A patient comes in with 3 weeks of relapsing, watery diarrhea. Stool polymerase chain reaction confirms Cyclospora cayetanensis. The treatment is straightforward — trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim), one-double strength tablet twice daily for 7-10 days, per the CDC guidance. But then you open the chart, and it says “sulfa allergy.”

This summer’s multistate cyclosporiasis outbreak — 10,468 confirmed cases across 47 states as of August 4 with more under investigation — has handed that problem to clinicians who don’t often see this parasite. TMP-SMX is the treatment of choice. But for the patient whose chart says sulfa allergy, the CDC said no highly effective alternative has been identified.

The Less Effective Alternatives

For a patient who is truly sulfa-allergic, the CDC lists three options: observation and supportive care, an alternative antibiotic, or supervised desensitization for selected patients without a life-threatening allergy.

The alternative antibiotics, however, are less effective. Nitazoxanide is reported at roughly 71%-87% efficacy, but the evidence in sulfa-allergic patients with cyclosporiasis is thin. A 2019 review of the parasite’s treatment could point only to a handful of reports: a 2007 case report of a single sulfa-allergic patient who cleared infection on nitazoxanide after ciprofloxacin failed, and a 2003 Mexican study of broad-spectrum antiparasitic treatment in children, in which Cyclospora was a small fraction of cases.

Ciprofloxacin has even less evidence behind it. The CDC calls it likely ineffective in immunocompetent patients. Of the two, Geehan Suleyman, MD, medical director of infection prevention and antimicrobial stewardship at Henry Ford Health in Detroit, said she prefers nitazoxanide, which has more consistent activity against Cyclospora.

That said, cost is a real barrier. Suleyman said nitazoxanide is often substantially more expensive than TMP-SMX and may not be covered by all insurance plans. Access and affordability, according to her, become important practical considerations when selecting therapy. “This is one reason why accurate evaluation of sulfa allergy labels is important; many patients labeled as allergic may ultimately be able to receive the preferred therapy.”

Whether to Treat at All

The weakness of the alternatives raises the question: Does an otherwise healthy patient need treatment at all?

Suleyman said her institution doesn’t recommend testing or empiric treatment for most acute diarrhea, and reserves Cyclospora testing for severe, prolonged, and relapsing cases. For the immunocompromised, the elderly, and the children — who face higher risks for dehydration — Suleyman said they are not discouraging empiric therapy. But she pointed to the drug’s own risks. “We’ve had some patients who had side effects from sulfa, so it’s not a benign drug.” In a self-limiting illness, the drug’s own side effects become part of the decision to treat.

A scenario where a sulfa-allergic, actively infected patient who is also pregnant is challenging to deal with. Rajan Ravikumar, MD, who published this year on beta-lactam oral challenge in pregnancy, said comfort with penicillin challenge during pregnancy is growing, and that there is also some emerging data on cephalosporins, but nothing yet for sulfonamide challenge in pregnant individuals. “I think it’d be an interesting study to look at,” he said.

Most Sulfa Labels Don't Hold Up

An allergy assessment, though, is often inaccurate, according to allergists who spend their careers testing these assumptions. Working around that label instead of questioning it in the first place, they said, is what costs patients the one drug that works. Not every label can be dismissed, but most don’t survive a close look.

The sulfa allergy determination is not uncommon. Reported hypersensitivity to sulfonamide antibiotics ranges from 3.5% to 7.4%, compared to penicillin allergy, reported by roughly 10% of the global population.

“Really ask the questions and find out what’s the story and then analyze that story against risk assessments that have been published,” said Cosby Stone, MD, MPH, an allergist and assistant professor of medicine at Vanderbilt University Medical Center in Nashville, Tennessee. Every week or 2, Stone gets a referral for a sulfa-labeled patient with active cyclosporiasis.

Everything starts with the reaction history, Stone said. A history of severe skin reaction, organ injury, or blood involvement takes a patient out of the running for a challenge. Sulfa is now following the path penicillin took over the past decade, with its own validated risk score SULF-FAST, adapted from the penicillin tool PEN-FAST.

But Kimberly Blumenthal, MD, MSc, a drug-allergy professor at Mayo Clinic in Jacksonville, Florida, flagged what makes sulfa different from penicillin in terms of reactions. These antibiotics are one the highest culprits for severe cutaneous reactions like Stevens-Johnson syndrome, she said, so the history must screen for them specifically.

Also, the reactions that do slip through tend to be delayed. “Sulfa antibiotics most of the time cause delayed reactions like hives, shortness of breath, swelling, or anaphylaxis,” she said. Because those delayed reactions can surface days later, a single-dose challenge can’t fully rule them out — so it depends on a genuinely mild, remote history.

According to Ravikumar, a clinical associate professor of allergy and immunology at the University of Michigan in Brighton, the general understanding about any antibiotic allergy is that if somebody has had a reaction more than 5 years ago, and if there was only cutaneous involvement, there is less than 5% chance that that patient is truly allergic now.

Published data confirm that over 95% of patients with a recorded penicillin allergy label successfully pass antibiotic drug challenges and can be safely delabeled.

What a Clinician Without an Allergist Can Do?

A considerable percentage of patients during this outbreak will be managed in primary care or urgent care, leaving the practical question of what those clinicians can safely handle.

More than they might assume, Stone said. Challenging a low-risk patient carries roughly 1 1%-2% chance of rash, across the hundreds of challenges his group has done. Being ready for that means watching the patient for a couple of hours and being able to treat a reaction, something that Stone said most offices can already do.

Blumenthal broke it into two steps. The first is delabeling on history alone when the reported reaction was plainly a side effect rather than an allergy — isolated fever, headache, fatigue, and gastrointestinal upset. She suggested asking the patients directly whether the reaction was bad enough that they’d want it kept on their record, knowing it would keep them from the drug even if they needed it later. Framed that way, Blumenthal said, patients get to give a careful reconsideration. The second step is an observed first dose in the office, after which patients go home to finish the course, with instructions to call and photograph any rash since sulfa reactions can appear days later.

Suleyman said her system’s guideline already folds in the sulfa risk-stratification approach, a structured evaluation that can be done by pharmacists or non-allergist physicians. Though most delabeling happens with admitted patients, catching the label in a clinic or urgent care is the harder gap to close, according to Suleyman.

The Cross-Reactivity Myths That Strand Patients

Some sulfa labels rest on improper immunologic reasoning, Ravikumar noted.

A patient who once reacted to a nonantibiotic sulfonamide, like a diuretic or a sulfonylurea, often gets told to avoid sulfa antibiotics — it is a mistake, said Ravikumar. The part of the molecule that provokes reactions to sulfa antibiotics isn’t the shared “sulfa” moiety the class is named for. But it’s the N4 aromatic amine group and its attached ring that the diuretics and sulfonylureas simply don’t have.

For example, in a nearly 20,000 patient cohort from a 2003 study, the authors found no cross-reactivity between sulfonamide antibiotics and the nonantibiotic sulfonamides. “People oftentimes get these erroneous labels put on their chart because of this fear of cross-reactivity that does not exist,” Ravikumar said.

Patients who’ve reacted to sulfites — food additives — aren’t at risk for a reaction to sulfonamide antibiotics, immediately or delayed, Ravikumar said, though the worry still ends up on charts as an allergy.

Stone emphasized that the allergy label is where the conversation starts and not where it ends. “Don’t assume an allergy must be an allergy just because it’s in the chart,” he said. And for a patient who needs Bactrim but carries a sulfa label, he compared the situation to penicillin for syphilis: an old drug that many patients report an allergy to, and still the first-line treatment. “Oftentimes, the very thing you want to treat is the thing that the patient worries that they’re allergic to,” he said. Testing might not always change the treatment approach for the current infection, but it protects the patient for the rest of their life.

The experts cited in this article had no relevant disclosures.