Discussion

Penicillin allergy labels (PAL) are ubiquitous and associated with increased morbidity, mortality, and cost. Direct provocation testing is the gold standard for removing or verifying penicillin allergy, as skin testing and in vitro tests alone do not demonstrate 100% sensitivity or specificity. ^{Reference Cooper, Harbour, Sneddon and Seaton7} Challenging low-risk penicillin allergies via single-dose DOPT is safe, as shown by our study of over 1700 patients with zero severe reactions (anaphylaxis, angioedema, need for epinephrine) and a low rate of any reaction (3.7%). This low-risk profile contrasts with the significant risks of maintaining a false penicillin allergy label, such as increased use of broad-spectrum antibiotics, Clostridium difficile infections, and increased healthcare costs. ^{Reference Blumenthal, Lu, Zhang, Walensky and Choi2,Reference Blumenthal, Lu, Zhang, Li, Walensky and Choi3}

Our findings are consistent with a previously published meta-analysis and systematic reviews by Powell, Cooper, and Blumenthal et al, all of which reported that DOPT in low-risk patients was associated with very low rates of severe reactions. ^{Reference Powell, Stephens and Kohl6–Reference Blumenthal, Smith and Mann8} Our study adds significant value by focusing solely on a single-dose, nongraded DOPT performed by a nonallergist. Our inclusion and exclusion criteria were intentional. First, we aimed for simplicity. Despite the several well-designed systematic reviews and meta-analyses, the 2022 drug allergy guidelines found insufficient evidence to recommend a particular DPT protocol over another. ^{Reference Khan, Banerji and Blumenthal10} Similarly, a 2023 study found ∼ 50% of patients believed their PAL were permanent, while only 4% of primary care providers referred low-risk PAL patients for testing. ^{Reference Coleman, Stone, Wei and Phillips11} Second, we selected the least resource-dependent protocol. In resource-limited areas, a single dose of amoxicillin at 250 mg would enable twice as many patients to undergo DOPT as an amoxicillin 500 mg protocol would. Similarly, the longer the observation period (60 mins vs 120 mins, e.g.,), the fewer patients a single provider can evaluate and the less likely a patient is willing or able to undergo the testing. Thus, at the cost of excluding additional studies and a larger sample size, we gained simplicity, with the hope of improving scalability.

There are several limitations to our study. The primary limitation is the lack of a comparator group. While we demonstrate the safety of single-dose DOPT, we cannot directly compare its effectiveness to other delabeling strategies, such as skin testing followed by oral challenge. When considering this limitation from an effectiveness perspective, it is important to remember that DPT is the gold standard for allergy testing; any patient who undergoes skin testing still requires DPT. Similarly, the recently published PALACE trial mitigates this limitation from a safety perspective. ^{Reference Copaescu, Vogrin and James12} This randomized controlled trial found no difference in the rate of severe reactions between single-dose DOPT in low-risk patients and those who underwent skin testing + DOPT. ^{Reference Copaescu, Vogrin and James12} Next, as all of the studies were observational with no comparator, they were at risk for selection bias. The investigators may have consciously or unconsciously selected patients with PALs who were at lower risk than the general population. Lastly, while all the included studies used risk stratification tools with similar criteria, there was no consensus on defining a low-risk patient. Moving forward, we recommend uniformly adopting the PEN-FAST assessment tool, given that it is the only scoring system validated in a randomized controlled trial. Therefore, our findings cannot and should not be extrapolated to high-risk patients for true penicillin allergy.

Despite these limitations, our findings provide compelling evidence for the safety and feasibility of single-dose DOPT by nonallergists in low-risk patients. This approach has the potential to significantly improve penicillin allergy delabeling rates, reduce the burden of false PAL, and improve patient outcomes. Healthcare providers should feel comfortable evaluating and challenging low-risk penicillin allergies using this simplified protocol. Future research should focus on implementing this approach in broader clinical settings, evaluating its cost-effectiveness, and assessing long-term outcomes.