Suspected penicillin allergy: risk assessment using an algorithm as an antibiotic stewardship project

SUMMARYSevere cutaneous adverse drug reactions include Stevens-Johnson syndrome, toxic epidermal necrolysis and acute generalised exanthematous pustulosis. These eruptions are a type of delayed hypersensitivity reaction and can be life-threatening.The assessment of a severe cutaneous drug reaction requires a detailed clinical history and examination to identify the culprit drug and evaluate the allergy. Allopurinol, antibiotics and anticonvulsants are often implicated.Patch testing and delayed intradermal testing can assist in determining if the reaction was allergic, however there is limited evidence about the sensitivity and specificity of skin testing in severe cutaneous adverse drug reactions. If the testing is non-conclusive or negative, it is recommended to avoid the suspected culprit drug and any structurally similar drug in future.Any decision to reintroduce a drug should be made after considering the harm–benefit ratio. Caution is also needed if considering a possibly cross-reactive drug in a patient with a history of severe cutaneous adverse drug reactions.

Risk stratification algorithms (RSAs) can reduce antibiotic duration (AD) and length of stay (LOS) for early-onset sepsis (EOS). Because of higher EOS and antibiotic resistance rates and limited laboratory capacity, RSA implementation may benefit low- and middle-income countries (LMIC). Our objective was to compare the impact of 4 RSAs on AD and LOS in an LMIC nursery. Neonates <5 days of age admitted for presumed sepsis to a Kenyan referral hospital in 2019 (n = 262) were evaluated by using 4 RSAs, including the current local sepsis protocol ("local RSA"), a simplified local protocol ("simple RSA"), an existing categorical RSA that uses infant clinical examination and maternal risk factors (CE-M RSA) clinical assessment, and the World Health Organization's Integrated Management of Childhood Illness guideline. For each RSA, a neonate was classified as at high, moderate, or low EOS risk. We used к coefficients to evaluate the agreement between RSAs and McNemar's test for the direction of disagreement. We used the Wilcoxon rank test for differences in observed and predicted median AD and LOS. Local and simple RSAs overestimated EOS risk compared with CE-M RSA and the Integrated Management of Childhood Illness guideline. Compared with the observed value, CE-M RSA shortened AD by 2 days and simple RSA lengthened AD by 2 days. LOS was shortened by 4 days by using CE-M RSA and by 2 days by using the local RSA. The local RSA overestimated EOS risk compared with CE-M RSA. If implemented fully, the local RSA may reduce LOS. Future studies will evaluate the prospective use of RSAs in LMICs with other interventions such as observation off antibiotics, biomarkers, and bundled implementation.

We describe two cases of Stevens–Johnson syndrome (SJS) caused by nevirapine, a non-nucleoside reverse transcriptase inhibitor for HIV therapy. It frequently causes adverse cutaneous events: rash (32–48% within 2–6 weeks after starting therapy); severe cutaneous reactions (8% grade 3–4 of WHO scale); and SJS (0.3–1%) [1]. Case 1 A 37-year-old intravenous drug using white man, an HIV patient (Centers for Disease Control 1993 stage B3), with hepatitis C virus (HCV) chronic hepatitis, secondary mild thrombocytopenia and cryoglobulinaemia, chronic gasthritis, mild hypertension, had been receiving, since 1998, stavudine, lamivudine and methylprednisolone (25 mg a day, as maintenance therapy), ranitidine, enalapril and trimethoprim/sulphamethoxasole, for HIV-related opportunistic infection prophylaxis. In October 1999 he started nevirapine with a standard treatment schedule (a lower lead-in dose: 200 mg/day for 15 days, then 200 mg twice a day) for the suboptimal effect of previous antiretroviral therapy (CD4 cell count 109 cells/mm3 and HIV-RNA level 35 000 copies/ml). Twenty days later, the patient had malaise, a generalized skin rash, characterized by erythematoviolaceous targoid lesions of his trunk, arms, legs and painful oral erosions, sparing the anogenital mucosal membranes. He was taking no other medications and had no history of previous drug allergies. He was afebrile and his platelet count was 36 000 cells/mm3, his hepatic function was altered, but consistent with HCV mild chronic hepatitis (serum glutamic-oxaloacetic transaminase 60 UI/l, serum glutamate-pyruvate transaminase 85 UI/l), and cryoglobulinaemia was present, although at a low percentage of cryocritous. The patient did not accept a skin biopsy. We investigated all other related syndromes or HIV opportunistic infections but we excluded other diagnoses. Despite a high dosage of steroids (methylprednisolone 50 mg a day) and prompt discontinuation of nevirapine, the rash lasted for 20 days, then slowly faded. The patient continued steroids, stavudine and lamivudine, without rechallenge nevirapine. A complete resolution of the skin lesions, leaving a hyperpigmented halo, was obtained after 2 months, and a recurrence of the rash was not observed. Case 2 A 35-year-old, heterosexual white man, with HIV transmission risk, had already been diagnosed with AIDS as a result of neurotoxoplasmosis and HIV-related encephalopathy, and was also affected by oral thrush, lower limb neuropathy, HCV chronic hepatitis, and secondary mild thrombocytopenia. He was already receiving treatment with highly active antiretroviral therapy and secondary prophylaxis for toxoplasmosis with clindamycin and pyrimethamine as a result of allergy to sulphamidics. The patient was not taking steroid treatment. In August 2000 he needed a shift in his highly active antiretroviral therapy schedule, as a result of virological failure and antiretroviral genotypic resistance: stavudine, lamivudine, nelfinavir plus nevirapine at standard doses. At this time, his CD4 cell count was 195 cells/mm3 and his plasma HIV-RNA level was 32 000 copies/ml, his aspartate aminotransferase/alanine aminotransferase value was 84/85 UI/l and his platelet count was 42 000 cells/mm3. In spite of keeping the strict lead-in period of treatment with nevirapine (200 mg/day for 15 days, then 200 mg twice a day), after 29 days of therapy, the patient, in the absence of prodromal symptoms, showed low-grade fever, diffuse erythematoviolaceous maculopapular cutaneous rash with targoid lesions over the palms and foresurface of the legs. Considering the allergic diathesis of the patient, all clinical investigations for a differential diagnosis of the nevirapine cutaneous reaction were performed. The patient was not taking other drugs beside his therapeutic schedule. The IgE dosage was increased (110 UI/l) but was not clearly demonstrative for atropy. A skin biopsy was not performed. The skin lesions completely disappeared after the early discontinuation of nevirapine and 20 days of corticosteroid therapy (betamethasone 2 mg a day). After this the patient took regular antiretroviral therapy with zidovudine, lamivudine, nelfinavir and efavirenz. Patients infected with HIV are at increased risk of developing severe cutaneous or mucocutaneous drug reactions [1]. The identification of a single drug as the cause of a drug eruption is difficult because antiretroviral agents are not used in monotherapy, and are often associated with many other drugs, such as antibiotics [1]. SJS is defined as a hypersensitivity cutaneous drug reaction [2]. Its pathogenesis, during treatment with nevirapine, is unclear and has rarely been described [3]. In our observations, we point out the peculiar clinical aspects: rare incidence (1%), difficult differential diagnosis [4,5], risk of developing SJS notwithstanding long-term steroid therapy (0.5 mg/kg a day) [6,7], and the prolonged course of SJS in spite of early nevirapine withdrawal and high-dose steroid treatment. Clinical guidelines have been developed to reduce the frequency of cutaneous rash and to avoid further toxicity after a severe rash [8]. Ferdinando Dodi Anna Alessandrini Marco Camera Lorenzo Gaffuri Norberto Morandi Gabriella Pagano

To the Editor: We appreciate the questions and concerns raised by Drs Biss and Jaffray about bleeding risk and the use of risk stratification for thromboprophylaxis in young, hospitalized, patients with inflammatory bowel disease (IBD). This discussion offers us an opportunity to elaborate on our earlier suggestions. As clinicians, each of us accepts risk differently. The experience at our institution, and anecdotally from others, concerns more than the rate of thromboembolism (TE) in IBD. Our actions are influenced by the severity of TE within this population. After patients with IBD at our institution experienced several devastating thromboembolic events, both hematologists and gastroenterologists were compelled to collaborate and develop a standardized approach to this patient population. Before this collaborative approach, we found misaligned concerns at our institution. Gastroenterologists were worried about thrombosis. Consulting hematologists were worried about bleeding risk (as described in the above letter). After reviewing the literature regarding the safety of anticoagulation in this population, we found no evidence of increased bleeding, and even some suggestion of improved bleeding with anticoagulation. This was supported by our review of therapeutic anticoagulation (eg, enoxaparin 1 mg/kg sc bid), which is often double the prophylactic dose, which has also not resulted in increased bleeding (1). Although we agree that rectal bleeding in patients with IBD warrants careful monitoring, it should not preclude thromboprophylaxis of those at high risk for TE. Furthermore, guidelines for adult inpatients with IBD recommend anticoagulation for all patients older than 18 years. So theoretically an 18-year-old patient admitted to an adult hospital across the street from our institution could receive enoxaparin thromboprophylaxis, but historically at our pediatric institution, would receive no prophylactic anticoagulation. Ultimately, a multidisciplinary consensus discussion at our center concluded that our concern should be focused more on thrombotic risk than on bleeding risk in this population. Furthermore, the present trend at pediatric institutions is toward hospital-wide prophylaxis after risk stratification (2). More important, thromboprophylaxis may not prevent all TE; however, prevention of even one severe TE or a decrease in the severity of TE would represent a meaningful improvement. At our center, had our risk stratification algorithm been in place, 7 of the 10 patients with IBD and TE would have received prophylaxis. We expect that recent experiences at other centers may favor different interpretations of these data, and that other centers may not be ready to used this algorithm. Furthermore, we agree that additional data will improve our risk-stratification algorithm. We are taking a 3-pronged approach to gathering further data including prospective analysis of current use of this algorithm at our center, conversion of this algorithm for multicenter enrollment, and initiation of a biomarker study to systematically evaluate hematologic and immunologic factors that may lead to improved risk stratification for TE. We welcome suggestions for improvement and participation in multicenter evaluation of this algorithm as we strive together to improve the risk of TE complications in our patients with IBD.

Quarantine of health care workers (HCWs) exposed to COVID-19-confirmed cases is a well-known strategy for limiting the transmission of infection. However, during a pandemic situation in a resource-constraint setting, we require an evidence-based guideline for quarantining HCWs. We developed an algorithm for exposure-based risk stratification and quarantine of HCWs. We did contact tracing and risk stratification of 3853 HCWs, of whom 560 (14.5%) were categorized as high-risk contacts. High-risk contacts were quarantined for 14 days and underwent testing for COVID-19, while low-risk contacts continued their work with adherence to physical distancing, hand hygiene, appropriate use of personal protective equipment, and self-monitoring of symptoms. Overall, 118 (3.1%) contacts tested positive for COVID-19. The positivity rate among high-risk contacts was 7.1% (95% confidence interval = 5.2-9.6). Our strategy of risk stratification prevented 3215 HCWs from being quarantined and thus saved 45 010 person-days of health workforce in the institution.

BackgroundAdverse drug reactions are frequent, with cutaneous manifestations being the most common. In the hospital environment, the incidence of cutaneous drug reactions varies from 2% to 3%. ObjectiveTo analyze the profile of cutaneous drug reactions, relating clinical forms, suspected medications, histopathological alterations, systemic repercussions, treatment and course. MethodsClinical, retrospective and observational study of patients seen by the Dermatology Interconsultation team from January 2013 to December 2016. ResultsThe frequency of cutaneous drug reactions among the evaluated patients was 13.6%, with 219 cases diagnosed. In 65.7%, the reaction was considered mild, of which the most common was exanthema, while in 34.2%, the reaction was considered severe, with DRESS being the main form of reaction(18.2%). Antibiotics (36.5%) and anticonvulsants (10%) were the most involved drugs. In addition to drug discontinuation, systemic corticosteroids were prescribed in 47% of cases and intravenous immunoglobulin (IVIg) in 4.5%. Of the mild forms, in 62%, expectant management and/or exclusive use of symptomatic treatment was used. Study limitationsRetrospective study, with limitations inherent to this type of investigation; lack of some information in medical records; long evaluation period, with a possible change in external validity. ConclusionThe most frequently identified clinical form was exanthema, and antibiotics and anticonvulsants were the most frequently involved drug classes. About one-third of the patients had severe cutaneous drug reactions, with DRESS being the main one. Cutaneous drug reactions are frequent in clinical practice, and the dermatologist should be called in as soon as possible to assist in the diagnosis and management of these cases.

123 Background: Clinical stage T2c is a nebulous factor in the algorithm for prostate cancer risk stratification. According to D’Amico risk stratification cT2c is high-risk category where NCCN guidelines place this stage in intermediate-risk. As diagnostic work up with the use of MRI continues to escalate clinical staging may become more important. As cT2c represents a possible decision fork in treatment decisions we sought to investigate which risk group the clinical behavior of cT2c tumors more closely resembles. Methods: We retrospectively analyzed data from 1089 men who underwent radical prostatectomy (RP) from 1988 to 2009 who did not have low-risk CaP from the SEARCH database. We compared time to BCR between men with cT2c disease, those with intermediate-risk (PSA 10-20 ng/ml or Gleason sum (GS) =7), and those with high-risk (PSA&gt;20 ng/ml, GS 8-10, cT3) using Cox regression models adjusting for age, race, year of RP, center, and percent cores positive. We also compared predictive accuracy of two Cox models wherein cT2c was considered either intermediate- or high-risk by calculating concordance index c. Results: A total of 68 men (3.4%) had cT2c tumors. After a median follow-up of 47.5 months, there was no difference in BCR risk between men with intermediate-risk CaP and those with cT2c tumors (HR=0.90; p=0.60). In contrast, there was a trend for men with high-risk CaP to have nearly 50% increased BCR risk compared to men with cT2c tumors (HR=1.50; 95% CI=0.97-2.30; p=0.07) which did not reach statistical significance. Concordance index c was higher in the Cox model wherein cT2c tumors were considered intermediate-risk (c=0.6147) as opposed to high-risk (c=0.6106). Conclusions: BCR risk for patients with clinical stage T2c was more comparable to men who had intermediate-risk CaP than men with high-risk. In addition, a model which incorporates cT2c disease as intermediate-risk has better predictive accuracy. These findings suggest men with cT2c disease should be offered treatment options for men with intermediate-risk CaP. As clinical staging more routinely incorporates MRI there is the potential to better identify bilateral organ-confined CaP and further establish risk classification.

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

A 5-month old female domestic shorthair cat developed lethargy and severe ulcerative skin lesions that covered more than half of its body after routine administration of rabies vaccine, anthelmintic, and ear medication. Clinical and histologic findings were consistent with a severe cutaneous drug reaction or erythema multiforme. The cat's condition continued to deteriorate despite drug withdrawal and supportive care. Administration of human intravenous immunoglobulin was well tolerated by the cat and led to rapid resolution of ulcerative cutaneous lesions, accompanied by substantial improvement in the cat's demeanor within 8 days. Human intravenous immunoglobulin appears to be a novel promising treatment for life-threatening cutaneous drug reactions.

Systemic therapy for metastatic renal cell carcinoma has continuously evolved over the last two decades. Significant improvements in overall survival and quality of life of patients with advanced disease have been observed. With the approval of combination therapies with PD(L)-1 immune checkpoint inhibitors (ICI) as first-line therapy in 2019, the previous standard VEGFR-TKI monotherapy has been replaced as the primary treatment option. In addition to immunotherapy with nivolumab and ipilimumab, three VEGFR-TKI/ICI combinations are now approved. Therapy selection should be preceded by risk stratification using defined criteria from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Clinical parameters, as well as detailed patient counseling on differences in the efficacy profile (response rate, long-term progression-free survival), potential side effects, and impact on quality of life, are of key importance in the individual treatment decision.

Historically, cardiovascular prevention has been predominantly focused on stress-induced ischemia, but recent trials have challenged this paradigm, highlighting the emerging role of vulnerable, non-flow-limiting coronary plaques, leading to a shift towards integrating plaque morphology with functional data into risk prediction models. Coronary computed tomography angiography (CCTA) represents a high-resolution, low-risk, and largely available non-invasive modality for the precise delineation of plaque composition, morphology, and inflammatory activity, further enhancing our ability to stratify high-risk plaque and predict adverse cardiovascular outcomes. Coronary artery calcium (CAC) scoring, derived from CCTA, has emerged as a promising tool for predicting future cardiovascular events in asymptomatic individuals, demonstrating incremental prognostic value beyond traditional cardiovascular risk factors in terms of myocardial infarction, stroke, and all-cause mortality. Additionally, CCTA-derived information on adverse plaque characteristics, geometric characteristics, and hemodynamic forces provides valuable insights into plaque vulnerability and seems promising in guiding revascularization strategies. Additionally, non-invasive assessments of epicardial and pericoronary adipose tissue (PCAT) further refine risk stratification, adding prognostic significance to coronary artery disease (CAD), correlating with plaque development, vulnerability, and rupture. Moreover, CT imaging not only aids in risk stratification but is now emerging as a screening tool able to monitor CAD progression and treatment efficacy over time. Thus, the integration of CAC scoring and PCAT evaluation into risk stratification algorithms, as well as the identification of high-risk plaque morphology and adverse geometric and hemodynamic characteristics, holds promising results for guiding personalized preventive interventions, helping physicians in identifying high-risk individuals earlier, tailoring lifestyle and pharmacological interventions, and improving clinical outcomes in their patients.

Exposure to opioids after surgery is the initial contact for some people who develop chronic opioid use disorder. Hence, effective postoperative pain management, with less reliance on opioids, is critical. The Perioperative Opioid Quality Improvement (POQI) program developed (1) a digital health platform leveraging patient-survey-reported risk factors and (2) a postsurgical pain risk stratification algorithm to personalize perioperative care by integrating several commercially available digital health solutions into a combined platform. Development was reduced in scope by the COVID-19 pandemic. This pilot study aims to assess the screening performance of the risk algorithm, quantify the use of the POQI platform, and evaluate clinicians' and patients' perceptions of its utility and benefit. A POQI platform prototype was implemented in a quality improvement initiative at a Canadian tertiary care center and evaluated from January to September 2022. After surgical booking, a preliminary risk stratification algorithm was applied to health history questionnaire responses. The estimated risk guided the patient assignment to a care pathway based on low or high risk for persistent pain and opioid use. Demographic, procedural, and medication administration data were extracted retrospectively from the electronic medical record. Postoperative inpatient opioid use of >90 morphine milligram equivalents per day was the outcome used to assess algorithm performance. Data were summarized and compared between the low- and high-risk groups. POQI use was assessed by completed surveys on postoperative days 7, 14, 30, 60, 90, and 120. Semistructured patient and clinician interviews provided qualitative feedback on the platform. Overall, 276 eligible patients were admitted for colorectal procedures. The risk algorithm stratified 203 (73.6%) as the low-risk group and 73 (26.4%) as the high-risk group. Among the 214 (77.5%) patients with available data, high-risk patients were younger than low-risk patients (age: median 53, IQR 40-65 years, vs median 59, IQR 49-69 years, median difference five years, 95% CI 1-9; P=.02) and were more often female patients (45/73, 62% vs 80/203, 39.4%; odds ratio 2.5, 95% CI 1.4-4.5; P=.002). The risk stratification was reasonably specific (true negative rate=144/200, 72%) but not sensitive (true positive rate=10/31, 32%). Only 39.7% (85/214) patients completed any postoperative quality of recovery questionnaires (only 14, 6.5% patients beyond 60 days after surgery), and 22.9% (49/214) completed a postdischarge medication survey. Interviewed participants welcomed the initiative but noted usability issues and poor platform education. An initial POQI platform prototype was deployed operationally; the risk algorithm had reasonable specificity but poor sensitivity. There was a significant loss to follow-up in postdischarge survey completion. Clinicians and patients appreciated the potential impact of preemptively addressing opioid exposure but expressed shortcomings in the platform's design and implementation. Iterative platform redesign with additional features and reevaluation are required before broader implementation.

Management of pulmonary embolism

Background. Standard HLA typing and simple allele mismatch counts do not always provide an objective assessment of rejection risk. Platforms PIRCHE (Predicted Indirectly ReCognizable HLA Epitopes) and HLAEMMA (HLA Epitope MisMatch Algorithm) estimate donor–recipient HLA incompatibility at the epitope level, based on low-resolution HLA typing. Objective: To evaluate the predictive ability of PIRCHE and HLA-EMMA for stratifying the risk of heart allograft rejection within the first year after orthotopic heart transplantation. Materials and Methods. This retrospective study included 160 heart recipients. During the first-year post-transplantation 77 recipients (control group) showed no rejection (ACR 0R–1R and/or pAMR 0–1). Eighty-three recipients experienced an adverse event: a rejection episode (ACR 2R–3R and/or pAMR 2–3) or death from any cause without preceding rejection. HLA incompatibility was calculated using the PIRCHE-T2, PIRCHE-B, and six HLA-EMMA algorithms. The prognostic significance was assessed using the Kaplan-Meier method. Results. Statistically significant differences between groups were observed for five algorithms: Allele-MM-L2, AA-MM-L1, AA-MM-L2, SA-L2, and PIRCHE-T2. PIRCHE-T2 demonstrated the strongest predictive value with a threshold &gt;80: adverse events occurred in 73.7 % (28/38) of recipients with PIRCHE-T2 &gt;80 versus 45 % (55/122) with PIRCHE-T2 ≤80. Conclusion. The obtained results indicate the potential utility of the PIRCHE-T2 with a threshold value of &gt;80 for risk stratification during the first post-transplant year.

The management of pulmonary embolism