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Tazobactam/piperacillin and meropenem are commonly used as an empiric treatment in patients with severe bacterial infections. However, few studies have investigated the cause of tazobactam/piperacillin- or meropenem-induced liver injury in them. Our objective was to evaluate the association between tazobactam/piperacillin or meropenem and liver injury in the intensive care unit patients. We evaluated the expression profiles of antibiotics-induced liver injury using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Further, in the retrospective observational study, data of patients who initiated tazobactam/piperacillin or meropenem in the intensive care unit were extracted. In FAERS database, male, age, the fourth-generation cephalosporin, carbapenem, β -lactam and β -lactamase inhibitor combination, and complication of sepsis were associated with liver injury ( p  < 0.001). In the retrospective observational study, multivariate logistic regression analyses indicated that the risk factors for liver injury included male ( p  = 0.046), administration period ≥ 7 days ( p  < 0.001), and alanine aminotransferase ( p  = 0.031). Not only administration period but also sex and alanine aminotransferase should be considered when clinicians conduct the monitoring of liver function in the patients receiving tazobactam/piperacillin or meropenem.

Voriconazole is a second-generation azole used to treat serious fungal infections. Visual hallucinations constitute a representative adverse event caused by voriconazole. However, its mechanism of action remains unclear. In patients with schizophrenia or Parkinson’s disease, the frequency of visual hallucinations is associated with brain dopamine levels. This study investigated the frequency of visual hallucinations in patients treated with voriconazole alone or in combination with dopaminergic medicines or dopamine antagonists, using data collected from the Food and Drug Administration Adverse event Reporting System (FAERS). The frequency of visual hallucinations with voriconazole alone and in combination with a dopaminergic medicine (levodopa) or dopamine antagonists (risperidone and chlorpromazine) was compared using data from the FAERS between 2004 and 2023, using the reporting odds ratio (ROR) with relevant 95% confidence intervals (CI). The reference group comprised patients who had been administered voriconazole without dopaminergic medication or dopamine antagonists. Of the patients, 22,839, 90,810, 109,757, 6,435, 20, 83, and 26, respectively were treated with voriconazole, levodopa, risperidone, chlorpromazine, voriconazole plus levodopa, voriconazole plus risperidone, and voriconazole plus chlorpromazine. The occurrence of visual hallucinations increased when used in combination with levodopa (ROR = 12.302, 95% CI = 3.587–42.183). No increase in incidence was associated with the concomitant use of dopamine antagonists (risperidone, ROR = 1.721, 95% CI = 0.421–7.030; chlorpromazine, ROR = none, 95% CI = none). Dopaminergic medicine may increase the risk of visual hallucinations in patients treated with voriconazole. Whether voriconazole positively modulates dopamine production warrants further investigation using a translational research approach.

Despite implementation of therapeutic drug monitoring (TDM) for voriconazole, the incidence of hepatotoxicity remains high. The albumin-bilirubin (ALBI) score may be useful for estimating voriconazole-induced hepatotoxicity. This pilot study aimed to investigate whether the ALBI score could estimate voriconazole-induced hepatotoxicity during TDM implementation. This single-center, retrospective cohort study included 134 patients. The primary outcome was voriconazole-induced hepatotoxicity. The cutoff value of the ALBI score was determined using a receiver operating characteristic curve. The cumulative risk of hepatotoxicity was evaluated using Kaplan–Meier curve analysis with a log-rank test for the cutoff value and ALBI grade. Moreover, the group of patients with the trough concentration of voriconazole 1−4 μg/mL was also investigated. The incidence of hepatotoxicity was 13.4% (18/134). The cutoff value of the ALBI score was -1.91 (sensitivity, 0.611; specificity, 0.655; area under the curve, 0.615). The cumulative risk of hepatotoxicity was significantly higher in the ALBI score ≥-1.91 group than in the ALBI score <-1.91 group (P = 0.024) and patients with higher ALBI grades tended to be at higher risk (P = 0.080). The cumulative risk tended to be higher with ALBI ≥-1.91 in the trough concentration 1−4 μg/mL group; however, no significant difference was found (P = 0.134). The pilot study indicated that the ALBI score ≥-1.91 may be an indicator for voriconazole-induced hepatotoxicity even when TDM is conducted. Because this study was a single-center and small cohort design, further studies should be conducted using a large datasets and translational research.

IntroductionThe incidence of antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is rare, and its management has not yet been established. This study aimed to investigate the predictors for advanced stage and healing of ARONJ to establish an appropriate treatment strategy.Materials and methodsWe retrospectively analyzed patients diagnosed with ARONJ at Kobe City Medical Center General Hospital between April 2014 and March 2020. Outcomes were defined as stage ≥ 2 ARONJ (primary) and healing of ARONJ (secondary). Multivariate logistic regression analysis was used to detect factors associated with the outcomes, and odds ratios (OR) and 95% confidence intervals (CI) were calculated.ResultsThis study included 143 patients (stage ≥ 2 ARONJ, 51%; healing of ARONJ, 60%). Multivariate logistic regression analysis revealed that advanced age (per year) (OR 1.037; 95% CI 1.003–1.072; p = 0.028) and serum albumin (per g/dL) (OR 0.430; 95% CI 0.213–0.869; p = 0.018) were significantly associated with stage ≥ 2 ARONJ. Furthermore, multivariate logistic regression analysis revealed that cancer (yes) (OR 0.099; 95% CI 0.029–0.339; p < 0.001), conservative surgical treatment (yes) (OR 15.42; 95% CI 5.657–42.0; p < 0.001), C-reactive protein (per mg/dL) (OR 0.599; 95% CI 0.415–0.864; p < 0.001), and vitamin D analog (yes) (OR 0.167; 95% CI 0.034–0.827; p = 0.028) were factors associated with healing.ConclusionOur findings suggest that age and hypoalbuminemia are associated with the severity of ARONJ, and cancer, high inflammation, and vitamin D analog may impair healing. In contrast, conservative surgical treatment can overcome the poor treatment outcomes associated with ARONJ.

Gentamicin is an aminoglycoside antibiotic that is mostly used for the pediatric population. While the pediatric population is classified into neonates, infants, children, and adolescents based on developmental or maturational changes, infants are often overlooked in research. Three infant cases receiving gentamicin are presented to illustrate the pharmacokinetics and optimum dosage of gentamicin. Three infant patients received gentamicin (5.6–7.5 mg/kg/day) for urinary tract infections (UTIs) or bacteremia caused by Enterobacter aerogenes. The trough (Cmin) and peak (Cpeak) concentrations of gentamicin were 0.2–1.8 and 8.9 mg/L, respectively. The Cmin of a patient receiving gentamicin at 9.0 mg/kg/day was 3.3 mg/L, and the patient showed a decrease in urinary volume. The other two patients fully recovered from the infection and did not experience any adverse events. Additionally, we reviewed three studies regarding infant patients receiving gentamicin. The studies used gentamicin therapy for Gram-negative pathogen infections and UTIs caused by Escherichia coli and Enterococcus faecalis. The Cmin and Cpeak of patients receiving gentamicin at 2.2–7.5 mg/kg/day were 0.58–2.15 mg/kg and 4.67–8.88 mg/L, respectively. All patients were cured without any adverse events. Gentamicin dosages below 7.5 mg/kg/day may be effective and safe for use in infant patients. However, the optimal dosing regimen of gentamicin in infant patients is controversial, and limited data are available.

Background Unlike in urban areas, community healthcare in medically underpopulated areas in Japan is constantly challenged because of the uncertainty in effectively using the limited resources. However, no study has focused on human resources or identified the actual state of pharmacists’ support in the community. Therefore, our study identified the actual status and problems of pharmacists involved in home medical care in medically underpopulated areas and discussed the roles required of pharmacists and specific methods of support. Methods The content of semi-structured interviews with care managers involved in home healthcare in Misugi town, Tsu City, between November 10, 2023 and March 13, 2024, was analyzed qualitatively using the grounded theory approach. Results Five care managers participated in the study. Semi-structured interviews on the actual situation and challenges faced by pharmacists indicated that the following roles were required for pharmacists: as in other regions, it was observed that elderly people with dementia and those living alone managed their medicines, adjusted leftover medicines, collaborated with other professions, bridged with physicians, checked medication status through frequent visits, and adhered to internal medication regimens. Issues related to the characteristics of depopulated areas were identified including human resources, limitations of healthcare resources, economic burden, limits on the number of visits by pharmacists. As a characteristic of communities with no pharmacies and only in-hospital prescribing, pharmacists were expected by care managers to manage the problems caused by in-hospital prescribing. Conclusions Our findings suggest that pharmacists should ensure the number of visits and collaborate with attending physicians, visiting nurses, and care managers to conduct drug management for patients with dementia and older adults living alone. Community healthcare specialists and those involved in the healthcare planning system can also utilize these findings while planning home healthcare to those who live in medically underpopulated areas in Japan.

BackgroundThis study aimed to investigate changes in the hepatic venous pressure gradient (HVPG) by partial splenic embolization (PSE) and to identify the determinants of a clinically meaningful postoperative HVPG reduction.MethodsSixty-eight patients with cirrhosis and hypersplenism who underwent PSE at our department between September 2007 and June 2020 were included. The HVPG was evaluated pre- and immediately post-PSE. The patients were divided into three groups according to their preprocedural HVPG: low-HVPG (< 10 mmHg, n = 22), intermediate-HVPG (10 mmHg ≤ HVPG < 16 mmHg, n = 33), and high-HVPG (≥ 16 mmHg, n = 13).ResultsOverall, PSE significantly reduced HVPG from 12.2 ± 4.0 to 9.4 ± 3.6 mmHg (p < 0.01) with a relative decrease of 22.2 ± 20.4%. In addition, HVPG reductions were 19.4 ± 28.7%, 24.0 ± 15.9%, and 22.5 ± 13.3% in the low-, intermediate-, and high-HVPG groups, respectively, indicating no significant difference in HVPG reduction between the groups. An HVPG decrease of ≥ 20% from the baseline, defined in this study as a clinically significant HVPG response to PSE, was achieved in 55.9% of all patients. Multivariate logistic regression and receiver operating characteristic curve analyses identified splenic non-infarction volume as an independent determinant of a 20% decrease in HVPG (p < 0.05), with a cut-off of 139.2 cm3 (sensitivity, 76.3%; specificity, 60.0%; p < 0.05).ConclusionsThe splenic non-infarction volume, namely the residual functional spleen volume, independently determines a clinically significant HVPG response to PSE in patients with cirrhosis and hypersplenism.

Teicoplanin can cause acute kidney injury, but little is known about the risk of acute kidney injury when teicoplanin is co-administered with loop diuretics (a powerful diuresis), which can alter renal hemodynamics and glomerular filtration rate. We performed a signal detection analysis using a Japanese adverse event database to determine the additive impact of loop diuretics on acute kidney injury associated with teicoplanin. The dataset originated between April 2004 and August 2022. Disproportionality analysis was performed to detect the signals for acute kidney injury (the Standardized MedDRA Query) when co-administered teicoplanin or vancomycin (a positive control) with individual diuretics, including loop diuretics. Multivariate logistic regression analysis was tested to estimate the adjusted reporting odds ratio (aROR) and 95% confidence interval (95% CI). There were 147 and 515 events of acute kidney injury associated with teicoplanin and vancomycin, respectively. A significant positive signal for acute kidney injury when teicoplanin was co-administered with loop diuretics was present (aROR 4.83, 95% CI 3.52–6.61, p < 0.0001). Contrastingly, no significant signals were observed when vancomycin was co-administered with any diuretics. These findings suggest that co-administered loop diuretics may have an unfavorable effect on acute kidney injury while undertaking teicoplanin but not vancomycin.

Data on the clinical effectiveness and adverse events of daptomycin in pediatric patients, considering dosage and renal function, are limited. In this study, we aimed to investigate the clinical effectiveness of daptomycin, incidence of related adverse events, and associations between clinical outcomes and risk factors, including dosage and renal function, in pediatric patients. Medical records of pediatric patients treated with daptomycin between September 2011 and December 2022, were retrospectively reviewed. Clinical effectiveness was categorized as cure, improvement, failure, or non-evaluable. The clinical success rate was defined as the sum of cured and improved cases. We classified doses based on the approved ranges: underdose (>1 mg/kg less than the approved dose), adequate dose (approved dose ±1 mg/kg), and overdose (>1 mg/kg more than the approved dose). Obesity was defined as a body mass index ≥ 30 kg/m2, with adjusted body weight used for dosing in these patients. We enrolled 54 patients, achieving a clinical success rate of 91%. Four (7%) patients died, particularly those with microbiological failure (P = 0.004) and underdosing (P < 0.001). The underdose group comprised a higher proportion of younger patients (P = 0.020). Additionally, seven (13%) patients experienced daptomycin-related adverse events, including creatine phosphokinase elevation, eosinophilic pneumonia, rhabdomyolysis, liver failure, and drug fever, occurring regardless of renal function. Five patients received an approved dose, while two received an overdose. Adequate daptomycin dosing improved clinical effectiveness and the mortality rate. However, continuous monitoring of adverse events remains critical for patients receiving the approved dose, including those with a normal renal function.

Variceal hemorrhage may cause high rebleeding and mortality rates. Preventing the first episode of variceal bleeding is mandatory in patients with high-risk esophageal varices (EV). This study aimed to identify factors that predict the recurrence of EV after endoscopic treatment (ET), and to develop a reasonable therapeutic strategy for EV in cirrhosis. From January 2012 to December 2014, 45 patients with cirrhosis and high-risk EV underwent ET, including sclerotherapy and/or ligation. Statistical analyses identified factors associated with the recurrence of EV after ET, and the Kaplan-Meier method determined the cumulative variceal recurrence rates. The 1-, 2-, and 3-year cumulative posttreatment recurrence rates for EV were 13.3%, 29.5%, and 32.2%, respectively. No significant differences were evident between the patients with and without variceal recurrences at 1-year posttreatment. The multivariate regression analyses identified a history of partial splenic embolization (PSE) and the pretreatment Child-Pugh classification as independent predictors of variceal recurrences at 2 years (p < 0.05) and 3 years (p < 0.05) posttreatment. While EV did not recur after ET and splenic artery embolization in cases with Child-Pugh class A, the overall posttreatment variceal recurrence rates were 0% and 66.7% when PSE was performed before and after ET, respectively, in those with Child-Pugh class B or C. Splenic artery embolization significantly reduced the hepatic venous pressure gradient and markedly lowered the Child-Pugh score in 15 patients. Adjunctive PSE and pretreatment Child-Pugh class A could be independently associated with reduced cumulative recurrence rates of EV post-ET. From the perspectives of portal hemodynamics and hepatic function, splenic artery embolization before or after ET could prevent posttreatment variceal recurrence in patients with Child-Pugh class A, and PSE before ET could achieve the long-term eradication of EV following ET in those with Child-Pugh class B or C.