Introduction of a penicillin allergy de-labelling program with direct oral challenge and its effects on utilization of beta-lactam antimicrobials: a multicenter retrospective parallel cohort study.

BACKGROUND: Self-reported penicillin allergy labels are common and often inaccurate after assessment. These labels can lead to reduced use of first-line beta-lactam antibiotics and worse outcomes. We measured the impact of a previously performed inpatient proactive systematic penicillin allergy de-labelling program on subsequent antibiotic use. This prior program included assessment, risk-stratification, and low risk direct oral amoxicillin challenge. METHODS: We performed a retrospective comparison of parallel cohorts from two separate tertiary care hospital campuses in Ottawa, Canada across two penicillin de-labelling intervention periods across April 15th to April 30th, 2021, and February 15th to March 8th, 2022. Outcomes, including penicillin allergy labelling and antibiotic use, were collected for the index admission and the subsequent 6-month period. Descriptive statistics and multivariate regression analyses were performed. RESULTS: A total of 368 patients with penicillin allergy label were included across two campuses and study periods. 24 (13.8%) patients in the intervention groups had sustained penicillin allergy label removal at 30 days from admission vs. 3 (1.5%) in the non-intervention group (p < 0.001). In the 6-months following admission, beta-lactams were prescribed more frequently in the intervention groups vs. the non-intervention groups for all patients (28 [16.1%] vs.15 [7.7%], p = 0.04) and were prescribed more frequently amongst those who received at least one antibiotic (28/46 [60.9%] vs.15/40 [37.5%], p = 0.097). In a multivariate regression analysis, the intervention groups were found to be associated with an increased odds of beta-lactam prescribing in all patients (OR 2.49, 95%CI 1.29-5.02) and in those prescribed at least one antibiotic (OR 2.44, 95%CI 1.00-6.15). No drug-related adverse events were reported. CONCLUSIONS: Proactive penicillin allergy de-labelling for inpatients was associated with a reduction in penicillin allergy labels and increased utilization of beta-lactams in the subsequent 6-months.

Resource utilization and cost assessment of a proactive penicillin allergy de-labeling program for low-risk inpatients.

BACKGROUND: Resource utilization and costs can impede proactive assessment and de-labeling of penicillin allergy among inpatients. METHODS: Our pilot intervention was a proactive penicillin allergy de-labeling program for new inpatients with penicillin allergy. Patients deemed appropriate for a challenge with a low-risk penicillin allergy history were administered 250 mg amoxicillin and monitored for 1 h. We performed an explorative economic evaluation using various healthcare professional wages. RESULTS: Over two separate 2-week periods between April 2021 and March 2022, we screened 126 new inpatients with a penicillin allergy. After exclusions, 55 were appropriate for formal assessment. 19 completed the oral challenge, and 12 were directly de-labeled, resulting in a number needed to screen of 4 and a number needed to assess of 1.8 to effectively de-label one patient. The assessor's median time in the hospital per day de-labeling was 4h08 with a range of (0h05, 6h45). A single-site annual implementation would result in 715 penicillin allergy assessments with 403 patients de-labeled assuming 20,234 annual weekday admissions and an 8.9% penicillin allergy rate. Depending on the assessor used, the annual cost of administration would be between $21,476 ($53.29 per effectively de-labeled patient) for a pharmacy technician and $61,121 ($151.67 per effectively de-labeled patient) for a Nurse Practitioner or Physician Assistant. CONCLUSION: A proactive approach, including a direct oral challenge for low-risk in-patients with penicillin allergy, appears safe and feasible. Similar programs could be implemented at other institutions across Canada to increase access to allergy assessment.

Fungal zymosan induces leukotriene production by human mast cells through a dectin-1-dependent mechanism.

BACKGROUND: Fungi are capable of causing or exacerbating inflammatory disease in the airways. We have previously demonstrated that zymosan and peptidoglycan induce the production of cysteinyl leukotrienes from human mast cells. However, the mechanisms of pathogen-induced leukotriene production by immune effector cells are very poorly understood. The coreceptor dectin-1, through a Syk tyrosine kinase-dependent pathway, can mediate some responses to fungal challenge, but its expression by mast cells and its involvement in lipid mediator responses have not been assessed. OBJECTIVE: In the current study, the potential role of dectin-1 in zymosan-induced leukotriene production from human mast cells was examined. METHODS: Human mast cells were examined for dectin-1 mRNA and protein expression. Human mast cells were incubated with either zymosan or peptidoglycan in the presence or absence of specific inhibitors for dectin-1 or Syk tyrosine kinase and mediator production examined. RESULTS: Human mast cells were found to express a functional isoform of dectin-1. Both peptidoglycan and zymosan induced significant amounts of leukotriene (LT)-B4 and LTC4. The dectin-1 inhibitors laminarin and glucan phosphate reduced the LTC4 response to zymosan by more than 60% but did not alter peptidoglycan responses. Inhibitors of Syk tyrosine kinase activity significantly decreased LTC4 production in response to both peptidoglycan and zymosan. CONCLUSION: These data demonstrate mast cell expression of the coreceptor dectin-1 and a role for this molecule in the generation of cysteinyl leukotrienes. CLINICAL IMPLICATIONS: These findings suggest new approaches to the selective inhibition of lipid mediator production in response to fungal infection or exposure.

Cutting edge: distinct Toll-like receptor 2 activators selectively induce different classes of mediator production from human mast cells.

Mast cells play a critical role in host defense against bacterial infection. Murine mast cells produce cytokines in response to bacterial peptidoglycan and LPS via Toll-like receptor (TLR) TLR2- and TLR4-dependent mechanisms. The expression of TLRs by human mast cells and responses to known TLR activators was examined. Human mast cells expressed mRNA for TLR1, TLR2, and TLR6 but not TLR4. Bacterial peptidoglycan and yeast zymosan were potent inducers of GM-CSF and IL-1beta and also induced substantial short-term cysteinyl leukotriene generation. In contrast, a synthetic triacylated lipopeptide induced short-term degranulation but failed to induce cysteinyl leukotriene production. The TLR4 activator Escherichia coli LPS did not induce a GM-CSF, IL-1beta leukotriene, or degranulation response. These data demonstrate highly selective production of different classes of mast cell mediators in response to distinct TLR activators of potential importance to the host response to bacterial or fungal pathogens.