Pharmacoepidemiology

Background: The extensive use of antibiotics has contributed to the development of antibiotic resistance. Understanding the factors behind the attitude of physicians in prescribing antibiotics may be useful to address educational interventions to sensitize them to a more rational use of these drugs. This study aimed to evaluate the general practitioners’ (GPs) characteristics potentially associated with antibiotic prescription in community-dwelling adults from 2000 to 2019. Method: Multivariable linear regression models were performed to evaluate the association of GPs’ characteristics with the mean number of different antibiotics prescribed and the mean number of Defined Daily Doses (DDD) prescribed per patient. Results: We found that GPs older than 60 years prescribed a smaller number of different antibiotics per patient compared to 30–40 years old GPs (mean (standard error) 1.4 (0.5) vs. 1.8 (0.4)). In contrast older GPs prescribed more DDD compared to younger ones (28.9 (0.1) vs. 27.3 (0.3)). GPs prescribed 29 (0.1) DDD for >200 patients on polypharmacy vs. 28 (0.1) DDD for <100 patients on polypharmacy. The mean number of DDD prescribed increased by 5 units and by 16 units for each refill and switch, respectively. Conclusions: Age and number of patients in polypharmacy in charge were found to be associated with higher antibiotic prescriptions. The knowledge of the GPs-related factors could allow the stakeholders to design interventions to sensitize them to a more appropriate use of antibiotics in view of the increasing issue of antibiotic resistance. Full article

We examined eligibility criteria from recent oncology clinical trials to see whether real-world data (RWD) from electronic health records (EHRs) could be used to create external control groups for clinical trials. Trials were identified from the Aggregate Analysis of ClinicalTrials.gov database; the selected trials were for oncology drugs approved by the FDA in 2020. Verbatim text from trial inclusion and exclusion criteria was qualitatively assessed by an expert panel to determine if criteria could be ascertained from structured and unstructured EHR data. Identified criteria were categorized (cancer-related, comorbidity-related, demographic, functional status, and trial operations) and subcategorized. Among 53 identified trials, 20 met the requirements for study inclusion, which included 463 eligibility criteria. Percentages of criteria by category were as follows: cancer-related factors (46%), comorbidities (20%), functional status (18%), trial operations (14%), and demographics (2%). For 18 of the 20 trials, 80% of the eligibility criteria could be ascertained with RWD; for 4 of the 20, it was 100%. When trial operation-specific criteria were excluded, all 20 met the 100% threshold. Our study indicates that both structured and unstructured data from community-based oncology-specific EHRs can be used for determining patient eligibility for external control arms for clinical trials. Full article

This study aimed to systematically review and explore the impact of study methods on the cost of managing adverse drug reactions (ADRs) among hospitalized patients to guide policymakers and researchers. A literature search was conducted in MEDLINE, EMBASE, CINAHL, Cochrane Library, and Google Scholar. The search was restricted to studies from 2000 to 2017. Two authors independently reviewed the studies, assessed their risk of bias, and extracted information for analysis. Data abstraction was based on the study design, ADR reporting, and costing approaches. Of 677 studies identified, 12 were included for analysis. All studies defined ADR according to WHO classifications. The percentage of admission due to ADR ranged from 0.03% to 17.11%. All studies adopted a healthcare provider perspective, using either a micro-costing (n = 7), case-mix group costing (n = 3), or average-per-diem costing (n = 2) approach. The cost per ADR widely fluctuated from USD 65.00 to USD 12,129.90 based on various factors. The micro-costing approach generally had a lower cost compared to other approaches. The cost per ADR in high-income countries was also 10 times higher than in lower- or middle-income countries. This study evidenced that the methodological heterogeneity across studies has resulted in a wide range of cost estimations for ADR management. Full article

Propylene glycol (PG) and benzyl alcohol (BA) have been shown to inhibit the metabolizing enzyme for acetaminophen in the liver. Ethanol has unpredictable effects on acetaminophen metabolism. Critically ill neonates commonly receive drug formulations containing PG, BA, and ethanol as excipients. Until now, there have been no reports on the influence of BA, PG, and ethanol as excipients in patients undergoing concomitant acetaminophen therapy. We devised the present study to evaluate whether any significant differences in plasma acetaminophen concentrations, liver function tests, and serum creatinine exist between neonates receiving excipients containing drugs compared to those without. We included neonates that were administered intravenous acetaminophen with at least one concomitant drug containing either BA, PG, or ethanol as excipients. Plasma acetaminophen concentrations and levels of liver function were evaluated using tests. The doubling of alanine aminotransferase levels was considered to be a marker of hepatotoxicity. Elevation of serum creatinine >1.5 times higher than the baseline value was considered to be indicative of an acute kidney injury. Fifty-seven neonates were recruited in the study. No significant differences in the serum acetaminophen concentrations, liver and renal function tests, and rates of successful closure of ductus arteriosus were observed between the groups. No significant changes in the serum acetaminophen levels and the clinical outcomes were observed due to the presence of BA, PG, or ethanol in concomitant drugs as excipients. Probably, drugs containing these excipients can be safely administered, and even formulations containing these excipients with acetaminophen are likely to be safe for critically ill neonates. Full article

People with HIV (PWH) experience higher rates of cardiovascular events (CVEs) compared with the general population. A substantial body of evidence supports that select biomarkers of inflammation (soluble CD14 [sCD14], soluble CD163 [sCD163], highly sensitive C-reactive protein [hs-CRP], interleukin-6 [IL-6]) and coagulation (D-dimer) are elevated in PWH and related to increased rates of CVEs. Our previous work showed that smoking compared with nonsmoking was associated with significantly elevated sCD14, a biomarker of monocyte activation. We aimed to explore the effect of electronic cigarette (EC) provision on inflammatory biomarkers in PWH who smoked daily and then switched to an EC. Nineteen PWH were enrolled in a pilot study in which an EC and e-liquid were provided weekly for 8 weeks. Blood specimens for inflammatory biomarker analysis were obtained at baseline (BL) and at week 8. Biomarker levels were high at BL and did not differ significantly at week 8. There were small nonsignificant reductions in sCD163 and CRP levels. Non-significant increases in IL-6, D-dimer, and sCD14 levels were also noted. Use of ECs for 8 weeks does not appear to significantly increase or decrease inflammatory biomarker levels in SWH. Further research with larger samples and a control group is needed. Full article

COVID-19 antiviral medications approved or authorized for emergency use by the U.S. Food and Drug Administration are reported to have high efficacy in preventing severe illness, hospitalizations, and deaths. However, reports for some of these antivirals use relative risk reductions from clinical trials without absolute risk reductions. The present paper reappraises recently published clinical trial data for the COVID-19 antivirals paxlovid, remdesivir, and molnupiravir, and reports absolute risk reductions, relative risk reductions, as well as number needed to treat to reduce severe illness, hospitalizations, and deaths. Relative risk reductions are 88.88% for paxlovid (95% CI: 72.13–95.56%), 86.48% for remdesivir (95% CI: 41.41–96.88%), and 30.41% for molnupiravir (95% CI: 0.81–51.18%), while absolute risk reductions are much lower at 5.73% for paxlovid (95% CI: 3.79–7.68%), 4.58% for remdesivir (95% CI: 1.79–7.38%), and 2.96% for molnupiravir (95% CI: 0.09–5.83%). Low absolute risk reductions and the high number of patients needed to treat to reduce severe COVID-19 infections, hospitalizations, and deaths challenge the clinical efficacy of antivirals approved or authorized by the U.S Food and Drug Administration. These findings apply to other populations with similar control event rates. Accurate information should be disseminated to the public when selecting treatments for COVID-19. Full article

Atrial fibrillation has been described as a global epidemic with a three-fold increase in prevalence in the last 50 years. As the prevalence of atrial fibrillation continues to grow, multiple landmark trials have been designed to determine the best method to treat atrial fibrillation. Initial trials have stated that rate control was not inferior to rhythm control, however, as the efficacy of rhythm control of atrial fibrillation has improved, a benefit in rhythm control has been shown. Because of this trend towards increased rhythm control, more patients have been placed on anti-arrhythmic medications. This paper will review the epidemiology and clinical impact of the utilization of anti-arrhythmic medications. As we enter the era of rhythm control, increased awareness is needed regarding the monitoring and potential adverse events that can occur with these medications. Providers must balance the increased emphasis on rhythm control with the overall clinical impact on their patients due to drug-to-drug interactions and adverse effects that can occur with different co-morbidities. If the clinical momentum towards rhythm control continues, real-world data analysis will be needed to evaluate the clinical impact of the use, risk, and benefits of anti-arrhythmic medications. Full article

This study aimed to investigate the knowledge and practices among dental practitioners in Saudi Arabia regarding the use of antimicrobials for periodontal diseases. An online questionnaire was sent to senior dental students and dental practitioners including interns, general dental practitioners (GDP), and periodontists in Saudi Arabia. Two hundred and twenty-three dental practitioners responded and participated in the study. The potential associations between the use of antimicrobials and different variables were assessed by a chi-square test. The majority of the participants (84.3%) reported prescribing systemic antimicrobials for a periodontal abscess or acute necrotizing periodontal disease. Surprisingly, 31% of participants reported prescribing systemic antimicrobials for deep localized periodontal pockets or for acute gingivitis associated with herpes simplex in children. Noteworthy is that 66% of the participants thought that mechanical periodontal treatment alone, without adjunctive antimicrobial therapy, is adequate to resolve the clinical condition in most cases of periodontal diseases. Almost half of the participants recommended the use of local antimicrobials for a periodontal pocket (45.3%), a recurrent periodontal pocket (45.4%), and refractory periodontitis (43.7%). The barriers against the use of local antimicrobials were a lack of knowledge and a lack of continuous education after graduation, as reported by 64% of the participants. In conclusion, knowledge and practices regarding antimicrobial use for periodontal diseases were inadequate, especially among practitioners other than periodontists. Full article

The objective of this study was to describe pregnancy- and birth-related experiences of postpartum women during the third wave of the COVID-19 pandemic and their association with mental health outcomes. An online questionnaire was distributed in five European countries (Belgium, The Netherlands, Norway, Switzerland, UK) between June and August 2021. Participants were recruited though social media platforms including pregnancy- and motherhood-related websites, pregnancy fora, and apps. Postpartum women were asked eleven specific questions about pregnancy- and birth-related changes and the presence of support during delivery. The Edinburgh Depression Scale was used to assess depressive and anxiety symptoms. Covariates included sociodemographics, health and reproductive characteristics, and COVID-19 status. Associations were estimated with logistic regression. The study included 1730 postpartum women. Frequent changes included the exclusion of the partner from pregnancy care appointments (83.2%), changed prenatal care settings (64.4%), and cancellation of hospital information visits (42.7%). Few women, however, were without support apart from medical staff during delivery (1.4%). The number of pregnancy- and birth-related changes was associated with each woman’s mental health status, as well as the type of change. Experiencing changes related to delivery and cancellation or reduction of prenatal examination was associated with a doubling in the odds of symptoms of major depression and anxiety postpartum. These findings highlight the importance of ensuring adequate maternity care for women’s mental health postpartum, as well as during a pandemic. Full article

Irrational and inappropriate prescribing of antibiotics is a major problem that can lead to the development of antimicrobial resistance (AMR). In Zambia, there is insufficient information on the prescribing patterns of antibiotics according to the World Health Organization (WHO) AWaRe classification. Therefore, this study assessed the prescribing patterns of antibiotics using the AWaRe classification during the COVID-19 pandemic at the University Teaching Hospital in Lusaka, Zambia. A cross-sectional study was conducted using 384 patient medical files at the University Teaching Hospital in Lusaka, Zambia, from August 2022 to September 2022. All antibiotics were classified according to the WHO “AWaRe” tool and assessed for appropriateness using the 2020 Zambian Standard Treatment Guidelines. Of the 384 patient medical files reviewed, antibiotics were prescribed 443 times. The most prescribed antibiotics were ceftriaxone (26.6%), metronidazole (22.6%), amoxicillin (10.4%), amoxicillin/clavulanic acid (5.6%), and azithromycin (5%). The prescribing of 42.1% of “Watch” group antibiotics was greater than the recommended threshold by the WHO. Most antibiotics were prescribed for respiratory infections (26.3%) and gastrointestinal tract infections (16.4%). The most prescribed antibiotic was ceftriaxone, a Watch antibiotic. This is a worrisome observation and calls for strengthened antimicrobial stewardship and implementation of the AWaRe framework in prescribing antibiotics. Full article

Heart disease and cancer are the main causes of morbidity and mortality worldwide. As the number of cancer survivors increases, cardiotoxicity associated with cancer treatment has become a major concern as it presents a substantial challenge in the follow-up of these patients. Here, we aimed to map the clinical indicators for cardiovascular risk in adult patients undergoing chemotherapy. A scoping review protocol adhering to the PRISMA-P statement and in accordance with the JBI guidelines will be conducted. Cochrane Library, MEDLINE/PubMed, Cochrane Library, EMBASE, Scopus, Web of Science, and PsycINFO as well as register sites such as ClinicalTrials.gov and WHO-ICTRP will be searched. Additional sources, including Google Scholar, The British Library, and medRXiv, will also be searched, with no date or idiom restrictions. A combination of subject headings, MeSH terms, Emtree terms, CINAHL Headings, and APA Thesaurus, using the Boolean terms AND/OR, will be performed. In addition, two independent researchers will conduct the overall steps of this review. The results will be presented via narrative summaries, considering the types of clinical indicators. To the best of our knowledge, this will be the first scoping review in the cardio-oncology field to map, via a rigorous review method, the clinical indicators for cardiovascular risk in adult cancer patients receiving chemotherapy. Full article

Although 5-Aminosalicylate (5-ASA) has been shown to act on the local mucosa, when 5-ASA is orally administered, most of it is absorbed in the upper gastrointestinal tract and does not reach the large intestine, where lesions are present. Therefore, different drug delivery systems have been developed for each oral 5-ASA formulation. Currently, the oral 5-ASA formulation approved in Japan is salazosulfapyridine (SALAZOPYRIN^®; Pfizer Japan Inc.: Tokyo, Japan), in which 5-ASA and sulfapyridine are azo-bonded. In addition, there are several 5-ASA release formulations, including ASACOL^®; ZERIA Pharmaceutical Co., Ltd.: Tokyo, Japan (delayed release formulation dependent on pH), PENTASA^®; KYORIN Pharmaceutical Co., Ltd.: Tokyo, Japan (delayed release formulation dependent on time), and LIALDA^®; MOCHIDA Pharmaceutical Co., Ltd.: Tokyo, Japan (delayed release formulation dependent on pH and time). Adverse events may occur because of differences in the drug delivery systems of these products. In this study, we focused on the adverse events of different 5-ASA formulations and investigated differences in the detection of safety signals for each 5-ASA formulation using disproportionality analysis. There were 15 adverse events detected only with SALAZOPYRIN^®. On the other hand, ASACOL^®, PENTASA^®, and LIALDA^® have different drug delivery systems. Although the detected signal intensities varied, the detected adverse events were not significantly different. These findings provide important insights, which should be considered by physicians during treatment selection and drug manufacturers during drug development. Full article

We aimed to evaluate the adverse birth outcomes of anticancer drug prescription during pregnancy using a Japanese claims database from 2005 to 2019. We applied validated claims-based algorithms to identify pregnant women with birth outcomes, and evaluated drug prescription during pregnancy. The causal relationship between anticancer drugs and adverse birth outcomes was evaluated using the Council for International Organizations of Medical Sciences Working Group VI criteria. Thirteen women with anticancer drugs prescription during pregnancy were identified (mean age: 34.6 years). Atrial/ventricular septal defect was observed in one infant after exposure to cyclophosphamide and doxorubicin for breast cancer in the second and third trimesters. One woman on several anticancer drugs (cyclophosphamide, cytarabine, daunorubicin, l-asparaginase, methotrexate, nelarabine, and vincristine) for acute lymphoblastic leukemia, one on imatinib for chronic myeloid leukemia, and one on cisplatin and fluorouracil for cervical cancer had miscarriages after exposure in the first trimester. A relationship between those anticancer drugs and miscarriage could not be ruled out, while no relationship was identified regarding the atrial/ventricular septal defect considering the period of exposure and organogenesis. Our results suggest increased risk of miscarriage with the use of several anticancer drugs such as methotrexate, imatinib, cisplatin, and fluorouracil in the first trimester. Full article

Unique aspects of New Zealand’s (NZ) health system allow for a novel pharmacoepidemiologic approach to conducting population-based clinical research. A defined cohort of surgical and trauma patients would facilitate future studies into opioid utilisation, outcomes, and other questions related to surgery and trauma. We aimed to describe all patients admitted to a NZ hospital with trauma or to undergo surgery between 1 January 2007 to 31 December 2019. This was a retrospective population-based study involving all hospital centres in NZ. We excluded patients with hospitalisation episodes for surgery or trauma one year before the event. We identified 1.78 million surgical only patients, 633,386 trauma only, and 250,800 trauma with surgery patients. Trauma only patients had the highest prevalence of death within one year of event (17.8%), history of opioid dispensing (18.3%), mental health disorders (17.0%) and chronic pain (2.3%). Moreover, trauma patients also had the highest prevalence of those with higher comorbidity burden. We plan to use this dataset for future research into the prevalence and outcomes of persistent opioid use, and to make our dataset available to other researchers upon request. Our findings of significant differences between cohorts suggest studies should treat surgical and trauma patients separately. Full article

Opioid use disorder (OUD) is a chronic disease requiring long-term treatment and is associated with opioid overdose and increased risk of mortality. However, existing randomized clinical trials focused on short-term treatment engagement and detoxification rather than overdose or mortality risk due to limited follow-up time and ethical considerations. We used a hypothetical trial framework to conduct a retrospective cohort study to assess the effectiveness of time-varying buprenorphine-naloxone on opioid overdose and death. We identified 58,835 insured adult patients with OUD diagnosis in the US, 2010–2017. We fit a marginal structural model using inverse probability weighting methods to account for measured baseline and time-varying confounders, as well as selection bias due to possibly differential loss-to-follow-up. We found that receipt of buprenorphine-naloxone was associated with reduced risk of opioid overdose (hazard ratio (HR) = 0.66, 95% confidence interval (CI): 0.49, 0.91), death (HR = 0.24, 95% CI: 0.08, 0.75), and overdose or death (HR = 0.58, 95% CI: 0.40, 0.84). The E-value for death was 7.8, which was larger than the upper 95% CI of the association between each measured baseline variable and all-cause death, which implies that the unmeasured confounding itself may not explain away the estimated effect of treatment on the endpoint of all-cause mortality. Full article

Background: Spironolactone is a mineralocorticoid receptor antagonist indicated for the management of heart failure with reduced ejection fraction (HFrEF). In a previous clinical trial, spironolactone significantly lowered the incidence of heart failure (HF) hospitalizations among HF patients with preserved ejection fraction (HFpEF). Real world utilization of spironolactone in HFrEF and HFpEF is unknown. Methods: We conducted a retrospective cohort study using data from FDA’s Sentinel System. We identified patients with HFrEF or HFpEF using diagnosis and procedure codes from a previously validated algorithm. We required patients to be continuously enrolled in the 183 days prior to HF diagnosis. Follow-up started on the day of HF diagnosis and ended at the earliest occurrence of a spironolactone dispensing, disenrollment, death, or end of data. We calculated the proportion of spironolactone utilization, and for those initiating treatment, we estimated the dose and duration of the first continuous treatment episode. Results: Among 2,009,529 HFrEF patients, 57.8% were male, and mean age was 73.8 ± 12.1 years. Among 9,257,514 HFpEF patients, 42.7% were male, and mean age was 73.0 ± 12.1 years. The proportion of spironolactone utilization following HFrEF diagnosis was 20.7% versus 7.6% after HFpEF. The median time (days) to initiation of spironolactone after HFrEF diagnosis was 90 (IQR: 19–385) versus 286 (IQR: 57–851) after HFpEF diagnosis. The median duration (days) of first treatment episode in HFrEF patients was 120 (IQR: 44–321) and 114 (IQR: 32–301) for HFpEF patients. The median dose was similar (25 mg/day) for both HF cohorts. Conclusion: Findings of low real-world utilization of spironolactone from our large, geographically, and demographically diverse multi-site study in the US are consistent with reports from smaller studies in the literature. Similar spironolactone dosing and duration were observed in both the HFpEF and HFrEF cohorts. Future research characterizing spironolactone treated and untreated HFpEF cohorts will be needed to identify treatment gaps. Full article

This cross-sectional study sought to quantify medication use and change in use of prescription-only medications purchased in the past in Syria without medical prescription versus today in Norway in an adult population originating from Syria and living in western Norway. Data on adults born in Syria and living in Norway during December 2019–January 2020 were collected via a self-administrated questionnaire in Arabic. Participants were recruited at a community pharmacy and at a refugee center. We included 148 participants (mean age 36.4 years; 38.5% females and 60.8% males) of whom 62.6% had lived in Norway for 4–6 years. Most participants had low (45.9%) or medium (39.2%) health literacy. Painkillers and analgesics were the most widely used medications, in both Norway (69.6%) and Syria (78.4%). Use of antibiotics declined significantly in Norway (31.1%) relative to Syria (65.5%); 70.9% participants used prescription-only medications in both countries, while 6.1% and 13.5%, respectively, did so only in Norway or only in Syria. This study reports a relatively high rate of medication use, particularly painkillers and analgesics both in Syria and in Norway. Participants with low health literacy reported greater use of antibiotics than those with high level in Syria but not in Norway. Use of antibiotics decreased substantially in Norway relative to the past in Syria, reaching a comparable prevalence with that in the host community. Although uncommon, prescription-only medication use only in Norway was reported by some participants. Full article

Depolarization-blocking drugs (DB drugs) used for cardiac disease increase the risk of cardiac arrhythmia (ventricular tachycardia/ventricular fibrillation [VT/VF]) and out-of-hospital cardiac arrest (OHCA) in specific patient groups. However, it is unknown whether drugs for non-cardiac disease that block cardiac depolarization as the off-target effect increase the risk of OHCA on a population level. Therefore, we aimed to investigate OHCA risk of non-cardiac, DB drugs in the community. We conducted a population-based case-control study. We included OHCA cases from an emergency-medical-services-attended OHCA registry in the Netherlands (ARREST:2009–2018), and age/sex/OHCA-date matched non-OHCA controls. We calculated adjusted odds ratios (OR_adj) of use of non-cardiac DB drugs for OHCA using conditional logistic regression. Stratified analyses were performed according to first-registered rhythm (VT/VF or non-VT/VF), sex, and age (≤50, 50–70, or ≥70 years). We included 5473 OHCA cases of whom 427 (7.8%) used non-cardiac, DB drugs and 21,866 non-OHCA controls of whom 835 (3.8%) used non-cardiac, DB drugs and found that non-cardiac, DB-drug use was associated with increased OHCA-risk when compared to no use (OR_adj1.6[95%-CI:1.4–1.9]). Stratification by first-recorded rhythm revealed that this applied to OHCA with non-VT/VF (asystole) (OR_adj2.5[95%-CI:2.1–3.0]) but not with VT/VF (OR_adj1.0[95%-CI:0.8–1.2]; p-value interaction < 0.001). The risk was higher in women (OR_adj1.8[95%-CI:1.5–2.2] than in men (OR_adj1.5[95%-CI:1.2–1.8]; p-value interaction = 0.030) and at younger ages (OR_adj≥70yrs1.4[95%-CI:1.2–1.7]; OR_{adj50–70yrs}1.7[95%-CI:1.4–2.1]; OR_adj≤50yrs3.2[95%-CI:2.1–5.0]; p-value interaction < 0.001). Use of non-cardiac, DB drugs is associated with increased OHCA risk. This increased risk occurred in patients in whom non-VT/VF was the first-registered rhythm, and it occurred in both sexes but more prominently among women and more strongly in younger patients (≤50 years). Full article

The issue with the overlapping clinical symptoms from an electronic cigarette (e-cigarette) or vaping product use-associated lung injury (EVALI) and coronavirus disease 2019 (COVID-19) sometimes leads to incorrect diagnosis and, consequently, wrong treatment regimen. The purpose of this review is to study the burden of vaping-associated health consequences on the diagnosis and treatment of COVID-19 in young adults and adolescents with a misconception of e-cigarettes as a safer alternative to smoking. The online reference databases, including PubMed, Google Scholar, Web of Science, Medline, and Centers for Disease Control and Prevention (CDC), were used in the literature search, as we analyzed the complexity of timely diagnosis and treatment in the current COVID-19 era with the use of e-cigarettes. This study briefly describes the dysbiosis of the oral microbiome in e-cigarette users that could potentially aggravate the COVID-19 symptoms and lead to the complexity of timely diagnosis and treatment. Additionally, the patient case reports with a history of vaping and symptoms similar to COVID-19 disease are reviewed. Full article