Oral challenge vs routine care to assess low-risk penicillin allergy in critically ill hospital patients (ORACLE): a pilot safety and feasibility randomised controlled trial

The ORACLE study is a pilot, multicentre, parallel, 2-arm, open-label, randomised clinical trial. It was conducted in four teaching hospital ICUs in Melbourne, Australia (Austin Hospital, Monash Medical Centre, The Royal Melbourne Hospital/Peter MacCallum Cancer Centre, Alfred Hospital). The rationale and design of the ORACLE study have been previously published [18]. The study was designed and overseen by a Trial Management Group (electronic supplementary material, ESM, 1). Study administration, data management, and statistical analyses were performed at Austin Health (Melbourne, Victoria, Australia). All deaths and complications were reviewed by intensive care clinicians as part of standard quality processes in each participating intensive care unit. Serious adverse events were independently reviewed by two antibiotic allergy clinicians and two critical care clinicians.

The trial protocol [18] (ESM 2) was approved by the Austin Health Human Research Ethics Committee (HREC/59438/Austin-2020) and subsequently by the independent institutional review boards at each site. Written informed consent was provided by participants or their designated medical treatment decision maker in keeping with clinical circumstances and local ethics committee requirements.

Patients admitted to the ICU, labelled with a penicillin allergy, with a calculated PEN-FAST score of less than 3 (ESM 3) and expected to remain in ICU for ≥ 24 h post-assessment, were eligible for enrolment. PEN-FAST was utilised as previously published and validated [10, 11]. Allergy phenotyping to enable PEN-FAST utilisation was performed using the antibiotic allergy assessment tool (AAAT) [19]. Key exclusion criteria included age less than 18 years, need for high dose vasoactive infusion (≥ 0.1 µg/kg/min norepinephrine (base) or any dose adrenaline within 4 h prior to randomisation), high ventilatory support requirement (any of: (i) ventilation mode other than spontaneous, (ii) peak end expiratory pressure > 5 cmH₂O, (iii) FiO₂ > 40%) and receipt of more than stress-dose steroid therapy (> 200 mg total daily dose of hydrocortisone or equivalent). Patients who could not receive oral/enteral medications were excluded. Patients with allergy histories of severe non-cutaneous reactions such as severe delayed organ, neurological, or haematological reactions were also excluded. The full inclusion and exclusion criteria are provided in the protocol [18] and in ESM 2. Site investigators confirmed eligibility prior to participant randomisation.

Participants were randomised in a 1:1 ratio to either the intervention group (direct enteral penicillin challenge) or the control group (routine care). Randomisation was performed via sealed sequentially numbered envelopes (at a single study site, Austin Hospital) and a centralised web-based REDCap [20] (Austin Health) at all other sites, by permuted block design (block sizes ranging from 2 to 6), stratified by hospital site. Group allocation was concealed until randomisation. Blinding post-randomisation was not possible. The sequence was computer generated by the trial statistician (SV). Trial investigators enrolled the participants and performed randomisation.

Open-label administration of 250 mg enteral (oral/nasogastric/percutaneous endoscopic gastrostomy tube (PEG)) penicillin (either amoxicillin or implicated penicillin) was performed by bedside nursing staff. Participants were directly observed (monitoring for adverse events and measurement of vital signs at baseline and at 30-min intervals) for 2-h post-challenge. Patients in the control arms were directly observed for 2-h post-randomisation. Safety evaluation and the outcome of enteral challenges was undertaken by site investigators.

Patients in the intervention arm received a repeat penicillin challenge once they met all the following criteria: (a) at least 48 h since the first challenge, (b) resolution of critical illness (discharged from ICU or remaining in ICU due solely to bed access restrictions), (c) negative initial penicillin challenge.

Site investigators reviewed all participants at 24 h and 5 days post each period of direct observation to assess for any delayed adverse events and assess post-testing antibiotic utilisation.

The primary outcome measures were the proportion of eligible patients that consented to enrol in the study (a ratio of ≥ 50% was used as the primary determinant of feasibility) and the proportion of patients who experienced an antibiotic-associated immune-mediated or serious adverse event (a proportion of < 5% was used to determine safety). Exploratory outcomes included subsequent antibiotic utilisation, length of stay and mortality (Table 3).

Given Australian national penicillin allergy prevalence data (9%) [1] and local ICU observational data [3], 200 patients would be expected to be eligible in a 12-month study period. Assuming 50% recruitment and 85% completion, a pool of 85 eligible participants in 1 year was projected. As such, a total of 80 enrolments and 1:1 randomisation (40 in each arm) was planned.

Between March 20, 2021, and November 1, 2023, 533 patients were screened, with 80 patients enrolled from four ICUs (Fig. 1). The characteristics of the participants are presented in Table 1. The median age of participants was 64.5 years (IQR 53.5, 74) with 40 (50%) female participants. Median Charlson comorbidity index was 4 (IQR 2, 6) and median ICU admission Sequential Organ Failure Assessment (SOFA) and acute physiology and chronic health evaluation (APACHE) II scores were 4 (IQR 2, 6) and 11 (IQR 6.5, 14) respectively. At the time of randomisation, two (5%) patients in the intervention arm and one (2.5%) patient in the control arm were mechanically ventilated.

Reported penicillin allergies included penicillin unspecified (n = 60), amoxicillin (n = 10), penicillin (n = 5), flucloxacillin (n = 4), and amoxicillin clavulanate (n = 1). PEN-FAST scores were 0 (n = 34 (42%)), 1 (n = 35 (44%)), and 2 (n = 11 (14%)). In 31/80 (39%), the reaction had occurred > 10 years prior to screening and 51/80 (64%) participants described an unknown latency between antibiotic exposure and reaction. The most common allergy phenotype was a mild rash (57 of 88 (65%) reported symptoms) and 47/80 (59%) participant’s reactions resolved without treatment. Allergy phenotypic distributions, as characterised by the Antibiotic Allergy Assessment Tool [19], are listed in ESM 4.