Regulatory aspects of quality and safety for live recombinant viral vaccines against infectious diseases in Japan.

Recombinant viral vaccines expressing antigens of pathogenic microbes (e.g., HIV, Ebola virus, and malaria) have been designed to overcome the insufficient immune responses induced by the conventional vaccines. Our knowledge of and clinical experience with the new recombinant viral vaccines are insufficient, and a clear regulatory pathway is needed for the further development and evaluation of recombinant viral vaccines. In 2018, the research group supported by the Ministry of Health, Labour and Welfare, Japan (MHLW) published a concept paper to address the development of recombinant viral vaccines against infectious diseases. Herein we summarize the concept paper-which explains the Japanese regulatory concerns about recombinant viral vaccines-and provide a focus of discussion about the development of recombinant viral vaccines.

Fulminant colitis from Clostridium difficile infection, the epidemic strain ribotype 027, in Japan.

In December 2012, a 32-year-old woman with no previous medical history and no previous antibiotic treatment had a fever and diarrhea 2 days after a cesarean section in which cefazolin was used as a prophylactic antimicrobial agent. She was transferred to our hospital 5 days after the cesarean for severe colitis. A rapid test of stool for Clostridium difficile toxin A and B was positive. Although oral vancomycin (0.5-2.0 g/day) and intravenous immunoglobulin (5 g/day) were administered after her transfer, 7 days after admission emergency exploratory surgery was performed because of poor response to therapy. Bowel perforation was noted and a temporary colostomy was created without colectomy. Vancomycin (2.0 g/day) was administered via the colostomy, in addition to a vancomycin enema (2.0 g/day), oral metronidazole (1500 mg/day), and oral vancomycin (2.0 g/day). Three days after the operation, linezolid (1200 mg/day IV) was added. She was treated with antibiotics against C. difficile for a total of 18 days after the operation. The same strain was not isolated from other patients in the same ward. Microbiological analysis of the isolate revealed housekeeping gene (tpi), toxin A gene (tcdA), toxin B gene (tcdB), and binary toxin gene (cdtA and cdtB). DNA sequencing of tcdC revealed a base 117 deletion and contained an 18-bp tcdC deletion. PCR ribotyping showed ribotype 027 patterns. The MIC of moxifloxacin was >32 µg/ml, indicating resistance to fluoroquinolones. This isolate was considered as the epidemic strain. Our case of fulminant colitis is apparently the first case involving the epidemic strain ribotype 027 in Japan.

Effectiveness of antibiotic combination therapy as evaluated by the Break-point Checkerboard Plate method for multidrug-resistant Pseudomonas aeruginosa in clinical use.

Multidrug-resistant Pseudomonas aeruginosa (MDRP) strains are defined as having resistance to the following 3 groups of antibiotics: carbapenems, aminoglycosides, and fluoroquinolones. Antibiotic combinations have demonstrated increased activity in vitro compared with a single agent. As an in vitro method of determining the combination activity of antibiotics, the Break-point Checkerboard Plate (BC-plate) can be used routinely in clinical microbiology laboratories. We evaluated the effectiveness of the BC-plate for MDRP infections in clinical settings. We retrospectively selected cases of MDRP infection treated with combination therapy of antibiotics in Tokyo Medical University Hospital (1015 beds), Tokyo, Japan, from November 2010 to October 2012. A total of 28 MDRP strains were clinically isolated from 28 patients during the study period. This study design is a case series of MDRP infection. Six infections among the 28 patients were treated based on the results of the BC-plate assay, and the 6 strains tested positive for MBL. One patient had pneumonia, 3 had urinary tract infections, 1 had vertebral osteomyelitis, and 1 had nasal abscess. The combination of aztreonam with amikacin demonstrated the most frequently recognized in vitro effect (5 patients). Next, aztreonam with ciprofloxacin and piperacillin with amikacin revealed equivalent in vitro effects (3 patients, respectively). The clinical cure rate was 83.3% (5/6 patients). Antibiotic combination therapy based on the results of the BC-plate assay might indicate the effective therapy against MDRP infection in clinical settings.