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Are You Up for the Challenge? Updates on Beta-Lactam Allergies

Updated: 17 hours ago

By Kayla C. Godfrey, PharmD and Deanna McDanel, PharmD, BCPS, BCACP


Penicillin allergies are reported by approximately 10% of patients; however, clinically significant IgE-mediated significant reactions are found in less than 5% of patients.(1) Additionally, it has been cited that approximately half of patients with a true IgE-mediated penicillin allergy lose sensitivity 5 years after reacting, and 80% lose sensitivity in 8-10 years.(2)

The American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma, and Immunology (ACAAI) released the Drug Allergy 2022: A Practice Parameter Update providing updates to the prior 2010 guidance. In relation to beta-lactam allergies, this update focused on the de-emphasis on the use of skin testing prior to drug challenge in patients with nonanaphylactic, nonsevere cutaneous drug allergy histories and a role of shared decision-making in evaluation. Additionally, it supports proactive efforts to de-label penicillin allergies to reduce the use of less effective, more toxic, or more costly antibiotics, as well as mitigating longer hospital stays and increased mortality related to the need for alternative antibiotics.(1)

Penicillin Allergy Evaluation

Previous guidance recommended penicillin skin testing (PST) prior to the completion of any drug challenge.(3) The new practice parameter now supports reserving PST for high-risk patients with a history of anaphylaxis or a recent (i.e. <5 years) suspected IgE-mediated reaction (Figure 1). This recommendation is driven by evidence that despite approximately 10% of the population reporting a penicillin allergy, over 90% of these individuals tolerate penicillins.(1) For both pediatric and adult patients with nonanaphylactic and benign cutaneous reactions, such as morbilliform drug eruption (MDE) or hives, occurring >5 years ago (for adults), a direct drug challenge is recommended without the need for a preceding skin testing.

The new practice parameter also emphasizes shared decision-making with patients when determining the appropriate drug allergy testing. Upon obtaining a history, patients should be presented options for testing their allergy. Some patients may be uncomfortable doing a direct oral challenge without prior skin testing. It is reasonable to consider PST to reassure the patient that a subsequent drug challenge is safe. This discussion may also be relevant when patients report non-IgE mediated reactions, such as nausea, diarrhea, or headache, or when they have a label due to a family history of penicillin allergy. Although these patients do not require testing to be de-labeled, patient comfortability should be considered.

Beta-Lactam Cross Reactivity

Cross-reactivity between penicillin and cephalosporins were originally estimated to be 8%.(1) Since this time, several studies have shown cross-reactivity is likely much lower at 2.0 to 4.8%.(1) Additionally, the attention has shifted from the beta-lactam ring to the R1 side chains due to several studies indicating this portion of the molecule more often leads to allergic reactions.(4) For this reason, the structure of beta-lactam antibiotics should be taken into consideration when determining medication administration, as well as appropriate allergy testing strategies.

The biggest practice change in the updated practice parameter is no testing is necessary prior to administering a cephalosporin to a patient with a history of a nonanaphylactic allergic reaction to a penicillin derivative or another cephalosporin (Table 1). Structural similarity needs to be considered when evaluating the use of a cephalosporin in a patient with a history of a nonanaphylactic reaction to another cephalosporin or an anaphylactic reaction to a penicillin. Cephalosporin allergies are not as common as penicillin, and as such the guidance is more conservative for these patients.

A 2019 systematic review looked at the cross-reactivity of carbapenems and other beta-lactams and found the risk was 0.87%.(5) This along with the low incidence of carbapenem allergy (0.3-3.7%) has led to an update in the need for testing prior to administration. Previously PST was advised, but the new parameter suggests administration of a carbapenem without testing or additional precautions in patients with penicillin or cephalosporin allergies.

It is important to recognize that beta-lactam allergy labels are common in the general population; however, the vast majority are not truly allergic. Efforts to de-label can be multidisciplinary and should be initiated by all clinicians, not limited to those from Allergy and Immunology.(6) Identifying individuals who should be offered proactive de-labeling, such as oncology, pre-surgical, pre-transplant, pregnant, and pediatric patients, can be initiated by many health care professionals, including pharmacists. Pharmacists can also play a direct role in obtaining patient drug allergy histories and recommending an approach to de-labeling. For additional resources, visit the AAAAI Penicillin Allergy Center. After reading this, we hope you are up for the challenge to stomp out excessive beta-lactam allergy labels!

Figure 1. Evaluation for Patients with a Penicillin Allergy Label

Table 1. Evaluation Based on Beta-Lactam Drug Allergy Label*

* Note, these are the most common options for evaluation, but other options due exist based on individual patient risk. Please refer to the practice parameter for full details. Khan et al. Drug allergy: A 2022 practice parameter update.


1. Khan DA, Banerji A, Blumenthal KG, et al. Drug allergy: A 2022 practice parameter update. J Allergy Clin Immunol. 2022;150(6):1333-1393. doi:10.1016/j.jaci.2022.08.028.

2. Executive summary of disease management of drug hypersensitivity: a practice parameter. Joint Task Force on Practice Parameters, the American Academy of Allergy, Asthma and Immunology, the American Academy of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol. 1999;83(6 Pt 3):665-700.

3. Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105(4):259-273. doi:10.1016/j.anai.2010.08.002.

4. Banerji A, Solensky R, Phillips EJ, Khan DA. Drug Allergy Practice Parameter Updates to Incorporate Into Your Clinical Practice. J Allergy Clin Immunol Pract. 2023;11(2):356-368.e5. doi:10.1016/j.jaip.2022.12.002.

5. Picard M, Robitaille G, Karam F, et al. Cross-Reactivity to Cephalosporins and Carbapenems in Penicillin-Allergic Patients: Two Systematic Reviews and Meta-Analyses. J Allergy Clin Immunol Pract. 2019;7(8):2722-2738.e5. doi:10.1016/j.jaip.2019.05.038.

6. American Academy of Allergy, Asthma and Immunology. Penicillin Allergy Evaluation Should Be Performed Proactively in Patients with a Penicillin Allergy Label – A Position Statement of the American Academy of Allergy, Asthma & Immunology. Published August 2023. Accessed September 8, 2023.


Kayla C. Godfrey, PharmD

PGY2 Ambulatory Care Pharmacy Resident

University of Iowa Hospitals and Clinics, Iowa City, IA


Deanna McDanel, PharmD, BCPS, BCACP

Clinical Pharmacy Specialist, Ambulatory Care

Clinical Associate Professor

PGY2 Ambulatory Care Pharmacy Residency Program Director

University of Iowa Hospitals and Clinics, Iowa City, IA

University of Iowa College of Pharmacy, Iowa City, IA

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