What are sulfa drugs used for?

What Are Sulfonamides?

‘Sulfa drugs’ were some of the original antibiotics, and are still in use today.

Sulfonamides, or “sulfa drugs,” are a group of medicines used to treat bacterial infections.

They may be prescribed to treat urinary tract infections (UTIs), bronchitis, eye infections, bacterial meningitis, pneumonia, ear infections, severe burns, traveler’s diarrhea, and other conditions.

Sometimes, the medicines are also used to help control seizures and treat other medical concerns.

The drugs won’t work for viral infections, such as a cold or the flu.

Sulfonamides work by preventing the growth of bacteria in the body.

They come in different formulations and may be taken as an oral, topical, vaginal, or ophthalmic (eye) medicine.

The discovery of sulfonamides paved the way for the widespread use of antibiotics. The first sulfonamide, Prontosil, was tested in the 1930s.

Common Sulfonamides

Commonly prescribed sulfonamides include:

  • Gantrisin (sulfisoxazole)
  • Bactrim or Septra (trimethoprim and sulfamethoxazole)
  • Sulfadiazine
  • Azulfidine (sulfasalazine)
  • Zonegran (zonisamide)

Side Effects of Sulfonamides

Side effects of sulfonamides may include:

  • Skin rash
  • Itching
  • Headache
  • Dizziness
  • Diarrhea
  • Tiredness
  • Nausea or vomiting
  • Pale skin
  • Joint pain
  • Sensitivity to light

Allergies to Sulfonamides

Allergies to sulfonamides are common.

Tell your doctor if you have allergies to food dyes, preservatives, or animals.

Let your doctor know right away if you experience signs of a severe allergic reaction (anaphylaxis), which may include rash, hives, difficulty breathing, chest tightness, or swelling of the face, lips, or tongue.

Sulfonamide Warnings

Tell your doctor about all medical conditions you have — especially kidney, liver, or blood disorders — before taking a sulfonamide.

Sulfonamides may cause blood problems, especially if they’re taken for a long period of time.

These medicines can also cause a serious, even life-threatening, skin rash. Tell your doctor right away if you notice a rash or unusual skin changes.

Your doctor will want to carefully monitor your body’s response to this medicine with frequent observation. Keep all appointments with your doctor’s office and laboratory.

These medicines shouldn’t be given to infants under 2 months old.

Elderly people may be more sensitive to the side effects of sulfonamides. Talk to your doctor if you’re over 65.

Tell your doctor about all prescription, non-prescription, illegal, recreational, herbal, nutritional, or dietary drugs you’re taking before using sulfonamides.

Let your healthcare provider know you’re taking a sulfonamide before having any type of medical procedure, including a dental exam or procedure.

These drugs may make your skin more sensitive to the sun. Avoid unnecessary exposure to sunlight, and wear sunscreen and protective clothing while outdoors.

Sulfonamides may make you dizzy. Don’t drive or perform activities that require alertness until you know how your medicine affects you.

Tell your doctor if your symptoms don’t improve or worsen after starting on a sulfonamide.

Sulfonamides and Pregnancy

Animal studies have shown that sulfonamides may cause birth defects.

Tell your doctor if you’re pregnant, or might become pregnant, before taking any of these drugs.

These medicines can also pass into breast milk. Don’t breastfeed while taking a sulfonamide.

Sulfa Antimicrobials: Frequently Asked Questions Answered

Hello. Paul Auwaerter here with Medscape Infectious Diseases, from the Johns Hopkins Division of Infectious Diseases. I would like to discuss 4 points about sulfa/sulfonamide antimicrobials that often come up in infectious diseases consultative practice.

Consider potential adverse reactions. The first is that these drugs are widely used. Many of us have used them for years, yet there is always a nagging concern about the potential for severe or adverse reactions. How frequent are severe reactions? The most feared are Stevens-Johnson syndrome and toxic epidermal necrolysis, which occur in 1 in a million cases. That is something that we hope never to see, and the chances are slim to none. More common are general rashes, effects on the bone marrow, cytopenias, and kidney injury.

From an allergic perspective, it’s important to note that there are cross-reactivities. Many people write “sulfa allergy,” and we find that we can’t use furosemide because it has a sulfa moiety. To be clear, it’s a specific sulfa aspect — an arylamine component, which is specific to such drugs as sulfamethoxazole. It is a component of Septra® or Bactrim®, and is not cross-reactive with drugs in the non-steroidal anti-inflammatory drug class or so on. However, it is present in sulfasalazine or diaminodiphenyl sulfone (Dapsone), so that is where you have to make a distinction. So, there is no cross-reactivity in non-antimicrobial sulfa-containing drugs.

Respond to a patient’s allergy report. The second issue is, what do you do with a patient who reports a sulfa allergy. Could it be a gastrointestinal effect? Could it be an effect on the bone marrow, or could it be a rash? If it is a severe rash that led to admission to a burn unit, or involved a serious reaction, such as DRESS (drug rash with eosinophilia and systemic symptoms) or Stevens-Johnson syndrome, we would never use it. However, we often must come to grips with whether we should try again.

The jury there is mixed. Years ago, on the HIV service, we would try to desensitize people using a graduated dosing of medicine. I have cited the Health Resources and Services Administration (HRSA) guideline for desensitization, but others have said that there is no role for that because the reaction is not IgE-mediated.

Perhaps it would be best to rechallenge a patient and be aware that if a reaction occurs, that you should stop the medication. The largest trial of sulfa sensitization had only 48 patients, so there is no vast experience for deciding how to manage this. Both options are available.

Remember that trimethoprim is not a sulfa drug. The third point about sulfa drugs is to remind everyone that trimethoprim is not a sulfa drug. For urinary tract infections, you can use trimethoprim alone and avoid the sulfa moiety if you are concerned about sulfa reactions.

Consider that kidney concerns are not that rare. The last point is about renal issues. For years, many of us have had the opinion (based on postmarketing surveys from when the drug was first approved) that any effect on the kidneys was very uncommon. It was thought that kidney injury was rare. Although we have seen hyperkalemia to some degree, such effects as interstitial nephritis or acute tubular necrosis were thought to be very uncommon. More common was an artifactual rise in serum creatinine because of interference with how this is assayed in the laboratory.

That dogma was challenged a couple of years ago in a nice paper by Fraser and colleagues, who studied 573 patients retrospectively at a Veterans Affairs hospital system and determined that 64 of those patients met criteria for acute kidney injury, including a rise in serum blood urea nitrogen and creatinine, along with active urine sediment. It was interesting that 0.9% of patients had only a rise in serum creatinine (which might suggest an artifactual rise), but 5.8% had probable kidney injury and 4.9% possible kidney injury, with other confounding factors. Thus, more than 10% were thought to have acute kidney injury from the drug.

That’s clearly different from what most of us believed. I have been guilty of sometimes watching a patient’s creatinine level rise and attributing it to creatinine assay, especially in elderly patients or in patients with other comorbid conditions or those taking drugs that might affect the kidneys.

Although this study didn’t gauge the clinical impact of acute kidney injury or track whether any medications were discontinued, in resolution, it does provide some insight, at least for this type of patient, that up to 10% may have trouble with a sulfa antimicrobial agent. You might see a significant rise in serum creatinine as early as the first 2-3 days of therapy, and this should beg the question of whether you should switch to an alternative agent.

Those are 4 things to consider about sulfa agents — and the one that really caught my eye was this study. It’s worth reading. You will get a little more insight and perhaps change your practice. Thanks for listening.

Sulfonamides

Sulfonamides (sulphonamides) are a group of man-made (synthetic) medicines that contain the sulfonamide chemical group. They may also be called sulfa drugs.

Many people use the term sulfonamide imprecisely to refer only to antibiotics that have a sulfonamide functional group in their chemical structure. However, there are several non-antibiotic sulfonamides that have been developed by exploiting observations made during the clinical evaluation of the antibiotic sulfonamides. These are used for a range of conditions such as diabetes and pain relief.

Sulfanilamide was the first sulfonamide developed in 1906, although it was not used as an antimicrobial agent until the late 1930s. Sulfonamide antimicrobials are bacteriostatic (stop bacteria from reproducing but don’t necessarily kill them) and work by interfering with the synthesis of folic acid in bacteria, which is essential for nucleic acid formation and ultimately DNA and RNA. Humans obtain folic acid from their diet, but bacteria need to synthesize it. Sulfonamide antimicrobials may be combined with trimethoprim to make them bactericidal (kill bacteria), because trimethoprim acts on a different enzyme in the folic acid synthesis pathway.

Non-antibiotic sulfonamides are thought to have anti-inflammatory or immunomodulatory properties although the exact way they work in some conditions is not known.

What are sulfonamides used for?

Sulfonamides represent a diverse range of medicines with a diverse range of actions. Examples of some conditions that may be treated with sulfonamides include:

  • Bacterial infections: eg, sulfamethoxazole/trimethoprim, sulfisoxazole
  • Crohn’s disease: eg, sulfasalazine
  • Diabetes: eg, glyburide, tolbutamide
  • Fluid retention: eg, chlorothiazide, furosemide, hydrochlorothiazide
  • Gout: eg, probenecid
  • High blood pressure: eg, chlorothiazide, hydrochlorothiazide
  • Pain and inflammation: eg, celecoxib
  • Rheumatoid arthritis: eg, sulfasalazine
  • Ulcerative colitis: eg, sulfasalazine.

What are the differences between sulfonamides?

Sulfonamide antibiotics have an N4 amine group in their structure which is thought to contribute to their higher incidence of allergic-type reactions. Non-antibiotic sulfonamides lack this structure.

Sulfonamide antibiotics

Oral sulfonamides are rapidly excreted and very soluble in urine and are commonly used to treat infections of the urinary tract.

Generic name Brand name examples
sulfacetamide topical Klaron, Ovace
sulfadiazine Generic only
sulfamethoxazole/trimethoprim Bactrim, Septa, SMZ-TMP
sulfisoxazole Gantrisin Pediatric, Truxazole

Non-antibiotic sulfonamides

Many classes of drugs contain a sulfonamide structure including carbonic anhydrase inhibitors; sulfonylureas; and thiazide, thiazide-like and loop diuretics.

Generic name Brand name examples
acetazolamide Diamox
bumetanide Bumex
celecoxib Celebrex
chlorothiazide Diuril
chlorthalidone Thalitone
dapsone Generic
dorzolamide opthalmic Trusopt
furosemide Lasix
glibenclamide Not available in the U.S.
gliclazide Not available in the U.S.
glipizide Glucotrol
glyburide Micronase
hydrochlorothiazide (HCTZ) Aquazide H, Microzide
indapamide Lozol
probenecid Benemid
sulfasalazine* Azulfidine, Sulfazine
sumatriptan Imitrex
tolbutamide Orinase, Tol-tab

*Sulfasalazine also has an antibacterial effect.

Are sulfonamides safe?

Sulfonamide-containing drugs are frequently implicated in allergic and non-allergic reactions.

The term “sulfa allergy” (or “sulfur allergy”) most commonly refers to an immunological response to sulfonamides, and it is a term that is often misused and misinterpreted. It should not be confused with a sulphite allergy (sulphites are substances used to preserve foods); nor with an allergy to the element sulphur or sulphates (allergic reactions to these naturally occurring substances are extremely rare). Non-antibiotic sulfonamides are thought to be less likely than antibiotic sulfonamides to cause severe allergic reactions.

Sulfonamide allergic reactions affect 1.5-3% of the population but are 10 times more likely in people with HIV. Management depends on the type and severity of the reaction. Mild reactions can be treated with drug discontinuation and antihistamine administration. More severe reactions may require topical or oral steroids and possibly hospital admission.

Sulfonamide allergies can manifest in several different ways, for example as:

  • Sulfonamide drug hypersensitivity syndrome: Symptoms usually start 7 to 14 days after sulfonamide initiation and include fever and a generalized rash; internal organs may be affected
  • Fixed drug eruptions: Symptoms develop within 30 minutes to 8 hours of taking the drugs and include well-defined, round or oval patches of redness and skin swelling, sometimes surmounted by a blister
  • Type I immediate, IgE-mediated, true allergic response: Hives occur within 30 minutes of drug administration. Anaphylaxis is rare
  • Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN): Serious, potentially fatal skin reaction that usually develops within the first week of taking the drug. Symptoms include sheets of skin detachment exposing red, oozing dermis
  • Erythema nodosum: Symptoms include red, hot and painful lumps on the shins or about the knees and ankles, often associated with joint pains or fever
  • Erythema multiforme: Symptoms include the appearance of skin lesions that look like targets (show three concentric zones of color). May involve any body site and the lips.

Sulfonamides may also rarely cause changes in the blood such as anemia (destruction of red blood cells), leukopenia (destruction of white blood cells), and other hematological side effects.

Renal side effects have been reported with sulfonamide use; more commonly crystals in the urine (risk is higher in people who are dehydrated) and, rarely, interstitial nephritis and tubular necrosis.

Note: Sulphites or drugs with a sulfhydryl or sulfate group in their structure (eg, captopril, morphine sulfate, heparin sulfate) do not need to be avoided by people with a sulfonamide allergy.

For a complete list of severe side effects, please refer to the individual drug monographs.

What are the side effects of sulfonamides?

Common side effects reported with sulfonamides include:

  • Gastrointestinal effects (such as diarrhea, nausea, stomach upset, vomiting)
  • Candidiasis (overgrowth of the yeast Candida causing conditions such as thrush) (sulfonamide antibiotics)
  • Dizziness
  • Fatigue
  • Folate deficiency
  • Headaches
  • Itchy skin
  • Rash.

For a complete list of side effects, please refer to the individual drug monographs.

Sulfa, Sulfur, Sulfate, Sulfite: Which Causes an Allergy?

Question

What constitutes a sulfa allergy?

Response from Lauren R. Cirrincione, PharmD
Postdoctoral Research Associate, Department of Pharmacy Practice, University of Nebraska Medical Center, Omaha, Nebraska
Response from Kimberly K. Scarsi, PharmD
Associate Professor, Department of Pharmacy Practice, University of Nebraska Medical Center, Omaha, Nebraska

A chart review of 2.4 million patients in California found that approximately 4% reported an allergy to sulfonamide antimicrobials. The term “sulfonamide antimicrobial” includes trimethoprim/sulfamethoxazole (TMP/SMX), sulfadiazine, and erythromycin/sulfisoxazole. Sulfonamide antimicrobials differ in chemical structure from nonantimicrobial sulfonamides, and those structural differences are implicated in hypersensitivity associated with sulfa antimicrobials.

Drug allergy, broadly called “hypersensitivity,” is an immune-mediated response against a medication. Hypersensitivity reactions may present either immediately (within 1 hour) or be delayed (between 1 and 48 hours). Immediate hypersensitivity is generally immunoglobulin E (IgE)-mediated urticaria, angioedema, rhinitis, bronchospasm, or anaphylaxis. Delayed hypersensitivity is T-cell dependent, presenting as either a maculopapular rash or more serious blistering and mucosal involvement, presaging Stevens-Johnson syndrome or toxic epidermal necrolysis.

Sulfonamide antimicrobial hypersensitivity is predominantly T-cell mediated, presenting as delayed cutaneous reactions, such as a pruritic maculopapular rash,that occurs 1-2 weeks after exposure. IgE-mediated allergic responses have been reported; however, immediate hypersensitivity is less common.

Skin involvement is the hallmark of most drug allergies. A study of 94 patients found that 63% of reported TMP/SMX allergies were rash and hives. Sulfonamide-induced rashes usually start at the trunk and spread toward the limbs and generally resolve within 2 weeks after discontinuation of the medication. If mucosal membranes are involved or blistering is present, the patient may require hospitalization. More severe cases can present as a syndrome, including fever and organ damage, in addition to a generalized maculopapular rash. Rarely, sulfonamide antimicrobials have been associated with toxic epidermal necrolysis and Stevens-Johnson syndrome.

The American Academy of Allergy, Asthma, and Immunology (AAAAI) has guidance on assessing and managing drug hypersensitivity reactions. This resource provides step-by-step instruction on identifying and managing medication allergies, including an algorithm for patient care during a suspected drug allergy.

Patient-specific risk factors include a history of other drug allergies and previous use of the suspected medication or medication class. Females are reported to have more reported drug hypersensitivity, and individuals with comorbidities, such as HIV infection and systemic lupus erythematosus, also are known to be more susceptible to drug hypersensitivity.

Drug-specific factors, including duration of exposure and dose, should be considered to differentiate drug toxicities from drug allergies. If a drug allergy is suspected, a detailed review of the patient’s current medications, including nonprescription medicines and supplements, is critical, because this may help determine whether a sulfonamide agent is solely responsible for symptoms.

A variety of desensitization protocols are available, but implementing such a protocol should be delayed for 1 month after symptoms have resolved. And although these desensitization protocols have been evaluated, their results are limited to patients with HIV owing to the use of TMP/SMX prophylaxis.

Cross-reactivity with nonantimicrobial sulfonamides is a theoretical consideration for patients with a reported “sulfa allergy.” Commonly prescribed nonantimicrobial sulfonamides include furosemide, hydrochlorothiazide, acetazolamide, sulfonylureas, and celecoxib. Clinically significant cross-reactivity between antimicrobial and nonantimicrobial sulfonamides is not a concern. A retrospective cohort study of 969 patients with reported sulfa allergy concluded that there were no clinically significant allergic responses in patients with a documented sulfonamide allergy to subsequently administered nonantimicrobial sulfonamides. Currently, the AAAAI concludes that there is no evidence to support cross-reactivity with nonantimicrobial sulfonamides in patients with reported allergy to antimicrobial sulfonamides.

Sulfites are found in processed foods and medication preparations, and they can trigger asthma exacerbations in patients with a history of asthma. Sulfites are chemically different from sulfonamides, so this reaction is unrelated to sulfonamide hypersensitivity. There is no risk for cross-sensitivity between antimicrobial sulfonamides and sulfur-containing compounds, such as sulfites.

Sulfur and sulfate are found naturally in the body; sulfa-containing amino acids (eg, cysteine) and sulfate-containing drugs (eg, ferrous sulfate) and dietary supplements (eg, glucosamine sulfate) are not allergenic in patients with antimicrobial sulfonamide hypersensitivity. In contrast, topical sulfonamides, such as silver sulfadiazine and ophthalmic sulfacetamide/prednisolone, are contraindicated in patients with documented sulfonamide allergy. One small study (5 participants) reported cross-reactivity with sulfasalazine and antimicrobial sulfonamides owing to similarities in chemical structures.

In conclusion:

  • The onset and types of symptoms, as well evaluation of pertinent patient data—including previous exposure to an offending mediation—can guide in the differential diagnosis of an allergic reaction to a suspected agent.

  • Sulfonamide hypersensitivity reactions frequently present as a maculopapular rash that resolves approximately 2 weeks after discontinuation of the sulfonamide.

  • Clinicians should be aware of signs of potentially serious delayed reactions, including blistering and involvement of mucosal membranes.

  • Cross-reactive hypersensitivity between sulfonamide antimicrobials and nonantimicrobials is unlikely.

  • Cross-sensitivity with sulfur-containing compounds, such as sulfites, and sulfonamide antimicrobials does not occur.

  • Sulfur and sulfate-containing drugs are not allergenic in patients with antimicrobial sulfonamide hypersensitivity.

  • Topical sulfonamide antimicrobials are contraindicated in patients with sulfonamide hypersensitivity.

Editors’ Recommendations

  • Sulfa Antimicrobials: Frequently Asked Questions Answered

How Sulfa Drugs Work

Bacillus anthracis.CDC/ Dr. William A. Clark

Researchers have finally found out how sulfa drugs—the first class of antibiotics ever discovered—work at the molecular level. The finding offers insights into designing more robust antibiotic therapies.

Sulfa antibiotics were first used in the 1930s, and they revolutionized medicine. After a few years, bacteria started to develop resistance to the drugs, and eventually penicillin replaced them as a first-line treatment. While antibiotic resistance remains a problem for this class of antibiotics, sulfa drugs are still commonly used to treat a variety of bacterial infections.

Sulfa drugs work by binding and inhibiting a specific enzyme called dihydropteroate synthase (DHPS). This enzyme is critical for the synthesis of folate, an essential nutrient. Mammals get folate from their diet, but bacteria must synthesize this vitamin. Folate synthesis requires a chemical reaction between 2 molecules, DHPP and PABA, that is catalyzed by DHPS.

Bacteria resistant to sulfa drugs often have mutations in the DHPS enzyme. These mutations occur on 2 floppy loops that sit near the enzyme’s active site. Previous research had described most of the structure of DHPS, but the structure of the floppy, highly conserved loops remained elusive. Moreover, researchers didn’t know how the chemical reaction occurs between DHPP and PABA.

A team of scientists led by Dr. Stephen White of St. Jude Children’s Research Hospital set out to determine the structure of the loops and the chemical reactions that are helped along by DHPS. Their research, which appeared in the March 2, 2012, issue of Science, was funded primarily by NIH’s National Institute of Allergy and Infectious Disease (NIAID).

The scientists isolated the DHPS enzyme from 2 bacterial species: Bacillus anthracis, which causes anthrax, and Yersinia pestis, which causes plague. The scientists embedded DHPP and PABA in crystals of the enzyme. They then used X-ray crystallography to find high-resolution structures of these molecules at different stages of the chemical reaction.

The researchers found that the 2 floppy loops wrap around PABA early on and hold the molecule in place. The chemical reaction linking portions of PABA and DHPP takes place, and then the loops release the chemical reaction product. The structures also revealed the exact chemical reaction steps that occur between PABA and DHPP.

Sulfa antibiotics work because they fit into the DHPS active site and take PABA’s place. By embedding sulfa antibiotics into the enzyme crystals, the scientists found that the sulfa drugs are held in place by the floppy loop structures. However, a small portion of the drug sticks out of the binding pocket. The researchers discovered that DHPS mutations in drug-resistant bacteria occur near this small stuck-out portion.

“The structure we found was totally unexpected and really opens the door for us and others to design a new class of inhibitors targeting DHPS that will help us avoid side effects and other problems associated with sulfa drugs,” says White.

—by Lesley Earl, Ph.D.

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