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Infectious Agents Surveillance Report (IASR) https://www.niid.go.jp/niid/ja/iasr.html 3, 4, JANIS 5, 6, 8, 9, KPC 11, : 12, 13, 14, EV-D68 15 Vol. 40 No. 2 2019. 2 117 Vol.40 No. 2 No.468 ISSN 0915-58132019 2 162-8640 1-23-1 Tel 03 52851111, 1,, 2 :,,, CRE CRE, - Escherichia coli Klebsiella pneumoniae CRE,,,,,,,, NESID: CRE 2014 9 19 5 https://www.mhlw.go.jp/bunya/kenkou/ kekkaku-kansenshou11/01-05-140912-1.html CRE 20152017 1,600, 2018 12 25 48 2,000 1 4 80 65,,,, 5 43 10 2015 35, 2016 38, 2017 2018 48 39 2 2018 4 Enterobacter cloacae, Klebsiella aerogenes 2017, K. pneumoniae, E. coli, 2017 K. aerogenes, 3 : CRE CPE-, CPE, CRE 8 CPE,,, CRE CPE, 6 2017 3 28, CRE, 3 2,200 75 2,000 6574 n 1,800 1564 1,600 014 1,400 1,200 1,000 800 894 512 600 408 389 422 400 200 170 72 317 323 282 362 0 59 13 41 39 47 56 2014 2015 2016 2017 20182 (n=314) (n=1,669) (n=1,573) (n=1,660) (n=2,074) 825 910 1,144 1 201438 919521228 2 20181 114812 2 117 19 1099 100 2018 1 114812 2 2

218 Vol. 40 No. 2 2019. 2, 0 10 20 30 40 50 60 70 80 90 100 3 IMP, 1 NDM, KPC, 2014 78 101 40 39 49 8 314 OXA-48 2015 480 550 206 148 261 32 1,669, 2016 466 486 176 145 242 58 1,573, IASR 2017 564 482 162 141 257 55 1,660 2 35: 283-284, 2014 2018 781 595 184 143 296 78 2,074 Klebsiella aerogenes Enterobacter cloacae Escherichia coli, Klebsiella pneumoniae 1 201438919521228 2 201811148122 2017 239, 2018 123, IMP 2017 227, 2018 111 2017 CRE IMP IASR 39: 162-163, 2018, 6, 2018 KPC 11 NDM 12, 9 2018 AMR, CRE, NESID, 4 JANIS : JANIS, 2,000, NESID,, CRE 2017 7,000 JANIS CRE, NESID, CRE CRE NESID, K. aerogenes JANIS 2017 5 : CRE AMR,,,,, WHO, OIE, 3 FAO AMR NAP 2016-2020,,, JANIS, JVARM,, ; https://www.mhlw. go.jp/content/10900000/000415561.pdf, 2018 13 AMR : 2015 WHO AMR GAP, 2016 NAP 2016-2020 https://www.mhlw. go.jp/f ile/06-seisakujouhou-10900000-kenkoukyoku/ 0000120769.pdfNAP, AMR,,,, WHO AMR AMR 2017 NAP AMR JANIS E. coli K. pneumoniae 0.2 NAP 2017 K. pneumoniae 0.4, NESID 2018,,

Vol. 40 No. 2 2019. 2 19 3,, 2019 1 15 2017 3 0328 4, CRE,,,,, 2017 1 1 1231 865 1 2018 1 1 6 30, 2018 575 2019 1 15,, 13 PCR, -,, IMP, NDM, KPC, OXA-48,, VIM, GES, IMI, KHM, SMB, 2018, Carba NP test CIM,,, NDM, KPC, OXA-48 18, 2, 1, 13, 12, 1, 165, 1 PCR, 2 PCR, 2017 798, 2018 566 CRE 2017 1,660 2018 1027, 2018 1 6 849 2018 1214, 2017 48, 2018 67 2017 56, 2018 80, 50 2017 26, 2018 36,, 100, 1, CRE 2017, 1,.

420 Vol. 40 No. 2 2019. 2 NESID,, *,, 2017 3 CRE, NESID *,, *,,,, /, * NESID ID ID,,, 1IASR 39: 162-163, 2018,, NESID ID,,, Infectious Disease Surveil- 2014 9, carbapenem-resistant Enterobacteriaceae: CRE National Epidemiological Surveillance of Infectious Diseases: NESID 5,

Vol. 40 No. 2 2019. 2 5 21 * 20181030-1225 lance Center: IDSC Antimicrobial Resistance Research Center: AMRRC, 2018 10, CRE,, CRE,,,,,, IDSC,, AMRRC,, 8 NESID, 2018 1 1 1 12 2 48, NESID 2,074 2018 1225, 1,154 56, NESID ID 982 85 2019 1 7, NESID ID,, 10,000 8,000 6,000 4,000 2,000 JANIS JANIS,, CRE, 2014, 2015 JANIS NESID,,,, 30, JANIS https://janis.mhlw.go.jp/report CRE 20142017 4, JANIS CRE, 1 2015 9,254 CRE, 2016 7,827, 2017 7,572 JANIS https:// janis.mhlw.go.jp/hospitallist/index.html, CRE CRE, 1 0 8,582 0.49 9,254 0.36 (%) 7,827 7,572 0.29 0.27 2014 2015 2016 2017 1. CRE 0.6 0.4 0.2 0

622 Vol. 40 No. 2 2019. 2 Proteus mirabilis, 1.0% Enterobacter asburiae, 0.8% Klebsiella oxytoca, 2.0% Enterobacter sp., 2.8% Citrobacter freundii, 2.9% Serratia marcescens, 4.3% Escherichia coli, 7.0% Klebsiella pneumoniae, 8.9% 2. CRE, 4.5% Klebsiella aerogenes, 35.2% Enterobacter cloacae, 30.5% 3. CRE -2017, 3 2017, 0.25, 75 0.33, 90 0.42, 0.08, 0.53 Shapiro- Wilk p=0.33, 90 4,, JANIS, CRE, CRE, 81.0 2014, 70.5 2015, 63.0 2016, 56.4 2017,, CRE 2016 2017 0.29 0.27,, 0.90 2016, 0.83 2017, 2017 CRE, 2 Klebsiella aerogenes 35.2, Enterobacter cloacae 30.5 6, Klebsiella pneumoniae 8.9, Escherichia coli 7.0, Serratia marcescens 4.3, JANIS, JANIS,, https://janis.mhlw.go.jp/report/kensa_prefectures. html, CRE 2016, 3,,,,, CRE, JANIS 11, 3 CRE,, 75, 90,, CPE, 2014 5 carbapenemase-producing Enterobacteriaceae; CPE, -, CPE, 1, CPE IMP, IMP IMP-6,, minimum inhibitory concentration ; MIC 1 g/ml MIC 0.251g/mL,, CPE, Clinical and Laboratory Standards Institute CLSI 2 Carba NP test, modif ied Carbapenem Inactivation Method mcim, -

Vol. 40 No. 2 2019. 2 7 23, Carba NP test, ph, mcim,,, Escherichia coli ATCC 25922, Carba NP test,,,, KPC, -- SMA-,,,, polymerase chain reaction PCR,, PCR,,, - IMP, VIM, KPC, NDM, OXA, GES, multiplex PCR -c, d,,,,,, ESBL AmpC,,,,, CPE -a CPE -b,, -,,, CPE,, CPE,,

824 Vol. 40 No. 2 2019. 2 1, 63: 187-197, 2015 2CLSI, Performance Standards for Antimicrobial Susceptibility Testing, 27th Informational Supplement, 2017 CRE CRE, IPM MIC2g/mL CMZ MIC 64g/mL, MEPM MIC 2g/mL,, Klebsiella, Enterobacter, Serratia, Proteus,,,, CRE 5, 2016 1,581 1 Enterobacter cloacae 31.3, Klebsiella aerogenes 30.6, Klebsiella pneumoniae 11.7, Escherichia coli 9.8,, 32.4, 24.8, 20.6 2014 9 2016 12 CRE,,, 31, 24, 21, 14, 3 CRE, CRE, empiric therapy CRE, CRE CRE,,,, 2,, -,, 29 MEPM MIC 2g/mL A 13 B 16, CPE A, -,, CPE,, 3 CRE CRE, CPE K. pneumoniae carbapenemase: KPC, 4 CRE, : CRE, MIC,, MIC1g/mL, MIC2g/mL 5, MIC8g/mL 6 pharmacokinetics/pharmacodynamics, 4 : Serratia Proteus, MIC 4, 7, 8 :

Vol. 40 No. 2 2019. 2 9 25,, 9 :,,, 4 CRE, 10,, CPE, 11,, CRE, CPE, 14 30 20 40 3, 10, 11 2016, 3.4, 29, 26, CRE, CPE,, CRE, 2, 4 1IDWR, https://www.niid.go.jp/niid/ja/cre-m/ cre-idwrs/7393-cre-20170613.html 2, 64: 742-749, 2016 3Tamma PD, et al., Clin Infect Dis 64: 257-264, 2017 4Morrill HJ, et al., Open Forum Infect Dis, doi: 10.1093/of id/ofv050, 2015 5Patel TS, et al., J Clin Microbiol 53: 201-205, 2015 6Daikos GL, et al., Antimicrob Agents Chemother 58: 2322-2328, 2014 7Liu Y-Y, et al., Lancet Infect Dis 16: 161-168, 2016 8, 2015 5 9, 2014 10Tzouvelekis LS, et al., Clin Microbiol Infect 20: 862-872, 2014 11Gutierrez-Gutierrez B, et al., Lancet Infect Dis 17: 726-734, 2017 CPE, 2020, CPE, CPE CPE,,,, -- IMP-1, -6, -34,,,,,, KPC CPE KPC Ambler class A --, 2001 Klebsiella pneumoniae,, KPC, IMP, KPC,, 11 2019 1, KPC 37 NDM CPE NDM 2009, -

1026 Vol. 40 No. 2 2019. 2, OXA-48 MEPM MEPM, 36kDa 2010, K. pneumoniae IPM MEPM bla OXA-48 family bla OXA-181 bla CTX- M-15 7, bla OXA-181 K. pneumoniae 2015, bla OXA-181 - NDM-1 NDM-1, 1, NDM-1 2, MIC bla NDM-1, 2013 NDM-3 3, 2013 NDM-5, 2014 NDM-5 K. pneumoniae 4 2019 1, NDM 24 OXA-48-like CPE OXA - OXA-10,,,, OXA-10 143, 157 OXA-11 5, OXA-48-like 2001 K. pneumoniae 11978, 46 6, OXA, 2019 1 779 OXA-48 K. pneumoniae 11978 -, bla OXA-181, bla OXA-181, ISEcp1, ISEcp1,, K. pneumoniae 11978, OmpK36,,, 1Chihara S, et al., Clin Infect Dis 52: 153-154, 2011 2, 86, 2012 3Tada T, et al., Antimicrob Agents Chemother 58: 3538-3540, 2014 4Nakano R, et al., Antimicrob Agents Chemother 58: 7611-7612, 2014 5Paterson D, et al., Clin Microbiol Rev 18: 657-686, 2005 6Poirel L, et al., Antimicrob Agents Chemother 48: 15-22, 2004 7Kayama S, et al., Antimicrob Agents Chemother 59: 1379-1380, 2015

Vol. 40 No. 2 2019. 2 1127 KPC 2017 12 KPC Klebsiella pneumoniae carbapenemase carbapenem-resistant Enterobacteriaceae: CRE 2017 1 2 192018 1 9, 3 CRE,, 2018 1 18, 3 KPC 3 A 2 80, 70, D 1 80 3 KPC CRE,,, CRE, 2017 10 1,,, 3 11 3, 6, 16 3 C 20, 70, 40 16 C 10 3080, 5, A B 1 40, 60, D 2 70, 1 80, 1 80, A 3, B 1, C 13, D 3, C, 60 80, KPC CRE, FETP,, KPC CRE,,,,,,,,,,,,,,,,, 2019 1,,, KPC CRE KPC 2018 1 18 CRE, KPC 1 18,, FETP,,,,,, 2,,,, 2019 1 22,,,, AMR antimicrobial resistance :, 1 1219 1 261219 2

1228 Vol. 40 No. 2 2019. 2 :, 1, 2 2, 1NDM NDM-1 -- Acinetobacter pittii 1 OXA-48 Klebsiella pneumoniae OXA-48, OXA-48, NDM-1 A. pittii / PIPC/TAZ-, IPM MEPM MIC8g/mL, A. pittii sequence type ST220 bla NDM-1 26,940bp Acinetobacter sp. pndm-jn02 accession no. KM210088 99.99 26,936bp/26,940bp bla OXA-213-family gene, A. pittii ST220 bla OXA-213-family accession no. CP029610100, 12,265 bp 99.99 12,264bp/12,265bp, AmpC bla ADC-25 NDM-1 2High Care Unit HCU 1 IMP-1 Enterobacter cloacae GES-24 Citrobacter freundii msupercarba, PIPC/TAZMIC, IPM MEPM MIC 1g/mL C. freundii Clinical and Laboratory Standards Institute mcim, MEPM,, inti1, aaca4, Klebsiella variicola bla GES-24 3 1, GES-24 A GES - extended-spectrum -lactamase, GES-4 GES-24 GES,, Kotay, P Escherichia coli 1 1, 4 National Institutes of Health Clinical Center 5, 1.4, 3.2, 12.5, 78.9 5,,,, AMR,, AMR AMR 1Vergara-L ópez S, et al., Clin Microbiol Infect 19: E490-E498, 2013 2White L, et al., J Hosp Infect 93: 145-151, 2016 3Gomi R, et al., Antimicrob Agents Chemother, doi:10.1128/aac.02501-17, 2018 4Kotay S, et al., Appl Environ Microbiol, doi: 10.1128/AEM.03327-16, 2017 5Weingarten RA, et al., MBio 9, doi:10.1128/mbio. 02011-17, 2018 bla GES-24

Vol. 40 No. 2 2019. 2 1329 IMP, 1, KPC-2 Klebsiella pneumoniae ST11 2, KPC-2,,, KPC-2 2016,,,,, 2018 30 :,, AMR AMR,, -, CRE 3 CRE, 2020, WHO Global Sewage Surveillance Project GSSP 90 4 GSSP, AMR, AMR,,,

1430 Vol. 40 No. 2 2019. 2 5, 6, AMR, AMR, AMR :,, 1Gomi R, et al., Antimicrob Agents Chemother 62 5: e02501-17, 2018 2Sekizuka T, et al., msphere 3 5: e00314-18, 2018 3Montezzi LF, et al., Int J Antimicrob Agents 45 2: 174-177, 2015 4http://www.compare-europe.eu/Library/Global- Sewage-Surveillance-Project 5Nakayama T, et al., Infect Drug Resist: 391-395, 2018 6Woerther PL, et al., J Travel Med. suppl_1: S29-S34, Review, 2017,, 4 NA,,,, 2018 2, 3, PA 38 I38T/M/F, 1 III 12 9.7, 12 23.4,, 1, 2,,,, 2017/18 3, 4 2018 12,, 80120 PA I38T 2 5 2, 2018 12, 6 7 4 4 2 3, 1, 1 2 AH3N2 4, A/ /133/2018 A//135/2018, PA I38T, A//136/2018 A//134/2018, 2 PA I38T,,, 4, IC 50 50, PA I38T A//133/2018 A//135/2018, 2,, 120 76, 4 NA,,,, PA I38T, 4 2,000, 0.32, 4.1 6, 5 NA, 0 1.9, 2018/19 2019 1, 250 NA 4, World Health Organization: WHO WHO NA,,

Vol. 40 No. 2 2019. 2 1531,,,,,,, 3 2, D68 EV-D68 EV-D68,, 1Omoto S, et al., Sci Rep 8: 9633, 2018 3 2Hayden FG, et al., N Engl J Med 379: 913-923, 2, 2018,, 3Takashita E, et al., Front Microbiol 9: 3026, 3 2 2018 EV-D68 4 http://www.nih.go.jp/niid/ja/inf lu-resist.html 1 : 16 5Takashita E, et al., Euro Surveill 24: pii=1800698, : 2018 8 X 2019 3, 6Aoki FY, et al., Antivir Ther 12: 603-616, 2007 11, 28 : EV 5UTR-V 2 semi nested-rt PCR 1, EV-D68 PCR 2, PV L-20B RD-A 3 :,,, 16, 23 24 EV RV, 2 PV 2 : 6 : 2018 9 X,,, 1 2,,,, 5,, 6, 9 EV-D68, 2018 5 1, 5 34, 47 118, 5 1, 7, 15 12 10 8 6 4 2 0 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 1. 201818

1632 Vol. 40 No. 2 2019. 2 Clade : EV 5UTR-VP2 semi nested- GER/03-01/14-15_KP189399 Fermon AF081348 RT PCR 1 CAN14-344_KP455284, PV L-20B RD-A US/KY/14-18951_KM851229 A GER/NW/15-34/Germany/2013 KR066455 3, IRL_LOUTH_2014_49 KU645362 GER/NW/15-34/Germany/2013_ KR066455 SWE_013_2016_MH674165 ITA/PV-38818/2016_MF073354 : 6, GER_992165_MH470372 SWE_042_2016_MH674157,, 7, TW-03464_2015_MH341112 FRA/0906R002_KY272953 7 9 EV- DE/BY/16-741/2016_KX830913 NY234_16_KY385891 D68 EV RV A194-OsakaC-JPN-2015_LC107892* 992 NY75_16_KX957762 USA/FL/2016-19504_KX675261, PV SP22612-2016-AFP3601VI_KX949564 NY188_16_KY385888 3 : 15 DE/BW/16-674/2016_KX830910 TW-03495_2015_MH341113 : 2018 10 X, A250-OsakaC-JPN-2015_LC107900* L1882-Yamagata-2015_LC203572* 1 38.5, 3 SMC-15-Sendai881_KX789267* B 1758-Yamagata-2015_LC203575* 5 A241-OsakaC-JPN-2015_LC107898* A244-OsakaC-JPN-2015_LC107899*, 953 ITA/PV/38993-2016_MF073350 6 : EV 5UTR-VP2 semi nested- United_Kingdom_2015_MH361028 ITA/PV-37298/2016_MF073346 30180384EVD68VP1106 974 30180504EVD68VP11115 FRA_2009R0048_KY272957 CUHK-PAE08/15_MG739639 US/CA/14-6092_2014_KP100792 RT PCR 1, EV-D68 PCR 2, 1000 NY210_2014_KP745757 NY120_2014_KP745751 EV-D68 nested-rt PCR 3, PV L-20B RD-A 3, 2124-Yamagata-2005_AB667892 ITA/26868/08_KC763172 JPOC10-404_Osaka_City_2010_AB601885 2167-Yamagata-2010_AB614439 C JPOC10-396_Osaka_City_2010_AB601884 0.01 2015 2. :VP1 :,, 369 bootstrap value > 950, 5,, 6 EV-D68 EV RV, PV, 2 2, 369 100, 2015 Clade B, bootstrap value 974/1,000, 2, 2018, 2015 2, EV-D68, 2 3, 3 3,,, 15,, EV EV 5UTR-VP2 semi nested-rt PCR 1,, EV-D68 PCR 2, EV-D68 nested-rt PCR 3, EV-D68, 2015, 4,,, EV- D68,, i, ii PV EV PV,, 1, 27: 283-293, 1999 2Wylie TN, et al., J Clin Microbiol 53 8: 2641-2647, 2015 3, 91 3: 376-385, 2017 4Chong PF, et al., Clin Infect Dis 66 5: 653-664, 2018

IASR Reporting situation of carbapenem-resistant Enterobacteriaceae in the Infectious Agent Surveillance System... 19 Effective utilization of carbapenem-resistant Enterobacteriaceae infection surveillance data... 20 Carbapenem-resistant Enterobacteriaceae: data from the Ministry of Health, Labour and Welfare s Japan Nosocomial Infections Surveillance (JANIS) system... 21 Microbiological testing methods for carbapenemase-producing Enterobacteriaceae in hospital settings... 22 Treatment of carbapenem-resistant Enterobacteriaceae infections... 24 Description of carbapenemase-producing Enterobacteriaceae from overseas... 25 Nosocomial infections of KPC-type carbapenem-resistant Enterobacteriaceae in the jurisdictional area of the Koriyama Local Health Center, Fukushima Prefecture, 2017... 27 Carbapenemase-producing bacteria detected at a hospital sink: the importance of the hospital environment as a reservoir for antimicrobial resistant bacteria... 28 Monitoring antimicrobial resistance in the environment: contributions to a One Health approach... 29 Detection of influenza virus exhibiting resistance to the novel influenza antiviral drug baloxavir marboxil, 2018... 30 Testing of patients with acute flaccid paralysis and case reports of patients detected with EV-D68, Osaka Prefecture, 2018... 31 <THE TOPIC OF THIS MONTH> Carbapenem-resistant Enterobacteriaceae (CRE) Infection, Japan Carbapenem-resistant Enterobacteriaceae (CRE) infection is a broad term for infections caused by certain types of Enterobacteriaceae such as Escherichia coli and Klebsiella pneumoniae that are resistant to carbapenem and broad spectrum ß-lactam antibiotics. These antibiotics, such as meropenem, are most important for the treatment of Gram-negative bacterial infections. CRE mainly cause infections in patients with compromised immune systems, patients in their postoperative period, and patients who are administered antibiotics over a long period of time. Infection can result in infectious diseases, including respiratory infections, such as pneumonia, urinary tract infections, infections of surgical sites, skin, and soft tissues, medical device-associated infections (e.g. catheter-associated), sepsis, and meningitis, often causing hospital-acquired infections (HAIs). CRE can occasionally infect healthy individuals. In addition, there is often asymptomatic carriage of the bacteria such as in the digestive tract. National Epidemiological Surveillance of Infectious Diseases (NESID) Since September 19, 2014, CRE infection has been included in the list of category V infectious diseases (for the notification criteria, see: https://www.niid.go.jp/niid/images/iasr/35/418/de4181.pdf). Additionally, in this surveillance system, only those who developed clinical manifestations are eligible for notification. While approximately 1,600 CRE infection patients were notified annually between 2015 and 2017, more than 2,000 cases were notified prior to December 25 (week 48) in 2018 (Fig. 1). Over a period of four years, approximately 80% of cases were found in patients aged 65 years or older. By prefecture, Tokyo, Kanagawa, Aichi, Osaka, and Fukuoka were the top five prefectures reporting the largest number of cases, accounting for 43% of all notifications. There were 35 prefectures whose number of annual notifications exceeded 10 in 2015, but this gradually increased to 38 in 2016, and 39 in 2017 and 2018 (through week 48 in 2018) (Fig. 2). Regarding the distribution of notifications by bacteria species, the top four species with the largest proportions were Enterobacter cloacae, Klebsiella aerogenes (N.B. the scientific name was changed in 2017), K. pneumoniae, and E. coli through 2018; the proportion of K. aerogenes began to increase from 2017, and it has since become the most notified bacteria species (Fig. 3 in p. 18). Infectious Agents Surveillance System Among CRE, carbapenemase-producing Enterobacteriaceae (CPE), which produce enzymes that break down carbapenem, are often resistant to antibiotics other than ß-lactam antibiotics, and bacteremia caused by CPE has been reported to have a poorer therapeutic prognosis than that caused by non-carbapenemase-producing CRE (see p. 24 of this issue). In addition, as the carbapenemase gene in CPE is located on mobile genetic elements, such as plasmids, in many cases, the drug-resistant property can be spread across bacterial species. Thus, distinguishing CPE from other CRE is considered to be necessary for both countermeasures against hospitalacquired infections and for therapy, and requires the implementation of carbapenemase gene examinations (see p. 22 of this issue). Based on the notice issued on March 28, 2017 by the Director of the Tuberculosis and Infectious Diseases Control Division, Health Service Bureau, Ministry of Health, Labour and Welfare, in the event of a CRE infection notification, prefectural and municipal public health institutes (and other relevant entities) are requested to conduct testing for the carbapenemase gene (resistance gene) in order to ascertain the situation in the area (see p. 19 of this issue). There are several known varieties of carbapenemase; the type frequently found in Japan is the IMP type, and the NDM, KPC, and OXA-48 types are spreading overseas. The types found overseas are often multidrug-resistant, frequently demonstrating resistance not only to carbapenem but also to other antibacterial drugs, and require particular attention in terms of infection control (IASR 35: 283-284, 2014). Of the strains registered in the Infectious Agents Surveillance System, at least one of the carbapenemase genes was detected in Figure 1. Age distribution of notified carbapenem-resistant Enterobacteriaceae infection cases by year, 2014-2018, Japan 2,200 Age group (year) 2,000 75 1,800 65-74 n=no. notified cases 1,600 15-64 1,400 0-14 1,144 1,200 894 825 910 1,000 800 512 600 408 389 422 400 200 170 72 317 323 282 362 0 59 13 41 39 47 56 2014 2015 2016 2017 20182 (n=314) (n=1,669) (n=1,573) (n=1,660) (n=2,074) Year 1 week 38-52, 2014 2 week 1-48, 2018 (National Epidemiological Surveillance of Infectious Diseases: as of 25 December 2018) No. notified cases Vol. 40 No. 2 (No. 468) February 2019 Infectious Agents Surveillance Report https://www.niid.go.jp/niid/en/iasr-e.html 1 17 Figure 2. Yearly number of notified carbapenem-resistant Enterobacteriaceae infection cases by prefecture, 2015-2018, Japan No. of notified cases by prefecture 1-9 10-99 100- ISSN 0915-5813 National Institute of Infectious Diseases and Tuberculosis and Infectious Diseases Control Division, Ministry of Health, Labour and Welfare 2015 2016 2017 2018 Year week 1-48, 2018 (National Epidemiological Surveillance of Infectious Diseases: as of 25 December 2018) Continued on page 18

IASR Vol. 40 No. 2 Feb. 2019 2 18 THE TOPIC OF THIS MONTH-Continued Figure 3. Yearly number and proportion of notified carbapenem-resistant Enterobacteriaceae infection cases by bacterial species, 2014-2018, Japan 0 10 20 30 40 50 60 70 80 90 100 3 Year No. notified 1 cases 2014 78 101 40 39 49 8 314 2015 480 550 206 148 261 32 1,669 2016 466 486 176 145 242 58 1,573 2017 564 482 162 141 257 55 1,660 2 2018 781 595 184 143 296 78 2,074 Klebsiella aerogenes Enterobacter cloacae Escherichia coli Klebsiella pneumoniae difficulty in isolation Other or not described 1 week 38-52, 2014 2 week 1-48, 2018 3 No. notified cases differ from the sum of notifications by bacterial species because multiple strains were isolated from some cases. (National Epidemiological Surveillance of Infectious Diseases: as of 25 December 2018) 239 and 123 strains in 2017 and in the first half of 2018, respectively; the IMP type was detected in 227 and 111 strains in 2017, and during the first half of 2018, respectively, making it the most common type. In 2017, the proportion of CRE with IMP-type strain detection exhibited large regional differences in bacterial species and genetic types (see IASR 39: 162-163, 2018). On the other hand, six local governments reported cases of overseas-type carbapenemase gene-positive strains, and the majority were identified in patients who had no history of overseas travel. Moreover, in 2018, there was an outbreak caused by a KPC-type carbapenemase gene-positive strain (see p. 27 of this issue) and a report concerning contamination of the hospital environment by an NDM-type carbapenemase gene-positive strain (see p. 28 of this issue). Therefore, there is concern regarding the spread of overseas-type carbapenemase gene-positive strains into the community or hospital environments (see p. 25 of this issue). Since 2018, the Antimicrobial Resistance Research Center and the Infectious Disease Surveillance Center (both part of the National Institute of Infectious Diseases; NIID) have been jointly conducting a weekly teleconference on notified cases of CRE infection, sharing patient information from the NESID system along with the pathogen detection information, conducting risk assessment of notified cases, and contacting local governments as needed (see p. 20 of this issue). Japan Nosocomial Infections Surveillance (JANIS) system of the Ministry of Health, Labour and Welfare The Testing Division of JANIS continuously collects and collates all bacterial testing data obtained from over 2,000 participating medical institutions, representing the isolation status of major drug-resistant bacteria in Japan. Unlike the NESID system, no distinction is made between colonization and disease manifestation; data are compiled for bacteria isolated at the participating medical institutions that fulfill the laboratory criteria for notification under the Infectious Diseases Control Law. Although the number of patients with CRE continues to decrease, there were over 7,000 in 2017. As the number of patients with CRE isolation in the JANIS system is markedly higher than the number of patients included in the NESID system (limited to symptomatic cases), it is possible that there are many carriers of CRE. The proportions of CRE bacteria species reported by JANIS are consistent with those reported by NESID, and the increased proportion of K. aerogenes was also observed in the 2017 JANIS data (see p. 21 of this issue). Nippon AMR One Health Report (NAOR) Measures for responding to the antimicrobial resistance (AMR) problem, including CRE, require the One Health Approach, i.e., multi-sectoral cooperation and collaboration among the medical care, animal husbandry, and environmental sectors. On the global stage, organizations such as the World Health Organization (WHO), the World Organization for Animal Health (OIE), and the Food and Agriculture Organization (FAO) play a central role in this effort. The AMR National Action Plan (NAP) 2016-2020 stipulates that comprehensive One Health Surveillance be implemented for drug-resistant bacteria isolated from humans, animals, food, and the environment. JANIS releases information on resistance rates for human-derived pathogenic bacteria isolated from participating medical institutions, and the Japanese Veterinary Antimicrobial Resistance Monitoring System (JVARM) and local public health institutes release information on resistance rates among animal- and food-derived pathogenic bacteria (resistant bacteria as a proportion of all identified bacteria). The AMR One Health Surveillance Committee summarizes these data (Nippon AMR One Health Report 2017: https://www.mhlw.go.jp/file/06-seisakujouhou-10900000-kenkoukyoku/0000204347.pdf). Environmental AMR surveillance, which deals mainly with rivers and sewage, was initiated by a research group and has been funded by a Health and Labour Sciences Research Grant (HLSRG) since 2018 (see p. 29 of this issue). National Action Plan and Performance Indicators The Global Action Plan (GAP) for AMR was adopted at the 2015 World Health Assembly (WHO), and in 2016, Japan drew up its own AMR National Action Plan (NAP) 2016-2020. In response to the NAP, a wide variety of domestic and overseas AMR-related data are collected, and in order to feedback the information to the clinical settings, utilize the information for research, and provide policy guidance to WHO and other stakeholders, the AMR Research Center was established in 2017 in NIID to function as a comprehensive think-tank for AMR. The resistance rates for human-derived pathogenic bacteria, which is used as a performance indicator by NAP, is calculated based on JANIS data managed by the AMR Research Center in NIID. A resistance rate of 0.2% against carbapenem (imipenem and meropenem) for E. coli and K. pneumoniae is established as the performance indicator by NAP. In 2017, a meropenem resistance rate of 0.4% was found in K. pneumoniae, which was higher than the performance indicator, and the number of patients notified under the NESID system also increased in 2018. Therefore, in order to ascertain the epidemiological situation in each region of Japan and strengthen the ability to respond, continued implementation of national surveillance is necessary. The statistics in this report are based on 1) the data concerning patients and laboratory findings obtained by the National Epidemiological Surveillance of Infectious Diseases undertaken in compliance with the Act on the Prevention of Infectious Diseases and Medical Care for Patients with Infectious Diseases, and 2) other data covering various aspects of infectious diseases. The prefectural and municipal health centers and public health institutes (PHIs), the Department of Environmental Health and Food Safety, the Ministry of Health, Labour and Welfare, and quarantine stations, have provided the above data. Infectious Disease Surveillance Center, National Institute of Infectious Diseases Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, JAPAN Tel (+81-3)5285-1111

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