The importance of meropenem resistance, rather than imipenem resistance, in defining carbapenem-resistant Enterobacterales for public health surveillance: an analysis of national population-based surveillance
Authors: Ikenoue Chiaki , Matsui Mari , Inamine Yuba , Yoneoka Daisuke , Sugai Motoyuki , Suzuki Satowa ,   the Antimicrobial-Resistant Bacteria Research Group of Public Health Institutes (AMR-RG-PHI), Matsui Mari , Suzuki Satowa , Takahashi Yohei , Kamitaka Nozomi , Takahashi Shiho , Kanno Nami , Ishi Takuya , Shimada Ryo , Takahashi Hiroko , Ogawa Mayumi , Kikuchi Koji , Ueno Hiroyuki , Tomari Kentaro , Yoshihara Junko , Ando Naoshi , Katakura Takako , Matsumoto Yuko , Anzawa Yoko , Haruna Satoko , Hosoya Mikako , Watahiki Masanori , Shiroza Mika , Yokoyama Koji , Noda Makiko , Furuta Ayako , Kawahara Ryuji , Umeda Kaoru , Yamaguchi Takahiro , Nakanishi Noriko , Kuroda Kumiko , Saito Etsuko , Inoue Yumiko , Kawakami Yuta , Aota Tatsuaki , Masuda Kanako , Ohtsuka Hitoshi , Fukuda Chiemi , Seki Kazumi , Iwashita Yoko , Asano Yukiko , Fukuguchi Yuka , Arikawa Emi , Maeda Rika , Kudeken Tsuyoshi 
Published: February 2024

Abstract
Background
In Japan, carbapenem-resistant Enterobacterales (CRE) infections were incorporated into the National Epidemiological Surveillance of Infectious Diseases (NESID) in 2014, necessitating mandatory reporting of all CRE infections cases. Subsequently, pathogen surveillance was initiated in 2017, which involved the collection and analysis of CRE isolates from reported cases to assess carbapenemase gene possession. In this surveillance, CRE is defined as (i) minimum inhibitory concentration (MIC) of meropenem ≥2 mg/L (MEPM criteria) or (ii) MIC of imipenem ≥2 mg/L and MIC of cefmetazole ≥64 mg/L (IPM criteria). This study examined whether the current definition of CRE surveillance captures cases with a clinical and public health burden.

Methods
CRE isolates from reported cases were collected from the public health laboratories of local governments, which are responsible for pathogen surveillance. Antimicrobial susceptibility tests were conducted on these isolates to assess compliance with the NESID CRE definition. The NESID data between April 2017 and March 2018 were obtained and analyzed using antimicrobial susceptibility test results.

Results
In total, 1681 CRE cases were identified during the study period, and pathogen surveillance data were available for 740 (44.0%) cases. Klebsiella aerogenes and Enterobacter cloacae complex were the dominant species, followed by Klebsiella pneumoniae and Escherichia coli. The rate of carbapenemase gene positivity was 26.5% (196/740), and 93.4% (183/196) of these isolates were of the IMP type. Meanwhile, 315 isolates were subjected to antimicrobial susceptibility testing. Among them, 169 (53.7%) fulfilled only the IPM criteria (IPM criteria-only group) which were susceptible to meropenem, while 146 (46.3%) fulfilled the MEPM criteria (MEPM criteria group). The IPM criteria-only group and MEPM criteria group significantly differed in terms of carbapenemase gene positivity (0% vs. 67.8%), multidrug resistance rates (1.2% vs. 65.8%), and mortality rates (1.8% vs 6.9%).

Conclusion
The identification of CRE cases based solely on imipenem resistance has had a limited impact on clinical management. Emphasizing resistance to meropenem is crucial in defining CRE, which pose both clinical and public health burden. This emphasis will enable the efficient allocation of limited health and public health resources and preservation of newly developed antimicrobials.