Effectiveness and safety of the simulation-based first-dose design of voriconazole.

BACKGROUND: We investigated whether the initial voriconazole (VRCZ) dosing design, as determined using simulation software with a population pharmacokinetic model of Japanese patients, impacts the effectiveness and safety when compared with VRCZ initiation according to the package insert. METHODS: In this single-center retrospective observational study, we employed records from Tosei General Hospital (a 633-bed hospital), dated April 2017 to September 2023. Eligible patients were divided into the software-based simulation group, comprising patients administered initial VRCZ dosage adjustment by pharmacists using software-based simulation, and the standard therapy group, whose dosage was administered by a physician following the package insert recommendations without simulation. The primary objective of this study was to determine the efficacy of VRCZ first-dose design in reducing the incidence of hepatotoxicity and visual symptoms. RESULTS: The median ages of enrolled participants (n = 93) were 75 (68-79) and 72 (65-78) years in the software-based simulation and standard therapy groups, respectively. Regardless of formulation, initial trough concentrations were lower in the VRCZ software-based first dosage adjustment group and higher rate within the appropriate range (1-4 µg/mL). The incidence of all-grade hepatotoxicity or visual symptoms was significantly lower in the software-based simulation group. The log-rank test revealed a significant impact on the occurrence of ≥grade 2 hepatotoxicity in the software-based first dosage adjustment group compared to that in the standard therapy group. CONCLUSIONS: The initial VRCZ dosing design using simulation software improved the achievement of appropriate initial trough concentrations and resulted in fewer occurrences of hepatotoxicity (≥grade 2) when compared with the standard therapy.

Real-World Experience of the Comparative Effectiveness and Safety of Molnupiravir and Nirmatrelvir/Ritonavir in High-Risk Patients with COVID-19 in a Community Setting.

Molnupiravir (MOV) and nirmatrelvir/ritonavir (NMV/r) are efficacious oral antiviral agents for patients with the 2019 coronavirus (COVID-19). However, little is known about their effectiveness in older adults and those at high risk of disease progression. This retrospective single-center observational study assessed and compared the outcomes of COVID-19 treated with MOV and NMV/r in a real-world community setting. We included patients with confirmed COVID-19 combined with one or more risk factors for disease progression from June to October 2022. Of 283 patients, 79.9% received MOV and 20.1% NMV/r. The mean patient age was 71.7 years, 56.5% were men, and 71.7% had received ≥3 doses of vaccine. COVID-19-related hospitalization (2.8% and 3.5%, respectively; p = 0.978) or death (0.4% and 3.5%, respectively; p = 0.104) did not differ significantly between the MOV and NMV/r groups. The incidence of adverse events was 2.7% and 5.3%, and the incidence of treatment discontinuation was 2.7% and 5.3% in the MOV and NMV/r groups, respectively. The real-world effectiveness of MOV and NMV/r was similar among older adults and those at high risk of disease progression. The incidence of hospitalization or death was low.

A Long-Term Study of the Reduction in Drug-Related Incident Reports and the Impact on Patients by Pharmacist Intervention in the Emergency Department.

In Japan, pharmacists have begun working in emergency departments (ED) over the last decade. However, no reports exist on the contribution of pharmacists' activities in the ED to patient safety. We investigated whether pharmacists' long-term duties influence the number of incident reports in the ED. Of the 862 incidents reported, 152 (17.6%) were drug-related reports. Further investigations revealed that 42 cases occurred during pharmacists' usual working hours, four cases (9.5%) occurred when a pharmacist was present in the ED, and 38 cases (90.5%) occurred in the absence of a pharmacist in the ED. The number of incident reports was significantly reduced by pharmacists optimizing pharmacotherapy in the ED (p=0.002). There was a decrease in the degree of impact on patients through pharmacist duties compared to pharmacist absence (intercepting errors prior to patient administration: 4.8 vs. 31%; medication misadministration: 4.8 vs. 59.4%). Medical staff-associated factors and time of patient arrival at the ED did not have a significant impact on incident reports for any time. Long-term pharmacist duties in the ED can reduce the number of incident reports and contribute to safe medication care in the ED.

Safety Evaluation of Remdesivir for COVID-19 Patients with eGFR < 30 mL/min without Renal Replacement Therapy in a Japanese Single-Center Study

There are limited reports on the safety of remdesivir for patients with severe kidney disease. We investigated the safety of remdesivir administration for COVID-19 patients with estimated glomerular filtration rate (eGFR) <30 mL/min. This single-center retrospective study was conducted between March 2020 and April 2022 at Tosei General Hospital, Japan. Propensity score matching was performed between patients with eGFR ≤ 30 mL/min and eGFR >30 mL/min with remdesivir administration. The primary outcome was 30-day mortality after the first administration. Adverse events, including development of acute kidney injury (AKI), liver function disorder, anemia, and thrombocytopenia 48 h after the end of remdesivir administration, were evaluated. After propensity score matching, 23 patients were selected from each group. There were no differences in the 30-day mortality (risk ratio [RR] 1.00; 95% confidence interval [CI] 0.18−5.56). Development of AKI and liver function disorder was not statistically different between the two groups (RR 1.05; 95% CI 0.96−1.14 and RR 0.48; 95% CI 0.04−5.66, respectively). There was no trend toward a significant increase in adverse events in the eGFR < 30 mL/min group and severe renal dysfunction had little effect on the safety of remdesivir treatment.

Influence of Change of Full-Time Equivalents on Post-prescription Review with Feedback Interventions in an Antimicrobial Stewardship.

Few studies have investigated the influence of more full-time equivalents (FTEs) of infectious disease (ID) pharmacists on the likelihood of a post-prescription review with feedback (PPRF) intervention. This study focused on this in community hospitals before and after the Japanese medical reimbursement system was revised to introduce antimicrobial stewardship (AS) fees. We collected data for two periods: before (April 2017 to March 2018) and after (April 2018 to March 2019) AS fee implementation. The efficacy of the PPRF by the ID pharmacist was assessed based on the usage of broad-spectrum antimicrobials in days of therapy (DOT) per 100 patient-days. Further, we generated the susceptibility rate for antimicrobial-resistant organisms. The number of PPRF drugs was 2336 (2596 cases) before AS fee implementation and 2136 (1912 cases) after implementation. The overall monthly FTE for AS for an ID pharmacist increased from [median (interquartile range; IQR)] 0.34 (0.33-0.36) to 0.63 (0.61-0.63) after AS fee implementation. The DOT of the broad-spectrum antibiotics decreased from 10.46 (9.61-12.48) to 8.68 (8.14-9.18). The DOT of carbapenems and quinolones decreased significantly from 4.11 (3.69-4.41) to 3.07 (2.79-3.22) and 0.96 (0.61-1.14) to 0.37 (0.19-0.46), respectively (p < 0.05). Furthermore, the rate of levofloxacin (LVFX)-susceptible Pseudomonas (P.) aeruginosa improved from 71.5 to 84.8% (p < 0.01). We observed that increasing the FTE of ID pharmacists influences the DOTs of broad-spectrum antibiotics; a higher FTE contributes to fewer DOTs. Further, the susceptibility of P. aeruginosa to meropenem and LVFX increased as the FTE increased.

Effectiveness of monoclonal antibody therapy for COVID-19 patients using a risk scoring system.

INTRODUCTION: Monoclonal antibody therapy has been reported to be highly effective for preventing hospitalisation and severe cases in patients with Coronavirus Disease 2019 (COVID-19). However, since the drug is not readily available, it is important to rapidly and appropriately identify high-risk patients who can benefit most from therapy. Therefore, we designed a risk scoring system to identify at-risk COVID-19 patients in our region during the largest surge of COVID-19, from July to September 2021. METHODS: According to the risk scores, confirmed COVID-19 patients were introduced to receive REGN-CoV-2 to our hospital by regional health centre from 18th August (Term 3). The primary outcome was the comparison of the number of hospitalisation and severe condition with other periods, the 4th wave (Term 1) and the early part of the 5th wave (Term 2) in Japan. RESULTS: During Term 3, 115 patients were stratified with the scoring system and administered REGN-COV-2. The number of hospitalisation vs severe cases were 60 (5.2%) vs 14 (1.2%), 8 (1.5%) vs 3 (0.6%) and 21 (1.2%) vs 2 (0.1%), in term 1, 2 and 3, respectively. Among those aged <60 years, compared with term 1, the relative risk of hospitalisation and severe condition were 0.25 (95% CI: 0.12-0.53) and 0.10 (95% CI: 0.01-0.80), respectively, in term 3. Drug adverse events were fever (3: 2.6%), headache (1: 0.9%) and neck rash (1: 0.9%), all events were resolved within 24 h wth no serious adverse event. CONCLUSIONS: The administration of monoclonal antibody therapy using a risk scoring system significantly reduced the number of hospitalisation and disease severity of COVID-19 without any serious adverse events and avoided regional medical collapse.

Severe Measles Encephalitis and Acute Disseminated Encephalomyelitis in an Immunocompetent Japanese Young Male.

Measles encephalitis rarely affects young adults and has no established treatment strategy. This brief report described the rare case of an immunocompetent 30-year-old man with severe measles pneumonia and encephalitis, following the autoimmune disease acute disseminated encephalomyelitis, during a large measles outbreak in 2018 in Japan. With multidisciplinary treatments, including corticosteroids, intravenous immunoglobulins, vitamin A, and therapeutic plasma exchange, the patient was successfully treated. This case provides a new strategy for treating measles encephalitis and its complications during measles outbreak.

Efficacy of baloxavir marboxil on household transmission of influenza infection.

BACKGROUND: Baloxavir marboxil (baloxavir) is a new anti-influenza virus agent that is comparable to oseltamivir phosphate (oseltamivir). Since the efficacy of baloxavir in preventing household transmission of influenza is not well established, we compared the secondary household influenza virus transmission rates between patients on baloxavir vs oseltamivir. METHODS: Between October 2018 and March 2019, we enrolled index patients (diagnosed with influenza and treated with baloxavir or oseltamivir) and household members. The secondary attack rate of household members was compared between index patients treated with baloxavir vs oseltamivir. Risk factors of household transmission were determined using multivariate logistic analyses. RESULTS: In total, 169 index patients with influenza type A were enrolled. The median age was 27.0 (interquartile range; 11-57) years. The number of index patients treated with baloxavir and oseltamivir was 49 and 120, respectively. The secondary attack rate was 9.0% (95% confidence interval [CI]: 4.6-15.6) in the baloxavir group and 13.5% (95% CI: 9.8-17.9) in the oseltamivir group. In the multivariate analysis, independent risk factors were 0-6 years of age (odds ratio [OR] 2.78, 95% CI: 1.33-5.82, p < 0.01) and not being on baloxavir treatment. (OR: 0.63, 95% CI: 0.30-1.32, p = 0.22). CONCLUSION: The household secondary attack rate of influenza was comparable in patients treated with baloxavir vs oseltamivir. Therefore, baloxavir can be used as an alternative therapy to oseltamivir in reducing household transmission of influenza. TRIAL REGISTRATION: Patients in this study were retrospectively registered. https://www.tosei.or.jp/clinical/pdf/2_influenza.pdf.

[The Effect of Increased Free Concentrations of Warfarin Due to Protein-binding Substitution in a Combination of Tolvaptan on the PT-INR].

We previously reported that tolvaptan may influence warfarin pharmacodynamics in vivo; however, the mechanism responsible for this influence was not clear. In this study, we investigated the drug-drug interactions between warfarin and tolvaptan by measuring warfarin blood concentrations in 18 patients who received warfarin therapy and in 24 who received warfarin+tolvaptan therapy. The free warfarin concentrations significantly increased in patients who were also receiving oral tolvaptan (p=0.04). In vitro albumin-binding experiments showed that the free warfarin concentrations significantly increased with the addition of tolvaptan, in a dose-dependent manner, through albumin-binding substitution (approximately 2.5 times). Both clinical and in vitro data showed that tolvaptan increased the unbound warfarin serum concentration. The prothrombin time-international normalized ratio (PT-INR) tended to increase within 2 weeks when tolvaptan was added at clinically used doses (p=0.14). Special attention is warranted in cases with a serum tolvaptan concentration of ≥125 ng/mL (≥7.5 mg/d) for at least 2 weeks following oral tolvaptan administration.

Two Cases of Dengue Virus Type 2 (DENV-2) Infection in a Japanese Couple Returning from the Maldives during the 2018 Dengue Outbreak.

Annually, more than 1.2 million travelers from other countries visit the Maldives for sightseeing, business, and honeymoon. In 2018, the largest dengue fever outbreak occurred, affecting more than 3,200 people. During this outbreak, we encountered a newly married Japanese couple returning from the Maldives on their honeymoon in October 2018, both were infected by the dengue virus type 2 during the travel. The number of imported dengue fever cases from the Maldives may increase; hence, physicians should stay up to date on dengue outbreak information worldwide.

Efficacy of prolonged tapered and pulsed vancomycin regimen on recurrent Clostridioides difficile infection in the Japanese setting: a case control study.

BACKGROUND: According to the Clinical Practice Guidelines for Clostridioides difficile, oral vancomycin is to be used in vancomycin tapered and pulsed regimen (VCM-TP) for recurrent Clostridium difficile infection (CDI). However, data on the efficacy of VCM-TP in Japanese patients with recurrent CDI are scarce. To address this gap, we investigated the efficacy of VCM-TP and performed a case-controlled study to assess the risk factors associated with treatment failure in these patients. FINDINGS: We conducted this study on all patients who were administered VCM-TP for recurrent episodes of CDI between January 2008 and December 2018 at Tosei General Hospital. All patients had documented follow-ups within 90 days after completion of the VCM-TP. Data were obtained for comparative analysis of treatment success or failure. Thirty-six patients were eligible for this study, and treatment success was documented in 23 patients (63.9%) following VCM-TP treatment. Treatment success was documented in 22 of 30 (73.3%) patients who received the recommended therapy according to the Clinical Practice Guidelines. The frequency of patients treated with the recommended therapy was higher in the treatment success group (95.7%) than in the treatment failure group (61.5%) (OR: 13.75, 95% CI: 1.39-136.39, p = 0.016). Vancomycin-resistant enterococci culture tests were performed in 20 patients (55.6%), and all results were negative. CONCLUSIONS: Our findings suggest that VCM-TP is a good therapeutic option for recurrent CDI in Japanese patients. Furthermore, administration of the recommended VCM-TP is important for achieving a high rate of treatment success. Hence, antimicrobial stewardship teams should support the implementation of recommended VCM-TPs.

The first case of third-generation cephalosporins resistant Kluyvera ascorbata biliary tract infection in Japan: A case report and review of the literature.

INTRODUCTION: Kluyvera ascorbata is a gram-negative, catalase-positive, oxidase-negative, aerobic fermentative bacterium with flagella. This organism colonizes in the human body and its pathogenicity is extremely low; few clinical cases of K. ascorbata infection have been reported. PRESENTATION OF CASE: We report on a patient who experienced severe sepsis and acute cholangitis due to K. ascorbata bacteremia and was treated with levofloxacin following antibiotic susceptibility testing. To our knowledge, this is the first case report of third-generation cephalosporins resistant K. ascorbata infection in Japan. DISCUSSION: Although this pathogen produces innate CTX-M type ß-lactamases and is generally resistant to first- and second-generation penicillins and cephalosporins, multi-drug resistant K. ascorbata infection, including ceftriaxone resistant infection has seldom been reported. CONCLUSION: The increase of drug-resistant pathogens is of concern; in such cases, rapid microbial identification and appropriate antibiotic selection are crucial for successful treatment.

[Treatment Strategy for Acute Type B Aortic Dissection with End-organ Malperfusion].

Therapeutic strategies for treating Stanford type B dissection with endo-organ malperfusion remain controversial, and whether surgery or conservative treatment should be performed is a matter of ongoing debate. In this study, we examined the treatment strategies used in cases of malperfusion in which treatment was initiated conservatively at the onset of symptoms without superior mesenteric artery (SMA) or limb artery obstruction. A total of 16 patients had organ ischemia in this series. The obstructed branches were the SMA in 5 patients, the artery of Adamkiewicz in 2, the bilateral renal arteries in 3, the celiac artery in 3 and limb arteries in 3. The surgical procedure included bypass grafting in 2 patients with SMA obstruction and extra-anatomical bypass in 2 patients with limb artery obstruction. A total of 11 patients were treated without surgery. Three patients died, including 2 patients with SMA obstruction. The remaining patient who died had limb artery obstruction and did not undergo surgery. The results suggest that patients with acute type B aortic dissection with endo-organ malperfusion who develop SMA or limb artery obstruction require early surgery.

Effect of cardiopulmonary bypass on cancer prognosis.

Adverse effects of cardiopulmonary bypass on cancer prognosis are expected but have not been confirmed. Seventy-four cancer patients who underwent cardiac surgery before cancer therapy were followed up for 42 ± 37 months; 45 had cardiac surgery with cardiopulmonary bypass. There was no significant difference in cancer recurrence (40.0%) and deaths (26.7%) among patients who had cardiopulmonary bypass and those who underwent off-pump cardiac surgery (27.6% and 24.1%). There were no significant differences in freedom from cancer-related death at 2 and 5 years after cardiac surgery (78.4% and 68.5%) in the cardiopulmonary bypass group compared to the 29 off-pump group (81.8% and 58.3%). Despite some limitations, this study detected no significant adverse effects of cardiopulmonary bypass on cancer prognosis. Although these results do not verify the safety of cardiopulmonary bypass from an oncologic aspect, they suggest it can be applied in cancer patients who require cardiac surgery.

Clinical characteristics of bicuspid aortic valves in surgical patients.

Of 413 patients undergoing surgery for aortic valve disease, 42 were confirmed to have congenital bicuspid aortic valve. There were 24 males and 18 females, with a mean age of 54.9 +/- 14.6 years. The etiology of the surgical indications in patients with bicuspid valves were degeneration, rheumatic disease, and infectious endocarditis. Thirty-two patients had aortic stenosis and 10 had aortic regurgitation. Infective endocarditis was seen mainly in patients < or =50 years of age at the time of surgery, while degenerative aortic stenosis occurred more often in older patients. The annular diameter measured during surgery was significantly narrower in the 42 patients with bicuspid valves compared to 371 patients with tricuspid valves who underwent aortic valve replacement during the same period. It is important to prevent infectious endocarditis in younger patients diagnosed with bicuspid aortic valve, whereas careful attention should be paid to decalcification during surgery in older patients because the vast majority suffer from degenerative aortic stenosis.

[The efficacy of function water (electrolyzed strong acid solution) on open heart surgery; postoperative mediastinitis due to methicillin-resistant Staphylococcus aureus].

Methicillin-resistant Staphylococcus aureus (MRSA) infection after cardiac surgery has recently increased. We compared the anti-inflammatory effect of an electrolyzed strong acid solution and a warm saline solution in patients with open heart surgery. These solutions were used for mediastinal irrigation before closing the sternum. Group A patients were irrigated by a warm saline solution, and group B patients were irrigated by an electrolyzed strong acid solution, administration of this water is safe, feasible, and easy for the prevention of MRSA infection. Postoperative infection was significantly decreased in the group B as compared in the group A. An electrolyzed strong acid solution may be effective on postoperative infection, particularly MRSA infection following open heart surgery.