The PALACE Trial: Direct Oral PCN Challenge in Patients with Low-Risk PCN Allergy?

Background: Many patients report a vague history of penicillin allergy. The vast majority of these self-reported allergies are untrue (< 5%) .  Literature including patients with penicillin allergies also show longer, more complicated hospital courses. Standard practice for identifying errant allergy reporting and removing them from the patients’ chart requires skin testing followed by an oral penicillin challenge.  This practice is both resource and time intensive thus limiting the number of people who can actually have their penicillin allergy removed from their chart. A rapid, safe approach to confirming or refuting allergies is needed.

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 (2^nd 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

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) 

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:

1. 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)