New molecules, new methods, and new concepts, these were my longstanding goals. For me who has been criticized or advised that the scope of research is too broad, by having the axis of biologically active small molecules produced by microorganisms, I was able to find a focused research area. This paper will focus on my researches after receiving the Sumiki-Umezawa Memorial Award, and I describe my own way of thinking about biologically active small molecules.

In the hospital, nosocomial outbreak of influenza from patients to hospital staffs or from staffs to patients can cause significant morbidity and mortality in inpatients and hinder the medical care service. Effective prophylaxis may reduce nosocomial transmission of influenza. The aim of the present study is to investigate the prophylactic efficacy of laninamivir octanoate (LO)in preventing influenza for hospital staffs.

This was a retrospective study to determine whether the inhalation of LO was effective in the prophylaxis of influenza for hospital staffs. Excluded 5subjects, 118 were vaccinated for influenza on November 2016. These 123 subjects were assigned to receive LO (20 mg or 40 mg) or not according to their wishes and were inhaled LO between January and February 2017. The primary end point was the proportion of subjects who developed clinical influenza during a 5-month period.

A total of 119 subjects excluded 4 who received oseltamivir were enrolled. The proportion of participants with clinical influenza was 4.8%(4/83)in the LO group and 22.2%(8/36)in the no LO group(p=0.005). The relative risk reduction compared with the no LO group were 78%. The proportion with clinical influenza was 4.5%(3/66)in the LO 20 mg group and 5.8%(1/17)in the LO 40 mg group. There was no significant difference between both groups (p=0.685). Two of 4 subjects with clinical influenza in the LO group developed within 2 days after the inhalation of LO and remaining 2 subjects developed after 3 months. The inhalation of LO for hospital staffs effectively prevented the development of influenza. The prophylactic effect of LO 20 mg was equal to that of LO 40 mg.

We examined the genotype of penicillin-binding protein(pbp) genes and macrolide-resistant genes (mefA and ermB), the capsular serotypes, and susceptibility to antibacterial agents of 138 strains of Streptococcus pneumoniae isolated at medical facilities in the Chubu region of Japan between April, 2015 and March, 2016. The results of this study were compared with previous surveillance results(2008 to 2009, 2010 to 2011, and 2011 to 2012).

Based on the genotype of pbp genes among the 138 strains of clinically isolated S. pneumoniae, the genotypic penicillin-susceptible S. pneumoniae (gPSSP) having the wildtype pbp1a, pbp2b, and pbp2x, genotypic penicillin-intermediate S. pneumoniae( gPISP) having 1 or 2 mutant genes, and the genotypic penicillin-resistant S. pneumoniae (gPRSP) having 3 mutant genes accounted for 10.9%, 59.4%, and 29.7%, respectively. The isolation frequency of strains not possessing the macrolide-resistant genes such as mefA and ermB was 2.9%, and it seemed to be decreasing over the years.

Among the 61 strains from children (≤15 years old), only the capsular serotypes of 3 and 19A contained in the 13-valent pneumococcal conjugate vaccine (PCV13) were isolated, accounting for 23.0% and 6.6%, respectively. Among the strains from adults(16 to 64 years old) and elderly(≥65 years old), the isolation frequency of serotype strains covered by PCV13 was as low as that in children, demonstrating the indirect effects of PCV13 childhood vaccination. Among the non-vaccine serotypes not included in PCV13 or in the 23-valent pneumococcal polysaccharide vaccine, the serotype of 35B was isolated most frequently at an isolation frequency of 9.4%, followed by the serotype 15A(7.2%).

The MIC₉₀ value of benzylpenicillin was 2μg/mL, and the susceptibility rate which was calculated based on the Clinical and Laboratory Standards Institute (CLSI) interpretive criteria (M100-S25) was 96.4%. The MIC₉₀ values of penicillins, cephalosporins, macrolides, and fluoroquinolones did not remarkably change compared with those for the 2011 to 2012 isolates investigated last time. However, the MIC₉₀ values of carbapenems were 2- or 4- times higher than those for the 2011 to 2012 isolates. Of note, the susceptibility rate of gPRSP to meropenem was 26.8%, and which was markedly lower than that of the 2011 to 2012 isolates.

In conclusion, changes were observed in the capsular serotype distribution and antimicrobial susceptibility, which may have been caused by the prevalence of pneumococcal vaccination to children in Japan. This suggests the importance of continuous surveillance for S. pneumoniae in order to assess the progression of antimicrobial resistance.

The effectiveness of repeated vaccination of the quadrivalent influenza vaccine is currently unknown. This study aims to estimate current and repeated vaccination effectiveness (VE) of the quadrivalent influenza vaccine. A test-negative casecontrol study was performed during the 2017–2018 season. The participants were Japanese children divided into four groups (6–11 months and ages 1–5, 6–12, and 13–15 years). Current VE: Overall, the adjusted VE was significant for influenza B (36.4; 95% confidence interval [CI]: 9.8–55.2); the adjusted VE was significant for any influenza (A+B; 47.3%; 95% CI: 12.2–68.3) and influenza B (56.2%; 95% CI: 17.9–76.6) only in the 1–5 year age group. In other groups, VE was not observed. Vaccine doses: Two vaccine doses significantly decreased the incidence of any influenza and influenza B compared to no vaccination or only one dose in only the 1–5 year old group. Repeated VE: The adjusted VE was significant for any influenza (72.6%; 95% CI: 27.1–89.7) and influenza B (69.7%; 95% CI: 4.5–90.4) in only the 1–5-year age group without vaccination in the previous season. It was also significant for influenza B (68.6%; 95% CI: 1.3–90.0) in the 6–12-year age group with two vaccination doses in the previous season. In other groups, repeated VE was not observed for any influenza types. The reason for that repeated VE may depend on age, repeated vaccination with two doses may be valuable in the 6–12 year age group, although current VE was not observed.

In the preceding report, we described that “The Minimum Requirements for Antibiotic Products of Japan; MRAPJ” was enacted in August of 1969 and regarded as the official guidelines for the quality control of antibiotic products. The Central Pharmaceutical Affairs Council (CPAC) of the Ministry of Health and Welfare (MHW) decided, through four major amendments by July of 2000, to integrate the MRAPJ into “The Japanese Pharmacopoeia; JP”.

In this report, we describe the results of our investigations, analyses of the challenges encountered, solutions to those challenges during the integration phase, and discuss the historical and hygienic significance of the integration process.

The JP Committee of the CPAC decided to withdraw antibiotic products from being subjected to the “Minimum Requirements” restrictions outlined in Article 42 of the Pharmaceutical Affairs Law. This decision was based on evidence that over 60% of the entities listed in the 1998 version of the MRAPJ were highly purified semi-synthetic antibiotics manufactured via chemical synthesis processes. The committee established “the First General Subcommittee” to work on the integration of all the listed items of the 1998 MRAPJ into the 14th Edition of JP(14th JP). The integration process commenced in March of 1999 and was scheduled to be announced in March of 2001. In the 1998 MRAPJ, there were 142 entities consisting of 174 active pharmaceutical ingredients(APIs)and 314 preparations manufactured from these APIs. As the first step, the integration work of these APIs into the JP began. With regard to antibiotic preparations, all items were transferred in advance to the newly enacted “The Japanese Pharmaceutical Codex Part IV( Antibiotic Drugs); JPC Part IV” in September of 1999.

In principle, the monographs in the MRAPJ were regarded as the “minimum standards” necessary in order to provide minimum quality specifications and test methods for the assurance of safety and efficacy of drugs. Furthermore, many necessary items were eventually included as “approved matters” and became known as “extra MRAPJ standards”. However, monographs in the JP are considered as “full standards” for which no approval is required. Therefore, the major tasks for the transference of the APIs listed in the MRAPJ into the JP were to combine the “minimum standards” and the “approved matters” of individual drugs. The end result was the creation of “full standards” that were appropriate for “the official drugs” of the JP. Due to the “intellectual property” nature of individual pharmaceutical companies involved, many complications arose prior to the disclosure of these “approved matters”. Eventually, a total of 47 APIs were integrated into the 14th JP as “full standards”. In addition, 18 relatively new APIs were integrated as “minimum standards” that were unique to the JP.

Prior to the announcement of the 14th JP, the MHW was reorganized into the Ministry of Health, Labour and Welfare in January of 2001. At that time, the integration work was accelerated and the name of “the First General Subcommittee” was changed to “the Antibiotics Committee”. Over the course of 27 meetings, 82 APIs were transferred from the MRAPJ to the 14th JP Supplement 1 enacted in December of 2002. As a result, no drugs were listed in the MRAPJ. Thereafter, the MRAPJ was abolished upon completion of its mission. For 33 years since its enactment, it served as the guidelines for the quality control of antibiotic drugs in Japan. Antibiotic preparations previously transferred to the JPC Part IV were subjected to transfer to the JP. Subsequently, after the creation of the “full standards” monographs, it is expected that 83 antibiotic preparations will be listed in the 17th JP Supplement 2 to be announced in May of 2019.

Background: Meropenem is used as empirical therapy for severe sepsis and various infections. It is important to understand the tolerability of meropenem to administer it at a sufficiently high dose (e.g. 1 g or 2 g every 8 or 12 hours) and ensure adequate time above the minimum inhibitory concentration. However, the dose tolerability and risk factors for hepatic and renal dysfunction in meropenem-treated patients with baseline renal dysfunction remain unclear.

Objectives: To confirm the dose tolerability of meropenem and to identify the factors affecting hepatic and renal dysfunction after meropenem treatment in Japanese patients with creatinine clearance rates of 10 to 50 mL/min.

Methods: This was a retrospective, single-center study, where 142 subjects with creatinine clearance rates ranging from 10 to 50 mL/min were administered meropenem between April 1, 2012 and October 31, 2015. Safety was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Abnormal hepatic function was evaluated based on alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels, and abnormal renal function was evaluated using serum creatinine (SCr) levels. Adverse events were considered as worsening if the grade of each item increased from baseline values.

Results: Worsening of ALT, ALP, and SCr grades was observed in 17.9%, 18.3%, and 4.2% of patients, respectively. Dose of 2 g/day or more, treatment duration, or the degree of patient’s renal function had no effect on hepatic and renal dysfunction. Thus, the risk factors for hepatic and renal dysfunction were not related to meropenem.

Conclusion: Meropenem dose and treatment duration are not risk factors for hepatic and renal dysfunction in Japanese patients with creatinine clearance rates of 10 to 50 mL/min.