Jason A. Trubiano

Antibiotic allergy labels (AALs) impact patient health and perioperative outcomes. Antibiotic allergy delabeling could improve antibiotic prescribing and infection-related outcomes perioperatively. To assess the feasibility and safety of antibiotic allergy assessment and delabeling in anesthesiologist-led preoperative assessment clinics and expand delabeling efforts outside of specialist allergy clinics. This randomized clinical trial was a multicenter, phase 2 feasibility and safety trial conducted between December 14, 2020, and October 31, 2023, at outpatient preoperative anesthesiologist-led clinics at 3 tertiary hospitals in Melbourne, Australia. Participants were adults (age ≥18 years) with a reported β-lactam AAL likely to require intravenous antibiotic therapy for perioperative prophylaxis. Randomization was carried out on a 1:1 basis. Enhanced allergy assessment by anesthesiologists using a smartphone application with a decision support algorithm adapted from a validated antibiotic allergy assessment tool. Risk scores guided antibiotic allergy testing: direct oral challenge (low risk) or skin testing followed by oral challenge (medium to high risk). The 2 primary feasibility outcomes were the proportion of patients randomized to intervention who received intervention per protocol and proportion of patients consenting to participate out of all eligible. The primary safety outcome was the proportion of the intervention group experiencing an antibiotic-associated adverse event (AE) within 90 days postsurgery. Of 150 patients enrolled, 74 were randomly assigned to receive the intervention and 76 to control. The median age was 67 years (range, 28-89 years); 78 (52%) were female and 72 (48%) were male. For feasibility of recruitment, 150 of 511 patients (29.4%; 95% CI, 25.4%-33.5%) with eligible AALs were enrolled. For feasibility of intervention delivery, 47 of 74 patients (63.5%; 95% CI, 51.5%-74.4%) randomized to intervention had allergy testing; 28 of 30 patients (93%) assessed as low risk and 19 of 44 patients (43%) assessed as moderate/high risk proceeded to allergy testing. Antibiotic-related AE were reported in 4 of 74 intervention patients (5.4%, 95% CI, 1.5%-13.3%), 1 event was immune mediated (benign rash) without a delay to surgery. There was less restricted antibiotic use in the intervention group (6 patients; 10.7%) compared with the control group (10 patients; 17.9%). Low-risk β-lactam AAL were successfully evaluated and delabeled by anesthesiologists in the preoperative clinic using the intervention. The absence of severe AE after the intervention provides reassurance that antibiotic allergy delabeling can be achieved as part of a preoperative workup without delaying surgery and may improve the choice of preferred β-lactam prophylaxis. anzctr.org.au Identifier: ACTRN12620001295932.

Co-trimoxazole is a leading global cause of severe cutaneous adverse drug reactions (SCAR) including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Co-trimoxazole-induced SCAR are associated with HLA class I alleles including HLA-B*13:01 and HLA-B*38:02 in Southeast Asian (SEA) populations. However, the global generalizability of these associations is unknown but critical for population-appropriate risk stratification and diagnosis. To determine HLA risk factors associated with co-trimoxazole-induced SJS/TEN and DRESS in populations from the United States (US) and South Africa (SA). We performed high-resolution HLA typing on dermatologist-adjudicated co-trimoxazole-induced SCAR patients in the US (n=63) and SA (n=26) compared to population controls. Peptide binding and docking analyses were performed using MHCcluster2.0 and CB-Dock2. In a multiple logistic regression model, HLA-B*44:03 (Pc<0.001, OR: 4.08), HLA-B*38:01 (Pc<0.001, OR: 5.66), and HLA-C*04:01 (Pc=0.003, OR: 2.50) were independently associated with co-trimoxazole-induced SJS/TEN in the US. HLA-B*44:03 was also associated with co-trimoxazole-induced DRESS in SA (Pc=0.019, OR: 10.69). Distinct HLA-B variants with shared peptide binding specificities (SPBS) and HLA-C*04:01 identified 94% and 78% of co-trimoxazole-induced SJS/TEN and DRESS in the US, respectively. The SEA risk allele HLA-B*13:01, with SPBS to HLA-B*44:03, was identified in just 1/63 US SCAR patients. HLA alleles with SPBS to SEA-related risk alleles including HLA-B*44:03 (SPBS with HLA-B*13:01) and HLA-B*38:01 (SPBS with HLA-B*38:02) but also HLA-C*04:01 predisposed to co-trimoxazole-induced SCAR in the US and SA. These findings provide biological plausibility and strategies for global risk prediction and diagnosis of co-trimoxazole-induced SCAR. What is already known about this topic?: HLA alleles including HLA-B*13:01 and HLA-B*38:02 are risk factors for co-trimoxazole-induced SCAR in Asian populations. However, the generalizability of these associations to other global populations is unknown but critical for population-appropriate risk stratification and diagnosis.What does this article add to our knowledge?: HLA alleles with shared peptide binding specificities (SPBS) to Asian-related risk alleles including HLA-B*44:03 (SPBS with HLA-B*13:01) and HLA-B*38:01 (SPBS with HLA-B*38:02) but also HLA-C*04:01 predisposed to co-trimoxazole-induced SCAR in the US and South Africa.How does this study impact current management guidelines?: HLA alleles previously associated with co-trimoxazole-induced SCAR do not identify risk across populations. However, HLA alleles with SPBS provide biological plausibility and strategies for global and population-appropriate clinical risk stratification and diagnosis of cotrimoxazole-induced SCAR.

Background: Consensus guidelines outline the recommended management of delayed drug hypersensitivity reactions (DHR), but clinical practices are largely expert-based and may vary significantly across populations and regions. This study evaluated the approach and management of healthcare specialists globally regarding DHR, including severe cutaneous adverse reactions (SCARs). Objective: To assess the current practices, knowledge, and availability of allergy testing for DHR, including SCARs, among relevant healthcare professionals globally. Methods: The GRASS (Global AppRoAch for Severe Cutaneous Adverse Reactions Survey) study is a prospective, web-based survey conducted using the Research Electronic Data Capture (REDCap) platform. The 10- to 15-minute survey was directed to 14 allergy/immunology and dermatology associations through international mailing lists across 48 countries. Results: Among the 8,561 members contacted, answers from 130 healthcare providers practicing in all six continents were analyzed. Most respondents identified as Caucasian (88/130; 68%) and female (79/130; 61%), representing a range of age groups and clinical expertise. Most practiced in dermatology (69/130; 53%), followed by allergy/immunology (46/130; 35.4%), and were based in an urban setting (127/130; 98%). Among the 45 respondents (34.6%) who managed SCARs, 27 (60%) had access to multidisciplinary care. Practices varied widely by clinical phenotype; for example, for maculopapular exanthema, 63 respondents indicated treating through the reaction (63/130; 49%), while 16 (16/130;12%) offered desensitization. Under patient education and follow-up, only 60 (60/130; 46.2%) participants organized a follow-up with the implicated specialist. Conclusions: Significant variability in the management of DHR was observed among the respondents. The results highlight the need for evidence-based protocols to standardize guidelines for managing DHRs.

In the evaluation of patient-reported penicillin allergy labels (PALs), the utility of skin testing to the penicillin major determinant, known as penicilloyl polylysine (PPL), and to the minor determinant mixture (MDM), has been questioned. A review of a clinical antibiotic allergy database from April 2015 to December 2023 at Austin Health (Melbourne, Australia) was performed. Patients with PALs who underwent skin prick testing (SPT) and intradermal testing (IDT) to a previously-published standardised beta-lactam panel were selected. Those with positive SPT or IDT to PPL and/or MDM were identified. A total of 1316 individuals were included in our analysis. Positive skin testing to any reagent was recorded for 168/1316 (12.77%). Positive results to PPL and/or MDM were recorded for 26/1316 (1.98%), including 6 with isolated positive results to PPL and/or MDM, and 20 with additional positive skin testing to at least 1 native penicillin. The number needed to test to confirm 1 additional penicillin allergy with the use of PPL and MDM was calculated at 217.39. Immediate hypersensitivities were reported by all 6 individuals testing positive to the penicillin determinants alone, including 4 with anaphylaxis. These results suggest limited yield in the routine inclusion of PPL and MDM in skin testing panels, particularly in evaluating delayed hypersensitivities. Restricting their use to select cohorts, such as those with anaphylaxis, may prove more efficient and cost-effective.

Background: Penicillin allergy labels (PALs) are reported in 1 in 10 hospitalised patients globally and associated with inferior patient, hospital and microbiological outcomes; however, the majority are incorrect and should be removed. Direct oral penicillin challenge has been demonstrated to be a safe and effective method for the removal of PALs. However, the question of whether a single dose is sufficient to ascertain true allergy status remains unanswered, with some studies suggesting that extended challenges of 3 or more days are superior for the exclusion of delayed immune reactions. The aim of the PROSPECTOR studies was to determine the feasibility (PROSPECTOR-1) of a definitive trial (PROSPECTOR-2) to evaluate the safety and effectiveness of prolonged oral challenge (ie, 5 days) versus single-dose oral challenge in patients with a delayed or unknown penicillin allergy phenotype (PROSPECTOR-2). Methods: A pair of double-blind two-arm parallel placebo-controlled trials will be undertaken-PROlonged versus Single dose in PEnicillin oral Challenge Testing double-blind parallel group randomised placebo-cOntrolled tRial (PROSPECTOR Studies). Patients with a reported delayed or unknown timing penicillin allergy who have passed a supervised single-dose oral amoxicillin challenge (with or without prior skin testing/single or split dose) will be recruited. Informed patient consent will be granted for sites to recruit patients and collect routine clinical data. PROSPECTOR-1 will assess the safety and feasibility of a placebo-controlled trial for single-dose amoxicillin challenge versus 5-day prolonged oral challenge. PROSPECTOR-2 will assess the superiority of the 5-day prolonged oral challenge compared with single-dose amoxicillin challenge in excluding a delayed immune reaction. PROSPECTOR-2 will commence immediately post completion of PROSPECTOR-1 in a vanguard design, with adjustments to the projected sample size for superiority made following completion of PROSPECTOR-1. PROSPECTOR-2 will commence recruitment immediately following closure of PROSPECTOR-1; however, data from each trial will be analysed separately. Background: These studies were reviewed and approved by the Austin Health Human Research Ethics Committee (PROSPECTOR-1: HREC/99740/Austin-2023 and PROSPECTOR-2: HREC/109785/Austin-2024). The results will be published in peer-reviewed journals and presented at relevant conferences. Background: PROSPECTOR-1: ACTRN12623001242617 and PROSPECTOR-2: ACTRN12624001107516.