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...