Inpatient Penicillin Allergy Delabeling Study
Condition: Penicillin Allergy; Penicillin Sensitivity; Penicillin Reaction; Penicillin Intolerance
MeSH terms: Hypersensitivity; Drug Hypersensitivity
Study type: Interventional
Phase: Phase 4

Summary: 
      The study will identify pediatric patients 3-18 years old who have penicillin allergy label
      in the electronic medical record. Those who are identified will be stratified into no-risk,
      low-risk and high-risk category using a screening questionnaire. The following definitions
      will be followed:

      No-risk: Patients who are historically labeled with penicillin allergy in the EMR based on
      family history alone OR those who have tolerated penicillin after a concerning incident
      without any reaction OR with penicillin allergy label but deny any history of reaction to any
      form of penicillin on screening questionnaire

      Low-risk: Patients with previous reaction not suggestive of anaphylaxis (defined below) AND
      not requiring hospitalization for the reaction OR reaction considered non- immunologic (e.g.
      diarrhea, nausea, yeast vaginitis) OR exposure to penicillin- containing antibiotic after the
      date of reported reaction with no anaphylaxis and hospitalization AND no serious types of
      delayed reactions such as Steven- Johnson syndrome (SJS), toxic epidermal necrolysis (TEN),
      acute interstitial nephritis (AIN), drug-induced hepatitis or other documented organ injury,
      drug rash eosinophilia systemic symptoms (DRESS), hemolytic anemia, drug-induced cytopenia,
      and serum sickness. Patients who had delayed reaction (onset more than 24 hours) of isolated,
      non-progressive symptoms (such as rash/hives alone) also belong to this group.

      High-risk: Patients with penicillin allergy label on EMR with previous reaction suggestive of
      anaphylaxis (defined below) OR requiring hospitalization/epinephrine administration for the
      reaction OR reactions considered immunologic (angioedema, joint pains) OR involving serious
      types of reactions such as Steven-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN),
      acute interstitial nephritis (AIN), drug-induced hepatitis or other documented organ injury,
      drug rash eosinophilia systemic symptoms (DRESS), hemolytic anemia, drug-induced cytopenia,
      and serum sickness. Patients who were previously diagnosed with penicillin allergy by an
      allergist also belong to the high-risk group.

      Patients in the no-risk group will be immediately delabeled. Patients in the high-risk group
      will be referred to allergy/immunology for further work up. The focus of this study is to
      identify the patients who belong to the low-risk group. This group of patients will be
      subjected to graded oral amoxicillin challenge testing. Those who will have reactions
      compatible with allergy will have their allergy status retained in the electronic medical
      record. Those that will not have reactions or those that will have reactions that are not
      compatible with allergy will be delabeled in the electronic medical record.
    

Detailed description: 
      A. Specific Aims and Hypotheses

      General Objective:

      To verify pediatric patients with reported penicillin allergy in electronic medical record
      (EMR) by performing direct oral amoxicillin challenge testing.

      Hypothesis: Pediatric patients with reported penicillin allergy in EMR can be verified by
      performing direct oral amoxicillin challenge testing.

      Specific objectives:

        1. To identify no-risk, low-risk and high-risk patients among pediatric patients with
           reported penicillin allergy in EMR through a questionnaire.

           Hypothesis: No-risk, low-risk and high-risk pediatric patients with reported penicillin
           allergy in EMR can be identified using a questionnaire.

        2. To be able to delabel pediatric patients with reported penicillin allergy in EMR who are
           identified as no-risk.

           Hypothesis: No-risk pediatric patients with reported penicillin allergy in EMR can be
           delabeled using a questionnaire.

        3. To be able to delabel identified low-risk pediatric patients with reported penicillin
           allergy in EMR who are verified not allergic to penicillin by direct oral amoxicillin
           challenge testing.

           Hypothesis: Identified low-risk pediatric patients with reported penicillin allergy in
           EMR using a questionnaire can be verified using direct oral amoxicillin challenge
           testing.

        4. To be able to provide proper referral guidance to patients identified as high-risk and
           those who failed oral amoxicillin challenge testing to allergy and immunology for
           further evaluation and management.

      Hypothesis: Proper referral guidance to patients identified as high-risk and those who failed
      oral penicillin challenge testing to allergy and immunology can be provided for their further
      evaluation and management.

      B. Background and Significance Penicillin remains a reliable class of antibiotics that
      addresses a majority of infections both in outpatient and inpatient settings.(1,2) It is also
      one of the cheapest antibiotics to use for empiric therapy for susceptible infections.(3,4)
      Emerging literature suggests that the number of patients with historical penicillin allergy
      is an overestimate. A growing number of studies show that only approximately 1-10 % of
      patients with historical penicillin allergy are truly allergic after verified allergy testing
      is done.(1-3,5,7,8,10,11,12) Despite this, efforts on antibiotic allergy delabeling remains
      sparse and penicillin allergy remains to be the most common drug allergy reported.

      Few institutions have implemented, much less conceptualized, protocols to determine truly
      allergic patients who have reported penicillin allergy when diagnosed with infections
      theoretically susceptible to penicillin.(6) One limitation perhaps is the absence of
      validated questionnaire that uniformly captures accepted levels of risk especially in the
      pediatric population.(7) As a result, these patients end up receiving alternative
      antimicrobial agents that pose a risk for emergence of resistance, development of unnecessary
      intestinal dysbiosis, and increased economic burden to health care resulting in suboptimal
      clinical outcome. (1-6) Studies aiming to validate direct oral challenge testing as a means
      of penicillin allergy delabeling is a fertile avenue for this clinical query to be addressed
      in a cost-effective and timely manner. (8-13)

      Identifying patients with no immunologically-mediated penicillin allergy and delabeling them
      in the electronic medical record (EMR) accordingly will mitigate the use of second-line
      antibiotics, aid in minimizing development of antimicrobial resistance, ameliorate
      unnecessary economic burden, and overall lead to positive impact in clinical outcome and
      patient care. (1,5,7,8,10,11,12) In the same way, this process will also identify patients
      with true penicillin allergy creating a point-of-care opportunity to provide them proper
      guidance on the importance of Allergy/Immunology follow-up for further evaluation and
      management.

      C. Methods

      Population of Interest:

      Patients 3-18 years old admitted at our institution will be screened for inclusion. We will
      screen approximately 800 patients and enroll 60 patients in our study (based on the weekly
      census) over a span of 3 months. HIPAA regulations will be strictly observed in data handling
      to protect patient privacy.

      Screening and consenting of patients:

      Signed parental consent and verbal consent from study team will be obtained prior to
      screening. Patients will be screened using a questionnaire to identify risk status. Patients
      identified as no-risk (EMR label based purely on family history of penicillin allergy,
      mislabeled patients) will be immediately delabeled in EMR. High-risk patients (those with
      reaction consistent with IgE mediated reaction or with history of anaphylaxis) will be
      excluded. Guidance on further care such as referral to an allergist will be recommended if
      not yet done. Low-risk patients (those with mild reaction not consistent with IgE mediated
      reaction, no history of serious delayed reaction or no reaction on subsequent penicillin
      receipt) will be identified to undergo graded direct oral amoxicillin challenge testing.

      Oral Amoxicillin Challenge Testing:

      Signed parental consent and patient assent (7 years and older) will be obtained prior to
      challenge testing. Only low-risk patients with parent/guardian in the room and no receipt of
      anti-histamine 48 hours prior will be challenged. Only patients who can tolerate enteral
      amoxicillin will be challenged. Rescue kits (containing diphenhydramine, epinephrine and
      albuterol) will be ready at bedside prior to challenging. Baseline vital signs will be
      obtained prior to challenging. Oral challenge testing will be graded: initial 10% of the dose
      followed by remaining 90% of the dose (total dose 45 mg/kg with maximum of 1000 mg) 30
      minutes apart. Vital signs will be repeated 30 minutes after the first dose, 30 minutes after
      the second dose and finally 60 minutes after the second dose. Study team will administer
      amoxicillin doses and monitor for signs of amoxicillin allergic reaction. Any reaction during
      the testing will be assessed by trained study team member. A clinical event note will be
      written in the EMR for any reaction occurring during the testing as well the management
      implored to mitigate reaction.

      Delabeling:

      Low-risk patients who passed the challenge testing will be delabeled in EMR. Documentation of
      the result will be sent to patient's primary care doctor (with permission from parent) for
      guidance on future use of penicillin.
    

Intervention name(s): Graded Oral Amoxicillin Challenge; De-labelling in electronic medical record; Referral to Allergy Immunology/Retention of Allergy Label
Intervention type(s): Drug; Other; Other
Intervention description(s): Oral amoxicillin at 45 mg/kg (maximum of 1000 mg) to be divided into two doses: 10 % initial dose and then 90% remaining dose - doses will be separated by 30 minute interval; Patients with No Risk for allergic reaction will be de-labelled for allergy in the electronic medical record.; Patients deemed to be High Risk for allergic reaction will be referred to Allergy Immunology as outpatient and allergy label will be retained.
Other intervention name(s): Amoxicillin Challenge
Intervention MeSH terms: Amoxicillin
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Intervention model description: Patients will be screened by questionnaire to determine No risk, Low risk, or High Risk for penicillin allergic reaction. Those that are deemed Low Risk based on questionnaire, will be subsequently challenged with graded oral amoxicillin challenge.
Masking: None (Open Label)
Primary purpose: Other
Keywords: Penicillin allergy; Penicillin delabeling