Patient Perceptions of Penicillin Allergy Testing in a Public Health System

Background: Unverified penicillin allergy has been linked to adverse patient events and increased healthcare expenditure owing to the usage of broad-spectrum, expensive antibiotics. Penicillin allergy test is the gold standard to diagnose penicillin allergy; and in this study, we present data from Qatar which have not been published before.Methods: Patients with a history of penicillin allergy who underwent penicillin allergy testing between January 2015 and December 2020 at the Allergy Division of the Hamad General Hospital were retrospectively reviewed from the division registry. Benzylpenicilloyl-polylysine (PPL) and minor determinant mixture (MDM) kit DAP-penicillin (0.04 mg +0.5 mg)/vial) (penicillin G, amoxicillin (20 mg/vial), and lately clavulanic acid (20 mg/vial) (DAP, Diater, Madrid, Spain) were used for skin and intradermal testing according to published guidelines. Patients with negative skin tests were administered direct oral challenge with amoxicillin/clavulanate (500/125 mg) and observed for 2 hours.Results: Of the 189 charts reviewed, 183 patients had a complete data set for analysis. Patients were predominantly women (n = 132, 72%) with an average age of 42 years. Of these patients, 149 (81.4%) had a history of an immediate allergic reaction to penicillin, 10 had a history of delayed reactions, and 24 had other or undefined reactions. A total of 39 (21.3%) patients were diagnosed with penicillin allergy (30 patients with positive skin test results and 9 using a direct oral challenge).Of the 30 patients with positive skin testing, 5 reacted to PPL, 8 to MDM, 13 to amoxicillin, and 4 to clavulanic acid.Conclusion: Previous studies indicate that 90% patients with a history of penicillin allergy were able to tolerate the drug (10% were truly allergic). Our data showed that 21% were truly allergic to penicillin. This high positive rate can be attributed to the high pretest probability based on the detailed history obtained before the test, which led to the exclusion of patients with symptoms incompatible with penicillin allergy from the test.

Fewer than 5% of patients labeled with a penicillin allergy are truly allergic. The standard of care to remove the penicillin allergy label in adults is specialized testing involving prick and intradermal skin testing followed by an oral challenge with penicillin. Skin testing is resource intensive, limits practice to specialist-trained physicians, and restricts the global population who could undergo penicillin allergy delabeling. To determine whether a direct oral penicillin challenge is noninferior to the standard of care of penicillin skin testing followed by an oral challenge in patients with a low-risk penicillin allergy. This parallel, 2-arm, noninferiority, open-label, multicenter, international randomized clinical trial occurred in 6 specialized centers, 3 in North America (US and Canada) and 3 in Australia, from June 18, 2021, to December 2, 2022. Eligible adults had a PEN-FAST score lower than 3. PEN-FAST is a prospectively derived and internationally validated clinical decision rule that enables point-of-care risk assessment for adults reporting penicillin allergies. Patients were randomly assigned to either direct oral challenge with penicillin (intervention arm) or a standard-of-care arm of penicillin skin testing followed by oral challenge with penicillin (control arm). The primary outcome was a physician-verified positive immune-mediated oral penicillin challenge within 1 hour postintervention in the intention-to-treat population. Noninferiority was achieved if a 1-sided 95% CI of the risk difference (RD) did not exceed 5 percentage points (pp). A total of 382 adults were randomized, with 377 patients (median [IQR] age, 51 [35-65] years; 247 [65.5%] female) included in the analysis: 187 in the intervention group and 190 in the control group. Most patients had a PEN-FAST score of 0 or 1. The primary outcome occurred in 1 patient (0.5%) in the intervention group and 1 patient (0.5%) in the control group, with an RD of 0.0084 pp (90% CI, -1.22 to 1.24 pp). The 1-sided 95% CI was below the noninferiority margin of 5 pp. In the 5 days following the oral penicillin challenge, 9 immune-mediated adverse events were recorded in the intervention group and 10 in the control group (RD, -0.45 pp; 95% CI, -4.87 to 3.96 pp). No serious adverse events occurred. In this randomized clinical trial, direct oral penicillin challenge in patients with a low-risk penicillin allergy was noninferior compared with standard-of-care skin testing followed by oral challenge. In patients with a low-risk history, direct oral penicillin challenge is a safe procedure to facilitate the removal of a penicillin allergy label. ClinicalTrials.gov Identifier: NCT04454229.

Patients with a penicillin allergy label (PAL) use more and broader-spectrum antibiotics, have worse health outcomes and cost more to treat than patients without a PAL. A significant proportion of penicillin allergy labels are incorrect; here we review the published evidence on the costs, health-related quality of life, and cost-effectiveness of penicillin allergy testing. We conducted a systematic review of published economic evaluations of penicillin allergy testing in accordance with Cochrane guidelines. We searched Medline, Embase, Scopus, Web of Science, EconPapers (RePeC) and the International HTA Database (INAHTA) and included reports of full or partial economic evaluations of costs and/or health benefits of penicillin allergy testing strategies. The outcomes of interest were healthcare resource use, medical costs, and health-related quality of life for patients with a penicillin allergy label and for patients with the label removed, and cost-effectiveness. We evaluated the methodological quality of the studies using a published checklist designed for systematic reviews. The review followed a narrative synthesis. Thirty-six studies met the inclusion criteria. Most studies analysed the effect of testing on the costs of antibiotic use among patients admitted to hospital with a PAL. Studies measured costs of testing (n = 19); antibiotic medication use (n = 23); adverse reactions with penicillin use (n = 4), alternative antibiotic drugs (n = 3); length of hospital stay (n = 5); subsequent health care use episodes (n = 4); and antibiotic medication use in subsequent care episodes (n = 3). The median cost of skin testing plus oral challenge across six primary costing studies was USD 246 (range: 164, 514), which contrasts with the USD 42-258 range of antibiotic cost savings during the initial hospital admission. Two studies presented evidence that penicillin allergy testing is cost-saving in an outpatient setting over 3.5-4.5 years. One model-based study reported that testing in inpatient settings is cost-saving. No reports on the effect of penicillin allergy testing on health-related quality of life were found and the two cost-effectiveness studies that accounted for this outcome employed the opinion of healthcare professional or an assumption of a common generic value for adverse reactions. While penicillin allergy testing shows promise in reducing antibiotic costs, the evidence remains insufficient to definitively establish whether these savings consistently outweigh testing costs across various healthcare settings.

Another Step Forward in the Optimization of Penicillin Allergy Delabeling Strategies in Children

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. To develop and validate a penicillin allergy clinical decision rule that enables point-of-care risk assessment of patient-reported penicillin allergies. 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. The primary outcome for the model was any positive result of penicillin allergy testing performed during outpatient or inpatient assessment. 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. 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.

Penicillin skin testing in the evaluation and management of penicillin allergy

DALES, Drug Allergy Labels in Elective Surgical patients: a prospective multicentre cross-sectional study of incidence, risks, and attitudes in penicillin de-labelling strategies

Background: Inappropriate penicillin skin testing practices can worsen allergy mislabelling and antimicrobial resistance. This issue is likely more pronounced in Mainland China due to mandatory pre-emptive penicillin skin testing prior to any penicillin prescriptions. In contrast, Hong Kong follows guidelines more aligned with international recommendations on penicillin allergy testing. This study aimed to explore the disparities in drug allergy labelling, penicillin consumption, and antimicrobial resistance between Mainland China and Hong Kong. Methods: This multi-centre, real-world study analyzed drug allergy label prevalence, antibiotic use, and AMR between 2018 to 2022 in Mainland China and Hong Kong. Results: Penicillin allergy labels were significantly higher in Mainland China (47.13%) compared to Hong Kong (21.57%, p<0.01). Penicillin consumption was lower in Mainland China, where antimicrobial resistance to amoxicillin-clavulanate was also lower. Penicillin allergy delabeling rates were significantly higher in Mainland China (99.26%) compared to Hong Kong (93.13%, p=0.03). Conclusion: Significant differences in drug allergy labeling and antibiotic use between Mainland China and Hong Kong highlight the impact of non-evidence-based penicillin skin testing practices in Mainland China. Urgent reforms are needed to adopt international guidelines and reduce allergy mislabeling.

Penicillin allergy is the most frequently reported allergy in hospitalized patients, although rarely confirmed. Given the negative outcomes associated with incorrect penicillin allergy diagnoses, implementation of programmatic delabeling strategies is important for successful antibiotic stewardship. This systematic review evaluates the effectiveness of different delabeling strategies and highlights elements and settings that facilitate or constrict their implementation. Following the PRISMA-statement PubMed/MEDLINE, EMBASE, Cochrane Library, and grey literature databases "Worldcat" and "OpenGrey" were searched for studies reporting on interventions to identify, evaluate, or rule out incorrect penicillin allergy in hospitalized adults. Data extraction included settings, intervention types, and their effectiveness, barriers, facilitators, and regulatory factors. This review included 42 studies, involving 6269 patients undergoing penicillin allergy delabeling, with 5017 (80%) successfully delabeled. Effectiveness varied from 32% to 99%. Skin testing had the highest success rate at 87%, followed by a combination of skin testing and oral challenge (84%), and direct oral challenges (77%). Direct delabeling alone had a lower effectiveness (67%), which improved to 80% when paired with oral challenges. Key facilitators included standardized algorithms and involvement of interdisciplinary teams. Barriers included patient refusal, staff resistance, time constraints, and financial limitations, particularly in smaller hospitals. Dependent on financial and staffing resources, oral challenges and direct delabeling after risk stratification may be alternatives to resource-intensive methods, such as skin testing, for successful delabeling. To address barriers to widespread delabeling implementation, patient and provider education must be improved, interprofessional collaboration enhanced, and standardized protocols developed.

About 6% of the UK general practice population has a record of a penicillin allergy but fewer than 10% of these people are likely to be truly allergic. Consequently, a significant portion of the population is denied first-line antibiotics. The ALlergy AntiBiotics And Microbial resistAnce (ALABAMA) trial aimed to determine if a penicillin allergy assessment pathway (PAAP) was safe and effective in de-labelling patients as allergic and improving antibiotic prescribing and patient health outcomes. To investigate patients' experiences of penicillin allergy testing (PAT) and their acceptance of de-labelling following a negative allergy test. This was a qualitative study using semi-structured interviews with patients who took part in the PAAP intervention arm of the ALABAMA trial. As part of a mixed-methods process evaluation embedded in the ALABAMA trial, we conducted interviews with patients in the PAAP intervention arm. Data from interviews with patients were analysed using thematic analysis. Of the 28 participants interviewed, two received a positive PAT result and 26 received a negative PAT result; of these, 24 accepted and two declined de-labelling. At point of trial recruitment, many patients already doubted that they were allergic to penicillin. Patients were happy to attend PAT and felt cared for and safe at the hospital. These factors led to most people trusting their negative test result and accepting de-labelling. The patients we interviewed engaged with the PAAP intervention and, when testing negative, were predominantly willing to have their allergy record changed and to take penicillin in future. We highlight factors that influenced patients' acceptance of de-labelling to facilitate future adoption of PAAP. These factors, which should be considered when planning for penicillin allergy testing services, were as follows: patients identifying themselves as low risk before the test; PAT being perceived as trustworthy and safe; patients' previous experience of penicillin allergy and reactions; patients' understanding of penicillin reactions; and clear communication after de-labelling.

We review the literature and discuss the logistics of testing pregnant patients for penicillin allergy. As in the general population, pregnant patients commonly report a penicillin allergy, but most patients are able to tolerate penicillin. Avoidance of beta-lactams in pregnancy is associated with increased morbidity: longer hospitalizations, more frequent infections, and more complications. Penicillin allergy testing is safe in pregnant patients, and obstetricians are eager for allergists to offer this procedure to their patients. As allergists, we can improve our patients' health outcomes by offering penicillin allergy testing in our practices. The protocols for testing both with and without skin testing in pregnant patients have been studied, and future studies will continue to clarify the safety and efficacy of penicillin allergy delabeling in pregnant patients.

A Proactive Approach to Penicillin Allergy Testing in Hospitalized Patients

Economic Burden of Patient-Reported Penicillin Allergy on Total Hip and Total Knee Arthroplasty

Background: Allergy to penicillin is commonly reported in many countries and is an overwhelming global public health concern. Penicillin allergy labels can lead to the use of less effective antibiotics and can be associated with antimicrobial resistance. Appropriate assessment of suspected penicillin allergy (often including skin testing, followed by drug provocation testing [DPT] performed by allergists) can prevent the unnecessary restriction of penicillin or delabelling. Many countries in the Asia Pacific (AP) have very limited access to allergy services, and there are significant disparities in the methods of evaluating penicillin allergy. Therefore, a clinical pathway for the management of penicillin allergy is essential. Objectives: To develop a risk-stratified clinical pathway for delabeling penicillin allergy, taking into account the distinct epidemiology, patient/sensitization profiles, and disparities of allergy services or facilities within the AP. Methods: A risk-stratified penicillin allergy delabeling clinical pathway was formulated by the Drug Allergy Committee of the Asia Pacific Association of Allergy, Asthma and Clinical Immunology. and members of the Penicillin Allergy Disparities survey in AP each representing one country/region of the AP. The clinical pathway was tested based on a database of anonymized patients who were sequentially referred for and completed penicillin allergy evaluation in Hong Kong. Results: The clinical pathway was piloted employing a “hub-and-spoke” approach to foster multidisciplinary collaboration between allergists and nonallergists. A simulation run of the algorithm on a retrospective Hong Kong cohort of 439 patients was performed. Overall, 367 (84%) of patients were suitable for direct DPT and reduced the need for skin testing or specialist’s care for 357 (97%) skin test-negative individuals. Out of the skin test-negative patients, 345 (94%) patients had a negative DPT. Conclusions: This risk-stratification strategy for direct oral DPT can reduce the need for unnecessary skin testing in patients with low-risk penicillin allergy histories. The hub and spoke model of care may be considered for further piloting and validation in other AP populations that lack adequately trained allergists.

Penicillin allergy is often misdiagnosed and is associated with adverse consequences, but testing is infrequently done in the hospital setting. This article reviews historical and contemporary innovations in inpatient penicillin allergy testing and its impact on antimicrobial stewardship. Adoption of the electronic medical record allows rapid identification of admitted patients carrying a penicillin allergy diagnosis. Collaboration with clinical pharmacists and the development of computerized clinical guidelines facilitates increased testing and appropriate use of penicillin and related β-lactams. Education of patients and their outpatient providers is the key to retaining the benefits of penicillin allergy de-labeling. Penicillin allergy testing is feasible in the hospital and offers tangible benefits towards antimicrobial stewardship. Allergists should take the lead in this endeavor and work towards overcoming personnel limitations by partnering with other health care providers and incorporating technology that improves the efficiency of allergy evaluation.