein-bound sulfonamides cannot be filtered by the glomeruli. Except for the poorly absorbed sulfonamides (sulfapyridine, sulfasalazine) only small amounts of sulfonamides are excreted in feces.

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