The PALACE Trial: Rethinking How to Assess, Document, and Code New Penicillin Allergies

This transcript has been edited for clarity.

Hello. I'm Kevin Fernando, a GP working near Edinburgh, in Scotland, and content advisor for Medscape Global and UK. Welcome to our new podcast, Medical Mentor, a bite-sized regular chat for all of us working in primary care. Podcasts will cover hot topics, practice pearls and hacks, and pitfalls to avoid, helping make our lives a little bit easier in primary care but ultimately helping improve the lives of our patients.

In this podcast, I'm going to talk about penicillin allergy in primary care — specifically, the consequences of errantly coded penicillin allergies and what we can do to rectify this, focusing on the practice-changing PALACE randomized, controlled trial, published during 2023.

I hope to convince you that an erroneously coded penicillin allergy is not a benign matter and has implications on quality of life and potentially quantity of life, too.

Let me start by setting the scene. It was during 1928 that Sir Alexander Fleming (a Scottish doctor, I'm proud to say) discovered that penicillin fungus had accidentally contaminated a staphylococcal petri dish in his lab, and that this fungus had created a bacteria-free circle around itself. He named the active substance of this fungus "penicillin." The rest is history, as they say.

In 1945, Fleming and his colleagues Ernst Boris Chain and Howard Florey were jointly awarded the Nobel Prize in Medicine for the discovery of penicillin and its curative effects in various infectious diseases. There is no doubt that penicillin has helped save millions of lives globally over the subsequent decades.

However, penicillin is also the most common drug allergy documented in medical records, with a prevalence ranging from 6% to 25% in the developed world. In the United Kingdom, it's estimated that 10% of the population have a reported penicillin allergy; however, less than 1%-2% of these individuals are truly allergic to penicillin.

Most penicillin allergies in adults relate to mild symptoms that occurred when they were children. Moreover, most individuals with a documented penicillin allergy had no immediate hypersensitivity reaction to penicillin (for example, urticaria, pruritus, or angioedema or anaphylaxis) within 1-6 hours of penicillin administration.

Also, most individuals had no evidence of a severe cutaneous adverse reaction, such as Stevens-Johnson syndrome. Instead, often a nonimmunologic phenomenon, such as a viral rash, had been misinterpreted as an allergy, or a drug intolerance, such as a headache, had been miscoded as an allergy.

Current UK guidance recommends that if individuals give a history of a minor rash or a rash that occurs over 72 hours after administration of penicillin, then this is unlikely to be a penicillin allergy, and penicillin should not be withheld unnecessarily.

The first case of penicillin anaphylaxis was reported in 1945. A subsequent report from the World Health Organization in 1968 suggested that the rate of death from anaphylaxis was 0.002%.

A review of 151 deaths secondary to penicillin use found that the onset of symptoms was within 15 minutes in most cases, and the majority of these individuals died within 1 hour of administration of penicillin. Although this loss of life is tragic, hopefully we in primary care can take some reassurance that death from penicillin anaphylaxis is incredibly rare.

Additionally, there is no suggestion that frequency of penicillin allergy has increased over the past 60 years, and it is well established that sensitivity to penicillin fades with time.

What impact does an erroneously coded penicillin allergy have? Well, there is compelling evidence that suspected but unverified penicillin allergy leads to significantly more time in hospital — for example, awaiting culture and sensitivity results for alternative antibiotics to penicillin — and individuals are exposed to the use of broader-spectrum antibiotics, such as clindamycin, vancomycin, and fluoroquinolones such as ciprofloxacin.

These antibiotics have more adverse effects, including higher rates of Clostridioides difficile infection and the development of drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE).

Moreover, increased hospital readmission rates and higher healthcare costs have been observed in those with a penicillin allergy label. You can see that a penicillin allergy label can worsen morbidity and potentially mortality, predominantly secondary to these multiple drug–resistant pathogens.

Additionally, there is still belief among some healthcare professionals that using cephalosporins (for example, cephalexin) in people with penicillin allergy results in increased rates of adverse reactions, further driving use of broad-spectrum antibiotics. We can be reassured, though, that there is only around 10% cross-reactivity with first- and second-generation cephalosporins, such as cefuroxime, and only around 2%-3% cross-reactivity with third-generation cephalosporins, such as cefotaxime.

Given the emergence of multidrug-resistant pathogens and the importance of antibiotic stewardship programs to preserve the effectiveness of antibiotics, we need strategies to reduce incorrectly labeled penicillin allergies in primary care. Current strategies and the current standard of care include skin prick testing followed by clinically supervised oral provocation testing with penicillin. This is resource- and time-intensive and disparately available to us in primary care — which makes, then, for the perfect segue to the PALACE randomized controlled trial (RCT).

The PALACE trial sought to determine whether a direct oral penicillin challenge was noninferior to standard-of-care penicillin skin testing followed by an oral penicillin challenge in people with a low-risk penicillin allergy. Risk for penicillin allergy was assessed using the PEN-FAST score. PEN-FAST is an internationally validated clinical decision tool that we can all use in primary care.

The five components of PEN-FAST start with whether a penicillin allergy (PEN) has been reported by the patient. If so, we can proceed with the decision tool. F: Have 5 years or less elapsed since the penicillin reaction? A is for the presence of anaphylaxis or angioedema alongside the penicillin reaction. S is for a severe cutaneous adverse reaction with penicillin (for example, Stevens-Johnson syndrome or toxic epidermal necrolysis). Finally, T: Was treatment required for the penicillin reaction (for example, treatment with steroids, antihistamines, or adrenaline)?

A PEN-FAST score less than 3 indicates a low risk for a positive penicillin allergy test. There are many online calculators available to calculate the PEN-FAST score, such as Calculate by QxMD.

In all, 382 adults were recruited to the PALACE trial, and they all had a PEN-FAST score of less than 3. In fact, most had a PEN-FAST score of 0 or 1. Of these adults, 187 were randomized to a direct oral penicillin challenge (the intervention arm) and 190 individuals were randomized to standard of care: penicillin skin testing followed by an oral penicillin challenge (the control arm).

What did the researchers find? A positive immune-mediated oral penicillin challenge occurred within 1 hour in one patient in the intervention arm and one patient in the control arm. There was no difference with either strategy.

What about delayed adverse effects? There was no imbalance in total adverse events between both arms of the trial up to 5 days postintervention, or postadministration of penicillin. Importantly, no anaphylaxis or angioedema was observed in either arm of the trial, which is very reassuring for us in primary care.

Subsequent to these PALACE results, a label of penicillin allergy was removed from 186 of 187 patients in the intervention arm, the direct oral penicillin challenge arm, and 186 of 190 patients in the control arm.

Limitations of this study included that only 5% of recruited individuals had a PEN-FAST score of 2, which limits generalizability of the PALACE results. Also, individuals with a history of anaphylaxis to any drug were excluded from this trial.

The authors concluded that a direct oral penicillin challenge in individuals with a low-risk penicillin allergy was noninferior to standard-of-care skin prick testing followed by an oral penicillin challenge, and was therefore a safe procedure to facilitate the delabeling of penicillin allergies.

The PALACE results are practice-changing for us in primary care. The PALACE RCT provides a scalable approach in a wide range of clinical settings to remove unverified penicillin allergy labels in a safe, fast, and economical manner.

This is a call to action for us all in primary care. We need to rethink how we assess, document, and code new penicillin allergies. Remember, if individuals give a history of a minor rash or a rash that occurs over 72 hours after administration of penicillin, then this is unlikely to be a penicillin allergy and it should not be coded as such.

Finally, we should all consider a direct oral penicillin challenge for those with a low-risk, unverified penicillin allergy label, a PEN-FAST score less than 3, which will help limit exposure to broad-spectrum antibiotics; reduce duration of inpatient stay; reduce treatment costs, and, most importantly, reduce morbidity and mortality, improving both quality and quantity of life.

Thank you all for listening. I hope you found this podcast helpful. Please do listen to our future Medical Mentor podcasts, which will be available on all major platforms.

Follow me on X, formerly Twitter, @drkevinfernando, or email me at kfernando@webmd.net if you have any questions, comments, or ideas for future podcasts.

Thank you again for listening.

Medscape Family Medicine © 2024 WebMD, LLC

Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.

Cite this: The PALACE Trial: Rethinking How to Assess, Document, and Code New Penicillin Allergies - Medscape - Feb 14, 2024.