Table 1:

Approaches to Immediate Hypersensitivity Penicillin Allergy Labels in an Individual Patient

Approach	De-labeling Approach	Strengths	Limitations	Level of Recommendation and Evidence
Select an alternative antibiotic50,61,67,82–88	No	No risk of provoking penicillin reaction in the individual patient	Alternative antibiotic may be less effective than penicillin Adverse effects from 2nd and 3rd line antimicrobials May promote drug resistance over time Does not provide any information on whether the patient can actually take the drug safely. Increased cost to patient and healthcare system	2c, benefits of using alternative agents are unclear, and there are clearly known adverse effects reported across high quality clinical studies. Would suggest use of other approaches
Desensitisation at point of care89–95	No	Patient can typically receive the drug that is needed at the point of care safely	Expensive, time and resource intensive, especially for patients with frequent antibiotic utilization (cystic fibrosis, cancer, immune suppressed) Does not provide any information on whether the patient can actually take the drug safely The majority of patients were not allergic to begin with and there is limited data examining post desensitisation testing to validate need for desensitisation	2c for selected patient populations (see text) but not recommended for general population
De-label using history alone96–98	Yes	Many histories are easily identified as incompatible with true allergy	The risk of many histories has not yet been validated Possibility for faulty memories or mistakes Patients may still be fearful to take the drug without objective testing Nonzero probability of immediate reaction when challenged in the future	2c, randomized clinical trials of this approach are lacking but observational clinical studies have been performed showing benefit. Currently limited by unclear knowledge of when to use this approach
De-label using direct ingestion challenge36,99–105	Yes	Safe testing approach in patients who are at low risk of immediate hypersensitivity Most patients are low risk of true allergy Provides definitive answer on whether the patient is at risk of immediate reaction Least resources used to provide an answer	Least conservative approach Some patients may have reactions during testing	2c, observational studies have been performed particularly in children showing benefit. Currently limited by unclear knowledge of when to use this approach and lack of large studies in adults
De-label using skin testing alone14,106–112	Yes	Negative skin testing using appropriate protocols reduces the pretest probability that a patient will react when challenged	No skin testing strategy has 100% negative predictive value Epidemiology of penicillin allergy has changed with changing patterns of parenteral beta lactam use Inadequate to determine true cross-reactivity patterns Future challenge might not be performed in a controlled setting	2c, randomized clinical trials of this approach are lacking but clinical studies have been performed showing benefit.
De-label using skin testing followed by ingestion challenge14,106–112	Yes	Most conservative testing approach Greatest reduction in probability of reaction prior to oral challenge Provides definitive answer on whether the patient is at risk of immediate reaction	Greatest testing costs (still cost effective compared to maintaining penicillin allergy label) Time and resource intensive Shortage of resources to perform the volume of penicillin skin testing that is currently needed	1b, absence of randomized double blind clinical trials of this approach, but a large body of historical evidence including large prospective cohort studies for its use as the current gold standard approach
Risk stratifying approach36,63,96,113–116	Yes	Assesses individual patient’s history to determine penicillin allergy testing strategy Low risk patients targeted for direct oral challenge Higher risk patients for preceding skin testing Provides definitive answer on whether the patient is at risk of immediate reaction Appropriate allocation of scarce testing resources	Most complex Need for validated risk assessment tools and decision support that have generalizability to different populations	2c, randomized clinical trials of this combination approach are lacking but clinical and quasi-experimental design studies have been performed showing benefit. Possibility for this approach to become a new gold standard

Level of evidence evaluated using the GRADE scoring system⁸¹: A “1” represents a strong recommendation, while a “2” represents weak recommendations/suggestions. “a, b, c,” represent the levels of available evidence, with “a” representing consistent evidence from well performed randomized, controlled trials or overwhelming evidence of some other form. Further research is unlikely to change our confidence in the estimate of benefit and risk. “b” represents evidence from randomized, controlled trials with important limitations (inconsistent results, methodologic flaws, indirect or imprecise), or very strong evidence of some other form. Further research (if performed) is likely to have an impact on our confidence in the estimate of benefit and risk and may change the estimate. “c” represents evidence from observational studies, unsystematic clinical experience, or from randomized, controlled trials with serious flaws. Any estimate of effect is uncertain.