SGEM#452: I’m Still Standing – After the Allergy Challenge - The Skeptics Guide to Emergency Medicine

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Date: September 12, 2024

Reference: Anderson et al. Full dose challenge of moderate, severe and unknown beta-lactam allergies in the emergency department. AEM August 2024.

Guest Skeptic: Dr. Kirsty Challen is a Consultant in Emergency Medicine at Lancashire Teaching Hospitals.

Case: It’s another day, another dollar in the emergency department (ED). The next patient is a 63-year-old woman with a cough and fever. After assessment, you diagnose her with pneumonia. You would normally prescribe ceftriaxone but during your assessment, she told you she had a bad reaction to amoxicillin in her twenties, with widespread hives and some facial swelling. You wonder if she could have an allergy challenge dose of ceftriaxone in the ED.

Background: Penicillin allergies are among the most reported drug allergies, with estimates suggesting that up to 10% of the US population claims to have a penicillin allergy. These “allergies” are often poorly documented and could potentially be more accurately described as intolerance [1]. However, once the penicillin allergy gets entered into the Electronic Health Record (EHR) it can last for years, despite up to 80% of penicillin allergies waning over 10 years [2].

In addition, the reliability of self-reported allergy to penicillin is highly questionable, especially in acute care settings where rapid decision-making is essential. A substantial body of evidence indicates that over 90% of individuals who report a penicillin allergy are not truly allergic. The mislabeling of penicillin allergy often leads to the unnecessary use of alternative antibiotics, which can be more expensive, less effective, and contribute to the development of antibiotic resistance.

Emergency Physicians frequently encounter ED patients with self-reported penicillin allergies. This scenario presents a unique challenge, as these patients may require immediate antibiotic therapy, and providers often have limited time to verify the accuracy of the reported allergy. Consequently, clinicians may resort to broad-spectrum or second-line antibiotics, which can be less ideal due to higher costs, a broader spectrum of activity, or increased adverse effects.

A pivotal study by Raja et al. highlighted that more than 90% of self-reported penicillin allergies in an ED setting were false positives when tested with penicillin skin testing, underscoring the need for reliable allergy verification methods in acute care [3].

Getting labelled as having a penicillin allergy not only restricts the use of penicillin but also limits the use of all beta-lactam antibiotics. Some authorities continue to warn about the potential cross-reactivity and ‘bio-similar sidechains’. However, recent changes in the understanding of beta-lactam allergy suggest that allergy may be driven by the R1 side chain of the antibiotic molecule rather than the beta-lactam ring [4]. It is therefore practical to use a full-dose beta-lactam challenge to support first-line beta-lactam use for antibiotic stewardship [5].

Dr. Eric Macy an allergist from San Diego gives a good historical account of how this myth about cross-reactivity developed [6]. If our American listeners are concerned about their medical-legal exposure of providing a beta-lactam to a patient with a reported penicillin allergy there is a systematic review of legal cases that may decrease the litigation fears of some clinicians [7]. Finally, there is a very good study done at the Kaiser Health system. Dr. Macy’s team removed the automated penicillin-cephalosporin cross-reactivity electronic health record (EHR) warnings in one large region. The result was an increase in cephalosporin use but no significant differences in anaphylaxis, new allergies, treatment failures or all-cause mortality.

The use of direct oral challenges has been tried in the intensive care unit (ICU) setting to de-label patients. Koo et al showed that offering amoxicillin oral challenges to ICU patients with low-risk penicillin allergies resulted in successful de-labeling for a significant proportion of patients without triggering severe allergic reactions [8].

However, this oral challenge to de-label beta-lactam patients has not yet been evaluated in an ED setting. This seems strange as we are probably the best equipped and skilled part of a hospital to identify and manage an allergic reaction!

With the growing emphasis on antimicrobial stewardship, there is an increased push to accurately assess and, where appropriate, remove penicillin allergy labels, especially in acute and critical care settings. By refining our approach to managing self-reported penicillin allergies, emergency medicine can improve antibiotic selection, reduce unnecessary healthcare costs, and combat the rising challenge of antibiotic resistance.

Clinical Question: What are the outcomes of patients with documented moderate, severe or unknown beta-lactam allergies challenged with a full-dose administration of a beta-lactam antibiotic in the ED?

Reference: Anderson et al Full dose challenge of moderate, severe and unknown beta-lactam allergies in the emergency department. AEM August 2024.

Population: Adult patients with documented moderate, severe or unknown beta-lactam allergy who received a full-dose beta-lactam allergy challenge in the ED January 2021 – December 2022.
- Excluded: Documented mild allergy or intolerance, previously documented tolerance to another beta-lactam.
Intervention: Full-dose beta-lactam allergy challenge.
Comparison: There was no comparison group.
Outcomes:
- Primary Outcome: Allergic reaction to beta-lactam challenge.
- Secondary Outcomes: Timing of any adverse reaction, whether the beta-lactam antibiotic was continued by the in-patient service, duration of hospital stay, documentation of the challenge and response.
Type of Study: Retrospective observational cohort study.

Dr. Adam Anderson

This is an SGEMHOP, and we are pleased to have the lead author, Dr. Adam Anderson on the show. Dr. Anderson is a Clinical Associate Professor of Emergency Medicine at Michigan State University College of Human Medicine. He works clinically as an emergency medicine attending physician at Trinity Health in Grand Rapids, Michigan. In this capacity, he is also Associate Program Director, Critical Care Track Director, and Global Health Track Assistant Director for the Trinity Health West Michigan Emergency Medicine Residency Program.

Authors’ Conclusions: “Full-dose direct challenge of beta-lactam allergies in patients with documented moderate, severe, or unknown beta-lactam allergies can be safely done in an ED with the support of a robust antimicrobial stewardship program.”

Quality Checklist for Observational Cohort Studies:

Did the study address a clearly focused issue? Yes
Did the authors use an appropriate method to answer their question? Yes
Was the cohort recruited in an acceptable way? Yes
Was the exposure accurately measured to minimize bias? Yes
Was the outcome accurately measured to minimize bias? Unsure
Have the authors identified all-important confounding factors? No
Was the follow-up of subjects complete enough? Yes
How precise are the results? Precise enough.
Do you believe the results? Yes
Can the results be applied to the local population? Yes
Do the results of this study fit with other available evidence? Yes
Funding? The authors have not declared any external funding or conflicts of interest.

Results: They included 184 participants in this study. The median age was 68 years, 65% female, and most patients were treated for pneumonia (36%) or urinary tract infections (32%). 90% of patients had a documented penicillin allergy, 7% had a cephalosporin allergy, and 3% had allergies to both penicillin and cephalosporin. Severe allergies were documented in 13% of patients, moderate in 43%, and unknown in 44%.

Key Result: Few participants (3%) experienced an allergic reaction after the beta-lactam challenge; none of these was an anaphylactic reaction.

Primary Outcome: Of the 184 ED encounters with full-dose beta-lactam challenges, only 5 patients (2.7%) experienced an allergic reaction after the challenge.
Secondary Outcomes:
- Among the patients experiencing an allergic reaction, one reaction (0.5%) occurred in the ED, and the remaining four reactions (2%) occurred after admission.
- No anaphylactic reactions were reported; all allergic reactions were limited to mild symptoms such as rash or itching.
- Most patients (99%) were challenged with a cephalosporin, and a beta-lactam was continued in 86% of cases after admission.
- The median length of hospital stay for these patients was reported as 5 days. However, the study did not compare this duration to a control group or assess changes specifically attributed to the intervention.

Listen to the SGEM podcast to hear Adam’s response to our five nerdy questions.

1. Retrospective design: You’ve recognized that there are limitations to using a retrospective observational study design rather than collecting data prospectively or doing a formal implementation study. Do you have any insights into what was happening before your study period, and what happens now?

2. Recruitment: From Figure 1 in the paper, it seems that you had 850 adults who initially met your inclusion criteria of documented allergy, beta-lactam in the ED and subsequent hospitalization. Only five seem to have declined the challenge dose in the ED, which suggests you have a well-established method of shared decision-making (and we like shared decision-making on the SGEM). Can you tell us more about it?

3. Outcomes: You had a robust method of chart review with a structured explicit data extraction form and a second investigator auditing a subset of the charts. However, you can only extract what is in the chart in the first place. Did you as a research team find missing or ambiguous data in the EHR was a challenge?

4. Confounding Factors: You didn’t have the opportunity to collect data on some confounding factors like family history of allergy, multiple antibiotic allergies, and atopic tendencies. Do you think these would be important to a clinician thinking of replicating your approach somewhere else?

5. Medical Records: Despite your established antibiotic stewardship program documenting the results of the allergy challenges, over a quarter of the patients didn’t have the allergy section of the EHR updated. Why do you think this is and do you have any suggestions for improving that?

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors’ conclusions.

SGEM Bottom Line: It is reasonable to offer a full-dose beta-lactam challenge to a patient with previously documented beta-lactam allergy in the ED and doing this has potential benefits for antibiotic stewardship.

Dr. Kirsty Challen

Case Resolution: You talk to the patient about the low rates of cross-reactivity between amoxicillin and ceftriaxone and she agrees to have a test dose of ceftriaxone in the ED. You ensure that this is administered in a closely monitored area and take the opportunity to explain to your nursing colleagues caring for her your rationale.

Clinical Application: You put an item on the agenda for the next ED staff meeting to work with your pharmacy and ID colleagues to formalize an antibiotic challenge policy.

Keener Kontest: Last week’s winner was Robby Allen. He knew one of the serious complications of consecutive rib fractures was a flail chest.

Listen to the SGEM podcast for this week’s question. If you know, then send an email to thesgem@gmail.com with “keener” in the subject line. The first correct answer will receive a shoutout on the next SGEM episode.

SGEMHOP: Now it is your turn SGEMers. What do you think of this episode on beta-lactam allergies? Tweet your comments using #SGEMHOP. What questions do you have for Adam and his team, ask them on the SGEM blog. The best social media feedback will be published in AEM.

Adam was kind enough to share additional information from this study. Click on the link to download the files:

REMEMBER TO BE SKEPTICAL OF ANYTHING YOU LEARN, EVEN IF YOU HEARD IT ON THE SKEPTICS’ GUIDE TO EMERGENCY MEDICINE.

References:

Albin S, Agarwal S. Prevalence and characteristics of reported penicillin allergy in an urban outpatient adult population. Allergy Asthma Proc. 2014;35(6):489-494.
Khan DA, Banerji A, Blumenthal KG, et al. Drug allergy: a 2022 practice parameter update. J Allergy Clin Immunol. 2022;150(6):1333-1393.
Raja AS, Lindsell CJ, Bernstein JA, Codispoti CD, Moellman JJ. The use of penicillin skin testing to assess the prevalence of penicillin allergy in an emergency department setting. Ann Emerg Med. 2009 Jul;54(1):72-7. doi: 10.1016/j.annemergmed.2008.12.034. Epub 2009 Feb 13. PMID: 19217696; PMCID: PMC8215513.
Chaudhry SB, Veve MP, Wagner JL. Cephalosporins: a focus on side chains and β-lactam cross-reactivity. Pharmacy. 2019;7(3):103.
Kuruvilla M, Shih J, Patel K, Scanlon N. Direct oral amoxicillin challenge without preliminary skin testing in adult patients with allergy and at low risk with reported penicillin allergy. Allergy Asthma Proc. 2019;40(1):57-61.
Macy E. Why Was There Ever a Warning Not to Use Cephalosporins in the Setting of a Penicillin “Allergy”? J Allergy Clin Immunol Pract. 2021 Nov;9(11):3929-3933. doi: 10.1016/j.jaip.2021.06.059. Epub 2021 Jul 22. PMID: 34303019.
Jeffres MN, Hall-Lipsy EA, King ST, Cleary JD. Systematic review of professional liability when prescribing β-lactams for patients with a known penicillin allergy. Ann Allergy Asthma Immunol. 2018 Nov;121(5):530-536. doi: 10.1016/j.anai.2018.03.010. Epub 2018 Mar 15. PMID: 29551402.
Koo G, Stollings JL, Lindsell C, Dear ML, Kripalani S, Nelson GE, McCoy AB, Rice TW, Phillips EJ, Stone CA Jr; Vanderbilt University Medical Center Learning Healthcare System. Low-risk penicillin allergy delabeling through a direct oral challenge in immunocompromised and/or multiple drug allergy labeled patients in a critical care setting. J Allergy Clin Immunol Pract. 2022 Jun;10(6):1660-1663.e2. doi: 10.1016/j.jaip.2022.01.041. Epub 2022 Feb 5. PMID: 35131513; PMCID: PMC9188986.