Drug Triggers and Clinic of Acute Generalized Exanthematous Pustulosis (AGEP): A Literature Case Series of 297 Patients

Acute generalized exanthematous pustulosis (AGEP) is a rare skin reaction, commonly caused by drugs. Available evidence mostly relies on small studies or case reports. We collected published AGEP case reports and, subsequently, described the patient characteristics, suspect and concomitant drugs, time to onset, disease management, and clinical prognosis. This study included 297 AGEP patients (64.3% women) obtained from 250 published case reports or case series with individual patient data. AGEP affected patients of all ages, but the majority of patients (88.2%) were ≥25 years old. The most frequently reported suspect drugs were anti-infectives for systemic use (36.5%), particularly antibacterials for systemic use (31.0%), and especially beta-lactam antibacterials (18.3%) and macrolides (4.3%). Other frequent suspect drugs were antineoplastics (12.2%), and anti-inflammatory/anti-rheumatic products (5.2%) plus hydroxychloroquine (12.8%). Mean time to onset was 9.1 days (standard deviation SD 13.94). Some patients developed fever (64.3%) and systemic involvement (18.9%), and most patients (76.4%) received pharmacological treatment for AGEP. Seven patients died, although five of them were already critically ill prior to AGEP. In conclusion, antibiotics remain the most common suspected cause of AGEP. While case mortality rate may be up to 2.5%, disentangling the role of AGEP on the fatal outcome from the role of the preexisting health conditions remains challenging.

Systematic analysis of drug-associated myocarditis reported in the World Health Organization pharmacovigilance database

While multiple pharmacological drugs have been associated with myocarditis, temporal trends and overall mortality have not been reported. Here we report the spectrum and main features of 5108 reports of drug-induced myocarditis, in a worldwide pharmacovigilance analysis, comprising more than 21 million individual-case-safety reports from 1967 to 2020. Significant association between myocarditis and a suspected drug is assessed using disproportionality analyses, which use Bayesian information component estimates. Overall, we identify 62 drugs associated with myocarditis, 41 of which are categorized into 5 main pharmacological classes: antipsychotics (n = 3108 reports), salicylates (n = 340), antineoplastic-cytotoxics (n = 190), antineoplastic-immunotherapies (n = 538), and vaccines (n = 790). Thirty-eight (61.3%) drugs were not previously reported associated with myocarditis. Antipsychotic was the first (1979) and most reported class (n = 3018). In 2019, the two most reported classes were antipsychotics (54.7%) and immunotherapies (29.5%). Time-to-onset between treatment start and myocarditis is 15 [interquartile range: 10; 23] days. Subsequent mortality is 10.3% and differs between drug classes with immunotherapies the highest, 32.5% and salicylates the lowest, 2.6%. These elements highlight the diversity of presentations of myocarditis depending on drug class, and show the emerging role of antineoplastic drugs in the field of drug-induced myocarditis.

Systematic review of spontaneous reports of myocarditis and pericarditis in transplant recipients and immunocompromised patients following COVID-19 mRNA vaccination

Objectives: To determine whether spontaneous reporting rates of myocarditis and pericarditis differed in immunocompromised patients compared to the whole population overall, and in terms of demographics, vaccine dose, and time-to-onset. Design: Systematic review of spontaneously reported data from the European Union/European Economic Area (EU/EEA) and the United States (US). Data Sources: EudraVigilance (EU/EEA) and Vaccine Adverse Event Reporting System (VAERS; US) spontaneous reporting databases were searched from date of vaccine launch to 30 November 2021. Eligibility criteria: Publicly available spontaneous reporting data for 'Myocarditis' and 'Pericarditis' from EU/EEA and US following COVID-19 mRNA vaccines. Reports with comorbidities or concurrent medication indicative of transplantation, HIV infection, or cancer ('immunocompromised' population) were compared with each overall database population. Data extraction and synthesis: Two researchers extracted data. Spontaneously reported events of myocarditis and pericarditis were presented for immunocompromised populations for each data source, stratified by age, sex, dose, and time-to-onset (where available). Seriousness of each event was determined according to the ICH E2A definition. Proportional Reporting Ratio (PRR) was calculated. Results: There were 106 reports of myocarditis and pericarditis amongst immunocompromised individuals overall. Seriousness was comparable between the immunocompromised and overall populations in both databases. No trends in age or sex were observed amongst immunocompromised individuals. Most reports (54.4%) to VAERS followed a second vaccine dose and 70.2% of events occurred within 14 days. The frequency of reporting was similar to the wider population (PRR=1.36 [95% CI= 0.89-1.82] for VAERS population). Conclusions: Myocarditis and pericarditis following COVID-19 vaccination are very rare, and benefits of COVID-19 vaccination continue to outweigh any perceived risks. Reporting rates of myocarditis and pericarditis were similar in immunocompromised individuals, however defining characteristics differed compared to the whole population; therefore, continued monitoring of adverse events following vaccination remains vital to understand differences between population subgroups.

Comprehensive Analysis of Bortezomib-Induced Adverse Events Using the Japanese Real-World Database

Background: Bortezomib is used as first-line therapy for multiple myeloma. Observational studies based on the FDA Adverse Event Reporting System (FAERS) database analysis and systematic reviews indicate that the incidence of peripheral neuropathy and tumor lysis syndrome (TLS) tends to be higher with bortezomib than that of other drugs. In a comprehensive analysis assessing drugs that cause peripheral neuropathy in Japanese patients, the incidence of bortezomib-induced adverse events (AEs) was reportedly high. However, a comprehensive assessment of bortezomib is lacking. Objectives: The purpose of this study was to determine the frequency of bortezomib AEs in Japanese patients and to determine the incidence, time to onset, and post hoc outcomes of unique AEs using the Japanese Adverse Drug Event Report (JADER) database. Method: To investigate the association between bortezomib and AEs, we analyzed the JADER database, which contains spontaneous AE reports submitted to the Pharmaceuticals and Medical Devices Agency from April 2004 to December 2020. Criteria indicating the presence of an AE signal were met when the following requirements were fulfilled: proportional reporting ratios (PRR) ≥ 2 and χ2 ≥ 4. Time to onset and post-event outcomes were analyzed for characteristic AEs. Results: Among 26 extracted AEs, 13 presented AE signals. The post-exposure outcomes of 12 AEs showed fatal outcomes at rates exceeding 10%, including cardiac failure (30%), lung disorder (24%), pneumonia (18%), and TLS (10%). Furthermore, a histogram of time to onset revealed that the 12 AEs were concentrated from the beginning to approximately one month after bortezomib administration. The median onset times for cardiac failure, lung disorder, pneumonia, and TLS were 28, 13, 42, and 5 days, respectively. Conclusions: Cardiac failure, lung disorder, pneumonia, and TLS had a higher rate of fatal clinical outcomes after onset than other AEs. These AEs exhibited a greater onset tendency in the early post-dose period. This study suggests that there is a need to monitor signs of cardiac failure, lung disorder, pneumonia, and TLS, potentially resulting in serious outcomes.

Time to Loss of Behavioral and Brainstem Responses of Ducks following Non-Stunned Slaughter

Non-stunned slaughter has been extensively described for other farmed species but there has been limited research on waterfowl. The study assessed 34 White Pekin ducks (Anas platyrhynchos) (study 1) in a non-stunned halal slaughterhouse in Brazil for time to loss of consciousness using various behavioral and brainstem indices (balance, cranial nerve reflexes, and muscle tension) and assessed the relationship between extent of clotting, location of neck cut, level of damage to neck vessels/tissues, and the time to onset of unconsciousness. In addition, operator practices were separately observed and neck pathology following the cut was examined in 217 carcasses after bleeding (study 2). In study 1 following the neck cut there was a wide variation between birds in the time to loss of behavioral and brainstem indices, ranging from 20 to 334 and 20 to 383 s for neck and beak tension, respectively. The median time to loss of balance following the neck cut was 166 ± 14 (22–355) seconds. There was a moderate correlation (R = 0.60 and 0.62) between distance of the neck cut and time to loss of balance and neck tension, respectively. This is the first investigation of the time to loss of consciousness following non-stunned slaughter of ducks in commercial conditions. The findings could be used to improve the welfare of ducks during non-stunned slaughter, such as recommending performance of the neck cut closer to the jaw line and ensuring appropriate waiting periods between slaughter and birds entering the scalding tanks.

Pharmacodynamics and the Bactericidal Activity of Bedaquiline in Pulmonary Tuberculosis

Bedaquiline is a diarylquinoline antimycobacterial drug and a key component of several regimens in clinical development for treatment of tuberculosis (TB), but with ongoing phase 3 trials that include assessment of simplified dosing. A pharmacokinetic-pharmacodynamic model of bedaquiline Mycobacterium tuberculosis killing kinetics in adults with pulmonary TB was developed to inform dose selection of bedaquiline-containing regimens. The model parameters were estimated with data from the 14-day early bactericidal activity (EBA) study TMC207-CL001 conducted in Cape Town, South Africa. The study included 60 adult males and females with drug-susceptible pulmonary TB, who were administered bedaquiline with loading doses on the first two days followed by once daily 100 mg, 200 mg, 300 mg, or 400 mg. The modeling results included expected values (mean±SD) for a maximum drug kill rate constant equal to 0.23±0.03 log 10 CFU/mL sputum/day, a half-maximum effect plasma concentration equal to 1.6±0.3 mg/L, and an average time to onset of activity equal to 40±7 h. Model simulations showed once daily 200 mg, 300 mg, and 400 mg (without loading doses) attained 40%, 50%, and 60%, respectively, of an expected maximum 14-day EBA equal to 0.18 log 10 CFU/mL/day, or 10 h/day assessed by liquid culture time to positivity (TTP). Additional simulations illustrated efficacy outcomes during eight weeks of treatment with the recommended and alternative dosages. The results demonstrate a general mathematical and statistical approach to analysis of EBA studies with broad application to TB regimen development.

The Influence of Diabetes on Labor Induction with Dinoprostone Vaginal Inserts

Objective The aim of this study was to compare duration of labor induction between diabetic and nondiabetic women receiving dinoprostone vaginal insert (10 mg). Study Design This is a secondary analysis of two large randomized controlled trials using dinoprostone vaginal inserts for labor induction. We compare time to active labor, overall delivery, and vaginal delivery between diabetic and nondiabetic women undergoing induction of labor with a 10-mg dinoprostone vaginal insert. Results Diabetic women receiving dinoprostone vaginal insert had a longer time to onset of active labor, overall delivery, and vaginal delivery than their nondiabetic counterparts. There was no difference in abnormal labor affecting fetal heart rate pattern in diabetic women compared with nondiabetic women. The rates of neonatal hyperbilirubinemia were higher in diabetic women. Conclusion Diabetes may represent an independent factor associated with prolonged induction among women undergoing induction of labor with dinoprostone. Dinoprostone is well tolerated in both diabetic and nondiabetic women. Key Points

Abstract 11394: Comparison Between Advanced Cardiovascular Life Support Course and a New Emergency Cardiovascular Care Course for Developing Countries

Introduction: Training and cardiovascular emergency care (CEC) is different in developing countries from developed countries. Emergency medicine specialty in developing countries is not established without a large number of specialists and the Advanced Cardiovascular Life Support course (ACLS) is a very common course. Objective: To compare the ACLS with the Advanced Cardiovascular Emergency Training course (TECA) developed in Brazil according to the needs of local doctors. Both courses with 16 hours of training but the TECA adding more skills training time in Arrhythmia, Stroke, Acute Coronary Care (ACC) and Acute Heart Failure (AHF) in addition to the traditional training in cardiac arrest management (CAM). Methods: The study included the participation of 119 senior medical students divided into 2 groups: 56 students submitted to TECA training and 63 students submitted to the ACLS course. Both groups performed a mannequin simulated CAM skills evaluation care before and after participating in each course and a multiple-choice test after training. Performance in simulated scenario was compared through structured assessment score, time to onset of chest compression and time to perform defibrillation after collapse, as well as the number of correct answers in the multiple-choice assessment. Results: TECA group presented statistical higher grade than the ACLS group in the evaluation of the simulated case attendance (10,0 points (9,00-10,00) vs 9,0 (8,00-10,00) points; p<0,001). There was no statistical difference between the groups in time to onset of chest compression (19,0 sec (16,25-23,00) vs 19,5 (15,75-25,25) sec; p = 0,500) and time to defibrillation (48,0 (39,00-53,00) sec vs 48,0 (39,00-55,00) sec; p = 0,740). TECA students had a better performance in questions related to AHF treatment (4,0 (3,00-4,00) vs 3,0 (2,00-3,00); p < 0,001). There was no significant difference in the number of correct answers on arrhythmia, CAM, ACC and stroke. Conclusions: TECA course provided greater adherence to CAM care protocol, without prejudice to the time to start chest compression or time to defibrillation. In addition, it added training in AHF management, suggesting to be a good option for cardiac emergency care training in developing countries.

Intrathecal Analgesia Via a Percutaneous Port For the Management of Movement-Evoked Breakthrough Cancer Pain of Refractory Lower Extremity Cancer Pain: A Retrospective Review and Commentary

Background and Objectives: Intrathecal analgesia (ITA) is a trusty treatment option for refractory and intractable cancer pain. However, there is still no general consensus on the analgesic effect of movement-evoked breakthrough pain (MEBTP) in the ITA setting. This study examined the effect of patient-controlled intrathecal analgesia (PCIA) on analgesic efficacy, emphasizing movement evoked breakthrough pain (MEBTP) in patients with refractory lower extremity cancer pain. Methods: A retrospective chart review included all patients with refractory lower extremity cancer pain who received Intrathecal morphine infusion therapy via percutaneous port (IMITPP) at our hospital between January 2017 and December 2020. Data on the numerical pain rating scales (NRS) scores, opioid doses, and complications were collected from medical records prior to IMITPP and at a one-month postimplant visit.Results: A total of 16 patients were included in the study group. Mean SRPI (spontaneous resting pain intensity) decreased from 8.75 pre- IMITPP to 3.75 post- IMITPP, (P < 0.001); mean MEPI (movement-evoked breakthrough pain intensity) fell from 8.83 pre- IMITPP to 4.25 post- IMITPP (P < 0.001); mean daily morphine equivalent dosing decreased from 360 mg/d to 48mg/d (P< 0.001); mean daily morphine equivalent dosing for MEBTP decreased from 87 mg/d to 6 mg/d (P< 0.001). Both total and breakthrough dosing of conventional opioid medications significantly decreased following the initiation of ITT with PCIA. The mean perceived time to onset with conventional movement evoked breakthrough medications was 38 minutes, and the mean perceived time to onset with PCIA was 8 minutes (P < 0.001). Conclusions: IMITPP was associated with improved pain control in patients with refractory lower extremity cancer pain. Compared with conventional MEBTP medication, appropriate PCIA provided superior analgesia and a much faster onset of action.