Study Objectives
To investigate the feasibility and safety of a direct oral penicillin challenge in adult ICU patients that have a low-risk penicillin allergy (PEN-FAST score < 3). Outcome measures are listed in Table 1 and include the primary outcomes of safety and feasibility of direct oral challenge. Secondary outcomes include proportion of allergy labels removed post-oral challenge, pre- and post-randomisation antimicrobial utilisation, in-hospital and 30-day mortality, and length of stay.
Table 1
Primary Outcome Measures
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Feasibility Outcome Measures
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Eligibility to screened ratio
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Proportion of patients that are eligible for intervention
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Recruitment to eligibility ratio
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Proportion of eligible patients consenting to participation in the study
(a ratio of ≥ 50% will be used as the primary determinant of feasibility)
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Intervention to recruitment ratio
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Proportion of patients randomised to the intervention arm that had the intervention delivered as per protocol
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Protocol Compliance
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Proportion of randomised patients that complete all study activities as per protocol
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Safety Outcome Measures
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Safety
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Proportion of patients with a penicillin allergy who experience an antibiotic associated immune mediated adverse event OR serious adverse event.
(a proportion of < 5% will be used as the determinant of safety)
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Exploratory outcome measures
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o Proportion of participants in the intervention arm successfully delabelled post oral challenge
o Utilisation of any penicillin during hospital admission
o Utilisation of any narrow spectrum beta-lactam during hospital admission
o Utilisation of vancomycin during hospital admission
o Utilisation of any restricted antibiotic during hospital admission
o In-Hospital and 30-day mortality
o ICU length of stay and hospital length of stay
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Design & Schedule
This is a pilot, feasibility, open-label randomised clinical trial that will be conducted in mixed medical/surgical ICUs in five tertiary referral teaching hospitals in Melbourne, Australia (Austin Health, Peter MacCallum Cancer Centre, Melbourne Health, Monash Health, Alfred Health). A summary of the study design is presented in Fig. 1. We will include 80 patients with a low-risk penicillin allergy and allocate them in a 1:1 ratio to the intervention group (oral penicillin challenge) and control group (standard of care). Oral challenge will be undertaken using the implicated oral penicillin if known (including penicillin VK, amoxicillin, flucloxacillin, dicloxacillin). Challenge for “penicillin unspecified” allergy labels will utilise amoxicillin (the most common community-prescribed oral penicillin in Australia)15 or penicillin VK (if the reaction occurred prior to amoxicillin availability).
Adult patients admitted to the ICU reporting a penicillin allergy will be identified by study investigators from a daily electronic medical record (EMR) list and assessed utilising a validated Antibiotic Allergy Assessment Tool (Appendix 1) to obtain allergy phenotype.16 Once the reported allergy phenotype has been determined the PEN-FAST clinical decision rule will be applied (Appendix 2). Informed consent will be sought from those with a PEN-FAST score < 3 who meet all eligibility criteria, and they will be randomised to the intervention arm or control arm. All other concomitant care and interventions will be undertaken according to local ICU and hospital protocols.
Eligibility Criteria
Inclusion criteria
Inclusion criteria will include adult (≥ 18 years) ICU inpatients reporting a penicillin allergy with a PEN-FAST assessment score of less than 3 (representing a low or very low risk of true penicillin allergy) and an expected ICU discharge date of > 24 hours post-randomisation.
Exclusion criteria
Patients will be excluded if their allergy history cannot be confirmed, are severely critically ill (unlikely to survive index admission, high ventilatory support requirements, high inotropic support requirements), confirmed pregnancy, are receiving medication that may interfere with allergy assessment (antihistamines, high-dose steroids), or report a history of non-penicillin drug-associated anaphylaxis or idiopathic urticaria/anaphylaxis/mastocytosis.
A full list of inclusion and exclusion criteria is presented in Table 2.
Table 2
ORACLE Study Eligibility Criteria
Inclusion Criteria
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1. Adult (≥ 18 years) ICU inpatient
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2. Reported penicillin allergy with a PEN-FAST score < 3
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3. Are expected to stay in the ICU at least 24 hours post assessment
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Exclusion Criteria (patient excluded if ONE of the following criteria present)
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1. Known pregnancy
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2. Death is deemed imminent or inevitable during this admission, and either the attending physician, patient or medical treatment decision maker is not committed to active treatment
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3. Any other illness that, in the investigator’s judgement, will substantially increase the risk associated with subject’s participation in this study
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4. Patients with known history of ANY non-penicillin drug-associated anaphylaxis
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5. Patients with a known history of idiopathic urticaria, idiopathic anaphylaxis or mastocytosis
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6. Patients where the allergy history was not able to be confirmed with patient or medical treatment decision maker
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7. Patients on antihistamine therapy (excluding H2-receptor antagonists)
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8. Patients receiving > 10 micrograms/minute of noradrenaline or any adrenaline therapy in last 4 hours
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9. High ventilator requirement if intubated (any of the following)
i. Any mode other than spontaneous
ii. Peak end expiratory pressure (PEEP) > 5cm H2O
iii. FiO2 > 40%
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10. Patients receiving more than stress dose steroid therapy (i.e., > 50 mg QID hydrocortisone or daily equivalent)
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Intervention And Control Arms
Intervention
The intervention is a single dose 250mg of oral penicillin (capsule or liquid via enteral route, including nasogastric/PEG/PEJ) following baseline observations being performed (i.e., temperature, heart rate, blood pressure, respiratory rate, skin check). The implicated penicillin will be administered if known. Amoxicillin will be administered for “penicillin unspecified” allergy labels (or penicillin VK if the reaction occurred prior to the availability of amoxicillin). The penicillin challenge dose will be charted by the study or ICU clinician (following review of baseline observations) and administered by bedside nursing staff. Clinical observations will be collected by the beside nursing staff at + 30, +60, + 90 and + 120 minutes post oral challenge. If at any stage an antibiotic associated adverse event is noted the treating and study clinicians will be informed. Treatment of the adverse event will be at the discretion of the treating clinician.
Patients will undergo a repeat single-dose oral penicillin (250mg) challenge following ICU discharge and at least 48 hours post initial challenge (if they remain an inpatient). Participants who no longer require ICU level care but have not yet been transferred out of the unit due to bed availability, may receive the repeat oral challenge within the ICU if at least 48 hours have passed since the primary challenge dose. A further set of clinical observations at 30-minute intervals over 2 hours will be collected following the repeat oral challenge. The repeat challenge is administered to assess for a potential false negative initial oral challenge secondary to critical illness. Participants will be reviewed at 24 hours and 5 days post-randomisation; 24 hours and 5 days post the second oral challenge and 90 days post randomisation. Participant review will assess for any serious or antibiotic-associated adverse events as per protocol definitions and will be undertaken in-person whilst an inpatient or via telephone or telehealth following hospital discharge. Participants with a positive initial challenge will not proceed to a repeat challenge.
Control
Routine management of penicillin allergy label as per local ICU protocols without oral penicillin challenge. Patients in the control arm will have observations performed at randomisation and at + 30, +60, + 90 and + 120 minutes post-randomisation by the beside nursing staff. A further set of clinical observations at 30minute intervals over 2 hours will be collected following ICU discharge and at least 48 hours after randomisation (if they remain an inpatient). Participants will be reviewed at 24 hours and 5 days post-randomisation; 24 hours and 5 days post the second observation period, and 90 days post randomisation. Participant review will assess for any serious or antibiotic-associated adverse events as per protocol definitions and will be undertaken in-person whilst an inpatient or via telephone or telehealth following hospital discharge. After the completion of the 90-day review, all participants in the control arm will be offered a referral to their nearest public antibiotic allergy assessment clinic for definitive assessment of their penicillin allergy label.
Participant Timeline
A timeline of the enrolment, interventions, and review of participants in the intervention and control arms is presented in Fig. 2.
Sample Size
This is a pilot study designed to assess the feasibility and safety of the ICU oral challenge program, as well as providing local estimates for subsequent power calculation for future trials.
With regard to the feasibility of penicillin allergy assessment within the ICU, we assume that 9% of all screened patients will report a penicillin allergy as per national data1, and in an observational study by Moran et al. in Austin Health ICU6 200 patients would be expected to be eligible in a 12 month study period. Assuming 50% recruitment and that 85% complete the randomised challenge/observation, this would generate a projected potential pool of 85 eligible participants in 1 year. As such, a total of 80 enrolments and 1:1 randomisation (40 in each arm) is planned.
Whilst the above assumptions may be true, (particularly for the primary study site, with an established clinical and research antibiotic allergy service) there are anticipated factors which may limit recruitment. The expected number of 200 eligible patients was calculated from a single tertiary ICU, the different patient populations of other ICUs may vary the number of eligible patients. Temporary disruptions are expected due to the ongoing SARSCo-V2 pandemic, with altered patient flow through ICUs and investigator availability. Delays in activating study sites may slow recruitment and consistent recruitment may be more challenging at sites with less robust allergy research services. Randomisation
Randomisation will be determined by means of an electronically generated allocation sequence using permuted block design, stratified by clinical site. Allocation concealment will be achieved via opaque sealed sequentially numbered envelopes at a single study site (Austin Health). All other study sites will undertake allocation using REDCap (Research Electronic Data Capture).
At Austin Health, generation of the randomisation sequence for the sequentially numbered envelopes will be performed by independent ICU research coordination staff.
The REDCap allocation sequence will be developed and uploaded to REDCap by a trial statistician and will remain concealed prior to allocation.
Allocation will be performed by study investigators (unsealing the opaque envelopes at Austin Health or via the REDCap database randomisation tool at all other sites).
Blinding
The participant, ICU team and treating clinicians will be blinded to the formal Allergy Assessment Tool result and PEN-FAST score. The participant, ICU team and treating clinicians will not however, be blinded to the result of eligibility to be randomised (i.e., low risk vs. high risk). The participant, ICU team and treating clinicians will not be blinded to the allocation or outcome of the oral penicillin challenge in participants of the intervention arm.
Data collection
For all participants, data will be collected during the study by investigators as per the electronic Case Record Form (REDCap). Data to be collected will include basic demographics, medical history, details of the index hospital admission (including diagnosis, critical illness severity, infective episodes and antimicrobial treatment and hospital and ICU length of stay), antimicrobial allergy history, penicillin challenge and/or observation data, and any identified antibiotic-associated adverse events during the study period (including serious adverse events). A full list of data points is listed in Appendix 3.
Statistical Methods
Data analysis will be performed on an intention-to-treat basis as well as per protocol. Summary statistics will be used to describe the clinical data and presented as mean ± standard deviation (SD), median with interquartile range (IQR) or percentages as appropriate.
Feasibility and safety outcomes will be reported as percentage with 95% confidence intervals. Logistic regression will be used to compare antibiotic utilization and mortality between groups. Results will be reported as odds ratios with 95% confidence intervals. Negative binomial regression will be used for comparison of length of stay (reported as incidence rate ratio with 95% CI). Results will be reported according to CONSORT guidelines.17
Data monitoring
As a pilot study with a small number of planned participants utilising an established safe allergy assessment protocol, a data monitoring committee will not be established. Any serious adverse events or antibiotic associated immune mediated adverse events will be referred to two independent clinicians with extensive experience in antibiotic allergy for adjudication.
Participant retention will be promoted through the offer of telephone follow-up for patients post hospital discharge.
Harms
Serious adverse events (SAEs) will be defined as any adverse drug event that, in the opinion of the investigators, is causal for any of these outcomes: (1) death; (2) life-threatening reaction; (3) inpatient hospitalisation; (4) results in persistent or significant disability/incapacity; (5) congenital anomaly or birth defect or (6) requires intervention to prevent permanent impairment or damage. SAEs that occur from the time of commencement of study treatment to 5 days after the second challenge/observation will be collected and reported to the approving ethics committee within 24 hours of study staff becoming aware of the event.
An antibiotic-associated immune-mediated adverse event will include any immune-mediated reaction within 48 hours of an antibiotic dose judged by two independent reviewers. An antibiotic-associated adverse event will be defined as any non-immune mediated reaction (e.g., diarrhoea, nausea, and vomiting) within 48 hours of an antibiotic dose judged by two independent reviewers.
Confidentiality And Dissemination
Confidentiality
Paper data and study related documents used in this study will be de-identified and only a master log will be maintained to identify participants and their study data. The log will be locked in a secure office. Electronic data will be stored in a password protected REDCap database hosted by Austin Health. All data for study will be retained for a period of fifteen years after which all electronic and paper data will be destroyed in accordance with hospital policy in place at the time. Only aggregated non-identifiable patient data will be presented or published.
Dissemination policy
The results of this pilot study will be submitted for publication in peer reviewed journals.