Mitsuhiro Okazaki

Patients views and experiences in online reporting adverse drug reactions: Findings of a national pilot study in Japan

Background Patients have been allowed to report adverse drug reactions (ADRs) directly to the government in some countries, which would contribute to pharmacovigilance. Objective We started a pilot study to determine whether web-based patient ADR reporting would work in Japan. This article aims to describe the characteristics of the patient reporters, and to clarify patient views and experiences of reporting. Methods Patients who submitted online ADR reports were contacted to respond to an ADR reporting questionnaire; only consenting reporters were included. Subjects with multiple responses were excluded from analysis. The questionnaire consisted of both closed and open questions. Questionnaire responses were examined using Pearson’s chi-squared test. Results A total of 220 web-based ADR reports were collected from January to December 2011; questionnaires were sent to 190 reporters, excluding those who gave multiple reports and those that refused to be contacted. Responses were obtained from 94 individuals (effective response rate: 49.5%). The median respondent age was 46.0 years. Sixty-three respondents found out about this pilot study on the Internet (67.0%). The numbers of respondents claiming that they had difficulty recalling the time/date of ADR occurrence were 16 patient reporters and three non-patient reporters. The number of reporters who found it difficult to complete the online reporting form was 22 patients (26.2%) and one non-patient (10%). Fifty-seven respondents (60.6%) expected feedback after reporting and many respondents wanted to know the process of ADR data collection and related information. Seventy-three respondents (77.7%) stated that they would report ADRs again in future. Conclusion Throughout the entire questionnaire, online patient ADR reporting was received with a forward-looking, positive approach. To facilitate smoother web-based reporting experiences in future, some improvements may be required in online ADR reporting forms, particularly with regard to respondent feedback.

Leukocyte activation by (1→3)-β-D glucans

We studied the activities of several kinds of β-glucans, including sonifilan, grifolan, Sclerotinia sclerotiorum glucan, laminarin and zymosan, on macrophages. Preculture of macrophages with inactive β-glucans rendered the cells unresponsive to subsequent stimulation with grifolan, suggesting a specific pathway in the β-glucan structure. The importance of protein C and phosphorylation of mitogen-activated protein kinase was demonstrated in the activation with grifolan or zymosan. Immunoprecipitation of complement receptor (CR3), coprecipitated other proteins carrying phosphotyrosine residues in stimulation with grifolan. These data suggest that protein kinase C and tyrosine kinases are essential for signal transduction, and that CR3 might participate in the activation through interaction with other intracellular proteins.

Phenotypic and genomic comparisons of highly vancomycin-resistant Staphylococcus aureus strains developed from multiple clinical MRSA strains by in vitro mutagenesis

The development of vancomycin (VCM) resistance in Staphylococcus aureus threatens global health. Studies of the VCM-resistance mechanism and alternative therapeutic strategies are urgently needed. We mutagenized S. aureus laboratory strains and methicillin-resistant S. aureus (MRSA) with ethyl methanesulfonate, and isolated mutants that exhibited high resistance to VCM (minimum inhibitory concentration = 32 μg/ml). These VCM-resistant strains were sensitive to linezolid and rifampicin, and partly to arbekacin and daptomycin. Beta-lactams had synergistic effects with VCM against these mutants. VCM-resistant strains exhibited a 2-fold increase in the cell wall thickness. Several genes were commonly mutated among the highly VCM-resistant mutants. These findings suggest that MRSA has a potential to develop high VCM resistance with cell wall thickening by the accumulation of mutations.

Temporal relationship between multiple drugs and multiple events in patient reports on adverse drug reactions: findings in a pilot study in Japan.

Patient reporting of suspected adverse drug reactions (ADRs) has been accepted as an essential component of pharmacovigilance.1,2 Important signals may be detected when combined with reports from health care professionals (HCPs)3 but also from “patient-only” dataset.4 In January 2011, the Health and Labour Sciences Research Grant study (“HLSRG study”) supported by the Ministry of Health, Labour andWelfare (MHLW) started a pilot study to determine whether the web-based patient reporting works in Japan. The online patient report form was linked from the main page of Pharmaceuticals and Medical Devices Agency (PMDA). To call for patient reports, a message was shown on the PMDAwebsite and in 955 (1.7%) of about 55000 community pharmacies, 1000 posters were displayed and 100000 flyers were handed to patients. The study was approved by the Research Ethics Committee of Faculty of Pharmacy, Keio University. In an interim analysis of the data collected during the first 2 months of the study, we found patients sometimes reported multiple drugs and multiple ADRs occurring at different occasions. It was often very difficult to specify the temporal relationship between the exposure to drugs and occurrence of ADRs. To improve the clarity of the temporal relationship, a revised form with multiple entry boxes for dates of ADR occurrence was used in the latter half of the study (see online Figure 1). At the end of the study, we conducted an ad hoc analysis to know whether the revised form worked as intended. The drugs were classified by the anatomical therapeutic chemical (ATC) classification. ADRs were coded by Japanese translation of lowest level terms of the medical dictionary for regulatory activities (MedDRA) version 14.0J and converted to preferred terms (PTs) by two of authors (AH and KK) and then further checked independently by each of two psychiatric specialists (AI and TK) because many of reported ADRs were classified under the primary systemic organ class (SOC) “nervous” or “psychiatry”. The temporal relationship was classified into “clear” (clear for all drug–event combinations), “clear/unclear” (clear for some but unclear for the other combinations) and “unclear” (unclear for all combinations) also by these two specialists. Any discrepancy between two specialists was resolved by discussion. We also analyzed the spontaneous reports submitted by HCPs directly or through the drug company to the PMDA (“HCP reports”) and reports submitted by the “consumer or other non-health professional” through the drug company (“indirect patient reports”) during the same period using Japanese Adverse Drug Event Report database (http://www.info.pmda.go.jp/) and compared with “direct patient reports” in the HLSRG study. Table 1 shows standardized differences5 for demographic and other characteristics between a total of 214 direct patient reports with at least one identifiable drug and one identifiable ADR and 657 indirect patient reports as well as 34843 HCP reports submitted to the PMDA between January and December 2011. In direct patient reports, median age of patients was 40 years old and much younger than “60’s” in other two report types. There was a difference of ADRs and drugs frequently reported between three reporter types. The 214 reports were submitted by 166 (78%) patients and 48 (22%) family members, and 16 (7%) reports had one or more over-the-counter drugs. As shown in Table 2, during the latter half of the study period where the revised form was used, two or more dates for ADR occurrence were often reported. The ratio of the odds of the clarity (“clear” vs. others (“clear/ unclear” or “unclear”)) in the latter half of the study period (51/3) to the odds in the first half (110/50) was 7.7 (95% CI:2.3–26.0). The logistic regression revealed that the “odds ratio” was 9.8 (95%CI:2.5–38.1) when adjusted for age and sex of reporters and other potentially relevant factors indicating that the revised form improved the clarity of the temporal relationship. The number of reports in the first to fourth quarter during the one-year study period was 108, 52, 30 and 24, respectively. This decrease was potentially because patients who used the internet regularly to avidly collect the information of ADRs tended to discover that the pilot study was in place and report ADRs they experienced early in the study period.

A 5 Year Longitudinal Study of Water Quality for Final Rinsing in the Single Chamber Washer-Disinfector with a Reverse Osmosis Plant

This report deals with the construction and management of the reverse osmosis (RO) water system for final rinsing of surgical instruments in the washer-disinfector. Numerous operational challenges were encountered in our RO water system and these were analyzed utilizing the Ishikawa Fishbone diagram. The aim was to find potential problems and promote preventive system management for RO water. It was found that the measures that existed were inappropriate for preventing contamination in the heat-labile RO water system. The storage tank was found to be significantly contaminated and had to be replaced with a new one equipped with a sampling port and water drainage system. Additional filters and an UV treatment lamp were installed. The whole system disinfection started 1.5 years later using a peracetic acid–based compound after confirming the material compatibility. Operator errors were found when a new water engineer took over the duty from his predecessor. It was also found that there were some deficiencies in the standard operating procedures (SOPs), and that on-the-job training was not enough. The water engineer failed to disinfect the sampling port and water drainage system. The RO membrane had been used for 4 years, even though the SOP standard specified changing it as every 3 years. Various bacteria, such as Rothia mucilaginosa, were cultured from the RO water sampled from the equipment. Because Rothia mucilaginosa is a resident in the oral cavity and upper respiratory tract, it is believed that the bacteria were introduced into the system by the maintenance personnel or working environment. Therefore, the presence of R. mucilaginosa implied the failure of sanitary maintenance procedures. This study suggests that water systems should be designed based on the plans for profound system maintenance. It also suggests that SOP and on-the job training are essential to avoid any operator errors. These results must be carefully considered when either constructing new RO systems or performing maintenance and periodical examination of the equipment. LAY ABSTRACT: Reverse osmosis (RO) water is used for final rinsing in our washer-disinfector. The authors used the Ishikawa Fishbone diagram to clarify the critical points for optimizing RO water quality. There existed no measures to prevent contamination in the heat-labile RO water system. The storage tank was significantly contaminated and had to be replaced with a new one equipped with a sampling port and water drainage system. Additional filters and an UV treatment lamp were installed. The whole system disinfection started 1.5 years later using a peracetic acid–based compound after confirming the material compatibility. Operator errors occurred when a new water engineer took over the duty from his predecessor. There were neither standard operating procedures (SOPs) nor on-the-job training. The new water engineer had failed to disinfect the sampling port and water drainage system. Rothia mucilaginosa was cultured from the RO water. It is a resident in the oral cavity and upper respiratory tract. This implied the possible failure of sanitary procedures in the system maintenance. The Ishikawa Fishbone diagram was useful for this study. It suggests that water systems should be designed with plans for system maintenance taken into account. It also suggests that SOP and on-the job training are essential in order to avoid operator errors.

Clinical and microbiological characteristics and occurrence of Klebsiella pneumoniae infection in Japan

Purpose Klebsiella pneumoniae is a pathogen that causes pneumonia and urinary tract infection. Hypervirulent K. pneumoniae strains often show hypermucoviscosity, are of the K1 or K2 serotype, and harbor the rmpA and magA genes. However, the differences in the prevalence of K. pneumoniae with these hypervirulent characteristics between the infection and colonization status are not well understood. Therefore, in this study, we compared the clinical and microbiological characteristics of K. pneumoniae isolated from urine or sputum samples of cases of infection and colonization. Patients and methods This retrospective study was conducted at a tertiary care teaching hospital in Tokyo, Japan. Patients whose sputum or urine tested positive for the presence of K. pneumoniae isolates were randomly included in the study. Clinical and microbiological data were collected from medical records. Results Of the 130 cases investigated, 68 and 62 cases showed the presence of K. pneumoniae in the sputum and urine, respectively. There were 49 infection cases, including 21 in the sputum group and 28 in the urine group. The infections were not accompanied by liver abscess. Of the 130 K. pneumoniae isolates, 25 (19.2%) showed capsular serotype K1 or K2, whereas 33 (25.4%) showed hypermucoviscosity. The prevalence of virulence genes magA, allS, rmpA, mrkD, uge, kfu-BC, and wabG was 10% (all in K1), 13.1%, 16.9%, 85.4%, 79.2%, 36.9%, and 91.5%, respectively. In both the sputum and urine groups, there was no difference in the characteristics of patients with infection and those with colonization. Analysis of microbiological characteristics revealed that only rmpA was significantly more frequent in the infection cases than in the colonization/asymptomatic cases in both the sputum and urine groups. Conclusion The rmpA-positive K. pneumoniae isolates were dominant in the infection cases compared with those in the colonization/asymptomatic cases, suggesting that rmpA may play a crucial role in the development of urinary tract infection and pneumonia.

Analysis of spontaneous inquiries about suspected adverse drug reactions posted by the general public on the electronic Japanese bulletin board “Yahoo! Japan Chiebukuro”

Purpose Spontaneous inquiries about the development of adverse drug reactions (ADRs) to medicines can be extracted based on the questions posted by the general public on the electronic Japanese bulletin board “Yahoo! Japan Chiebukuro”. Our aim was to clarify the characteristics related to people’s descriptions of suspected ADRs and determine the reasons for submitting a spontaneous inquiry. Methods Fifty brand names of medicines used for inquiry extraction were chosen by selecting 35 pharmaceutical products, based on the generic names that had the highest sales in Japan. Questions containing both the brand name of one of these medicines and the term “Fukusayō” (ADR in Japanese) that were posted from July 2004 to June 2009 were extracted from the site. Results Among 1,419 questions extracted, 614 questions had at least one identifiable brand name of a suspected medicine, an ADR description, and the extent to which the ADR appeared to be caused by the suspected medicine(s). Among these 614 questions, 589 described in detail the symptoms/signs that the inquirers themselves or their families had experienced as ADRs. The highest number of questions was found for Paxil (525). Posts asking whether the symptoms being experienced were due to an ADR accounted for the highest number of questions. In most cases, the inquirer suspected that a single medicine led to an ADR and was seeking advice from others taking the same medicine. Conclusion Our examination of spontaneous inquiries showed that people have sufficient knowledge to adequately report potential ADRs in terms of their symptoms, suspected medicines, and the disease for which the medicine was used. However, they often did not describe the start time when the ADR appeared or when the suspected medicine was started.

Diversity of vancomycin-resistant enterococci in a low endemicity area

Although vancomycin-resistant enterococci (VRE) are frequent nosocomial pathogens worldwide, in Japan their prevalence is low and their molecular epidemiology remains unclear. In The University of Tokyo Hospital (Tokyo, Japan), only five isolates of VRE (vanA-type Enterococcus faecium) were identified in the 20 years before 2010; however, nine isolates of vanB-type E. faecium were identified from 2011 to 2012. Multilocus sequence typing (MLST) revealed that they belonged to five sequence types (ST18, ST78, ST203, ST412 and ST612). Despite the limited isolation, including one from a medical tourist, there was significant diversity in genotypes. Increasing medical travel might enhance the diversity of VRE.