CLEAR-ing Penicillin and Cephalosporin Allergies

This article was reviewed by Society of Infectious Diseases Pharmacists committee members Sara Revolinski, PharmD, BCPS, and Esther Golnabi, PharmD, BCIDP.

Background

β-Lactam allergies are the most commonly reported drug allergies in the United States¹; however, true β-lactam allergies are rare. For example, approximately 10% of the US population reports having a penicillin allergy, but less than 1% are truly allergic.^1,2 Inaccurate allergy labeling leads to utilization of broad-spectrum second-line antimicrobial agents, which may lead to suboptimal treatment outcomes, increased resistance, longer hospital stays, and higher costs.³ Pharmacists are in a unique position to evaluate and address β-lactam allergies by conducting patient interviews, assessing allergy risk, and delabeling allergies when appropriate.

This article describes a practical framework that helps guide pharmacists during the process of assessing and addressing β-lactam allergies by using an easy-to-remember mnemonic, Collect allergy history, Label the risk, Engage decision-making tools, Act on assessed risk, and Reinforce and record (CLEAR).

Step 1: Collect allergy history. Evaluating reported β-lactam allergies involves conducting a detailed patient interview. During these interviews, pharmacists should inquire about the specific antibiotic involved, the nature of the reaction, when the reaction occurred, when the reaction began in relation to the antibiotic administration, how long the reaction lasted, whether any treatment was administered, and whether the patient has previously taken and tolerated other antibiotics following the allergic reaction. In addition to the interview, pharmacists should also review patients’ medical records for any additional objective information, such as antibiotic administration data.

Step 2: Label the risk and Engage decision-making tools. After obtaining the patient’s allergy history and documenting the symptom severity, the next step includes estimating the patient’s risk using clinically validated tools such as the penicillin allergy decision rule (PEN-FAST) or the cephalosporin allergy decision rule (CEPH-FAST). These tools are based on the same criteria and consolidate multiple factors related to the reaction to provide a cumulative score out of 5 and an estimated risk of having a positive allergy test to the index antibiotic (Figure^4,5). Two points are added if the patient experienced the reaction within the last 5 years, 2 points are added if the patient experienced anaphylaxis, angioedema and/or any severe cutaneous adverse reaction, and 1 point is added if the patient required treatment (eg, diphenhydramine, epinephrine) for the allergic reaction.^4,5

Step 3: Act on assessed risk. Once a patient’s risk is assessed and/or decision-making tools are utilized, an appropriate course of action should be recommended and discussed with the treatment team and patient. For example, patients with a PEN- or CEPH-FAST score less than 3 may undergo direct oral challenge, whereas those with a score of 3 or higher are considered moderate to high risk and may proceed with skin testing, desensitization, or use of an alternative antibiotic.^3,6 For patients with histories that are inconsistent with penicillin allergy (eg, headache or family history of penicillin allergy), testing is not required and the patient may be delabeled without oral challenge or skin testing.⁶ Before conducting an oral challenge, skin testing, or desensitization procedure, it is imperative that the patient fully understands and agrees to the recommended procedure.

Step 4: Reinforce and record. Pharmacists should educate patients on the findings of their allergy and on the results of any tests conducted. A wallet card or a written summary may be provided to the patient for future reference. A clear, concise progress note should also be documented in the medical record notes, and technology within the electronic health record should be leveraged to avoid readdition of the delabeled allergy.

Conclusion

Assessing and addressing β-lactam allergies through patient interviews and delabeling are essential for the optimization of antibiotic therapy. Pharmacists are well positioned to lead these efforts and can do so by following the CLEAR framework.

REFERENCES

1. Macy E. Penicillin and beta-lactam allergy: epidemiology and diagnosis. Curr Allergy Asthma Rep. 2014;14(11):476. doi:10.1007/s11882-014-0476-y

2. Bonilla FA, Khan DA, Ballas ZK, et al; Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma & Immunology; and the Joint Council of Allergy, Asthma & Immunology. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015;136(5):1186-1205.e1-78. doi:10.1016/j.jaci.2015.04.049

3. 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

4. Trubiano JA, Vogrin S, Chua KYL, et al. Development and validation of a penicillin allergy clinical decision rule. JAMA Intern Med. 2020;180(5):745-752. doi:10.1001/jamainternmed.2020.0403

5. Cox F, Vogrin S, Sullivan RP, et al. Development and validation of a cephalosporin allergy clinical decision rule. J Infect. 2025:90(6):106495. doi:10.1016/j.jinf.2025.106495

6. Copaescu AM, Vogrin S, James F, et al. Efficacy of a clinical decision rule to enable direct oral challenge in patients with low-risk penicillin allergy: the PALACE randomized clinical trial. JAMA Intern Med. 2023;183(9):944-952. doi:10.1001/jamainternmed.2023.2986