Tiffany Wong MD, FRCPC
Disclosures: I have received honoraria from Stallergenes-Greer and Pfizer. I am a member of Leo Pharma advisory board. I have received funding from PHSA Medical Staff Association Engagement Funding.
Mitigating Potential Bias: Only published trial data is presented. Treatments or recommendations in this article are unrelated to products/services/treatments involved in disclosure statements. Recommendations are consistent with published guidelines. Recommendations are consistent with current practice patterns.
Dr. Raymond Mak
Disclosures: I have received direct financial payments from Novartis (speaker honoraria on asthma) and Pediapharm (speaker honoraria on oral immunotherapy). I am a member of Sanofi – Dupilumab advisory board.
Mitigating Potential Bias: Recommendations are unrelated to the products involved in the disclosure statements and are consistent with current practice patterns.
What I did before
Between 5% to 10% of the population reports an allergy to penicillin. After careful assessment, over 90% of these individuals are found to carry a false allergy label.1 Having a penicillin allergy label carries many potential harms, including prolonged hospital stays, increased patient costs, risk of more side effects, and an increase in resistant organisms.2 As such, penicillin allergy has become a major public health concern.
Penicillin de-labelling, as part of antimicrobial stewardship, has demonstrated a positive impact on patients labelled erroneously with penicillin allergy.3 Given the high prevalence of reported penicillin allergy, the task of “de-labelling” patients is too large for allergists to tackle alone.
As an allergist, in the past, I would routinely skin test every patient with a reported penicillin allergy, regardless of the history provided. Skin testing involves injecting a tiny quantity of penicillin major and minor determinant intradermally and, 10 to 15 minutes later, assessing for the presence of a wheal. It requires specialized training to perform and interpret. It is a safe and highly sensitive procedure to rule out immediate-type reactions that have the potential to progress into anaphylaxis. For patient safety, I would only proceed to oral challenge with amoxicillin if the skin test results were negative. Ultimately, a drug challenge was usually necessary, as it is considered the “gold standard” test for ruling out a drug allergy.
The American Academy of Allergy Asthma and Immunology (AAAAI) published a position statement in 2017 encouraging “a wider spread and routine performance of penicillin allergy testing”. However, in BC, access to specialist care to administer the skin test and the cost of skin testing are barriers to timely access and widespread implementation.
What changed my practice
Since 2016, there has been mounting evidence that direct oral challenge to penicillin without preceding skin testing is safe and effective in carefully selected low-risk individuals. However, the definition of “low-risk” is variable between studies. In general, patients are considered low-risk if the penicillin allergy label was based on remote reactions, delayed rashes (often maculopapular), family history alone, or positive skin test with no history of ever receiving a beta-lactam.
|High (referral to an allergist)||
|Low (consider oral challenge)||
One of the first studies to employ direct oral challenge was in the pediatric population. Mill et al. recruited 818 children in Montreal. Of those children, 770 (94.1%) tolerated the oral challenge, 17 (2.1%) developed mild immediate reactions, and 31 (3.8%) developed nonimmediate reactions. No patients required epinephrine.4
In 2017, Tucker et al. published a retrospective cohort of 328 healthy marine recruits who received direct oral challenge with amoxicillin. Similar to Mill et al., rates of immediate reaction were low (1.5%) and no patients needed epinephrine.5
Confino-Cohen (2017) recruited 642 adult and pediatric patients. All patients had a history of delayed reactions and none had a history of immediate reaction. The patients received skin testing, the results of which were not revealed. Patients then received a 5-day oral challenge due to the low-risk nature of their initial reaction. As in previous studies, rates of immediate reaction were low (1.5%) to the first graded dose. Following this, the challenge results were compared with the skin test results. Many of the patients who reacted, did not have positive skin tests and conversely, the majority of those with positive skin tests did not have immediate reactions.
This study highlights that skin testing patients with a history of delayed reactions are poorly predictive.6 In the pediatric population, skin testing can cause potential harm as the procedure could be somewhat painful.
Similar safety outcomes have been reported in several smaller studies, adding to the growing body of literature. Direct oral challenge has also been studied in a variety of specific patient populations, including in the perioperative setting prior to surgery and in cancer patients.7,8
What I do now
I take a detailed penicillin history to risk-stratify patients. In general, patients with remote, benign, cutaneous, or isolated GI symptoms have a very low risk of being truly allergic. Observed administration of the medication provides conclusive evidence that there is no allergy. I do not perform direct oral challenges on patients who have a history of anaphylaxis or those with a history of severe cutaneous adverse reactions (SCAR), such as Stevens–Johnson syndrome (SJS). SCAR is an absolute contraindication to re-challenge. A variety of open access questionnaires, tool kits, and algorithms have been published to aid non-allergists in assessing their patient’s penicillin allergy and to decide on an appropriate course of action. For example, INESSS (Institut national d’excellence en santé et services sociaux) and the CPS practice point provides decision support tools for non-allergists. 9,10
Afterwards, I provide counselling to patients and explain that they were either never allergic or have outgrown their allergy. I explain that once they have tolerated a dose, their previous history of a reaction does not increase their future risk of a reaction compared with the general population. I give the patient written documentation indicating that an oral drug challenge was passed and there is no evidence of allergy, and ask the patient to inform their pharmacy and other healthcare providers that they are not allergic. Lastly, I fill out a form to update their Pharmanet status and update the hospital electronic record.
Although specific literature is limited for non-allergists performing drug challenges, by virtue of its low cost and ease of administration, low-risk direct oral challenge can be logistically performed by non-allergists. Although the published data shows a very low risk of anaphylaxis, it is prudent for clinics offering challenges to be prepared to manage anaphylaxis with the appropriate medications and equipment. As part of quality improvement, I have been involved in training pharmacists, nurses, and family physicians to identify low-risk patients and perform oral challenges to amoxicillin in their office. Family physicians interested in doing low risk can seek further training or guidance on how to proceed.
- Do you have a Penicillin Allergy? Vancouver Coastal Health. View
- Drug allergy consult outcome letter. BC Children’s Hospital Allergy Clinic. 2020. View
- Solensky R. Allergy to B-lactam antibiotics. J Allergy Clin Immunol. 2012;130(6):1442-1442. doi:10.1016/j.jaci.2012.08.021 (View with CPSBC or UBC)
- Macy E, Contreras R. Health care use and serious infection prevalence associated with beta-lactam “allergy” in hospitalized patients: a cohort study. J Allergy Clin Immunol. 2014;133(3):790-796. doi:10.1016/j.jaci.2013.09.021 (View with CPSBC or UBC)
- Trubiano JA, Thursky KA, Stewardson AJ, et al. Impact of an integrated antibiotic allergy testing program on antimicrobial stewardship: a multi-center evaluation. Clin Infect Dis. 2017;65(1):166-174. doi:10.1093/cid/cix244 (View)
- Mill C, Primeau MN, Medoff E, et al. Assessing the diagnostic properties of a graded oral provocation challenge for the diagnosis of immediate and nonimmediate reactions to amoxicillin in children. JAMA Pediatr. 2016;170(6):e160033. doi:10.1001/jamapediatrics.2016.0033 (Request with CPSBC or view UBC)
- Tucker MH, Lomas CM, Ramchandar N et al. Amoxicillin challenge without penicillin skin testing in evaluation of penicillin allergy in a cohort of Marine recruits. J Allergy Clin Immunol Pract. 2017;5(3):813-815. doi:10.1016/j.jaip.2017.01.023 (Request with CPSBC or view UBC)
- Confino-Cohen R, Rosman Y, Goldberg A, et al. Oral challenge without skin testing safely excludes clinically significant delayed onset penicillin hypersensitivity. J Allergy Clin Immunol Pract. 2017;5(3):669-675. doi:10.1016/j.jaip.2017.02.023 (Request with CPSBC or view UBC)
- Savic L, Gurr L, Kaura V, et al. Penicillin allergy de-labelling ahead of elective surgery: feasibility and barriers. BJA. 2019;123(1):e110-e116. doi:10.1016/j.bja.2018.09.009 (View with CPSBC or UBC)
- Trubiano JA, Smibert O, Douglas A, et al. The safety and efficacy of an oral penicillin challenge program in cancer patients: a multicenter pilot study. Open Forum Infect Dis. 2018;5(12):ofy306. doi:10.1093/ofid/ofy306 (View)
- Robitaille G, Karam D. Decision support tool for penicillin-related allergies. INESSS. Updated June 2017. Accessed May 7, 2020. (View)
- Wong T, Atkinson A et al. Beta-lactam allergy in the pediatric population. (View) Last updated Jan 30, 2020. Accessed Nov 23, 2020.