What's Behind Perioperative Anaphylaxis? Cefazolin Tops the List

Kimberly Blumenthal, MD, outlined how clinicians can approach drug allergy risk stratification ahead of surgery and identify the most likely triggers when anaphylaxis occurs in the operating room. Blumenthal presented on perioperative anaphylaxis and beta-lactam allergy earlier this year at the Eastern Allergy Conference (EAC) 2026, held May 28-31 in Palm Beach, Florida.¹

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.² 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.³

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.⁴

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.

Blumenthal has no reported disclosures.

References

1. Blumenthal K. Perioperative Anaphylaxis. Eastern Allergy Conference. Accessed July 2026. https://easternallergyconference.org/

2. Management of penicillin allergy in the perioperative setting. Antibiotics (Basel). 2024;13(2):157. https://www.mdpi.com/2079-6382/13/2/157

3. Blumenthal KG, Ryan EE, Li Y, Lee H, Kuhlen JL, Shenoy ES. The impact of a reported penicillin allergy on surgical site infection risk. Clin Infect Dis. 2018;66(3):329-336. https://doi.org/10.1093/cid/cix794

4. 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/