Comment

Tackling the burden of β-lactam allergy labels

Philip H Li, Kimberly G Blumenthal

Lancet Infect Dis 2025; 25: 834-835

Physicians frequently encounter patients who report suspected drug allergies. Many physicians adopt a cautious approach by labelling these unverified drug allergies in their medical records, which often results in patients avoiding the drugs indefinitely. However, it has been recognised that unverified β-lactam allergy labels (BALs), especially penicillin allergy labels, are associated with a multitude of adverse outcomes.

In The Lancet Infectious Diseases, Mengyuan Fu and colleagues¹ consolidate the international literature regarding the negative effects of BALs in a systematic review and meta-analysis. Patients with BALs need to use alternative antibiotics to β-lactams, which are often less effective and carry more adverse effects. In this review of 63 primary studies, BALs were found to be associated with an increased risk of surgical site infection, rates of infection or colonisation with multidrug-resistant organisms (MDRO) and Clostridioides difficile infections, and length of hospitalisation. BALs were also associated with death at or after 180 days but not with overall, in-hospital, or 30-day mortality. With the ever-growing crisis of antimicrobial resistance, these findings underscore the urgent need for public health interventions to tackle the global burden of unverified BALs. And now we ask, what comes next and which strategies are effective for tackling the burden of BALs?

Although reported BALs are common, proven β-lactam allergies are rare. Removing incorrect BALs (known as delabelling) has become a cornerstone of cost-effective antibiotic optimisation and stewardship and can improve antibiotic prescribing. In the USA and Europe, penicillin allergy testing can result in savings of US$657 for each inpatient encounter and $2746 for each outpatient encounter.² However, the long-term benefits of delabelling have been less well studied, and further prospective research is needed to determine whether there are direct improvements in rates of MDRO infection or colonisation or other adverse consequences following delabelling.

Traditional β-lactam allergy testing involves skin tests followed by drug challenges and has been the standard for decades. However, limited access to allergy specialists and resources remains a substantial barrier in many countries. Direct penicillin challenges without previous auxiliary testing has gained popularity for low-risk patients. Although the perceived risk of reactions remains a barrier to performing direct penicillin challenges, reactions occur at rates comparable to those seen with skin testing followed by direct penicillin challenge.³ In a 2024 systematic review and meta-analysis of 56 primary studies involving 9225 participants with penicillin allergy labels globally, just 438 experienced reactions to direct penicillin challenges, corresponding to an overall meta-analytic frequency of 3·5%.³ These data illustrate that the most crucial aspect of a drug allergy evaluation is the drug allergy history and the clinician's risk assessment, rather than the necessity for specialised allergy tests. As such, various international recommendations have been published to define so-called low-risk criteria and guide direct penicillin challenges for penicillin allergy delabelling.4, 5

However, it is important to note that a one-size-fits-all global delabelling strategy is unlikely to exist. Therefore, different regions and settings have tailored recommendations based on their specific drug allergy epidemiology, access to allergy resources, and medical infrastructures. In regions that are particularly resource-constrained and with few allergists, recommendations have encouraged non-allergists (eg, trained doctors, nurses, and pharmacists) to perform penicillin allergy delabelling independently.4, 6 For example, among low-risk individuals with a penicillin allergy label in Hong Kong, a head-to-head comparison between allergists and non-allergists showed comparable effectiveness and safety.⁷ Other regions have other ongoing delabelling initiatives led by non-allergists, with results informing approaches across different regions of the world.⁶

The systematic review and meta-analysis by Fu and colleagues highlighted that most studies were conducted in high-income countries, specifically in the Americas and Europe.¹ However, the challenge of unverified BALs and their associated adverse effects are a global concern. For instance, non-evidence-based allergy practices in China, such as requiring pre-emptive skin tests before first prescription of penicillins, exacerbate mislabelling and likely contribute to one of the world's largest sources of BALs.⁸ There is also a pressing need for further research on the prevalence and effects of BALs in low-income and middle-income countries.⁹ Interventions to prevent antibiotic mislabelling could be most effective when targeted towards populations at higher risk of mislabelling, such as children or individuals who are immunocompromised, and when they engage and educate non-specialists. Drug allergy education interventions based on evidence have shown promise in enhancing knowledge and empowering better drug allergy practices among non-specialists.¹⁰ Future interventions should harness modern technologies, such as web-based or smartphone-based applications or artificial intelligence-assisted simulations, to enable the broader implementation of drug allergy education and delabelling programmes and, hopefully, reduce β-lactam allergy mislabelling.

The burden of BALs remains high and will require ongoing international efforts to overcome. Crucial to this endeavour are multidisciplinary collaborations, novel delabelling strategies, and improved drug allergy education, all of which are essential for enhancing global antimicrobial stewardship.