Paper: Copaescu AM et al. Efficacy of a Clinical Decision Rule to Enable Direct Oral Challenge in Patients With Low-Risk Penicillin Allergy: The PALACE Randomized Trial. JAMA Intern Med 2023. PMID: 37459086
Clinical Question: Is direct oral penicillin challenge in adults with a low-risk penicillin allergy safe and effective compared to standard-of-care penicillin skin testing followed by an oral penicillin challenge?
What They Did:
- Parallel, 2-arm, noninferiority, open-label, multicenter, international randomized clinical trial
- Occurred in 6 specialized centers (3 in North America – US & Canada and 3 Outside of North America – Australia)
- Trial took place from June 2021 to December 2022
- Used PEN-FAST to risk stratify patients. This is a prospectively derived and internationally validated clinical decision rule
- Patients at low risk for PCN allergic reaction randomly assigned to one of two arms:
- Direct Oral Challenge (DOC) (Different sites used different antibiotics and dosages):
- Given in the lowest available therapeutic dose at each site
- Amoxicillin 250mg (Most common)
- Amoxicillin 500mg (2nd most common)
- Penicillin VK 250mg
- Penicillin VK 500mg
- Penicillin VK 300mg
- Flucloxacillin 250mg
- Standard-of-Care (SOC):
- Skin Prick Testing and Intradermal Testing – 2 Stage Skin Testing (Read at 15min)
- Ampicillin 25mg/mL
- Penicillin G 10,000U/mL
- Direct Oral Challenge performed with antibiotics in the intervention arm
- Skin Prick Testing and Intradermal Testing – 2 Stage Skin Testing (Read at 15min)
- Given in the lowest available therapeutic dose at each site
- Direct Oral Challenge (DOC) (Different sites used different antibiotics and dosages):
PEN-FAST Clinical Decision Rule:
- PEN: Penicillin allergy reported by patient (If yes, proceed with assessment)
- F: ≤5 years since last reaction (2 points)
- A: Anaphylaxis or angioedema OR S: Severe cutaneous adverse reaction (2 points)
- T: Treatment required for reaction (1 point)
- Total Points:
- 0 = Very low risk of positive penicillin allergy test <1% (<1 in 100 patients reporting penicillin allergy)
- 1 – 2 = Low risk of positive penicillin allergy test 5% (1 in 20 patients)
- 3 = Moderate Risk of positive penicillin allergy test 20% (1 in 5 patients)
- 4 – 5 = High risk of positive penicillin allergy test 50% (1 in 2 patients)
Outcomes:
- Primary: Physician-verified positive immune-mediated oral penicillin challenge within 1-hour postintervention
- Noninferiority was achieved if a 1-sided 95% CI of the risk difference (RD) did not exceed 5%
- Secondary:
- Feasibility:
- Proportion of patients referred to the outpatient allergy clinic that are eligible for intervention (i.e. randomization) as per protocol (i.e. eligibility to screened ratio)
- Feasibility of recruitment defined as proportion of patients consenting to participate in the study protocol from eligible patients (i.e. recruitment to eligibility ratio)
- Feasibility of intervention delivery defined as the proportion of patients randomized to the intervention arm who had intervention delivered as per protocol (i.e. intervention to recruitment ratio)
- Safety
- Proportion of patients with a penicillin allergy who experience and antibiotic-associated immune-mediated adverse event OR severe adverse drug reaction as per protocol definitions
- Proportion of patients with a penicillin allergy who experience an antibiotic associated, non-immune-mediated adverse event
- Proportion of patients who will respect the protocol (i.e. protocol compliance)
- Feasibility:
Inclusion:
- Adult patients (≥18 years of age) referred to the outpatient allergy clinic for a penicillin allergy history
- PEN-FAST score <3
- Willing and able to give consent
Exclusion:
- Patients <18 years
- PEN-FAST score ≥3
- Pregnancy
- Self-reported allergies (Included adverse reactions such as nausea/vomiting and/or diarrhea)
- Any other illness that, in the investigator’s judgement, will substantially increase the risk associated with the subject’s participation in this study, including neurological or psychological conditions
- Patients with a history of type A adverse drug reaction, drug-associated anaphylaxis, idiopathic urticaria/anaphylaxis, mastocytosis, serum sickness, blistering skin eruption or acute interstitial nephritis
- Unable to confirm allergy history
- On concurrent antihistamine therapy
- Receiving more than stress dose steroids (i.e. >50mg QID hydrocortisone [or steroid equivalent])
Results:
- 382 adults were randomized
- 377 patients included in the analysis
- >84% of patients received a single-dose amoxicillin challenge
- Median age: 51 years
- 5% were female
- 446 out of 643 screened patients were eligible to participate (69%)
- 382 out of 446 eligible patients were enrolled (86%)
- 92% of patients the intervention per protocol was completed
- Majority of patients had a childhood reaction to penicillin (61%)
- Physician-Verified Positive Immune-Mediated Oral Penicillin Challenge Within 1-Hour Postintervention (Primary Outcome):
- Direct Oral Challenge: 1 patient (0.5%)
- Standard-of-Care: 1 patient (0.5%)
- RD 0.0084%; 90% CI -1.22 to 1.24%
- 1-sided 95% CI was below noninferiority margin of 5% (Upper limit of the 1-sided 95% CI was 1.24)
- The 2 patients who had a positive challenge suffered a mild cutaneous skin reaction that resolved following a single dose of antihistamines
- Total Adverse Events Within 5 Days Postintervention:
- Direct Oral Challenge: 22 patients
- Standard-of-Care: 20 patients
- RD -0.36%; 95% CI -6.64 to 5.93%
- 5 Day adverse events occurred after a median of
- 4 hours in the oral penicillin challenge group
- 6 hours in the standard-of-care group
- No serious adverse events occurred (Anaphylaxis or Angioedema)
- No patients in either group required hospitalization or emergency department presentation/treatment
- Confirmed Immune-Mediated Adverse Events Within 5 Days Postintervention
- Direct Oral Challenge: 9
- Standard-of-Care: 10
- RD -0.45%; 95% CI -4.87 to 3.96%
- Penicillin Allergy Label Removal:
- Direct Oral Challenge: 186/187 (99.5%)
- Standard-of-Care: 186/190 (97.9%)
Strengths:
- Asks a clinically important question
- First randomized clinical trial to question the safety and utility of direct penicillin challenge without preceding skin testing in adults
- To ensure safety and well-being of patients adverse events were reviewed by an independent data and safety monitoring board every 2 months
- Two independent investigators (1 infectious disease & 1 allergist) unaware of group allocations, retrospectively determined true allergic reactions
- Groups were mostly balanced in their baseline characteristics
- Minimal loss to follow up (5 patients due to either missing outcome data or not meeting inclusion criteria)
- Used a validated tool (PEN-FAST) to risk stratify patients
Limitations:
- Subgroups were too small to derive any conclusions
- Dose and antibiotic used for oral challenge varied
- Majority of patients had a PEN-FAST score of 0 and 1 (≈95%). This limits generalizability to patients with a score of 2.
- Patients with a history of anaphylaxis with any drug were excluded from this trial
- Open-label study (i.e. both patients and physicians knew which treatments were being provided), but physicians determining immune-mediated and non-immune-mediated adverse reactions were blinded to group assignments
Discussion:
- In adult patients with low-risk penicillin allergy (PEN-FAST score <3) direct oral penicillin challenge was noninferior to current standard-of-care involving skin prick/intradermal skin testing followed by 1-step oral challenge. Additionally, there was no difference between immediate or delayed adverse events reported by day 5.
- Authors determined they would need to enroll 380 patients (190/group) to achieve a statistical power of 80%, assuming an event rate in the control group of 4% of which neither was achieved however if the control group had a lower prevalence of the outcome (i.e. 2%) the power of the study would be 95% which was achieved
- The inferiority margin of 5% allowed for more than double the risk of outcome in the control group and was chosen based on a consensus among investigators due to the rarity of the outcome, benefits of removal of the penicillin allergy label, cost, time, and resources required for sink testing
- Authors screened 643 patients with history of penicillin allergy. The most common reasons for exclusion included:
- PEN-FAST score ≥3
- Exclusion criteria met
- Refusal of consent
Author Conclusion: “In this randomized clinical trial, direct oral penicillin challenge in patients with a low-risk penicillin allergy was noninferior compared with standard-of-care skin testing followed by oral challenge. In patients with a low-risk history, direct oral penicillin challenge is a safe procedure to facilitate the removal of penicillin allergy label.”
Clinical Take Home Point: The PALACE randomized clinical trial supports an important validated strategy (PEN-FAST score <3 or a more conservative approach being a PEN-FAST score ≤1) to allow safe, fast, and cheap penicillin delabeling. Direct Oral Challenging is less resource and time intensive, less expensive, and provides a scalable approach to remove unverified penicillin allergy in multiple practice settings.
References:
- Copaescu AM et al. Efficacy of a Clinical Decision Rule to Enable Direct Oral Challenge in Patients With Low-Risk Penicillin Allergy: The PALACE Randomized Trial. JAMA Intern Med 2023. PMID: 37459086
Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)
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