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.

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.

Mortality and risk factor analysis for Candida blood stream infection: A multicenter study.

Candida blood stream infection (candidemia) is severe systemic infection mainly develops after intensive medical cares. The mortality of candidemia is affected by the underlying conditions, causative agents and the initial management. We retrospectively analyzed mortality-related risk factors in cases of candidemia between April 2011 and March 2016 in five regional hospitals in Japan. We conducted bivariate and multivariate analysis of factors including causative Candida species, patients' predisposing conditions, and treatment strategies, such as empirically selected antifungal drug and time to appropriate antifungal treatment, to elucidate their effects on 30-day mortality. The study enrolled 289 cases of candidemia in adults. Overall 30-day mortality was 27.7%. Forty-nine cases (17.0%) were community-acquired. Bivariate analysis found advanced age, high Sequential Organ Failure Assessment (SOFA) score, and prior antibiotics use as risk factors for high mortality; however community-acquired candidemia, C. parapsilosis candidemia, obtaining follow-up blood culture, and empiric treatment with fluconazole were associated with low mortality. Logistic regression revealed age ≥65 years (adjusted odds ratio, 2.13) and sequential organ failure assessment (SOFA) score ≥6 (6.30) as risk factors for 30-day mortality. In contrast, obtaining follow-up blood culture (0.38) and empiric treatment with fluconazole (0.32) were found to be protective factors. The cases with candidemia in associated with advanced age and poor general health conditions should be closely monitored. Obtaining follow-up blood culture contributed to an improved prognosis.

Prevalence of, and risk factors for, hematogenous fungal endophthalmitis in patients with Candida bloodstream infection.

PURPOSE: Endogenous fungal endophthalmitis (EFE) is a severe consequence of candidemia. The prevalence of, and risk factors for, EFE is not well studied. METHODS: We retrospectively collected cases of patients with candidemia who had undergone ophthalmological examination between April 2011 and March 2016 in five regional hospitals. We conducted bivariate and multivariate analyses using patients' age, gender, causative Candida species, diabetes status, corticosteroid use, cancer status, neutropenia, intensive care unit admission, presence of central venous catheter (CVC), presence of shock, prior antibiotic use, 30-day mortality, and highest Sequential Organ Failure Assessment (SOFA) score. Data on sustained positive blood culture, ß-D glucan, CVC removal, empirical antifungal drug used, and time to appropriate antifungal therapy were also collected if available. RESULTS: Of 174 patients with candidemia, 35 (20.1%) were diagnosed with EFE, including 31 (17.8%) with chorioretinitis and 4 (2.3%) with vitritis. Bivariate analysis (EFE group vs. non-EFE group) found that Candida albicans candidemia (77.1 vs. 34.5%, P < 0.001), neutropenia (14.3 vs. 5.8%, P = 0.141), CVC placement (94.3 vs. 71.2%, P = 0.004), and the presence of shock (28.6 vs. 16.5%, P = 0.145) were each higher in the EFE group. Multivariate logistic regression analysis found C. albicans candidemia (adjusted odds ratio 6.48; [95% CI 2.63-15.95]) and CVC placement (7.55 [1.56-36.53]) to be significant risk factors for EFE. CONCLUSIONS: Candida albicans is the most common causative agent for Candida EFE. Patients with candidemia and CVC placement should be closely monitored by ophthalmologists.

Polymerase chain reaction-based open reading frame typing (POT) method analysis for a methicillin-resistant Staphylococcus aureus (MRSA) outbreak through breast-feeding in the neonatal intensive care unit.

INTRODUCTION: The route of methicillin-resistant Staphylococcus aureus (MRSA) transmission in the neonatal intensive care unit (NICU) is not clearly explained. We investigate an MRSA outbreak involving five babies in the NICU. The molecular investigation using polymerase chain reaction-based open reading frame typing (POT) method was performed. PRESENTATION OF OUTBREAK: A MRSA outbreak occurred in a six-bed NICU affecting 5 babies. Within 13 days of the emergence of index case, all five babies including triplets and other two babies were found to colonize MRSA by the active surveillance culture. Environmental surveillance cultures revealed that the preserved breast milk provided by the triplets' mother was the only item in the NICU that was positive for MRSA. The mother had a bite wound on the nipples, and the breast milk was not pasteurized. The POT method revealed that MRSA strains detected from the triplets, the breast milk, and the other baby who was fed the triplets' mother's milk were genetically identical (POT index: 106-247-33). The all strains of MRSA carried Staphylococcal cassette chromosome mec (SCCmec) IV and had good susceptibility for the non-ß-lactam antimicrobial agents, suggesting the strains were community-acquired MRSA. CONCLUSIONS: The mother's milk contaminated with community-origin MRSA is serving as the reservoir of MRSA and one of the sources of MRSA outbreaks in the NICU. It is important to closely monitor the condition of the mothers of the children in the NICU. Pasteurization of breast milk should be considered when the skin on the nipple is broken.