Annals of Pharmacotherapy最新文献

Background: Cholinesterase inhibitors (ChEIs)-donepezil, rivastigmine, and galantamine-are beneficial in treating Alzheimer disease (AD). However, due to their impact on extra-cerebral acetylcholine signaling, concerns about cardiac adverse effects, including QT interval prolongation, persist. Despite this, evidence-based guidelines for electrocardiogram (ECG) monitoring during ChEI treatment are lacking, and prior studies on ChEIs and corrected QT intervals (QTc) yield inconsistent findings.

Objective: This study aimed to investigate the association between ChEI use and changes in QTc intervals among older adults.

Methods: We collected retrospective data from first-time visitors to the geriatric memory clinic of Turku City Hospital in 2017 and 2019. We included patients who were newly prescribed ChEIs and had ECG data available (n = 126, mean age 81.1 years, 56.3% female). QTc prolongation was defined as ≥460 ms in females and ≥450 ms in men. Paired t tests compared QTc means before and during ChEI use, and McNemar tests analyzed changes in the proportion of prolonged QTc.

Results: Mean ± SD QTc (ms) before versus during ChEI use was: 420.8 ± 24.0 versus 423.9 ± 28.0 (P = .13) for donepezil; 416.0 ± 20.4 versus 416.5 ± 26.1 (P = .92) for galantamine; 416.1 ± 22.3 versus 409.6 ± 20.1 (P = .30) for rivastigmine; and 419.7 ± 23.4 versus 421.5 ± 27.3 (P = .34) for all ChEIs. Prolonged QTc occurred in 7.9% of patients before versus 12.7% during ChEI use (P = .21).

Conclusion and relevance: We found no statistically significant association between ChEI use and QTc interval prolongation or an increased proportion of pathological QTc values during ChEI treatment. Larger studies are warranted to establish evidence-based recommendations on ECG monitoring during ChEI medication.

Background: Pseudomonas aeruginosa (PA) bacteremia is associated with poor clinical outcomes.

Objective: The purpose of this study was to evaluate treatment effect and patient outcomes from different antimicrobials for PA bacteremia from 2020 to 2022.

Methods: This was a retrospective review of 2020 to 2022 hospitalized patients with PA bacteremia at our institution. Patients from January 2020 to July 2022 with culture-positive PA were identified. Data collected included demographics, hospitalization and drug treatment length, vasopressor use or mechanical ventilation, and admission acute and physiologic health evaluation II score (APACHE II) score and hospital mortality. Directed therapy for PA, including dose, interval, and minimal inhibitory concentration (MIC) data, was evaluated. Data were analyzed by SPSS. Data are presented as mean ± SD or percentage. A priori significance was P ≤ 0.05.

Results: A total of 111 PA bacteremias occurred from 2020 to 2022; 65% of patients were male. Mean (± SD) age was 71 ± 13 years, and weight was 89.7 ± 23 kg. Mean hospitalization length and duration of antibiotics were 12 ± 13 days and 7.1 ± 5.9 days, respectively. The PA bacteremia was treated with piperacillin-tazobactam (45%) or cefepime (43%). Thirty- seven (33%) PA-infected patients expired. Significantly more 8 of 18 (44%) cefepime patients died when receiving 4 g/d (1 g q 6 h) compared with 1 (9%) of 11 receiving 6 g/d (2 g q 8 h) (P < 0.05). The APACHE II score was significantly higher for expired patients (survival 13.9 ± 5.7; expired 22 ± 8.3 group, P < 0.001).

Conclusions and relevance: The APACHE II score was significantly higher for PA bacteremic patients who expired. Treatment of the bacteremia with cefepime 4 g/d resulted in significant mortality compared to 6 g/d.

Background: Although guidelines recognize the utility of subcutaneous (SQ) insulin regimens in the management of mild to moderate diabetic ketoacidosis (DKA), the need to administer SQ insulin every 1-2 hours may discourage their use due to frequent lab testing and admission to higher level of care units.

Objective: The purpose of this retrospective cohort study was to compare the proportion of patients whose mild to moderate DKA resolved within 12 hours after receiving the new SQ insulin order set and the institution's intravenous (IV) insulin infusion order set.

Methods: The SQ order set included single doses of glargine (0.2 units/kg) and lispro (0.2 units/kg) upon therapy initiation, followed by lispro (0.1-0.2 units/kg) given every 3 hours until DKA resolution. The IV order set included a nurse-managed titratable infusion. Glucose and labs were checked every 3 hours in the SQ group, whereas glucose was checked hourly and labs were checked every 2 hours in the IV group. Patients were managed on units with a RN to patient ratio of 1:4-5 and 1:2-3 in the SQ and IV groups, respectively.

Results: The percentage of patients whose DKA resolved within 12 hours was 78% in the IV group and 90% in the SQ group (P = 0.1). The time to DKA resolution and rates of hypoglycemia and hypokalemia were comparable between the groups.

Conclusion and relevance: Our study highlights the utility of combining rapid-acting and basal SQ insulin in the management of DKA and adds to the limited literature evaluating this approach.

The Food and Drug Administration (FDA) exists to protect US consumers. However, while drug manufacturing has shifted dramatically to developing countries like India and China, the FDA first silently followed a "trust and not verify" strategy with virtually no overseas inspections until overwhelming evidence of patient harm had occurred. The implementation of the Generic Drug User Fee Act helped alleviate this problem, but the issue recurred after the COVID-19 pandemic set the FDA far behind in foreign inspections. Regardless, the FDA has never attained parity in inspection frequency and rigor in these countries versus the United States. The FDA still over relies on reports of adverse events, whistleblower reports, and independent laboratory findings to prompt an investigation. When serious issues are found in a manufacturing plant, they redact the products manufactured there so clinicians and patients are unprotected. This has directly harmed US citizens, exposed them to cancer-causing agents, and provided products without the expected benefits. When rates of adverse events were recently compared by manufacturer location, they were found to be markedly higher for manufacturers in emerging countries than advanced countries, especially when a drug's patent has been expired for a longer time. Clinicians may be dismissive of patients claiming that a new version of a generic drug isn't as effective as their previous one or is causing new adverse events, but that could be the case. Healthcare professionals should report these cases to the FDA to raise awareness of potential issues.

Objective: To review the efficacy and safety of gepotidacin for the treatment of uncomplicated urinary tract infections (uUTIs).

Data sources: A literature search was performed using PubMed and Google Scholar (both January 2010 to March 2025) with the search terms gepotidacin and GSK2140944. Other resources included conference abstracts, the manufacturer's web site, and prescribing information.

Study selection and data extraction: All relevant English-language studies assessing gepotidacin efficacy and safety for the treatment of uUTIs were included.

Data synthesis: Gepotidacin is a first-in-class triazaacenaphthylene antibiotic with a novel mechanism of action that is active against strains of Escherichia coli resistant to other classes of antibiotics, including the fluoroquinolones. Gepotidacin was non-inferior to nitrofurantoin in the treatment of healthy, non-pregnant females aged 12 years and older with uUTIs. Gastrointestinal effects are the most common adverse effects, and it has several potential drug-drug interactions. Relevance to Patient Care and Clinical Practice in Comparison to Existing Drugs Gepotidacin has been directly compared to nitrofurantoin for the treatment of uUTIs, but not to other commonly used drugs, such as trimethoprim/sulfamethoxazole, fosfomycin, beta-lactams, and fluoroquinolones. However, it may be active against organisms resistant to these traditionally used agents due to its novel mechanism of action, making it an attractive option for patients with UTIs due to multidrug-resistant organisms. It should be administered with food to help decrease gastrointestinal-related adverse effects.

Conclusions: Gepotidacin is an antibiotic with a novel mechanism of action that is efficacious in the treatment of women with uUTIs caused by common uropathogens, including resistant strains.

Background: Patients with a mechanical aortic valve replacement (AVR) require lifelong anticoagulation with warfarin. International normalized ratio (INR) goals for mechanical AVRs can change throughout treatment as risk factors change. Appropriate INR goal selection is crucial as goals that stray from evidence-based recommendations can lead to increased risk of bleeding, thrombosis or unnecessary monitoring.

Objective: The purpose of this study was to evaluate the appropriateness of INR goals in patients with mechanical AVRs and identify opportunities for pharmacist-led intervention.

Methods: A cross-sectional quality improvement study was conducted at a safety net academic medical center's outpatient anticoagulation clinic. This quality improvement project was not formally supervised by the Institutional Review Board per their policies. Adult patients with isolated mechanical AVR actively managed on warfarin were included. Pharmacists determined whether INR goals were justified by clinical context and American and European valvular heart disease guidelines. When goals lacked clear justification, pharmacists contacted referring providers to recommend INR goal adjustment.

Results: Of 100 identified patients, 81 met eligibility criteria including 24 (29.6%) with On-X valves and 57 (70.4%) with alternative mechanical AVRs. Nearly one-third of patients (23, 29.3%) had INR goals inconsistent with current guidelines. Pharmacist-led outreach resulted in 20 accepted recommendations (87.0%), representing 24.7% of the study population. On-X valve recommendations primarily involved reducing INR targets to 1.5 to 2.0 for patients at least 3 months postsurgery without other risk factors that would constitute a higher INR goal. The most common alternative mechanical valve interventions included increasing INR goals to 2.5 to 3.5 in those with thromboembolic risk factors and decreasing INR goals to 2.0 to 3.0 due to absence of thromboembolic risk factors.

Conclusion and relevance: This stewardship initiative highlights the need for periodic INR goal review, as risk factors in patients with mechanical AVRs can change over time.

Background: Glomerular filtration rate (GFR) is commonly estimated with equations using creatinine, cystatin C, or a combination of both. Drug dosages may differ depending on the which equation.

Objectives: This study determined estimated GFRs from 4 common equations, their correlations, and the subsequent variations of predicted vancomycin half-life (t_1/2).

Methods: Retrospective cohort study of critically ill adults with GFR estimations based on Cockcroft-Gault (CrCl_CG), 2021 CKD-EPI Creatinine (eGFR_cr), 2012 CKD-EPI Cystatin C (eGFR_cys), and 2021 CKD-EPI Creatinine-Cystatin (eGFR_cr-cys). Patients were excluded if pregnant, dialysis dependent prior to admission, or sampling occurred within 24 hours of renal replacement therapy. Statistical analyses used MANOVA and Pearson correlation coefficient (r²). Bayesian modeling population estimates predicted vancomycin t_1/2.

Results: Sixty-three patients with 104 GFR estimates were assessed. Mean age was 58.5 ± 15.2 years. Mean creatinine and cystatin C were 1.78 ± 2.1 mg/dL and 2.28 ± 1.2 mg/L, respectively. Mean estimated GFRs were 76.6 ± 59.2 mL/min, 72 ± 41.4 mL/min, 38 ± 27.5 mL/min, and 47.3 ± 32.7 mL/min for CrCl_CG, eGFR_cr, eGFR_cys, and eGFR_cr-cys, respectively (P < 0.0001). r² (all P < 0.0001) were 0.82 for CrCl_CG versus eGFR_cr, 0.54 for CrCl_CG versus eGFR_cys, 0.72 for CrCl_CG versus eGFR_cr-cys, 0.57 for eGFR_cr versus eGFR_cys, 0.77 for eGFR_cr versus eGFR_cr-cys, and 0.92 for eGFR_cys versus eGFR_cr-cys. Mean creatinine and cystatin C for vancomycin half-life estimations were 2.72 ± 3.48 mg/dL and 2.76 ± 1.1 mg/L, respectively. Mean predicted t_1/2 values from 17 patients with vancomycin monitoring were 33.3 ± 22.7 hours, 35.7 ± 27.5 hours, 43.2 ± 40.9 hours, and 38.7 ± 37.3 hours, respectively (P = 0.85).

Conclusions and relevance: GFR estimations varied substantially with creatinine-based equations resulting in higher values. Correlation analyses revealed moderate to strong associations between equations. Discrepancies between GFR estimations were more apparent at higher GFRs. The variable GFR estimations led to substantial differences in predicted vancomycin t_1/2. Clinicians must be aware that dosing disparities may occur based on the GFR estimation used.

Objective: The objective of the study is to critically review the literature about clinical evidence on the efficacy and safety of fitusiran among patients with hemophilia A or B.

Data sources: A targeted search of PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov was performed from inception through November 2025 using the terms fitusiran, antithrombin, RNA interference, siRNA, and hemophilia A or B.

Study selection and data extraction: Eligible studies were randomized controlled trials across all phases enrolling patients with hemophilia A or B. The review incorporated 2 phase 1 studies, 1 phase 2 study, and 4 phase 3 trials.

Data synthesis: Fitusiran prophylaxis reduced annualized bleeding rates by about 70% to 90% compared with on-demand therapy or previous prophylaxis using bypassing agents, and by up to 50% compared with prior prophylaxis with clotting factor concentrates. Between 50% and 65% of participants experienced no bleeds requiring treatment. Health-related quality of life improved, with mean reductions in Hemophilia-specific Quality of Life Questionnaire for Adults (Haem-A-QoL) scores ranging from -4.6 to -12.3. Safety evaluations showed aminotransferase elevations in 19% to 25%, gallbladder events in 13% to 15%, and thrombotic events in ≤5% of patients, primarily associated with low antithrombin levels or excessive factor use. Long-term extension studies confirmed sustained bleed protection and safety with antithrombin-guided dosing.Relevance to patient care and clinical practice in comparison to existing drugs:Fitusiran is a subcutaneous nonfactor prophylactic treatment that lowers antithrombin to rebalance coagulation with or without inhibitors in patients with hemophilia A and B. It is administered every 2 months, and associated with fewer bleeds, and improved quality of life compared with standard of care.

Conclusions: Fitusiran expands prophylactic options for hemophilia A and B, providing sustained bleed protection with infrequent dosing. Integration into practice requires monitoring of antithrombin activity to mitigate thrombotic or bleeding risk, and liver and gallbladder functions for safety.