Efficacy of a Clinical Decision Rule to

Enable Direct Oral Challenge

in Patients With Low-Risk Penicillin
Allergy
JAMA Intern Med.
doi:10.1001/jamainternmed.2023.2986
Published online July 17, 2023.
Importance and background

 Patient-reported penicillin allergies remain largely

unquestioned.

 These unverified penicillin allergy labels have been

associated with poor patient health outcomes, including
increased outpatient mortality, longer hospital stay,
inappropriate antibiotic prescribing, development of
antibiotic-resistant infections, and excess health care
costs.1-5
Importance and background

 Upwards of 10% of outpatients and 15% of inpatients

report a penicillin allergy.

 With such an ordinary occurrence, the frequent default is

use of second-line antibiotics, since this approach is often
more accessible than an evaluation for penicillin allergy.
Importance and background

 Fewer than 5% of patients labeled with a penicillin allergy

are truly allergic.

 More than 95% of patients labeled as penicillin

allergic will have negative penicillin allergy
testing and tolerate subsequent exposure.6
Delabeling, or removing this penicillin allergy
label, is increasingly recognized as an
essential pillar of global antimicrobial
stewardship.7,8
Importance and background

 The standard of care to remove the penicillin allergy label in

adults is specialized testing involving prick and intradermal
skin testing followed by an oral challenge with penicillin.

 Regardless of whether skin testing occurs first, oral

challenge is considered the necessary final step and is the
gold standard to remove the penicillin allergy label, as skin
testing alone lacks 100% negative predictive value.
Importance and background

 Skin testing is resource intensive, limits practice to

specialist-trained physicians, and restricts the global
population who could undergo penicillin allergy delabeling.

 So, this article is to determine whether a direct oral

penicillin challenge is noninferior to the standard of care of
penicillin skin testing followed by an oral challenge in
patients with a low-risk penicillin allergy.
Study Design

 This parallel, 2-arm, noninferiority, open-label, multicenter,

international randomized clinical trial occurred in 6
specialized centers, 3 in North America (US and Canada) and
3 in Australia, from June 2021, to December 2022.

 Eligible adults had a PEN-FAST score lower than 3. PEN-FAST

is a prospectively derived and internationally validated
clinical decision rule that enables point-of-care risk
assessment for adults reporting penicillin allergies.
PEN-FAST

 A validated Penicillin Allergy Decision Rule tool.

Eligibility criteria

 Inclusion:
 1. Adult patients (≥ 18 years) referred to the outpatient
allergy clinic for a penicillin allergy history;
 2. Willing and able to give consent
Exclusion:
 1. Patient age is < 18 years;
 2. Patients with a PEN-FAST score ≥3
 3. Pregnancy
 4. Any other illness thatwill substantially increase the risk
associated with the subject’s participation in this study, including
neurological or psychological conditions;
 5. Patients with a history of drug-associated anaphylaxis,
idiopathic urticaria/anaphylaxis, mastocytosis, serum sickness,
blistering skin eruption or acute interstitial nephritis;
 6. Patients where the allergy history was not able to be
confirmed;
 7. Patients on concurrent antihistamine therapy;
 8. Patients receiving more than stress dose steroids
Recruitment
flow
Participants
 A total of 382 adults were randomized, with 377
patients (median [IQR] age, 51 [35-65] years; 187 in
the intervention group and 190 in the control group.

 Most patients had a PEN-FAST score of 0 or 1.

Severe cutaneous adverse
reactions
 include potential Stevens-Johnson syndrome, toxic epidermal
necrolysis, drug reaction with eosinophilia and systemic
symptoms.

 Patients with a severe delayed rash with mucosal

involvement should be considered to have a severe cutaneous
adverse reaction.

 Acute interstitial nephritis, drug-induced liver injury, serum

sickness and isolated drug fever were excluded phenotypes
from the derivation and validation cohorts.
Randomization and Masking
 Patients were randomly assigned to either direct oral challenge with
penicillin (intervention arm) or a standard-of-care arm of penicillin skin
testing followed by oral challenge with penicillin (control arm).

 Participants were randomized in a 1:1 ratio to either the

intervention group (direct oral penicillin challenge) or the
control group (prick followed by intradermal testing
followed by 1-step oral challenge with penicillin, if
negative).

 Randomization was performed remotely using a

centralized web-based REDCap by permuted block design
(block sizes ranging from 4-14), stratified by hospital site.

 Group allocation was concealed until randomization, and

blinding post randomization was not possible. The
sequence was computer generated by the trial statistician.
Procedure

 The primary outcome was a physician-verified positive immune-

mediated oral penicillin challenge within 1 hour post intervention in
the intention-to-treat population.

 Participants were directly observed following the penicillin challenge

with measurement of vital signs at baseline, on any associated
symptoms as necessary, and at 60 minutes.

 Site investigators were responsible for safety evaluation.

 On day 5 following the oral challenge, study research personnel

contacted participants to prompt them to report any delayed
adverse events occurring after the period of in-clinic observation.
Baseline Characters
Baseline Characters
Baseline Characters
Outcome
In the 5 days following the oral penicillin
challenge, immune-mediated adverse events
were recorded in the intervention group and in
the control group .

No serious adverse events occurred.

Outcome
 The primary outcome of a positive oral penicillin challenge
consistent with an immune-mediated reaction occurred in 1 of
187 patients (0.5%) in the intervention group and 1 of 190
patients (0.5%) in the control group, with an RD of 0.0084 pp (90%
CI, −1.22 to 1.24 pp). Because the upper limit of the 1-sided 95%
CI is 1.24 pp, this is below the noninferiority margin.

 The risk ratio was 1.02 (90% CI, 0.10-10.34).

 Most of the patients in both groups (>84%) received a single dose

amoxicillin challenge. Both patients with positive challenges
presented a mild cutaneous skin reaction that resolved following a
single dose of antihistamines .
Conclusions
 In this international, multicenter, randomized
clinical trial that enrolled participants with low-risk
penicillin allergy (PEN-FAST score <3), direct oral
penicillin challenge was noninferior to the current
standard of prick followed by intradermal skin
testing followed, if negative, by 1-step oral
challenge based on the primary end point of
physician observed positive immune-mediated
penicillin challenge.

 There was also no difference between immediate

or delayed adverse events reported by day 5.
Conclusions

 In this randomized clinical trial, in patients with

low-risk penicillin allergy and a PEN-FAST score
of less than 3, direct oral challenge with
penicillin was a safe and effective3

 Compared with skin testing, a direct oral

penicillin challenge is less resource and time
intensive, is less expensive, and has the
potential to be performed outside of the
specialist allergy setting, providing a scalable
approach to address low-risk penicillin allergy in
diverse treatment settings internationally.
Conclusions

 For us, the inpatient setting is an optimal area to

institute direct oral challenges guided by PEN-
FAST outside of expert supervision. Hospitalized
patients have time to undergo challenges and
have a baseline level of supervision.
 Reference
 1. Trubiano JA, Chen C, Cheng AC, Grayson ML, Slavin MA, Thursky KA; National
Antimicrobial Prescribing Survey (NAPS). Antimicrobial allergy ‘labels’ drive inappropriate
antimicrobial prescribing: lessons for stewardship.J Antimicrob Chemother. 2016;71(6):1715-
1722. doi:10.1093/jac/ dkw008
 2. MacFadden DR, LaDelfa A, Leen J, et al. Impact of reported beta-lactam allergy on
inpatient outcomes: a multicenter prospective cohort study. Clin Infect Dis. 2016;63(7):904-
910. doi:10.1093/ cid/ciw462
 3. Trubiano JA, Pai Mangalore R, Baey YW, et al. Old but not forgotten: antibiotic allergies in
general medicine (the AGM study). Med J Aust. 2016;204 (7):273. doi:10.5694/mja15.01329
 4. Blumenthal KG, Lu N, Zhang Y, Li Y, Walensky RP, Choi HK. Risk of meticillin resistant
Staphylococcus aureus and Clostridium difficile in patients with a documented penicillin
allergy: population based matched cohort study. BMJ. 2018;361:k2400.
doi:10.1136/bmj.k2400
 5. Moran R, Devchand M, Smibert O, Trubiano JA. Antibiotic allergy labels in hospitalized and
critically ill adults: a review of current impacts of inaccurate labelling. Br J Clin Pharmacol.
2019;85(3):492-500. doi:10.1111/bcp.13830
 6. Blumenthal KG, Peter JG, Trubiano JA, Phillips EJ. Antibiotic allergy. Lancet. 2019;393
(10167):183-198. doi:10.1016/S0140-6736(18) 32218-9
 7. Antimicrobial stewardship interventions: a practice guide. World Health Organization.
2021. Accessed June 10, 2023. https://apps.who.int/ iris/bitstream/handle/10665/340709/
9789289054980-eng.pdf
 8. Trubiano J, Phillips E. Antimicrobial stewardship’s new weapon? a review of antibiotic
allergy and pathways to ‘de-labeling’. Curr Opin Infect Dis. 2013;26(6):526-537.
doi:10.1097/QCO. 0000000000000006
CASP Randomized Controlled Trial
Standard Checklist:
11 questions to help you make sense of a randomized controlled trial
(RCT):
Is the basic study design valid for a randomized controlled trial?
(Section A)
Was the study methodologically sound? (Section B)
What are the results? (Section C)
Will the results help locally? (Section D)
Section A
Section B
Thanks ！
Validate PEN-FAST in risk
stratification of reported penicillin
allergies