The basic formulas of the sulfonamides and their structural similarity to p-aminobenzoic acid (PABA) are shown in Figure 46–1*. 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.
Structures of some sulfonamides and p-aminobenzoic acid.
Mechanism of Action & Antimicrobial Activity
Sulfonamide-susceptible organisms, unlike mammals, cannot use exogenous folate but must synthesize it from PABA. This pathway (Figure 46–2) 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.
Combination of a sulfonamide with an inhibitor of dihydrofolate reductase (trimethoprim or pyrimethamine) provides synergistic activity because of sequential inhibition of folate synthesis (Figure 46–2).
Some bacteria lack the enzymes required for folate synthesis from PABA and, like mammals, depend on exogenous sources of folate; therefore, they are not susceptible to sulfonamides. Sulfonamide resistance may also occur as a result of mutations that (1) cause overproduction of PABA, (2) cause production of a folic acid-synthesizing enzyme that has low affinity for sulfonamides, or (3) impair permeability to the sulfonamide. Dihydropteroate synthase with low sulfonamide affinity is often encoded on a plasmid that is transmissible and can disseminate rapidly and widely. Sulfonamide-resistant dihydropteroate synthase mutants also can emerge under selective pressure.
Sulfonamides can be divided into three major groups: (1) oral, absorbable; (2) oral, nonabsorbable; and (3) topical. Oral absorbable sulfonamides are absorbed from the stomach and small intestine and distributed widely to tissues and body fluids (including the central nervous system and cerebrospinal fluid), placenta, and fetus. Protein binding varies from 20% to over 90%. Therapeutic concentrations are in the range of 40–100 mcg/mL of blood. Blood levels generally peak 2–6 hours after oral administration.
A portion of absorbed drug is acetylated or glucuronidated in the liver. Sulfonamides and inactive metabolites are then excreted in the urine, mainly by glomerular filtration. The dosage of sulfonamides must be reduced in patients with significant renal failure.
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 (formerly P carinii) pneumonia, toxoplasmosis, and nocardiosis.
A. Oral Absorbable Agents
Sulfamethoxazole is a commonly used absorbable agent; however, in the USA, it is available only as the fixed-dosed combination trimethoprim-sulfamethoxazole. Typical dosing and indications are discussed below.
Administration of sulfadiazine with pyrimethamine is first-line 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 (Figure 46–2). However, since 2015, there have been challenges with manufacturing, supply, and pricing of pyrimethamine in the USA. In some cases, clinicians have obtained a compounded product through specialty pharmacies or prescribed alternate agents, such as trimethoprim-sulfamethoxazole. 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 (see Chapter 52).
B. Oral Nonabsorbable Agents
Sulfasalazine (salicylazosulfapyridine) is widely used in ulcerative colitis, enteritis, and other inflammatory bowel disease (see Chapter 62).
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.
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.
TRIMETHOPRIM & TRIMETHOPRIM-SULFAMETHOXAZOLE MIXTURES
Trimethoprim, a trimethoxybenzylpyrimidine, selectively inhibits bacterial dihydrofolic acid reductase, which converts dihydrofolic acid to tetrahydrofolic acid, a step leading to the synthesis of purines and ultimately to DNA (Figure 46–2). Trimethoprim is a much less efficient inhibitor of mammalian dihydrofolic acid reductase. The combination of trimethoprim and sulfamethoxazole is often bactericidal, compared with the bacteriostatic activity of a sulfonamide alone.
Resistance to trimethoprim can result from reduced cell permeability, overproduction of dihydrofolate reductase, or production of an altered reductase with reduced drug binding. Resistance can emerge by mutation, although more commonly it is due to plasmid-encoded trimethoprim-resistant dihydrofolate reductases. These resistant enzymes may be coded within transposons on conjugative plasmids that exhibit a broad host range, accounting for rapid and widespread dissemination of trimethoprim resistance among numerous bacterial species.
Trimethoprim is usually given orally, alone or in combination with sulfamethoxazole, which has a similar half-life. Trimethoprim-sulfamethoxazole can also be given intravenously. Trimethoprim is well absorbed from the gut and distributed widely in body fluids and tissues, including cerebrospinal fluid.
Because trimethoprim is more lipid-soluble than sulfamethoxazole, it has a larger volume of distribution than the latter drug. Therefore, when 1 part of trimethoprim is given with 5 parts of sulfamethoxazole (the ratio in the formulation), the peak plasma concentrations are in the ratio of 1:20, which is optimal for the combined effects of these drugs in vitro. About 30–50% of the sulfonamide and 50–60% of the trimethoprim (or their respective metabolites) are excreted in the urine within 24 hours. The dose should be reduced by half for patients with creatinine clearances of 15–30 mL/min.
Trimethoprim (a weak base) concentrates in prostatic fluid and in vaginal fluid, which are more acidic than plasma. Therefore, it has more antibacterial activity in prostatic and vaginal fluids than many other antimicrobial drugs.
Trimethoprim can be given alone (100 mg twice daily) in acute urinary tract infections. Many community-acquired organisms are susceptible to the high concentrations that are found in the urine (200–600 mcg/mL).
B. Oral Trimethoprim-Sulfamethoxazole (TMP-SMZ)
A combination of trimethoprim-sulfamethoxazole is effective treatment for a wide variety of infections including P jiroveci pneumonia, urinary tract infections, prostatitis, and some infections caused by susceptible strains of Shigella, Salmonella, and nontuberculous mycobacteria. It is active against most Staphylococcus aureus strains, both methicillin-susceptible and methicillin-resistant, and against respiratory tract pathogens such as Haemophilus sp, Moraxella catarrhalis, and K pneumoniae (but not Mycoplasma pneumoniae). However, the increasing prevalence of strains of E coli (up to 30% or more) and pneumococci that are resistant to trimethoprim-sulfamethoxazole must be considered before using this combination for empiric therapy of upper urinary tract infections or pneumonia. Trimethoprim-sulfamethoxazole is commonly used for the treatment of uncomplicated skin and soft tissue infections.
One double-strength tablet (each tablet contains trimethoprim 160 mg plus sulfamethoxazole 800 mg) given every 12 hours is effective treatment for urinary tract infections, prostatitis, uncomplicated skin and soft tissue infections, and infections caused by susceptible strains of Shigella and Salmonella. Bone and joint infections caused by S. aureus can be effectively treated, typically at doses of 8–10 mg/kg per day of the trimethoprim component. One single-strength tablet (containing trimethoprim 80 mg plus sulfamethoxazole 400 mg) given three times weekly may serve as prophylaxis in recurrent urinary tract infections of some women. The dosage for children treated for shigellosis, urinary tract infection, or otitis media is trimethoprim 8 mg/kg per day and sulfamethoxazole 40 mg/kg per day divided every 12 hours.
Infections with P jiroveci and some other pathogens, such as Nocardia or Stenotrophomonas maltophilia, can be treated with high doses of the either the oral or intravenous combination (dosed on the basis of the trimethoprim component at 15–20 mg/kg/d). P jiroveci can be prevented in immunosuppressed patients by a number of low dose regimens such as one double-strength tablet daily or three times weekly.
C. Intravenous Trimethoprim-Sulfamethoxazole
A solution of the mixture containing 80 mg trimethoprim plus 400 mg sulfamethoxazole per 5 mL diluted in 125 mL of 5% dextrose in water can be administered by intravenous infusion over 60–90 minutes. It is the agent of choice for moderately severe to severe pneumocystis pneumonia. It has been used for Gram-negative bacterial sepsis, but has largely been replaced by extended spectrum β-lactams and fluoroquinolones. It may be an effective alternative for infections caused by some multidrug-resistant species such as Enterobacter and Serratia; shigellosis; or typhoid. It is the preferred alternate therapy for serious Listeria infections in patients unable to tolerate ampicillin. The dosage is 10–20 mg/kg/d of the trimethoprim component.
Pyrimethamine and sulfadiazine are used in the treatment of toxoplasmosis. The dosage of sulfadiazine is 1–1.5 g four times daily, with pyrimethamine given as a 200-mg loading dose followed by a once-daily dose of 50–75 mg. Leucovorin, also known as folinic acid, 10 mg orally each day, should be administered to minimize bone marrow suppression seen with pyrimethamine. Some clinicians recommend using trimethoprim-sulfamethoxazole as an alternate option if pyrimethamine is not available.
In falciparum malaria, the combination of pyrimethamine with sulfadoxine (Fansidar) has been used (see Chapter 52); however, it is no longer commercially available in the USA.
Trimethoprim produces the predictable adverse effects of an antifolate drug, especially megaloblastic anemia, leukopenia, and granulocytopenia. The combination trimethoprim-sulfamethoxazole may cause all of the untoward reactions associated with sulfonamides. Nausea and vomiting, drug fever, vasculitis, renal damage, and central nervous system disturbances occasionally occur. Patients with AIDS and pneumocystis pneumonia have a particularly high frequency of untoward reactions to trimethoprim-sulfamethoxazole, especially fever, rashes, leukopenia, diarrhea, elevations of hepatic aminotransferases, hyperkalemia, and hyponatremia. Trimethoprim inhibits secretion of creatinine at the distal renal tubule, resulting in mild elevation of serum creatinine without impairment of glomerular filtration rate. This nontoxic effect is important to distinguish from true nephrotoxicity that may be caused by sulfonamides.