The Immediate and Delayed Maximal Non-Irritating Skin Testing Concentrations of ß-lactam Antibiotics.

BACKGROUND: Maximal skin testing (ST) nonirritant concentrations (NICs) are consistent for penicillin and aminopenicillin amongst guidelines. However, there is variability amongst guidelines for maximal ST NICs of cephalosporins. OBJECTIVE: To determine maximal immediate and delayed ST NICs of 15 ß-lactams in ß-lactam-tolerant and ß-lactam-naïve participants. METHODS: We performed a single-center, nonrandomized prospective study between September 2019 and January 2022 in adult participants. Participants received skin prick testing (SPT) and intradermal test (IDT) injections at six increasing concentrations of 1 or more ß-lactams. A concentration was considered irritant when more than 5% of participants had a positive test. A positive test was defined as a wheal ≥3 mm than negative control accompanied by a ≥5 mm flare for SPT/IDT and induration ≥5 mm with associated erythema at 48 hours for delayed readings (dIDT). Sensitivity analyses using 3 alternative IDT positive criteria were conducted. RESULTS: A total of 747 participants with a median age of 64 (IQR 54-72), 52% males, 85% White, and 92% Non-Hispanic underwent 20,858 skin tests. All undiluted SPT concentrations were nonirritant. We found the following maximal IDT/dIDT NICs (mg/ml): ampicillin (41.6/125), ampicillin-sulbactam (93.8/187.5), aztreonam (6.3/25), cefazolin (55/165), cefepime (35/140), cefoxitin (45/90), ceftaroline (7.5/15), ceftriaxone (58.3/175), cefuroxime (55/110), ertapenem (16.6/50), imipenem-cilastin (6.3/25), meropenem (8.3/25), nafcillin (31.3/62.5), oxacillin (20.9/83.5), and piperacillin-tazobactam (112.5/225). dIDTs were almost all completely non-irritant close or at undiluted concentrations. There were no differences when we applied 3 IDT positivity criteria to our raw data. CONCLUSION: Our results suggest that SPTs with undiluted stock ß-lactam antibiotic concentrations are nonirritant. Compared to previously published nonirritant concentrations, we propose a 2 to 50-fold increase to the maximal IDT and dIDT NICs of 15 ß-lactam antibiotics. When performing dIDTs, a higher concentration should be used rather than the same IDT concentration.

Predicting Penicillin Allergy: A United States Multicenter Retrospective Study.

BACKGROUND: Using the reaction history in logistic regression and machine learning (ML) models to predict penicillin allergy has been reported based on non-US data. OBJECTIVE: We developed ML positive penicillin allergy testing prediction models from multisite US data. METHODS: Retrospective data from 4 US-based hospitals were grouped into 4 datasets: enriched training (1:3 case-control matched cohort), enriched testing, nonenriched internal testing, and nonenriched external testing. ML algorithms were used for model development. We determined area under the curve (AUC) and applied the Shapley Additive exPlanations (SHAP) framework to interpret risk drivers. RESULTS: Of 4777 patients (mean age 60 [standard deviation: 17] years; 68% women, 91% White, and 86% non-Hispanic) evaluated for penicillin allergy labels, 513 (11%) had positive penicillin allergy testing. Model input variables were frequently missing: immediate or delayed onset (71%), signs or symptoms (13%), and treatment (31%). The gradient-boosted model was the strongest model with an AUC of 0.67 (95% confidence interval [CI]: 0.57-0.77), which improved to 0.87 (95% CI: 0.73-1) when only cases with complete data were used. Top SHAP drivers for positive testing were reactions within the last year and reactions requiring medical attention; female sex and reaction of hives/urticaria were also positive drivers. CONCLUSIONS: An ML prediction model for positive penicillin allergy skin testing using US-based retrospective data did not achieve performance strong enough for acceptance and adoption. The optimal ML prediction model for positive penicillin allergy testing was driven by time since reaction, seek medical attention, female sex, and hives/urticaria.

The Nonirritating Concentrations of Neuromuscular Blocking Agents and Related Compounds.

BACKGROUND: Skin testing (ST) concentrations of neuromuscular blocking agents (NMBAs), NMBA-reversal agents, and the sugammadex-rocuronium inclusion complex (S-R-Cx) vary widely among reports. OBJECTIVE: To determine maximal ST nonirritant concentrations (NICs) of NMBAs (cisatracurium, rocuronium, succinylcholine, and vecuronium), NMBA-reversal agents (neostigmine and sugammadex), and S-R-Cx in NMBA-tolerant and NMBA-naïve participants. METHODS: A single-center, prospective study between October 2019 and November 2021 of adult participants with or without a planned surgical procedure. The reference standard was tolerance of medication tested during a procedure (NMBA-tolerant group) before ST. Participants received skin prick testing (SPT) and intradermal test (IDT) injections at 5-7 increasing concentrations of 1 or more medications. All medications were reconstituted according to package insert instructions and diluted with 0.9% saline. A concentration was considered irritant when more than 5% of participants had a positive test per ST positivity criteria (wheal ≥3 mm than initial wheal and associated erythema of the same size or greater than wheal). We also compared our results with current guidelines. RESULTS: A total of 187 participants (78% NMBA-tolerant) underwent 7812 skin tests. All undiluted SPT concentrations were nonirritant. We found the following maximal IDT NICs (mg/mL): cisatracurium (0.02), rocuronium (0.05), succinylcholine (0.8), vecuronium (0.01), neostigmine (0.2), sugammadex (50), and S-R-Cx (sugammadex 7.14 + rocuronium 2). CONCLUSION: Our results suggest that SPT may be performed with undiluted stock concentrations. We confirm maximal IDT NICs for cisatracurium and rocuronium. We also propose that currently recommended maximal IDT NICs of succinylcholine, neostigmine, sugammadex, and S-R-Cx could be increased, whereas the maximal IDT NIC of vecuronium could be decreased compared with current guidelines and prior reports.

State-of-the-art beta-adrenoreceptor agonists for the treatment of asthma.

INTRODUCTION: Asthma, a heterogeneous disease, is characterized by chronic airway inflammation and hyperreactivity. ß2-adrenoreceptor agonists (ß2-agonists) remain pivotal for asthma management. Short-acting ß2-agonists (SABAs) result in rapid symptomatic alleviation and bronchospasm prevention. Patients experience significant clinical benefits from therapy with long-acting ß2-agonists (LABAs) with efficacy to bronchodilate, and prolonged lung function betterment. Recently discovered ß2-agonists with longer half-lives offer once-daily dosing. AREAS COVERED: The authors provide a thorough review of the pharmacokinetics, pharmacodynamics, efficacy, tolerability, classification, and safety of ß2-agonists through an in-depth review of current literature using these databases: U.S. National Institutes of Health's National Library of Medicine (NIH/NLM), PubMed Central, and NLM clinical trials. EXPERT OPINION: ß2- agonists act primarily on airway smooth muscle cells and are quintessential for adequate asthma management. Given their pharmacodynamic and pharmacokinetic properties, SABAs are used as rescue medication. Notably, the current Global Initiative for Asthma (GINA) strategy document recommends using LABA/inhaled corticosteroid combinations both as a daily controller and as a rescue medication. Clinicians should assess this new treatment plan on a per-case basis, making sure to evaluate inhaler adherence and treat modifiable risk factors. The development of next-generation ß2- agonists is an exciting research area that could significantly improve patients' adherence to treatment regimens and, consequently, asthma control and quality of life.