Comparing the Dosing Period in Package Inserts of Antimicrobial Agents Between Japan and the United States.

Introduction: The duration of antimicrobial therapy is a critical evaluation index of antimicrobial stewardship (AS). The inclusion of the dosing period on package inserts provides a strong reason for clinical intervention by pharmacists in cases where physicians prescribe inappropriate dosing periods. This study investigated differences in the description of dosing periods in antimicrobial package inserts between Japan and the U.S. Methods: We conducted a survey comparing differences in the dosing period of oral and injectable antimicrobials approved and marketed in Japan and the U.S. as of May 1, 2021. The Fisher exact test was used to compare the presence or absence of a description of the dosing period on the package insert between these two countries. Results: We evaluated 69 antimicrobial agents, of which 34 were oral; and 35 were injectable agents. In Japan, 20 (29.0%) of the antimicrobials had package inserts stating the dosing periods, compared with 58 (84.1%) in the U.S. (p < 0.001). Conclusions: It was found that the information on the duration of administration was missing from the package insert in Japan compared to the U.S. Lack of information on the duration of administration may lead to long-term administration by the treating physician and also make it difficult for the pharmacist to inquire about the administration. It is expected that the inclusion of scientifically-based dosing periods in all package inserts will promote AS among physicians and pharmacists who are not specialists in infectious disease therapy.

Prevalence of therapeutic drug monitoring and adherence to imatinib in chronic myeloid leukemia in Japan.

OBJECTIVE: The effectiveness of imatinib, a tyrosine kinase inhibitor recommended for the treatment of chronic myeloid leukemia, is associated with high adherence and trough plasma imatinib concentrations of ~ 1,000 ng/mL. However, adherence and therapeutic drug monitoring (TDM) for imatinib have hardly been reported. This study evaluated the prevalence of TDM and adherence to imatinib for chronic myeloid leukemia in Japan. MATERIALS AND METHODS: Monthly insurance claims data for ~ 5.6 million individuals aged 20 - 74 years between June 1, 2005 and December 31, 2017 were studied. Patients with at least one prescription for imatinib were included to calculate adherence and the annual mean prevalence of TDM for imatinib. RESULTS: A total of 498 patients with 9,620 prescriptions of imatinib were included. After 2013, the number of imatinib prescriptions and the number of patients treated with imatinib were over 1,000 and 200, respectively. The mean annual prevalence of TDM for imatinib was 12.2% (95% confidence interval (CI), 8.1 - 16.1%). Antihyperuricemic drugs and steroids increased the likelihood of TDM. The medication possession ratio for assessment of adherence was 93.5% (95% CI: 91.8 - 95.5%). The annual mean prevalence of TDM for imatinib was low, although adherence was high. CONCLUSION: To encourage the measurement of plasma concentrations of imatinib in clinical settings, adding a package insert, a summary of product characteristics, and a patient information leaflet regarding the implementation of TDM is justified and warrants further attention.

Population Pharmacokinetic Analysis and Dosing Optimization of Prophylactic Fluconazole in Japanese Patients with Hematological Malignancy.

We conducted population pharmacokinetic (PPK) analysis and Monte Carlo simulations to determine the appropriate prophylactic dose of fluconazole to prevent invasive candidiasis in patients with hematological malignancies. Patients receiving chemotherapy or hematopoietic stem cell transplantation at Yokohama City University Hospital between November 2018 and March 2020 were included. Additionally, patients receiving oral fluconazole for prophylaxis were recruited. We set the free area under the curve/minimum inhibitory concentration (MIC) = 50 as the target and determined the largest MIC (breakpoint MIC) that could achieve more than 90% probability of target attainment. The blood fluconazole concentration of 54 patients (119 points) was used for PPK analysis. The optimal model was the one-compartment model with first-order administration and first-order elimination incorporating creatinine clearance (CLcr) as a covariate of clearance and body weight as a covariate of distribution volume. We conducted Monte Carlo simulation with fluconazole at 200 mg/day or 400 mg/day dosing schedules and patient body weight and CLcr ranging from 40 to 70 kg and 40-140 mL/min, respectively. The breakpoint MICs on the first dosing day and at steady state were 0.5-1.0 µg/mL and 1.0-2.0 µg/mL for 200 mg/day and 1.0-2.0 µg/mL and 2.0-4.0 µg/mL for 400 mg/day, respectively. The recommended dose was 400-700 mg/day for the loading dose and 200-400 mg/day for the maintenance dose. Our findings suggest that the optimal prophylactic dose of fluconazole in hematological malignancy patients depends on CLcr and body weight, and a sufficient loading and maintenance dose may be needed to completely prevent invasive candidiasis.

Species Distribution of Candidemia and Their Susceptibility in a Single Japanese University Hospital: Prior Micafungin Use Affects the Appearance of Candida parapsilosis and Elevation of Micafungin MICs in Non-parapsilosis Candida Species.

INTRODUCTION: Micafungin is a recommended echinocandin antifungal agent for candidemia treatment and prophylaxis. However, overuse of echinocandin antifungals may cause resistance. There is currently no information available regarding the low susceptibility associated with using micafungin. This study investigated the effect of micafungin use on changes in the detected Candida species and low susceptibility. METHODS: We conducted a retrospective survey and included records of Candida spp. detected in blood cultures from January 2010 to December 2018 in our hospital. Survey items included clinical outcomes at 30 days after positive cultures, patient characteristics, and drug prescription status. Patient background information included gender, previous hospitalization, stay in the intensive care unit, comorbidities, and history of surgery (within 90 days before candidemia onset) and drug exposure. Species detected and their minimum inhibitory concentrations (MICs) and amount of antifungal prescriptions by department were investigated. Risk factors for detecting C. parapsilosis and for low susceptibility to micafungin were evaluated using multivariate analysis. RESULTS: A total of 153 Candida clinical blood isolates were collected and C. albicans was the most prevalent species, followed by C. parapsilosis and C. glabrata. In the analysis by department, antifungal use and non-albicans Candida species were most frequently detected in the hematology department. Multivariate analysis showed that prior micafungin use increased the risk of C. parapsilosis (odds ratio (OR) 4.22; 95% confidence interval (CI) 1.39-12.79; p = 0.011). MIC90 of micafungin on C. glabrata and C. parapsilosis was 1.0 µg/mL. Prior micafungin use was clarified as a risk factor resulting in MIC > 0.06 µg/mL for micafungin in non-parapsilosis Candida species (OR 13.2; 95% CI 3.23-54.2; p < 0.01). CONCLUSION: Prior micafungin use increased the risk of C. parapsilosis and the MIC > 0.06 µg/mL of micafungin in non-parapsilosis Candida species. Since there are only a few antifungal options, further antifungal stewardship considering azole antifungal agents use is required.