Kimberly Blumenthal, MD

Credit: United States Drug Allergy Registry 

Kimberly Blumenthal, MD, MSc, from Mayo Clinic, sat down with 

and beta-lactam allergy. The conversation covered risk stratification for surgical patients with drug allergy labels, common and overlooked culprits behind intraoperative reactions, and how to counsel patients when a reaction's cause is never confirmed.

Underecognized triggers of perioperative allergy and what to do if you do not know the culprit

The perfect candidate for penicillin allergy de-labeling

Blumenthal also discussed her second EAC 2026 topic, penicillin allergy delabeling, including who qualifies, how the evidence has shifted between skin testing and graded drug challenge, and when it still makes sense to keep an allergy label in the chart even after a negative workup.

Q&A: Culprits in Perioperative Allergy, With Kimberly Blumenthal, MD

 How should clinicians risk-stratify patients with a suspected drug allergy ahead of surgery?

 Most surgeries happen in somebody who has at ≥ 1 drug allergy label, maybe a penicillin allergy history from childhood, or a pain medication like ibuprofen or an opiate. There are some labels that can interfere with care, so we want to know whether or not those allergies are real before they have the operation.

Drug allergy labels before surgery [are] important if they interfere with anesthesia. Also, since surgeries are painful, I think about pain medicines afterward. Do they have opioid allergies? Do they have NSAID allergies?

And then, [I think about] penicillin allergy and antibiotics. The most common antibiotics used are the beta-lactam antibiotics, and the most common single antibiotic in surgical prophylaxis today is cefazolin, or Ancef, a cephalosporin antibiotic.

A lot of people report a cephalosporin allergy, potentially from childhood. Since it's a beta-lactam, cross-reactivity is always a question if you had a penicillin allergy. But recent guidelines suggest there is no cross-reactivity between penicillin and cefazolin, so almost every patient with a penicillin allergy label can have cefazolin in the operating room.

[Drugs] with significant reactions you might want to avoid. [Drugs] that are lower or moderate risk, we could potentially test using a combination of skin testing and drug challenge tests.

What Are the Triggers of Perioperative Anaphylaxis?

What are the most common culprit agents in perioperative anaphylaxis, and how has that landscape shifted?

 The hardest thing is identifying the cause, because a lot of medications are given at once. We often rely on the anesthesia report, which dictates exactly when medications were administered and when the reaction started.

In the US, antibiotics are the most likely causative agent, usually cefazolin, the same medicine we want to use to prevent infections. Probably the closest second are the neuromuscular blocking agents, the agents we use to paralyze patients during surgery.

What are some of the underrecognized triggers?

 There are certain dyes used in surgery that can cause an allergy. Implantable devices might be coated in an antibiotic. Latex is another potential trigger.

And then the disinfectant. We clean the skin often with chlorhexidine gluconate, a very emerging cause of perioperative anaphylaxis, especially because patients are sometimes asked for multiple days beforehand to wash with it, and then they show up to the OR and get washed again. It's sensitization and then an allergic reaction in the operating room.

What To Do When Anaphylaxis Occurs in the Operating Room

 What steps should an operating room team take when anaphylaxis occurs intraoperatively?

 It's the safest place to have anaphylaxis. These patients are either already intubated or can be intubated, so their airway can be protected, and they have multiple lines of IV access to administer medications. Epinephrine can be given, along with other vasopressors like norepinephrine, steroids, and antihistamines.

The hardest thing is recognizing that it's anaphylaxis, because the patient might be covered and there might not be a visible rash. Low blood pressure has a larger differential diagnosis, so not all low blood pressure is anaphylaxis. But once it's identified, it's a very safe environment to be treated, though it often does lead to rescheduling of that procedure.

 For a patient who had perioperative anaphylaxis but no culprit was ever confirmed, how do you counsel them and their surgical team before a future operation?

 The best we can do is relay the results of all of our testing. If we had negative skin tests to a number of agents, it seems like that drug could be used again, and before the next surgery, we could start it with a test dose, giving a small amount first, watching the patient, then proceeding with the remainder.

The final thing we can do is suggest an alternative. Maybe we don't find a cause, but we think it might be the neuromuscular blocking agent, so we suggest using succinylcholine at the next surgery.

Is There an Ideal Candidate for Penicillin Allergy De-labeling?

 Who is a good candidate for penicillin allergy delabeling, and how do you approach that conversation with patients?

 Everybody with a penicillin allergy label is a candidate for delabeling because the diagnosis is frequently missed. Even a rash last year to amoxicillin might have been due to the infection, not the drug. The more recent the allergy history, the more you should approach it as confirmatory testing or delabeling.

For the majority of my patients, who are older and talking about a reaction from childhood that their mother told them about, 50, 60, 70 years ago, the likelihood of true allergy is quite low; the immune system and penicillins have both changed since then.

When I approach that conversation, I explain that if they weren't allergic to penicillin, it opens up 17 different drugs without concern for an allergic reaction. Most patients are receptive, but those with significant reactions carry more fear and should be referred to an allergist.

Skin Testing vs Graded Challenge for Beta-Lactam Allergy Evaluation

 How has the evidence evolved around skin testing versus graded challenge for beta-lactam allergy evaluation?

 In 2009 in the US, we got Pre-Pen back through the FDA, a product we can use for skin testing.

 When we were able to do more skin testing, we realized that in very low-risk people, the skin test isn't as good and produces false positives, so we should really be skin testing the higher-risk people.

At the same time, data came out showing direct challenge is safe in low-risk patients. The field has shifted: for lower-risk patients, direct drug challenge is the most effective way to safely remove the label, and for higher-risk patients, skin testing performs better.

 Are there situations where you'd recommend maintaining the allergy label even after a negative workup?

: Sometimes a patient requests it. I do a test and don't see an allergy, but the patient doesn't want to take penicillin again because overnight they had signs of an adverse effect, like a headache or a fever, something non-allergic. Then I discuss leaving it in the chart as an adverse effect, specifying it was headache only.

Another common scenario is patients feeling subjective itching without a rash. Itching alone is not an allergy, and I'd feel comfortable removing the label, but if the patient doesn't, I revise it to say “itching only,” not a full contraindication, to communicate to future doctors that I wasn't concerned about a significant reaction.

Watch the interview series with Kimberly Blumenthal, MD, here:

What's Behind Perioperative Anaphylaxis? Cefazolin

Hidden Operating Room Allergens: Dyes, Implants, Chlorhexidine, Overwash

Blumenthal K. Perioperative Anaphylaxis. Eastern Allergy Conference. Accessed July 2026. 

Magpantay G, Cardile AP, Madar CS, Hsue G, Belnap C. Antibiotic desensitization therapy in secondary syphilis and Listeria infection: case reports and review of desensitization therapy. 

Articles

Perioperative care frequently involves patients carrying drug allergy labels that can compromise anesthesia, analgesia, and antimicrobial prophylaxis. Contemporary guidance supports routine cefazolin use despite penicillin allergy histories, with antibiotics and neuromuscular blockers remaining the leading intraoperative anaphylaxis culprits. Underrecognized triggers include dyes, implant coatings, latex, and increasingly chlorhexidine after repeated pre-op exposure. Management hinges on prompt recognition and epinephrine in a highly controlled environment. Penicillin delabeling is broadly appropriate, favoring direct challenge in low-risk patients and skin testing for higher-risk profiles.

In this Q&A following EAC 2026, Blumenthal discusses perioperative anaphylaxis risk stratification, hidden OR triggers, and penicillin allergy de-labeling.

Culprits in Perioperative Allergy, With Kimberly Blumenthal, MD

Most Penicillin Allergy Labels Are Wrong, Blumenthal Says

label are not actually allergic, and clinicians should treat that label as a diagnosis in need of revisiting rather than a permanent fixture in the chart, according to Kimberly Blumenthal, MD, MSc, professor of medicine at Mayo Clinic College of Medicine and Science.¹ In an interview with

, Blumenthal said the label itself carries measurable harm, including greater rates of 

 infection, MRSA, and surgical site infections within 5 years of documentation.

Blumenthal said the strength of the recommendation for testing or delabeling depends heavily on how recently the reaction occurred. Patients reporting a reaction within the past few years may warrant confirmatory testing. Those citing a childhood reaction relayed secondhand, often decades old, are typically strong candidates for direct delabeling with little to no testing.

“We're talking 50, 60, 70 years ago,” Blumenthal said. “With all of that time that has passed, the likelihood of them being allergic is quite low.”

Risk Stratification Now Drives the Testing Pathway

The approach to confirming or removing a penicillin allergy label has shifted substantially since the 2009 FDA approval of the major determinant skin test reagent, Blumenthal said. Early widespread skin testing revealed that the test performs poorly in low-risk patients, generating false positives, while emerging safety data showed that direct drug challenges work well in that same low-risk group. Pooled data across thousands of pediatric challenges have shown reaction rates of roughly 3.5% to 6%, supporting direct challenge as the preferred pathway for lower-risk patients while reserving skin testing for higher-risk cases.

“If you are a lower-risk patient, direct drug challenge is the most effective way of getting that penicillin allergy label safely removed,” Blumenthal said. “If you're a higher-risk person, you should be focusing on skin testing.”

That shift toward direct oral challenge in low-risk patients is reflected in a 2024 systematic review and meta-analysis, which pooled 12 studies and found that direct drug challenge safely delabeled 97.13% of previously labeled patients, with no critical adverse events.

 Only 10 of 1070 participants developed mild immediate reactions.

Some Labels Stay in Modified Form, Even After Negative Testing

Blumenthal said a negative workup does not always mean the allergy label disappears entirely. When patients report symptoms like isolated itching or a headache without objective signs of an allergic reaction, she often revises the label to specify the milder concern rather than removing it outright.

“I would feel comfortable removing the allergy, but the patient doesn't,” she said. “In those cases, I revise the allergy label to say itching only—not a full contraindication to taking this medication again. I tried to specify in the comments to communicate to future doctors that I wasn't concerned that this patient was going to have a significant reaction.”

Check out parts 1 and 2 of our interview with Blumenthal here: 

What's Behind Perioperative Anaphylaxis? Cefazolin Tops the List

Hidden Operating Room Allergens: Dyes, Implants, Chlorhexidine Overwash

Blumenthal KG, et al. Penicillin allergy delabeling: a multidisciplinary opportunity. 

https://pmc.ncbi.nlm.nih.gov/articles/PMC8019188/

Blumenthal KG, Smith LR, Mann JTS, et al. Reaction Risk to Direct Penicillin Challenges: A Systematic Review and Meta-Analysis. 

Safe penicillin allergy delabeling in primary care: a systematic review and meta-analysis. 

https://www.jaci-inpractice.org/article/S2213-2198(24)00640-8/abstract

Videos

Kimberly Blumenthal, MD, discusses who qualifies for de-labeling and how risk stratification guides testing.

Underrecognized Exposures Complicate the Workup

 often traces back to agents that never make it into the medical record. Kimberly Blumenthal, MD, MSc, a professor of medicine at the Mayo Clinic College of Medicine and Science, told 

 that surgical dyes, antibiotic-coated implantable devices, and latex exposure from a surgeon's gloves or an all-latex operating room are all potential culprits that are inconsistently documented, leaving allergists to reconstruct exposures after the fact.

Blumenthal singled out chlorhexidine gluconate, the disinfectant used to clean the skin before incision, as an emerging cause of perioperative anaphylaxis. She noted that patients are sometimes instructed to wash with chlorhexidine for several days before surgery and are washed again on arrival, a repeated-exposure pattern that can sensitize patients before they ever reach the operating room. A recent case report similarly describes chlorhexidine as increasingly recognized as a perioperative anaphylaxis trigger capable of producing both immediate and delayed hypersensitivity reactions after repeated antiseptic exposure.¹

The OR Is a Controlled Setting for Treatment

Once anaphylaxis is recognized, Blumenthal said the operating room is one of the safer places for it to occur.

“It's the safest place to have anaphylaxis,” she said. “Maybe the allergist office is equally safe, but the anesthesia room patients are either already intubated or can be intubated, so they can have their airway protected. They have lines…of access intravenously to be able to administer medications. Once it's detected, the treatment is very easy…because they have access to all the medicines that are needed.”

The anesthesia team has immediate access to epinephrine and vasopressors such as norepinephrine and phenylephrine, steroids, and antihistamines.

The harder problem is recognition. Blumenthal explained that surgical drapes can hide a rash, and hypotension has a broad differential that includes routine medication side effects rather than allergy. A recent narrative review of perioperative anaphylaxis echoed this diagnostic challenge, noting that cutaneous findings may be absent, delayed, or concealed by drapes while hypotension, bronchospasm, and desaturation can stem from multiple causes occurring within minutes of each other.² Even when treatment goes smoothly, a reaction typically forces the procedure to be rescheduled.

Counseling Patients Without a Confirmed Culprit

When testing fails to identify a cause, Blumenthal said allergists rely on what negative results are available. Negative skin tests to specific agents support using those drugs again, ideally with a test dose that introduces a small amount first, followed by observation before the remaining dose is given.

Where no culprit is confirmed, Blumenthal said allergists can still recommend an alternative agent based on which exposure seems statistically or clinically most likely, such as switching neuromuscular blocking agents to succinylcholine. She said this guidance, while imperfect, generally allows patients to proceed through subsequent surgeries safely.

Read part 1 of our interview with Blumenthal on common triggers of perioperative anaphylaxis here: 

Sandoval Morales F, Pelletier F, Aubin F, Castelain F. Chlorhexidine-Induced Contact Anaphylaxis. 

Perioperative anaphylaxis: preparing for the next rocuronium, chlorhexidine, or antibiotic reaction. GlobalRPH. Published 2026. 

https://globalrph.com/2026/07/perioperative-anaphylaxis-preparing-for-the-next-rocuronium-chlorhexidine-or-antibiotic-reaction/

Kimberly Blumenthal, MD, MSc, explains how surgical dyes, antibiotic-coated implants, and more can trigger perioperative anaphylaxis without appearing in the chart.

Kimberly Blumenthal, MD, from Mayo Clinic, outlined how clinicians can approach drug allergy risk stratification ahead of surgery and identify the most likely triggers when 

occurs in the operating room. Blumenthal presented on perioperative anaphylaxis and beta-lactam allergy earlier this year at the 

Most Surgical Patients Carry At Least 1 Drug Allergy Label

Blumenthal noted that most patients undergoing surgery have ≥ 1 documented drug allergy, whether a childhood penicillin allergy, a reaction to a pain medication, or an adverse effect from ibuprofen or an opioid. She said the labels that matter most before an operation are ones that could interfere with anesthesia, such as a reported allergy to lidocaine, propofol, fentanyl, or versed.

Pain management after surgery is another consideration, since clinicians need to know whether a patient has an opioid or NSAID allergy on record. Antibiotic allergies are also central to preoperative planning because most surgeries require a prophylactic antibiotic to prevent infection at the incision site.

“[Collecting] the allergy history for all patients with drug allergy labels before surgery is important,” Blumenthal said. “Things that have significant reactions you might want to avoid. Things that are lower risk, [or] moderate risk, we could potentially test using a combination of skin testing and drug challenge tests.”

Penicillin Allergy History Should Not Exclude Cefazolin Use

Cefazolin, marketed as Ancef, is the most commonly used antibiotic for surgical prophylaxis and belongs to the cephalosporin class. Blumenthal said many patients report a childhood cephalosporin reaction to drugs such as cephalexin or cefadroxil, which raises questions about cross-reactivity in patients with a penicillin allergy history.

She pointed to recent data showing no meaningful cross-reactivity between penicillin and cefazolin.

 As a result, she said nearly all patients with a penicillin allergy label can safely receive cefazolin in the operating room, and lower-risk or moderate-risk labels can often be clarified with skin testing or drug challenge testing before surgery. Blumenthal's own research has shown that patients with dual allergies to penicillin and cefazolin are rare and that a reported penicillin allergy is linked to a higher surgical site infection risk when it leads clinicians to avoid first-line prophylaxis.

Identifying The Culprit Drug in Perioperative Anaphylaxis Remains Difficult

Perioperative anaphylaxis may be challenging to work up because multiple medications are typically administered within a short window during an operation, unlike a standard drug challenge where a single agent is given and monitored. Blumenthal said allergists often rely on the anesthesia report to establish a precise timeline of when each drug was given relative to the onset of the reaction, which helps narrow the list of likely culprits.

“We really don't get to see what causes it in all of the patients,” she said.

With testing, causative agents are identified in only about a third to half of patients who are evaluated by an allergist after a perioperative reaction. Blumenthal said antibiotics, most often cefazolin, appear to be the leading cause in the United States.

Neuromuscular blocking agents used to induce paralysis during surgery are a close second, though these reactions often stem from direct mast cell activation rather than a typical IgE-mediated mechanism. This makes them harder to test for and diagnose, Blumenthal said.

Management of penicillin allergy in the perioperative setting. 

Blumenthal KG, Ryan EE, Li Y, Lee H, Kuhlen JL, Shenoy ES. The impact of a reported penicillin allergy on surgical site infection risk. 

Khan DA. Perioperative hypersensitivity: recognition and evaluation to optimize patient safety. Anesthesia Patient Safety Foundation. Accessed July 2026. 

https://www.apsf.org/article/perioperative-hypersensitivity-recognition-and-evaluation-to-optimize-patient-safety/

Kimberly Blumenthal, MD, explains how to risk-stratify drug allergy labels before surgery and identify likely culprits in perioperative reactions.