Safety of cephalosporins in penicillin class severe delayed hypersensitivity reactions

Letter to the edito

Study protocol: Australasian Registry of Severe Cutaneous Adverse Reactions (AUS-SCAR)

Introduction Severe cutaneous adverse reactions (SCAR) are a group of T cell-mediated hypersensitivities associated with significant morbidity, mortality and hospital costs. Clinical phenotypes include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP). In this Australasian, multicentre, prospective registry, we plan to examine the clinical presentation, drug causality, genomic predictors, potential diagnostic approaches, treatments and long-term outcomes of SCAR in Australia and New Zealand. Methods and analysis Adult and adolescent patients with SCAR including SJS, TEN, DRESS, AGEP and another T cell-mediated hypersensitivity, generalised bullous fixed drug eruption, will be prospectively recruited. A waiver of consent has been granted for some sites to retrospectively include cases which result in early mortality. DNA will be collected for all prospective cases. Blood, blister fluid and skin biopsy sampling is optional and subject to patient consent and site capacity. To develop culprit drug identification and prevention, genomic testing will be performed to confirm human leukocyte antigen (HLA) type and ex vivo testing will be performed via interferon-γ release enzyme linked immunospot assay using collected peripheral blood mononuclear cells. The long-term outcomes of SCAR will be investigated with a 12-month quality of life survey and examination of prescribing and mortality data. Ethics and dissemination This study was reviewed and approved by the Austin Health Human Research Ethics Committee (HREC/50791/Austin-19). Results will be published in peer-reviewed journals and presented at relevant conferences

Blister fluid as a cellular input for ex vivo diagnostics in drug-induced severe cutaneous adverse reactions improves sensitivity and explores immunopathogenesis

Background Drug-induced severe cutaneous adverse reactions (SCARs) are presumed T-cell-mediated hypersensitivities associated with significant morbidity and mortality. Traditional in vivo testing methods, such as patch or intradermal testing, are limited by a lack of standardisation and poor sensitivity. Modern approaches to testing include measurement of IFN-γ release from patient peripheral blood mononuclear cells (PBMC) stimulated with the suspected causative drug. Objective We sought to improve ex vivo diagnostics for drug-induced SCAR by comparing enzyme-linked immunospot (ELISpot) sensitivities and flow cytometry-based intracellular cytokine staining (ICS) and cellular composition of separate samples (PBMC or blister fluid cells (BFC)) from the same donor. Methods IFN-γ release ELISpot and flow cytometry analyses were performed on donor-matched PBMC and BFC samples from four SCAR patients with distinct drug-hypersensitivity. Results Immune responses to suspected drugs were detected in both PBMC and BFC samples of two donors (Case 1 in response to ceftriaxone and Case 4 to oxypurinol), with BFC eliciting stronger responses. For two other donors, only BFC samples showed a response to meloxicam (Case 2) or sulfamethoxazole and its 4-nitro metabolite (Case 3). Consistently, flow cytometry revealed a greater proportion of IFN-γ-secreting cells in the BFC compared to PBMC. BFC cells from Case 3 were also enriched for memory/activation/tissue-recruitment markers over PBMC. Conclusion Analysis of BFC samples for drug-hypersensitivity diagnostics offers a higher sensitivity for detecting positive responses compared to PBMC. This is consistent with recruitment (and enrichment) of cytokine-secreting cells with a memory/activated phenotype into blisters

Development and validation of a penicillin allergy clinical decision rule

Importance Penicillin allergy is a significant public health issue for patients, antimicrobial stewardship programs, and health services. Validated clinical decision rules are urgently needed to identify low-risk penicillin allergies that potentially do not require penicillin skin testing by a specialist. Objective To develop and validate a penicillin allergy clinical decision rule that enables point-of-care risk assessment of patient-reported penicillin allergies. Design, Setting, and Participants In this diagnostic study, a multicenter prospective antibiotic allergy–tested cohort of 622 patients from 2 tertiary care sites in Melbourne, Australia (Austin Health and Peter MacCallum Cancer Centre) was used for derivation and internal validation of a penicillin allergy decision rule. Backward stepwise logistic regression was used to derive the model, including clinical variables predictive of a positive penicillin allergy test result. Internal validation of the final model used bootstrapped samples and the model scoring derived from the coefficients. External validation was performed in retrospective penicillin allergy–tested cohorts consisting of 945 patients from Sydney and Perth, Australia, and Nashville, Tennessee. Patients who reported a penicillin allergy underwent penicillin allergy testing using skin prick, intradermal, or patch testing and/or oral challenge (direct or after skin testing). Data were collected from June 26, 2008, to June 3, 2019, and analyzed from January 9 to 12, 2019. Main Outcomes and Measures The primary outcome for the model was any positive result of penicillin allergy testing performed during outpatient or inpatient assessment. Results From an internal derivation and validation cohort of 622 patients (367 female [59.0%]; median age, 60 [interquartile range{IQR}, 48-71] years) and an external validation cohort of 945 patients (662 female [70.1%]; median age, 55 [IQR, 38-68] years), the 4 features associated with a positive penicillin allergy test result on multivariable analysis were summarized in the mnemonic PEN-FAST: penicillin allergy, five or fewer years ago, anaphylaxis/angioedema, severe cutaneous adverse reaction (SCAR), and treatment required for allergy episode. The major criteria included an allergy event occurring 5 or fewer years ago (2 points) and anaphylaxis/angioedema or SCAR (2 points); the minor criterion (1 point), treatment required for an allergy episode. Internal validation showed minimal mean optimism of 0.003 with internally validated area under the curve of 0.805. A cutoff of less than 3 points for PEN-FAST was chosen to classify a low risk of penicillin allergy, for which only 17 of 460 patients (3.7%) had positive results of allergy testing, with a negative predictive value of 96.3% (95% CI, 94.1%-97.8%). External validation resulted in similar findings. Conclusions and Relevance In this study, PEN-FAST was found to be a simple rule that accurately identified low-risk penicillin allergies that do not require formal allergy testing. The results suggest that a PEN-FAST score of less than 3, associated with a high negative predictive value, could be used by clinicians and antimicrobial stewardship programs to identify low-risk penicillin allergies at the point of care

The role of In Vivo and Ex Vivo diagnostic tools in severe delayed Immune-Mediated adverse antibiotic drug reactions

Background The use of in vivo and ex vivo diagnostic tools for delayed immune-mediated adverse drug reactions is currently ill defined. Objective To determine whether the combination of skin testing and/or IFN-γ enzyme-linked immunoSpot assay (ELISpot) can aid diagnosis of these allergy phenotypes. Methods Patients with antibiotic-associated severe delayed immune-mediated adverse drug reaction hypersensitivity, including Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis, generalized bullous fixed drug eruption, and severe maculopapular exanthema, were prospectively recruited. In vivo testing was completed to the implicated drug(s), and ex vivo testing was performed with the patient's PBMCs stimulated with the relevant antibiotic concentrations for IFN-γ release ELISpot measurement. Results Eighty-one patients met the inclusion criteria, with DRESS (42; 51.9%) accounting for most cases. Among the 63 (78%) who had an ELISpot assay performed, 34 (54%) were positive to at least 1 implicated antibiotic (median spot-forming units/million cells, 99.5; interquartile range, 68-187), with glycopeptide being a strong predictor of positivity (adjusted odds ratio, 6.11; 95% CI, 1.74-21.42). In combination (in vivo and ex vivo), 51 (63%) of those tested were positive to an implicated antibiotic. For DRESS and severe maculopapular exanthema associated with penicillins and cephalosporins, this combination confirmed the culprit agent in 11 of the 12 cases and in 6 of 7 for DRESS associated with glycopeptides. Conclusions This study demonstrates that using in vivo in combination with ex vivo testing can enhance the diagnostic approach in these severe phenotypes by assisting with the identification of possible culprit antibiotics

The penicillin allergy delabeling program: A Multicenter Whole-of-Hospital health services intervention and comparative effectiveness study

Background Penicillin allergies are associated with inferior patient and antimicrobial stewardship outcomes. We implemented a whole-of-hospital program to assess the efficacy of inpatient delabeling for low-risk penicillin allergies in hospitalized inpatients. Methods Patients ≥ 18 years of age with a low-risk penicillin allergy were offered a single-dose oral penicillin challenge or direct label removal based on history (direct delabeling). The primary endpoint was the proportion of patients delabeled. Key secondary endpoints were antibiotic utilization pre- (index admission) and post-delabeling (index admission and 90 days). Results Between 21 January 2019 and 31 August 2019, we assessed 1791 patients reporting 2315 antibiotic allergies, 1225 with a penicillin allergy. Three hundred fifty-five patients were delabeled: 161 by direct delabeling and 194 via oral penicillin challenge. Ninety-seven percent (194/200) of patients were negative upon oral penicillin challenge. In the delabeled patients, we observed an increase in narrow-spectrum penicillin usage (adjusted odds ratio [OR], 10.51 [95% confidence interval {CI}, 5.39–20.48]), improved appropriate antibiotic prescribing (adjusted OR, 2.13 [95% CI, 1.45–3.13]), and a reduction in restricted antibiotic usage (adjusted OR, 0.38 [95% CI, .27–.54]). In the propensity score analysis, there was an increase in narrow-spectrum penicillins (OR, 10.89 [95% CI, 5.09–23.31]) and β-lactam/β-lactamase inhibitors (OR, 6.68 [95% CI, 3.94–11.35]) and a reduction in restricted antibiotic use (OR, 0.52 [95% CI, .36–.74]) and inappropriate prescriptions (relative risk ratio, 0.43 [95% CI, .26–.72]) in the delabeled group compared with the group who retained their allergy label. Conclusions This health services program using a combination of direct delabeling and oral penicillin challenge resulted in significant impacts on the use of preferred antibiotics and appropriate prescribing