Trial Sequential Analysis and Updated Meta-Analysis of Fluvoxamine on Clinical Deterioration in Adult Patients with Symptomatic COVID-19 Infection.

Preliminary meta-analyses suggested that fluvoxamine was effective in treating COVID-19 infection. However, the reliability of this evidence has not yet been examined. MEDLINE, CENTRAL, EMBASE, PsycINFO, and ClinicalTrials.gov were searched to identify any randomized controlled trials (RCTs) from the inception of the databases to 5 February 2023. We used trial sequential analysis (TSA) to examine the reliability of the current existing evidence on the benefits of fluvoxamine on COVID-19 infection. The primary outcome was clinical deterioration, as defined in the original study (reported as odds ratio (OR), with 95% confidence intervals), and the secondary outcome was hospitalization. In the TSA, we used the relative risk reduction thresholds of 10, 20, and 30%. The updated meta-analysis of the five RCTs showed that fluvoxamine was not associated with lower odds of clinical deterioration when compared with a placebo (OR: 0.81; 0.59-1.11). The effect of fluvoxamine lay within the futility boundary (i.e., lack of effect) when using a 30% relative risk reduction threshold. The effect estimates lay between the superiority and futility boundary using the 10% and 20% threshold, and the required size of information was not reached for these two thresholds. The effect of fluvoxamine on the odds of hospitalization was not statistically significant (0.76; 0.56-1.03). In conclusion, there is no reliable evidence that fluvoxamine, when compared to a placebo, reduces the relative risk of clinical deterioration among adult patients with COVID-19 infection by 30%, and a relative risk reduction of 20% or 10% is still uncertain. The role of fluvoxamine as a COVID-19 treatment cannot be justified.

Comparison of antipsychotic dose equivalents for acute bipolar mania and schizophrenia.

QUESTION: Are antipsychotic dose equivalents between acute mania and schizophrenia the same? STUDY SELECTION AND ANALYSIS: Six databases were systematically searched (from inception to 17 September 2022) to identify blinded randomised controlled trials (RCTs) that used a flexible-dose oral antipsychotic drug for patients with acute mania. The mean and SD of the effective dose and the pre-post changes in manic symptoms were extracted. A network meta-analysis (NMA) under a frequentist framework was performed to examine the comparative efficacy between the antipsychotics. A classic mean dose method (sample size weighted) was used to calculate each antipsychotic dose equivalent to 1 mg/day olanzapine for acute mania. The antipsychotic dose equivalents of acute mania were compared with published data for schizophrenia. FINDINGS: We included 42 RCTs which enrolled 11 396 participants with acute mania. The NMA showed that risperidone was superior to olanzapine (reported standardised mean difference: -022, 95% CI -0.41 to -0.02), while brexpiprazole was inferior to olanzapine (standardised mean difference: 0.36, 95% CI 0.08 to 0.64). The dose equivalents to olanzapine (with SD) were 0.68 (0.23) for haloperidol, 0.32 (0.07) for risperidone, 0.60 (0.11) for paliperidone, 8.00 (1.41) for ziprasidone, 41.46 (5.98) for quetiapine, 1.65 (0.32) for aripiprazole, 1.23 (0.20) for asenapine, 0.53 (0.14) for cariprazine and 0.22 (0.03) for brexpiprazole. Compared with the olanzapine dose equivalents for schizophrenia, those of acute mania were higher for quetiapine (p<0.001, 28.5%) and aripiprazole (p<0.001, 17.0%), but lower for haloperidol (p<0.001, -8.1%) and risperidone (p<0.001, -15.8%). CONCLUSIONS: Antipsychotic drugs have been considered first-line treatment for acute mania, warranting specific dose equivalence for scientific and clinical purposes.

Ramelteon for delirium prevention in hospitalized patients: An updated meta-analysis and trial sequential analysis of randomized controlled trials.

Although ramelteon has been examined as a relatively new therapeutic option for delirium prevention, current evidence to evaluate its efficacy is limited. We conducted an updated meta-analysis and examine the reliability of existing evidence regarding the effect of ramelteon on delirium prevention in hospitalized patients. Seven major electronic databases were systematically searched to identify randomized controlled trials examining the efficacy of ramelteon in delirium prevention. Data were pooled using a frequentist-restricted maximum-likelihood random-effects model. A trial sequential analysis was performed using relative risk reduction thresholds of 50%. The primary outcome was the incidence of delirium (reported as odds ratio with 95% confidence intervals). The secondary outcomes were the days of delirium, all-cause mortality, and all-cause discontinuation. Of 187 potentially eligible studies identified, 8 placebo-controlled randomized controlled trials (n = 587) were included. This updated meta-analysis showed that ramelteon was associated with lower odds of delirium occurrence than placebo (0.50; 0.29-0.86; I2 = 17.48%). In trial sequential analysis, the effect of ramelteon across the superiority boundary when using a relative risk reduction threshold ranging from 40% to 60%. In subgroup analyses, ramelteon compared with placebo was associated with lower odds of delirium occurrence in the elderly group (k = 5; 0.28; 0.09-0.85; I2 = 27.93%) and multiple dosage group (k = 5; 0.34; 0.14-0.82; I2 = 44.24%) but not in the non-elderly and non-multiple dosage groups. When considering surgical patients and medical patients separately, ramelteon showed a trend in the treatment of delirium prevention in both groups, while these findings were not statistically significant. No significant between-group differences were found in the secondary outcomes. The current meta-analysis provides updated and reliable evidence that ramelteon, in comparison with placebo, reduces the risk of delirium among hospitalized patients.

Carbapenem-resistant Enterobacteriaceae infection in children less than one year old in an Asian medical center.

BACKGROUND: The emergence of carbapenem-resistant Enterobacteriaceae (CRE) is a threat to public health worldwide. This study aimed to determine the risk factors and outcomes for CRE colonization and infection in infants. METHODS: Children aged <1 year hospitalized with CRE pathogens isolated from January 2016 to June 2019 were retrospectively analyzed. Demographic and clinical data were examined. RESULTS: A total of 48 infections were identified in 70 infants aged <1 year, and 66.7% (32/48) of these infants were born preterm. The infection rate in infants aged <1 month was higher than that of others (P = 0.005). The most commonly isolated CRE was Klebsiella pneumoniae (60.4%, 29/48), followed by Enterobacter cloacae complex (18.8%, 9/48). Sputum (37.5%, 18/48), blood (27.1%, 13/48), and urine (25.0%, 12/48) were the most common clinical samples. Urinary tract infection was common in infants aged 6-12 months. CRE infection was associated with mechanical ventilation (P = 0.037), central venous catheter (CVC) insertion (P = 0.034), and congenital heart disease (P = 0.027). The hospital stay of patients with CRE infection was longer (median, 75 days; SD, 66.4 days), and their all-cause mortality (6.4%) was higher than those with colonization. CONCLUSIONS: CRE infection was common in infants aged <1 month, and patients usually had longer hospitalization. Carbapenemase production was not common. Mechanical ventilation, CVC insertion, and congenital heart disease were associated with a higher risk of CRE acquisition in infants aged <1 year.

Clinical pharmacy interventions in intensive care unit patients.

WHAT IS KNOWN AND OBJECTIVE: The drug therapy of critically ill patients requires intensive evaluation and management due to their severity of illness. These patients often require complex medication regimens. This study analysed the pharmaceutical care provided by clinical pharmacists (CPs) in a single medical centre in Taiwan. In addition, we explored the drug-related problems (DRPs) experienced by patients in intensive care units (ICUs) to determine how to improve the quality and safety of drug therapy. METHODS: This retrospective study was conducted from February 2019 to January 2020. The CPs implemented Taiwan's National Health Insurance (NHI) Scheme for Improving Hospital Drug Safety and Quality programme to improve the safety and quality of drug therapy. The CPs included in the study had at least 2 years' clinical experience and had participated in an ICU team for at least 6 consecutive months. They provided individualized drug treatment evaluation and intervention. Content of care was documented in the Clinical Pharmacy Service Record. RESULTS AND DISCUSSION: A total of 4374 pharmacy care records were evaluated by 12 CPs. The major category of ICU pharmaceutical care was medication reconciliation (n = 2938; 67.2%). Most of the medication interventions were for errors in dosing or dosing frequency (n = 218; 55.8%). Patients with renal dysfunction required more pharmaceutical interventions than did patients with normal renal function (odds ratio = 1.63; 95% confidence interval 1.31-2.01). The main interventions were related to antimicrobial agents (n = 386; 81.3%). During the study period, 99.2% of interventions were accepted and 90.8% were changed within 24 hours. WHAT IS NEW AND CONCLUSION: Increased pharmaceutical interventions for patients with renal dysfunction compared with patients with normal renal function were observed. Most cases of inappropriate frequency of dosing or dosing of antimicrobial agents required intervention.

Association of prior fluoroquinolone treatment with survival outcomes of immune checkpoint inhibitors in Asia.

WHAT IS KNOWN AND OBJECTIVE: Gut microbiota plays an important role in shaping immune responses. Several studies have reported that antibiotics may alter gut microbiota diversity and compromise the therapeutic response to immune checkpoint inhibitors (ICIs). Nevertheless, the impact of a specific class of antibiotics on ICIs therapy is still not known. The aim of this study was to analyse the influence of antibiotics on the clinical outcomes of non-small cell lung cancer (NSCLC) patients treated with ICIs and to compare the effects of fluoroquinolones vs. other broad-spectrum antibiotics. METHODS: This retrospective cohort study (n = 340) analysed data from Chang Gung Research Database, which comprises work from seven medical institutions in Taiwan. Patients with NSCLC who received ICIs between January 2016 and March 2019 were evaluated. The data of patients who received antibiotics (ie fluoroquinolone) within 30 days prior to ICIs therapy were analysed. Overall survival (OS) was the goal of our study and was calculated from the time the ICIs therapy start. Survival analysis was estimated using the Kaplan-Meier and Cox statistics. RESULTS: A total of 340 patients were identified for analysis. Of the 340 patients, only over one third (38%) of patients received antibiotics 30 days prior to ICI therapy. These patients exhibited a shorter OS compared with those not receiving antibiotics (median OS, 266 days vs. 455 days; hazard ratio (HR), 2.9; 95% confidence interval (CI), 1.1-8.1, p = 0.003). In this study, 127 out of 128 patients who were exposed to antibiotics had received at least one broad-spectrum antibiotic. We observed patients who had received fluoroquinolone had a shorter OS compared with those receiving other broad-spectrum antibiotics (median OS, 121 days vs. 370 days; HR, 1.582; 95% CI 1.007-2.841; p = 0.047). WHAT IS NEW AND CONCLUSION: Antibiotic treatment, especially fluoroquinolone, prior to ICIs therapy was associated with poorer clinical efficacy in NSCLC patients. Antibiotics should not be withheld when there is a clear need for them despite the possibility of interfering with the microbiome, which may, in turn, adversely affect the ICI's effectiveness. However, one should consider avoiding the use of fluoroquinolones antibiotics.

Use of ICD-10-CM T codes in hospital claims data to identify adverse drug events in Taiwan.

WHAT IS KNOWN AND OBJECTIVE: Adverse drug events (ADEs) are a major public health concern worldwide and may prolong hospital stays, causing a burden on the healthcare system and increasing the associated costs. Therefore, optimizing medication use and reducing ADEs are priorities for public health. Medication safety can be monitored and improved by identifying ADEs. The utilization of diagnoses coded according to the International Statistical Classification of Diseases and Related Health Problems (ICD) system for the identification of ADEs has been firmly established. In Taiwan, however, the validity of recording ADEs on the basis of inpatient ICD-10-CM T codes has not been evaluated. Therefore, this study investigated the potential usefulness of ICD-10-CM T codes in routine hospital data for the identification of ADEs and for increasing the rate of reporting. METHODS: We use hospital claims data of hospitalized patients from one medical centre in northern Taiwan between 1 July 2016 and 30 June 2018. We defined an ADE to have taken place if an ICD-10-CM T code was present among the primary or secondary diagnosis codes. The inpatients who were discharged with T codes in a primary or secondary diagnosis were identified by the computerized T code information platform, and the retrospective review of the medical charts was performed by pharmacists to confirm the ADEs. RESULTS AND DISCUSSION: 1384 inpatients who were discharged with the relevant T codes in a primary or secondary diagnosis were identified during the study period. Code T36 (poisoning by, adverse effect of or underdosing of systemic antibiotics) was the most common code, accounting for 56.6%, followed by T42 (17.7%; poisoning by, adverse effect of or underdosing of antiepileptic, sedative-hypnotic or antiparkinsonism drug). Overall, 789 clinically significant ADEs were identified after medical chart review. The dermatologic system was the most commonly involved. The overall positive predictive value for a flagged code representing an ADE was 57%. Furthermore, the use of T codes to confirm the number of ADE cases increased the ADE reporting rate by 9.17%. WHAT IS NEW AND CONCLUSION: The PPV of ICD-10-CM T codes analysed in our study was insufficient for identifying ADEs during hospitalization. The sensitivity and specificity of this were inadequate. However, the T code system can be used as an auxiliary resource for pharmacists to identify potential ADEs and report the information as prompts on the physician order entry system. When a physician prescribes a drug that may cause an ADE in a patient, an alert is issued to ensure medication safety. In conclusion, the T codes did not perform well in our study and caution should be exercised in their use to identify ADEs on their own.

The efficacy and safety of elbasvir/grazoprevir treatment in HCV genotype 1 patients in Taiwan.

BACKGROUND: Elbasvir/grazoprevir (EBR/GZR) is a new generation, fixed-dose, combination antiviral drug used in chronic hepatitis C virus (HCV) genotype (GT) 1 or 4 infection. Our study evaluates the clinical efficacy and safety of EBR/GZR after its launch in Taiwan. METHODS: This is a retrospective observational study. Patients who had received EBR/GZR for chronic HCV GT 1 between June 2017 and April 2018 were recruited. Patients' age, sex, HCV GT, changes in HCV RNA level before and after treatment, sustained virologic response 12 weeks (SVR12) after the cessation of drug administration, side effects, and interaction effects were used to evaluate the clinical efficacy and safety. RESULTS: A total of 149 patients were recruited. Of them, 145 (97.3%) had HCV GT 1b, and the rest had HCV GT 1a; most of the EBR/GZR-related side effects in this study were mild. Three participants were discontinued because their alanine transaminase levels were elevated to over 10 times the upper limit of normal. The therapeutic effect analyses revealed a rapid virologic response rate of 95.3% and an SVR12 rate of 98%. Subgroup analyses performed using SVR12 as the outcome variable revealed three demographic factors HCV GT 1, hepatocellular carcinoma medical history, and noncirrhosis plus HCV RNA level. CONCLUSIONS: This study confirmed that EBR/GZR is safe and effective for treating patients with HCV GT 1 and exhibited excellent overall clinical efficacy in Taiwan. The therapeutic effects are unrelated to factors such as sex, HCV RNA level before treatment, and history of liver cirrhosis.

Coadministration of Erythromycin to Increase Tacrolimus Concentrations in Liver Transplant Recipients.

BACKGROUND: We evaluated the effects of using erythromycin (ERY) in liver transplant recipients to improve the early postoperative control of tacrolimus (TAC) concentration. METHODS: This study adopts a retrospective medical record analysis method from January 2015 to December 2017. Assessment items include TAC daily dose (D), TAC whole blood trough level (Co), rejection episodes, and adverse effects. The magnitude of ERY inhibition on TAC metabolism was decided by analyzing dose-corrected trough concentration (Co/D). Oral 250 mg ERY every day to every other day was prescribed when patients needed to swallow more than 10 capsules of TAC per day, TAC trough levels rose too slowly, and/or acute rejection occurred. TAC trough levels were obtained daily. ERY was stopped when the TAC trough level was above 10 ng/mL or rejection episode relieved. RESULTS: A total of 8 liver transplant recipients was collected. Oral ERY was administered at 6 to 13 days after transplantation. The duration of ERY regimen was 2 to 7 days. The average initial and maximum Co/D was 0.6 ± 0.0 and 1.8 ± 1.0. After ERY was deleted, Co/D was back to the value without ERY at about 2 to 20 days. The magnitude of interaction between tacrolimus and erythromycin is 1.4- to 4.6-fold. The highest dose of TAC was 10 to 12 mg/d. There were no drug-related complications during this period. Acute rejection relapsed in 1 patient after we stopped ERY. CONCLUSION: Coadministration of ERY and TAC is a strategic choice for liver transplant recipients whose TAC blood concentration was difficult in approaching therapeutic levels.

Risk factors and outcomes of Clostridium difficile infection in hospitalized patients.

BACKGROUND: The aim of this study was to identify risk factors for Clostridium difficile infection (CDI) and its attributable mortality and to propose methods to prevent CDI and improve patients' outcomes. METHODS: CDI was defined as diarrheal patients with stool samples that were positive for C. difficile toxin. Clinical presentations of all patients with CDI and two times as many age- and sex-matched culture-negative controls at the Chang Gung Memorial Hospital in 2014 were identified and compared by multivariate, nonparametric, and Kaplan-Meier survival analysis. RESULTS: There were no significant differences in ages, sex, or Charlson comorbidity indexes between the CDI group (n = 42) and the control group (n = 86). The multivariate analysis indicated that underlying peptic ulcer disease and previous use of gastric acid inhibitors or third-generation cephalosporins for at least 3 days were significantly more common in patients with CDI than in the controls. Charlson scores were associated with mortality due to CDI. Recommended treatment using oral vancomycin to treat patients with Charlson score ≥ 5 and oral metronidazole or vancomycin to treat those with moderate underlying disease (Charlson score ≥ 2 and ≤ 5) significantly increased survival in these patients (p = 0.001). CONCLUSIONS: Oral vancomycin given to patients with high Charlson scores and oral metronidazole or vancomycin to patients with moderate Charlson scores decreased mortality due to CDI. Restricting the use of third-generation cephalosporins and gastric acid inhibitors is recommended to prevent CDI in hospitalized patients.