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Streptococcus pneumoniae is a common bacterial pathogen that causes infections in children worldwide, even after administration of the pneumococcal conjugate vaccine. S. pneumoniae serotype 35B, especially the clonal complex 558 (CC558) lineage, has emerged globally following implementation of the 13-valent pneumococcal conjugate vaccine. Serotype 35B strains are also associated with multidrug resistance to both β-lactams and non-β-lactam drugs. In addition, a novel serotype, 35D, which is closely related to 35B and differs in polysaccharide structure, was recently reported. However, the genetic relationship among globally disseminating serotype 35B and D (35B/D) strains remains unknown. To investigate the molecular epidemiology of global serotype 35B/D strains, we conducted a genomic analysis of serotype 35B/D strains from various continents, including those from the Japanese national surveillance collection. A total of 87 isolates were identified as serotype 35B/D in the Japanese surveillance collection ( n  = 1,358). All the isolates were assigned to either CC558 or CC2755. Serotype 35D isolates were interspersed with serotype 35B isolates. Phylogenetic analysis revealed the formation of multiple clusters by the Japanese serotype 35B/D-CC558 isolates among the foreign isolates, which suggested multiple events of introduction of the clone into Japan. The global 35B/D-CC558 strains were found to share specific penicillin-binding protein profiles, pbp1a -4, pbp2b -7, and pbp2x -7, associated with penicillin, cephalosporin, and carbapenem nonsusceptibility. Moreover, 88.5% of the Japanese 35B/D-CC558 and 35B/D-CC2755 isolates were found to harbor the Tn 916 -like integrative and conjugative elements Tn 2009 , Tn 2010 , and Tn 6002 , associated with multidrug resistance to macrolides and tetracyclines. The results of this study imply that serotype 35B/D-CC558 strains could be frequently transmitted intercontinentally.

After the introduction of the seven-valent pneumococcal conjugate vaccine, the global spread of multidrug-resistant serotype 19A-sequence type 320 (ST320) strains of Streptococcus pneumoniae became a public health concern. In Japan, the main genotype of serotype 19A was ST3111, and the identification rate of ST320 was low. Although the isolates were sporadically detected in both adults and children, their origin remains unknown. Thus, by combining pneumococcal isolates collected in three nationwide pneumococcal surveillance studies conducted in Japan between 2008 and 2020, we analyzed 56 serotype 19A-ST320 isolates along with 931 global isolates, using whole-genome sequencing to uncover the transmission route of the globally distributed clone in Japan. The clone was frequently detected in Okinawa Prefecture, where the United States returned to Japan in 1972. Phylogenetic analysis demonstrated that the isolates from Japan were genetically related to those from the United States; therefore, the common ancestor may have originated in the United States. In addition, Bayesian analysis suggested that the time to the most recent common ancestor of the isolates from Japan and the U.S. was approximately the 1990s to 2000, suggesting the possibility that the common ancestor could have already spread in the United States before the Taiwan 19F-14 isolate was first identified in a Taiwanese hospital in 1997. The phylogeographical analysis supported the transmission of the clone from the United States to Japan, but the analysis could be influenced by sampling bias. These results suggested the possibility that the serotype 19A-ST320 clone had already spread in the United States before being imported into Japan.

To prevent invasive pneumococcal disease (IPD), pneumococcal conjugate vaccines (PCVs) have been implemented in many countries; however, many cases of IPD still occur and can be attributable to nonvaccine serotypes of Streptococcus pneumoniae. In Japan, the number of IPD cases attributable to serotype 12F increased from 4.4% in 2015 to 24.6% in 2017 after 13-valent PCV was introduced. To clarify the associated genetic characteristics, we conducted whole-genome sequencing of 75 serotype 12F isolates. We identified 2 sequence types (STs) among the isolates: ST4846, which was the major type, and ST6945. Bayesian analysis suggested that these types diverged in »1942. Among serotype 12F-ST4846, we identified a major cluster, PC-JP12F, whose time of most recent common ancestor was estimated to be »2012. A phylogeographic analysis demonstrated that PC-JP12F isolates spread from the Kanto region, the most populated region in Japan, to other local regions.

Since the introduction of pneumococcal conjugate vaccines, the prevalence of non-meropenem-susceptible pneumococci has been increasing in Japan. In an earlier study, we demonstrated that multidrug-resistant serotype 15A-ST63 in Japan has a specific pbp1a sequence ( pbp1a -13) that could promote meropenem resistance. To trace the origin of pbp1a , we analyzed isolates of serotype 19A-CC3111, which is the most prevalent non-meropenem-susceptible clone in Japan. We analyzed a total of 119 serotype 19A-CC3111 strains recovered in Japan using whole-genome sequencing. Of the 119 isolates, 53 (44.5%) harbored pbp1a -13, indicating that the clone may be the primary reservoir of the pbp1a type and that the pbp1a region may be horizontally transferred between different serotype strains. The single acquisition of pbp1a -13 seemed to cause only penicillin resistance and not multidrug resistance; a combination of penicillin-binding protein (PBP) recombination in the pbp2b and/or pbp2x region(s) with acquisition of pbp1a -13 caused multidrug resistance. Conserved amino acid motif analysis suggested that the pbp1a 370SXXK, pbp2b 448SXN, and pbp2x 337SXXN motifs were the candidates for amino acid substitutions increasing the MICs of meropenem, cefotaxime, and penicillin. We identified a specific clone that was correlated with multidrug resistance, although no correlation was observed between phylogenetic trees generated using core genomes and those generated with only the cps locus. All tested isolates were highly erythromycin resistant, and most harbored mefE within macrolide efflux genetic assembly (MEGA) elements and ermB within Tn 917 , which was inserted within Tn 916 and exhibited a structure identical to that of Tn 2017 ., (Copyright © 2019 American Society for Microbiology.)

Since the introduction of pneumococcal conjugate vaccines (PCVs), an increase in the incidence of disease attributable to serotype 15A-ST63 (sequence type 63) pneumococci has been observed in many regions worldwide. We conducted a nationwide pediatric pneumococcal infection surveillance study between 2012 and 2014 in Japan. In the surveillance study, we detected multidrug-resistant serotype 15A-CC63 (clonal complex 63) strains (resistant to macrolides, penicillin, cefotaxime, and meropenem); in this study, we analyzed these resistant isolates to determine the dynamics and mechanism of resistance using whole-genome sequencing. In most of the penicillin-, cefotaxime-, and meropenem-resistant strains, recombination occurred in the pbp2x region, resulting in the acquisition of cefotaxime resistance in addition to penicillin and meropenem resistance. In the multidrug-resistant serotype 15A-CC63 strains, we identified a specific clone with ST9084, and all of the isolates were recovered from the Yamaguchi prefecture in Japan. All of the serotype 15A-ST9084 isolates had a novel pbp2x type ( pbp2x -JP3) that was inserted by recombination events. The conserved amino acid motif profiles of pbp1a , pbp2b , and pbp2x of the strains were identical to those of serotype 19A-ST320. A Bayesian analysis-based date estimation suggested that this clone emerged in approximately 2002 before the introduction of the PCV in Japan. This clone should be monitored because serotype 15A is not contained in the currently used 13-valent PCV (PCV13), and it was resistant to beta-lactams, which are often used in a clinical setting., (Copyright © 2019 American Society for Microbiology.)

After the introduction of pneumococcal conjugate vaccines, the incidence of pneumococcal infections due to meropenem-resistant serotype 15A-ST63 strains increased in Japan. By using whole-genome sequencing and comparing sequences with those of clones from the United Kingdom, the United States, and Canada, we clarified the traits of the serotype 15A-ST63 clone. Our analysis revealed that the meropenem-resistant serotype 15A-ST63 strains from Japan originated from meropenem-susceptible strains from Japan. Recombination site prediction analysis showed that the meropenem-resistant strain-specific recombination regions included the pbp1a and pbp2b regions. A detailed analysis of the composition of these genes indicated that resistance seems to be caused by pbp1a recombination. The pbp1a gene in meropenem-resistant isolates was identical to that in multidrug (including meropenem)-resistant serotype 19A-ST320 pneumococci, which have spread in the United States. The global spread of pneumococci of this lineage is noteworthy because serotype 15A is not included in the currently used 13-valent pneumococcal conjugate vaccine.

Pneumococcal infection in children is a major public health problem worldwide, including in Japan. The pneumococcal conjugate vaccine 7 (PCV7) was licensed for use in Japan in 2010 followed by PCV13 in 2013. This report includes the results of a nationwide surveillance of invasive pneumococcal disease (IPD) and non-IPD in paediatric patients from January 2012 to December 2014. We collected 343 isolates from 337 IPD patients and 286 isolates from 278 non-IPD patients. Of the IPD isolates, the most identified serotypes included 19A, 24F, and 15A. The prevalence of non-PCV13 serotype isolates increased significantly from 2012 to 2014 (51.6-71.4%, p=0.004). Serotypes 19A, 15A and 35B were highly non-susceptible to penicillin, and the rates of non-susceptible isolates from IPD patients to penicillin and cefotaxime significantly declined during the study period (p=0.029 and p=0.013, respectively). The non-susceptible rate to meropenem increased, particularly for serotype 15A. The IPD isolates comprised clonal complex (CC) 3111 (93.8% was serotype 19A) followed by CC2572 (81.5% was serotype 24F) and CC63 (97.1% was serotype 15A). CC3111, CC63 and CC156 (33.3% was serotype 23A, 28.6% was serotype 6B, and 14.3% was serotype 19A) were highly non-susceptible to penicillin. Of the non-IPD isolates, the most identified serotypes included 19A, 15A, and 3. In conclusion, the introduction of PCV7 and PCV13 resulted in increasing non-PCV13 serotypes and clones, including antimicrobial resistant serotypes 15A and CC63 (Sweden(15A)-25 clone)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In order to understand the spread of the erythromycin-resistant serotype 3 Streptococcus pneumoniae clone in Japan, we have assessed the molecular characteristics of this clone. Among 156 S. pneumoniae isolates recovered from adults with community-acquired pneumonia between 2003 and 2005, 42 were serotype 3 and 40 were sequence type (ST) 180/Netherlands(3)-31 by multilocus sequence typing. Thirty-eight of the 40 ST 180 isolates had acquired resistance to erythromycin via the ermB gene. Although the ermB-positive ST180 clone isolates were more susceptible to penicillin and trimethoprim-sulfamethoxazole than ermB-positive non-ST180 isolates and contained a less mutated pbp1a or pbp2b gene, without a mefA gene, the ST180 clone was highly prevalent among ermB-positive isolates. Routine surveillance for the ST180 S. pneumoniae clone may soon become necessary.

Background and Objective: Streptococcus pneumoniae (S. pneumoniae) is the most common pathogen associated with community-acquired pneumonia and its resistance to antimicrobials is a worldwide problem. The aim of this study was to investigate the current drug susceptibilities of S. pneumoniae isolated from adult patients with community-acquired pneumonia in Japan., Methods: S. pneumoniae strains isolated from adult patients with pneumococcal pneumonia from 10 institutions were collected prospectively between May 2003 and October 2004 and tested for drug susceptibilities. Clinical data were analysed and the risk factors for drug resistance investigated., Results: A total of 141 isolates of S. pneumoniae were analysed. Of these S. pneumoniae isolates, 46.1% had intermediate penicillin resistance and the minimum inhibitory concentration (MIC) occurring in the greatest number of isolates and MIC90 value was 2 microg/mL. The prevalence of resistance to macrolides was 80%, with the MIC90 values being greater than or equal to 16 microg/mL. Approximately 40% of the strains were resistant to oral third-generation cephems. Penicillin and erythromycin resistance were both associated with the pre-existing chronic disease states., Conclusions: The cephem and macrolide resistance of S. pneumoniae was higher than penicillin resistance in adult patients with community-acquired pneumococcal pneumonia in Japan. We recommend that bacterial identification and sensitivities are determined in areas where the macrolide resistance to S. pneumoniae is high.

To prevent invasive pneumococcal disease (IPD), pneumococcal conjugate vaccines (PCVs) have been implemented in many countries; however, many cases of IPD still occur and can be attributable to nonvaccine serotypes of Streptococcus pneumoniae. In Japan, the number of IPD cases attributable to serotype 12F increased from 4.4% in 2015 to 24.6% in 2017 after 13-valent PCV was introduced. To clarify the associated genetic characteristics, we conducted whole-genome sequencing of 75 serotype 12F isolates. We identified 2 sequence types (STs) among the isolates: ST4846, which was the major type, and ST6945. Bayesian analysis suggested that these types diverged in »1942. Among serotype 12F-ST4846, we identified a major cluster, PC-JP12F, whose time of most recent common ancestor was estimated to be »2012. A phylogeographic analysis demonstrated that PC-JP12F isolates spread from the Kanto region, the most populated region in Japan, to other local regions. [ABSTRACT FROM AUTHOR]

After the introduction of pneumococcal conjugate vaccines, the incidence of pneumococcal infections due to meropenem-resistant serotype 15A-ST63 strains increased in Japan. By using whole-genome sequencing and comparing sequences with those of clones from the United Kingdom, the United States, and Canada, we clarified the traits of the serotype 15A-ST63 clone. Our analysis revealed that the meropenem-resistant serotype 15A-ST63 strains from Japan originated from meropenem-susceptible strains from Japan. Recombination site prediction analysis showed that the meropenem-resistant strain-specific recombination regions included the pbp1a and pbp2b regions. A detailed analysis of the composition of these genes indicated that resistance seems to be caused by pbp1a recombination. The pbp1a gene in meropenem-resistant isolates was identical to that in multidrug (including meropenem)-resistant serotype 19A-ST320 pneumococci, which have spread in the United States. The global spread of pneumococci of this lineage is noteworthy because serotype 15A is not included in the currently used 13-valent pneumococcal conjugate vaccine. [ABSTRACT FROM AUTHOR]

• The PCV7 and PCV13 coverage rates for IPD were 0.8% and 9.2%, respectively. • The IPD cases attributable to serotype 12F increased dramatically. • Serotype 15A-CC63 and serotype 35B-CC558 isolates were multi-drug resistant. • Non-IPD isolates were more resistant than IPD isolates. Streptococcus pneumoniae is still one of the major causes of morbidity and mortality worldwide. In Japan, pneumococcal conjugate vaccine (PCV)7 and PCV13 were licensed in 2010 and 2013, respectively. We conducted a nationwide paediatric invasive pneumococcal disease (IPD) and non-IPD surveillance study in Japan between 2015 and 2017. We collected 498 IPD isolates and 231 non-IPD isolates from a total of 187 medical institutions in Japan. We performed serotyping, antimicrobial susceptibility testing and multi-locus sequencing typing (MLST) for the collected isolates. Among the 498 IPD isolates, the most prevalent serotype was 24F, followed by 12F, 15A and 15B/C. However, 12F increased and 24F significantly decreased during the study period (p < 0.001), resulting in 12F becoming the most prevalent serotype in 2017. Among the IPD isolates, the PCV7 and PCV13 coverage rates were 0.8% and 9.2%, respectively. The most prevalent serotype among the non-IPD isolates was 15A, followed by 35B, 15B/C and 19A. The overall resistance rates to penicillin (PG), cefotaxime (CTX), meropenem (MEM), erythromycin (EM) and levofloxacin (LFX) were 40.5%, 12.2%, 19.4%, 91.8% and 0.5%, respectively. PG, CTX and MEM resistance rates were significantly higher in non-IPD isolates than in IPD isolates (p < 0.001). Serotype 15A-CC63 and serotype 35B-CC558 tended to be multi-drug resistant. In conclusion, the PCV13 coverage rate was significantly lower than that in a previous surveillance study in Japan between 2012 and 2014, and IPD cases attributable to serotype 19A also decreased. We should note the rapid increase in the prevalence of serotype 12F in IPD cases and the spread of the multi-drug resistant serotype 15A-CC63 and 35B-CC558 lineages. [ABSTRACT FROM AUTHOR]