Clinical trial NCT05020327
Conditions: Penicillin Allergy Penicillin Sensitivity Penicillin Reaction Penicillin Intolerance
Keywords: Penicillin allergy Penicillin delabeling
Sponsor: University Hospitals Cleveland Medical Center
Start date: 2021-09-22; Completion date: 2022-03-30
Enrollment: 40 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief 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.

Arms: arm 1: This is the group of patients who will undergo the graded oral amoxicillin challenge testing. Total dose of the amoxicillin will be 45 mg/kg (maximum of 1000 mg). 10 % of this dose will be given first followed by 90 % of the dose 30 minutes after. Each dose will be given only once. arm 2: Patients in the group will be de-labeled in the electronic medical record for No Risk for allergic reaction to amoxicillin based on screening questionnaire. arm 3: Patients in this group are deemed high risk for allergic reaction to penicillin based on screening questionnaire and will remain labeled with allergy in the electronic medical record. They will be referred as outpatient to allergy-immunology for further evaluation.
Interventions: intervention 1: Graded Oral Amoxicillin Challenge intervention 2: De-labelling in electronic medical record intervention 3: Referral to Allergy Immunology/Retention of Allergy Label
Intervention descriptions: intervention 1: 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 intervention 2: Patients with No Risk for allergic reaction will be de-labelled for allergy in the electronic medical record. intervention 3: Patients deemed to be High Risk for allergic reaction will be referred to Allergy Immunology as outpatient and allergy label will be retained.

Protocol documents:
Prot_SAP_001.pdf: 
Inpatient Penicillin Allergy Delabeling Pilot Project at University HospitalsRainbow Babies and Children’s 
Hospital in Cleveland, Ohio 
 
 
NCT05020327 
 
04/13/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Objectives 
 To verify pediatric patients with reported penicillin allergy in electronic medical record (EMR) by 
performing current standard of practice oral amoxicillin challenge testing.  
Hypothesis: 
 Pediatric patients with reported penicillin allergy in EMR can be verified by performing current standard 
of practice 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 standardized questionnaire.  
Hypothesis: No-risk, low-risk and high-risk pediatric patients with reported penicillin allergy in EMR 
can be identified using a standardized 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 standardized 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 current standard of practice oral amoxicillin challenge 
testing.  
Hypothesis: Identified low-risk pediatric patients with reported penicillin allergy in EMR using a 
standardized questionnaire can be verified using current standard of practice 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 
amoxicillin challenge testing to allergy and immunology can be provided for their further evaluation 
and management.  
 
Background 
 Penicillin remains a reliable class of antibiotic that addresses 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 10 % of 
patients with historical penicillin allergy are truly allergic after verified allergy testing is done. 1-3,5,7 
Despite this, efforts on antibiotic allergy delabeling remains sparse and penicillin allergy remains to be 
the most common drug allergy reported.  
 
Moreover, few institutions have validated, much less implemented, 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  
 
Thus, 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 resistance, ameliorate unnecessary economic burden and overall lead to 
positive impact in clinical outcome and patient care. 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 followup for further evaluation and management. 
 
Inclusion and Exclusion Criteria 
 
 
 


 
 
 
 
Number of Research Participants  
We will screen approximately 800 patients and enroll approximately 60 patients in our study based on 
the weekly census of Rainbow 3, 5 and 6 floors over a span of 6 months (September 22, 2021– March 
31, 2022). 
 


Recruitment Methods  
The research participants will be identified through the TheraDoc database system. TheraDoc database 
is a clinical surveillance system used to monitor antibiotic stewardship initiatives in healthcare systems. 
University Hospitals is one of the health care systems that employs the clinical surveillance services of 
TheraDoc. Patients admitted in Rainbow 3, 5 and 6 floors with penicillin allergy in the EMR will be 
identified through the TheraDoc system. Based on review of patient’s allergy reaction in the EMR, the 
patient will be deemed potential research participant or not. If the EMR record shows that patient’s 
penicillin allergy does not imply anaphylaxis or indicates an unclear non-anaphylactic reaction, the 
patient will be included in the patients to be screened through a standardized questionnaire (will be 
conducted with patient’s parent/s or duly designated legal guardian). Screening questionnaire is an 
integral part in standard of practice allergy delabeling process. The patient/parent or legal guardian will 
be approached directly in the patient’s room by the investigator where questionnaire will be completed. 
Only patients with parents/legal guardians who are physically present in the patient’s hospital room will 
be screened. Based on assessment of patient’s penicillin allergy status through the standardized 
questionnaire, patients will be identified as belonging to the no-risk, low-risk or high-risk groups. Only 
patients identified under low-risk group will be eligible to undergo oral amoxicillin challenge testing. 
Patients belonging to high-risk group will be given proper referral guidance to see allergy/immunology 
for further evaluation and management. Patients identified as no-risk group will immediately be 
delabeled in the EMR without oral amoxicillin challenge testing. All contact and communication with the 
patients and patient’s parent/s or legal guardian will be in person. 
 
Setting  
The conduct of this research project will be done at Rainbow 3, 5 and 6 floors inside patient’s hospital 
room. The oral amoxicillin challenge testing will also be done in the patient’s hospital room.  
 
Consent Process  
The study will be obtaining consent from patient’s parent/s and/or legal guardian.  
Consenting will be split in two parts. A separate consent will be done for screening. This will need to be 
signed prior to completing the screening questionnaire. If patient is categorized in the low-risk category, 
a separate consent will be done for the oral amoxicillin challenge testing. The study will also obtain 
assent from patients 7 years of age or older.  
 
Sharing of Results with Research Participants 
 The result of the study will be shared with the research subjects as this will have an impact to their 
future receipt of any penicillin. This will also be formally shared with their PCPs in the form of a letter 
that contains the oral challenge test result which will be given to parent/s or legal guardian at the end of 
the procedure. This is to ensure that PCPs will have proper guidance on the use of penicillin in the 
future. Verbal consent from parent/s or legal guardian will be obtained for study team to be able to 
share the oral challenge test result to patient’s PCP. 
 
Study Design  
This will be a single visit study. There will be no randomization involved 
 
Study Procedures 
 Methods:  
 
Prior to commencement of the study, all study team members will undergo training on the conduct of 
the oral amoxicillin challenge testing. During this training, the study team members will be educated 


about acute adverse reactions of amoxicillin including how to properly identify these reactions and the 
interventions that need to be done to address them. This will be conducted by a pediatric allergy 
attending study team co-investigator. A thorough briefing about the study protocol/algorithm will also 
be done so that a standardized understanding of the algorithm will be established.  
 
The algorithm/procedures on performing the oral challenge testing is based on empirical standard of 
practice for direct oral antibiotic allergy challenge testing patterned after successful studies that have 
aimed the same objectives. 
1. Over a 6-month period from September 22, 2021 - March 31, 2022, patients aged 3-18 years old 
admitted with reported penicillin allergy (either by historical report or allergy label on EMR) in 
Rainbow 3,5 and 6 will be identified through TheraDoc system.  
2. Once the patients with penicillin allergy label are identified in TheraDoc, a verbal permission 
from the primary treating team attending will be obtained before approaching the parent/s or 
legal guardian. Detailed plan which will include the timing of the conduct of the components of 
the procedure (from consenting, screening through a questionnaire and oral challenge testing if 
indicated) will be discussed with the primary treating team in order to coordinate these steps 
with the patient’s primary treatment plan. This is to avoid disruption of the flow of patient’s 
primary medical care. Once verbal consent from the primary team attending is obtained, an 
informed written consent from the parent/s or legal guardian will be obtained prior to 
administering the screening standardized questionnaire which the parent/s or legal guardian will 
be filling out with the assistance of a trained study team member. This screening questionnaire 
will be used to identify the level of risk of the patient.  
3. Identified patients with penicillin allergy in the TheraDoc system will be stratified into three risk 
groups: no risk group, low-risk group and high-risk group (see inclusion/exclusion criteria) based 
on responses on the standardized questionnaire.  
4. Patients in the no risk group will be automatically delabeled in the EMR. A clinical event note in 
the chart to document that the patient was delabeled based on historical verification showing 
absence of any clinical evidence suggesting of any signs and/or symptoms compatible with 
penicillin allergy (see Appendix C.1). This information will then be communicated to the 
patient’s primary care physician for guidance on future use of penicillin in a form of a letter. 
Permission from patient and parent/s or legal guardian to communicate the result to the PCP 
will be obtained. This letter will be handed to the parent/s or guardian for them to hand over to 
the PCP. Education on the patient’s change in allergy status will also be provided to the parents.  
5. Patients identified in the high-risk group will not undergo oral amoxicillin challenge testing. 
Patients in this group that have not been evaluated by an allergist will be referred to 
Allergy/Immunology (AI) for further evaluation and management. A clinical event note will be 
written in the chart to document that the patient is identified to have reactions highly 
compatible with true penicillin allergy by history/screening and that referral was made to AI (see 
Appendix C.2).  
6. Patients identified in the low-risk group will undergo a step-wise amoxicillin oral challenge 
testing. An extensive anticipatory guidance and explanation to parent/s or legal guardian about 
the steps of the testing as well as the risks of the procedure will be done prior to initiation of 
testing. Informed consent from a parent/s or legal guardian of the patient will be obtained to be 
able to proceed with testing. Assent will be obtained from patients 7-13 years of age. 
 
Before initiating the step-wise oral amoxicillin challenge testing, it will be ensured that these 
patients have not taken any antihistamine in the previous 48 hours. Any patients with receipt of 
antihistamine in the previous 48 hours cannot undergo the testing and will be excluded.  


The step-wise oral amoxicillin challenge allergy testing will ONLY be conducted during the day shift 
from 8:00AM-2:30 PM to make sure adequate medical personnel is present should untoward event 
occurs. Patients who have any of the exclusion criteria will not be eligible to proceed with the 
challenge testing (see exclusion criteria). 
 
The following criteria also need to be met in order for the challenge testing to be performed: 
- 
Parent/s or legal guardian present during the test  
- 
A medical provider is available on the floor  
- 
Rescue medications (refer to materials/appendix D – ordered and available at bedside prn)  
 
Only patients in the low-risk group who can tolerate enteral amoxicillin will be eligible to 
proceed to the step-wise oral amoxicillin challenge testing. This step will entail amoxicillin oral 
challenge test (either by mouth, by nasogastric tube or gastric tube). Patients not able to take 
the amoxicillin enterally will be excluded. A separate consent form will need to be signed for 
the oral amoxicillin challenge testing part of the study.  
 
This step is subdivided into two graded steps: administration of 10% of the standard dose 
followed by administration of 90% of the rest of the standard dose separated by 30 minutes 
time interval (see Appendix D). 
 
Administration of 10% of standard dose:  
A set of baseline vital signs will be obtained by a trained study team member before initiation of 
step-wise amoxicillin oral challenge allergy testing. If vital signs are normal and no apparent 
contraindication to perform the test is identified, the testing will be commenced.  
 
Patients will first receive 10% of the standard drug dose in the form of enteral amoxicillin (see 
Appendix D). A trained study team member will administer the oral amoxicillin dose and closely 
monitor and observe patients for 30 minutes at the bedside following dose administration for 
any sign or symptom of drug reaction.  
 
At any point the patient will have any reaction to the initial 10% dose, testing needs to be 
stopped immediately. A trained study team member needs to assess the patient right away at 
bedside and should consider giving diphenhydramine by mouth (or by IV or IM as clinically 
applicable) if reaction does not meet criteria for anaphylaxis (see definition of terms – attached 
document). Diphenhydramine will be available at bedside prior to initiation of the oral 
amoxicillin challenge testing. Administration of diphenhydramine will be done by the study 
team member. The patient needs to be monitored for the next 2 hours postadministration of 
diphenhydramine for the progression of symptoms. The reaction needs to be documented in 
the patient’s chart specifying the reaction observed and intervention given (see Appendix C.3).  
 
If the patient develops any symptom indicative of anaphylaxis (see definition of terms), 
epinephrine will be administered right away either by IV or IM (see Appendix D) and a rapid 
response alert or code will be called as indicated. Epinephrine will be available at bedside prior 
to initiation of oral challenge testing. Administration of epinephrine will be done by a trained 
study team member. Inhaled albuterol or supplemental oxygen will be administered if 
indicated. Administration of both will also be done by the study team member with the 
assistance of the patient’s nurse. The event needs to be documented in the patient’s chart 
specifying the reaction and the intervention given (see Appendix C.3). The patient will need to 


be monitored for progression of symptoms for the next 2 hours post-administration of 
epinephrine so a proper disposition can be made (remain on the floor or transfer to higher level 
of care)  
 
Any patient who develops any type of reaction at any point during the administration of the 
initial 10 % dose will be labeled to have failed the test. This will also be documented in the 
patient’s chart accordingly. The patient’s penicillin allergy status will then be retained in the 
chart (see Appendix C.3). The patient will be provided proper guidance and recommendation to 
follow up with an allergist for further evaluation and management. 
 
Administration of the remaining 90% of standard dose:  
If the patient did not develop any reaction to the 10% initial oral dose of amoxicillin following 
30 minutes of administration, another set of vital signs will then be obtained by a trained study 
team member. If vital signs are normal, then the patient can proceed to receive the remaining 
90% of the test standard dose of amoxicillin (see Appendix D). A trained study team member 
needs to be present at bedside for 30 minutes following the administration of the rest of the 
90% of the dose. Another set of vital signs will be obtained 30 and 60 minutes following the 
administration of the rest of the 90 % of the dose. 
 
Administration of the remaining 90% of standard dose: If the patient did not develop any 
reaction to the 10% initial oral dose of amoxicillin following 30 minutes of administration, 
another set of vital signs will then be obtained by a trained study team member. If vital signs 
are normal, then the patient can proceed to receive the remaining 90% of the test standard 
dose of amoxicillin (see Appendix D). A trained study team member needs to be present at 
bedside for 30 minutes following the administration of the rest of the 90% of the dose. Another 
set of vital signs will be obtained 30 and 60 minutes following the administration of the rest of 
the 90 % of the dose. 
 
If the patient develops any symptom indicative of anaphylaxis (see definition of terms), 
epinephrine will be administered right away either by IV or IM (see Appendix D) and a rapid 
response alert or code will be called as indicated. Epinephrine will be available at bedside prior 
to initiation of oral challenge testing. Administration of epinephrine will be done by a trained 
study team member. Inhaled albuterol or supplemental oxygen will be administered if 
indicated. Administration of both will also be done by the study team member with the 
assistance of the patient’s nurse. The event needs to be documented in the patient’s chart 
specifying the reaction and the intervention given (see Appendix C.3). The patient will need to 
be monitored for progression of symptoms for the next 2 hours post-administration of 
epinephrine so a proper disposition can be made (remain on the floor or transfer to higher level 
of care) 
 
Any patient who develops any type of reaction at any point during the administration of the 
remaining 90 % of dose will be labeled to have failed the test. This will also be documented in 
the patient’s chart accordingly (see Appendix C.3). The patient’s penicillin allergy status will 
then be retained in the chart. The patient will be provided proper guidance and 
recommendation to follow up with an allergist for further evaluation and management. 
 
If the patient did not have any reaction to the remaining 90% of standard dose at 120 minute-
mark following start of challenge testing, then the patient is deemed to not have allergy to 


penicillin. The allergy label in the EMR will then be removed with a notation “patient underwent 
direct oral amoxicillin challenge testing with no reaction on (date)”. The patient’s vital signs will 
again be obtained by a trained study team member and recorded for documentation (see 
Appendix C.4). 
 
The pediatric ID fellow will be present for 30 minutes following each dose of amoxicillin. The 
study team attending or the pediatric ID fellow will also oversee study team members who are 
still in residency training through direct supervision during critical portions of the procedure 
(within 30 minutes of challenge dose administration). The pediatric ID fellow will always be 
available in person within the campus for the resident team members for every patient 
challenged throughout the entire duration of the challenge testing. Anytime a patient is 
challenged, the pediatric ID fellow will be present not more than 3-5 minutes away from the 
study site and always reachable by a dedicated study team phone. Study team members will 
also be responsible to attend/respond to any reaction the patient may have that is related to 
the oral challenge testing procedure. 
 
All vital signs obtained throughout the procedure will be performed and recorded by trained 
study team members. Administration of the graded enteral amoxicillin doses and rescue 
medications if indicated will also be performed by the study team members. 
 
7. The result of the oral challenge testing be communicated to the patient’s primary care physician 
for guidance on future use of penicillin in the form of a letter that will be handed to the parent/s 
or guardian containing the result of the challenge testing. Permission will be obtained from 
parent/s or guardian before communication of result to PCP. Permission will be obtained during 
the consent process. Education on the patient’s change in allergy status will then be provided to 
the parents. 
 
Study Timeline  
The conduct of the challenge testing will be done only from 8:00 AM – 2:30 PM to ensure availability of 
full attendance of medical staff in the event untoward issues occur. The single visit from consent to the 
time amoxicillin oral challenge is done will take an average of approximately 3 hours. Enrollment and 
conduct of the study will be done over a 6-month period (September 22, 2021 – March 31, 2022). 
 
Data to be Collected for your study  
(AFTER consent and HIPAA Authorization have been obtained)  
Data that will be collected will include patient’s name, date of birth, age, sex, MRN, race (if available), 
penicillin allergy status (reaction description if stated), PCP’s name, PCP’s contact information, and the 
responses of parent/s or legal guardian to the screening questionnaire (see attached Appendix B) 
 
Data Analysis Plan  
Descriptive statistical tools will be used to analyze the data. A P-value of of <0.05 will be used to 
determine statistical significance in the result interpretation. 
 
The primary end point will be verification of patients’ penicillin allergy status through direct oral 
challenge testing with amoxicillin. 
 
Secondary endpoints will be:  


1. Identification of patients (no-risk patients and low-risk patients who passed the oral challenge 
testing) who will then be delabeled in the EMR.  
2. Identification of patients (no-risk patients and low-risk patients who passed the oral challenge 
testing) in order to provide proper guidance to their PCPs regarding use of penicillin in the 
future.  
3. Identification of high-risk risk patients and low-risk patients who failed the oral amoxicillin 
challenge testing in order to provide them proper guidance on referral to allergy/immunology 
for further evaluation and management. 
 
Risks to Research Participants  
Reasonable foreseeable risks include breach of confidentiality, discomfort, inconveniences both to 
parent/s or legal guardian and patients. These will be protected against through observance of HIPAA-
concordant practices in the conduct of the study as well as efficient and timely performance of challenge 
testing to avoid consuming too much of patients’ time. 
 
Reaction to the intervention is also one of the foreseeable risk to the patients in this study. Potential 
reactions to the intervention (amoxicillin challenge testing) include skin rash, nausea, vomiting, diarrhea, 
and very rarely anaphylaxis.  
 
Oral diphenhydramine can potentially cause sedation, sleepiness, dizziness, disturbed coordination, 
epigastric distress and thickening of bronchial secretions as the most common known adverse reactions.  
 
Epinephrine can potentially cause anxiety, apprehensiveness, restlessness, tremor, weakness, dizziness, 
sweating, palpitations, pallor, nausea, vomiting, headache, tachycardia, hypertension and very rarely 
respiratory difficulties. 
 
Albuterol can potentially cause tachycardia, hyperactivity, hypokalemia, sleeplessness, headache, 
abnormal heart rate, hypertension, muscle cramps, drying and irritation of oropharynx and sometimes 
hypersensitivity reaction such as rash or urticaria.  
 
These are ameliorated by proper and strict adherence to the selection criteria stipulated in the 
standardized questionnaire, strict attendance of medical personnel available at the critical portions of 
the testing, performing the challenge testing within hours of maximal medical personnel attendance 
(see attached Appendix E), and making sure that rescue medications are ready at bedside before 
initiation of the challenge testing. 
 
Provisions to Protect the Privacy Interests of Research Participants  
Conversations with parent/s or legal guardian and patients (screening, consenting and disclosure of 
challenge testing results) will only be done inside the confines of the patient’s hospital room with the 
door closed. Only the study team members would have access to the conduct of the study. Strict 
adherence to HIPAA guidelines will be observed to protect the patient’s privacy. 
 
Potential Benefit to Research Participants  
The main benefits of this study to the research participants will be determination of their allergy status 
to penicillin (will play a big role in their potential for future receipt of penicillin that may be both life-
saving and cost-saving) and the need to be referred for a formal allergy/immunology evaluation to verify 
penicillin allergy status if indicated. 
 


Withdrawal of Research Participants  
The patient or the parent/s or legal guardian can opt to withdraw on behalf of the patient from 
enrollment at any time during the conduct of the study. Research participants as well have the liberty to 
withdraw from the study anytime. Admission and retention of patients to remain enrolled in the study is 
purely voluntary. 
 
Alternatives to Participation  
Participation to this research project is fully voluntary. The alternative to participation is not to 
participate. 
 
Costs to Research Participants  
The cost of the delabeling procedure will be free to the patient/s. This would otherwise be a relatively 
expensive procedure if done in an allergist’s clinic. The cost of the challenge medications (amoxicillin) 
will be billed to the patient/s insurance as these are medications used in standard of practice allergy 
delabeling process and as this study entails standard of practice delabeling procedure. If the patient/s 
will develop reaction to the challenge testing, the cost of the rescue medications will be part of the 
patient’s standard of care cost and will be billed to the patient/s insurance as well. 
 
Research Participant Compensation  
There will be no compensation, in any form, given to research participants. 
 
Provisions to Monitor the Data to Ensure the Safety of Research Participants 
Data collection will take place at UH RBC premises. Data will be managed by the PI (Dr. Desai) and co-
investigators (Dr. Lim, Dr. Ruda-Wessell, Dr. Lopes, Dr. Miller and Leanne Moore) using REDCap 
database. REDCap (Research Electronic Data Capture) is a secure web application for building and 
managing online surveys and databases. Only the study PI (Dr. Desai) and study team members will have 
access to identifiable private information. The study team will monitor at least every 1- 2 weeks for 
accuracy and adherence to protocol. 
 
Drugs and Devices 
Amoxicillin – standard full dose is 45 mg/kg/dose (maximum total dose 1000 mg) – to be given only by 
enteral route (naso-gastric tube, oro-gastric tube, gastric-tube) in two graded doses: 10% initial dose 
and 90% dose. 
 
Indication: “Challenge Dose Amoxicillin” in order  
 
Diphenhydramine - 1 mg/kg PO or IV (maximum dose 50 mg) – 12.5 mg/5 ml formulation and 50 
mg/vial preparation  
 
Albuterol – 2.5 mg/3ml nebule  
 
Oxygen – to be given by nasal cannula to maintain oxygen saturation more than 92 %  
 
Normal saline (0.9 % NaCL IV solution) - 20 ml/kg as bolus as needed for hypotension  
 
Epinephrine 1:1000 for rescue medication: 
 
<50 kg: Epinephrine (1mg/mL) at 0.01 mg/kg/dose – will be given as Epinephrine Jr 0.15 
mg/0.3 ml auto-injector 


 
>50 kg: Epinephrine (1mg/mL) at 0.5 mg/dose – will be given as Epinephrine 0.3 mg/0.3 ml auto-
injector 
 
Additional Information  
Please see attached protocol algorithm (Appendix A), screening questionnaire (Appendix B) and clinical 
event notes (Appendix C). 
 
References 
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