(2024) 24:209
Ikenoue et al. BMC Infectious Diseases
https://doi.org/10.1186/s12879-024-09107-4

BMC Infectious Diseases

Open Access

RESEARCH

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
Chiaki Ikenoue1,2, Mari Matsui3, Yuba Inamine3, Daisuke Yoneoka4, Motoyuki Sugai3, Satowa Suzuki3* and the
Antimicrobial-Resistant Bacteria Research Group of Public Health Institutes (AMR-RG-PHI)3

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 wereobtained 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 weresusceptible to meropenem, while 146 (46.3%) fulfilled the MEPM criteria (MEPM criteria group). The IPM criteria-onlygroup 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 clinicalmanagement. Emphasizing resistance to meropenem is crucial in defining CRE, which pose both clinical and public*Correspondence:
Satowa Suzuki
suzukiss@niid.go.jp
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Ikenoue et al. BMC Infectious Diseases(2024) 24:209

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health burden. This emphasis will enable the efficient allocation of limited health and public health resources
and preservation of newly developed antimicrobials.
Keywords Carbapenem-resistant Enterobacterales, Carbapenemase-producing Enterobacterales, Surveillance
definition, Meropenem, Imipenem, IMP-type metallo-β-lactamase, Multidrug resistance

Background
Carbapenem-resistant Enterobacterales (CRE) havebeen represents a global public health concern, and theimportance of surveillance is well recognised [1–3]. Furthermore, carbapenemase-producing Enterobacterales(CPE) have been prioritised as the target in CRE surveillance because of their potential to exhibit multidrug
resistance and cause outbreaks in healthcare settings [1,4, 5]. However, practical application of the definition of
CRE for surveillance based on the antimicrobial susceptibility test (AST) in clinical diagnostic laboratories iscumbersome because the minimum inhibitory concentrations (MICs) of carbapenems for CPE might be below
the clinical breakpoints, Enterobacterales consists ofdiverse bacteria species, and their mechanisms of carbapenem resistance are complex and inconsistent.
In Japan, patient-based CRE case surveillance wasincluded in the National Epidemiological Surveillance ofInfectious Diseases (NESID) in 2014, followed by CRE
pathogen surveillance in 2017 [6]. In this national surveillance, CRE was defined as follows:(i) MIC of meropenem ≥2 mg/L (MEPM criteria) or(ii) MIC of imipenem ≥2 mg/L and cefmetazole≥64 mg/L (IPM criteria).
The characteristics of this Japanese definition of CRE isa low MIC cutoff (meropenem/imipenem MIC ≥2 mg/L)
and the combined usage of imipenem resistance andcefmetazole resistance (MIC ≥64 mg/L).
In establishing these criteria, numerous discussions
occurred regarding the IPM criteria. It was acknowledged that imipenem was not recommended for detecting CPE because of its overlapping MIC distribution
among wild-type isolates and carbapenemase producers, particularly in several species of Enterobacterales [7,8]. However, imipenem was inevitably included in the
CRE definition because in Japanese clinical settings in
2014, carbapenem susceptibility was primarily assessedusing imipenem rather than meropenem. However, a low
MIC cutoff for carbapenems was deemed necessary toenhance the sensitivity of CPE detection. The reason for
combining cefmetazole resistance with imipenem resistance was to exclude intrinsic imipenem non-susceptible
Proteus mirabilis and CTX-M-type extended-spectrum
β-lactamase (ESBL) producers, which are endemic toJapan [9, 10].

Imipenem resistance is usually included in the definition of CRE in other countries. The current definition
provided by the Centers for Disease Control and Prevention of United States (US-CDC) for CRE is Enterobacterales that are resistant to any carbapenem (i.e., MIC
of ≥4 mg/L for doripenem, meropenem, or imipenem
or ≥ 2 mg/L for ertapenem) or documented carbapenemase production [11]. The European Antimicrobial
Resistance Surveillance Network has focused on carbapenem resistance using imipenem or meropenem, as wellas multidrug resistance (defined as resistance to a combination of fluoroquinolones, third-generation cephalosporins, and aminoglycoside) in Escherichia coli andKlebsiella pneumoniae [12].
The CRE definition in national surveillance has a substantial impact on clinical management, infection control
policy, and clinical research. However, since the introduction of Japanese CRE surveillance, no study has evaluated whether the IPM and MEPM criteria facilitate theeffective detection of CPE and identification of CRE casesthat truly pose a clinical and public health burden.

Methods
This population-based observational study aimed toassess the current CRE definition used in Japan by analyzing data collected between April 2017 and March2018 by national case and pathogen surveillance and theantimicrobial susceptibilities of isolates obtained from
reported CRE cases.
National surveillance data of cases of CRE infectionsin Japan

Physicians must report all diagnosed CRE cases to public health centres within 7 days of diagnosis. The definition of CRE used in this surveillance program was as
described in the Background. CRE infection was reported
if CRE was isolated from aseptic clinical specimens orfrom non-aseptic clinical specimens, followed by clinical confirmation that the isolated CRE was the causative
infectious pathogen.
Information collected in the surveillance reporting form includes patient demographics, type of infection, CRE species, clinical specimen, date of diagnosis,
and date of death, if applicable. We considered all cases
whose date of death was reported as fatal within 7 days ofdiagnosis, to analyse the all-cause 7-day mortality.

Ikenoue et al. BMC Infectious Diseases(2024) 24:209

This study analyzed the data of CRE cases diagnosed
between April 1, 2017 and March 31, 2018, and the data
were obtained from the NESID system on October 10,
2018. The per capita incidence of CRE infection was calculated using national statistics obtained from the Statistics Bureau of Japan. The estimated total population ofJapan was 126,706,000 as of October 1, 2017.
National pathogen surveillance data for CRE

In March 2017, pathogen surveillance for CRE was initiated as part of the NESID program in which the results ofcarbapenemase gene investigations have been registered.
The Public Health Institute (PHI) of each local government conducted genotypic analysis of the CRE isolates
from the reported CRE cases, examining the major carbapenemase genes (blaIMP, blaKPC, blaNDM, and blaOXA48-like) using polymerase chain reaction and conducting
phenotypic tests for carbapenemase production using
metallo-β-lactamase inhibitors (sodium mercapto-acetic
acid or EDTA) and a KPC-type carbapenemase inhibitor (boronic acid). All PHI personnel in charge of theseanalysis were trained at the National Institute of Infectious Diseases (NIID) for standardized surveillance. In
this study, pathogen data were obtained from the NESID
pathogen surveillance system on October 23, 2018 andintegrated with the data of CRE cases.
Antimicrobial susceptibility

Because AST data are not included neither in CRE casesurveillance nor pathogen surveillance, isolates registeredin the pathogen surveillance from the PHIs were collectedin this study, and their MICs were determined for ten
types of antimicrobials (flomoxef, ceftriaxone, cefepime,
piperacillin–tazobactam, aztreonam, imipenem, meropenem, levofloxacin, amikacin, and tigecycline) using
the MicroScan Neg MIC EN 2 J panel (Beckman Coulter,
Brea, CA, USA) at NIID. Susceptibility breakpoints foreach antimicrobial were determined with reference tothe 26th edition of the Clinical and Laboratory Standards
Institute (CLSI) M100 [13]. The breakpoints for flomoxef
and tigecycline, which are not included in the CLSI criteria, were defined as follows: flomoxef, ≤8 mg/L forsusceptible and > 32 mg/L for resistant; and tigecycline,≤0.5 mg/L for susceptible and > 0.5 mg/L for resistant.
Statistical analysis

The Wilcoxon rank-sum test was used to analyze statistically significant differences in continuous variables,
whereas categorical variables were analyzed using Fisher’s exact test.
The statistical association between the variables ofinterest and all-cause 7-day mortality was evaluated using
a logistic regression approach. Statistically significant risk

Page 3 of 10

factors identified by univariate logistic regression were
further evaluated using multivariable logistic regression.
Statistical tests were two-sided, and p < 0.05 denoted
statistical significance. Hommel-type corrections wereconducted for multiple tests when necessary to appropriately identify the statistical association between
outcomes and mortality. In addition, when a clear association was observed with mortality prior to the tests,
the significance was subjected to one-sided testing with athreshold of p < 0.05. Statistical analyses were performed
using JMP 13.2.1 (SAS Institute Inc., Cary, NC, USA) and
RStudio (2021.09.0 + 3519).

Results
Description of CRE cases in Japan

In total, 1681 cases of CRE infection were reported
across all 47 prefectures of Japan between April 2017 andMarch 2018; thus, the annual incidence was 1.33 cases
per 100,000 population.
Pathogen surveillance data were available for 740(44.0%) of the 1681 reported cases. Carbapenemase
gene-positive Enterobacterales (CgPE) infection was confirmed in 196 cases (26.5%, Table 1). The clinical featuresof CgPE and carbapenemase gene-negative Enterobacterales (CgNE) infections were generally similar, exceptthat CgPE cases were less likely to involve intra-abdominal infection than CgNE cases. Four species, namely
Klebsiella aerogenes, Enterobacter cloacae complex(ECC), K. pneumoniae, and E. coli, accounted for approximately 80% of the reported pathogens. No isolates of K.
aerogenes, the most reported species, were CgPE, and K.
pneumonia, and E. coli were observed more frequently in
CgPE cases than in CgNE cases. The predominant carbapenemase gene was blaIMP (183, 93.4%), whereas few
other carbapenemase genes were observed [blaNDM andblaKPC in eight (4.1%) and five cases (2.6%), respectively].
The all-cause 7-day mortality was 4.5% among 740 CRE
cases with pathogen surveillance data, and the rate washigher for CgPE cases (6.1%) than for CgNE cases (3.9%),
although the difference was not statistically significant.
Seven‑day mortality risk analysis

Thirty-three (4.5%) of the 740 CRE cases under pathogen
surveillance were fatal (Supplemental Table 1). Univariate
and multivariate analyses (Table 2) revealed that bloodstream infections, respiratory tract infections, and E. coli
infections were significant risk factors for 7-day mortality, whereas carbapenemase gene positivity was not significant [odds ratio (OR) = 1.62, 95% confidence interval(CI) = 0.78–3.37, p = 0.225].
When the assessment specifically focused on determining the 7-day mortality risk among CgPE infections, positivity for the KPC/NDM-type carbapenemase gene was

Ikenoue et al. BMC Infectious Diseases(2024) 24:209

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Table 1 Baseline characteristics of cases with carbapenem-resistant Enterobacterales infection reported to the National
Epidemiological Surveillance of Infectious Diseases
Characteristic

All reported cases

Cases with pathogen
surveillance data

CgPE cases

CgNE cases(N = 1681)(N = 740)(N = 196)(N = 544)

P value

Age, median [IQR]

76 [67–83]

77 [68–84]

78 [69–85]

76 [67–84]

0.085

Male (N, %)1045 (62.2%)454 (61.4%)

112 (57.1%)

342 (62.9%)

0.171Type of infection (N, %)Urinary tract infection

542 (32.2%)

244 (33.0%)

76 (38.8%)

168 (30.9%)

0.051

Bloodstream infection

491 (29.2%)

208 (28.1%)

64 (32.7%)

144 (26.5%)

0.115

Intra-abdominal infection

454 (27.0%)

207 (28.0%)

31 (15.8%)

176 (32.4%)< 0.001

Respiratory tract infection

368 (21.9%)

171 (23.1%)

53 (27.0%)

118 (21.7%)

0.913

Bone and soft tissue infection

138 (8.2%)

61 (8.2%)

16 (8.2%)

45 (8.3%)

1.000

Others16 (1.0%)

6 (0.8%)1 (0.5%)5 (0.9%)1.000

Not specified

5 (0.3%)2 (0.3%)0 (0%)

2 (0.4%)0Multiple types of infection

305 (18.1%)

144 (19.5%)

40 (20.4%)

104 (19.1%)

0.752

Bacterial species (N, %)Klebsiella aerogenes

595 (35.4%)

241 (32.6%)

0 (0%)

241 (44.3%)< 0.001Enterobacter cloacae complex

487 (29.0%)

202 (27.3%)

60 (30.6%)

142 (26.1%)

0.226

Klebsiella pneumoniae

165 (9.8%)

86 (11.6%)

53 (27.0%)

33 (6.1%)< 0.001

Escherichia coli

129 (7.7%)

68 (9.2%)

38 (19.4%)

30 (5.5%)< 0.001

Serratia marcescens

71 (4.2%)

29 (3.9%)4 (2.0%)25 (4.6%)

0.135

Others192 (11.4%)

97 (13.1%)

37 (18.9%)60 (11.0%)

0.007

Not reported

48 (2.9%)18 (2.4%)

4 (2.0%)14 (2.6%)

0.793–

Detected carbapenemase gene (N, %)blaIMP–

183 (24.7%)

183 (93.4%)–

blaNDMa–

8 (1.1%)8a (4.1%)––

blaKPCb–

5 (0.7%)5b (2.6%)––

blaOXA-48-like–

0 (0%)

0 (0%)––

Cases with reported date of death (N, %)68 (4.0%)33 (4.5%)

12 (6.1%)

21 (3.9%)

0.225

IQR interquartile range: CgPE carbapenemase gene-positive Enterobacterales: CgNE carbapenemase gene-negative EnterobacteralesaBacterial species for blaNDM-positive isolates were K. pneumoniae (n = 5) and E. coli (n = 3).bAll isolates carrying blaKPC were K. pneumoniae

a significant independent risk factor compared to IMPtype carbapenemase (Table 3). Cases associated with the
KPC/NDM-type carbapenemase gene most frequently
manifested as bloodstream infection, which was identified as one of the significant risk factors in the 7-day
mortality risk analysis for CRE. Conversely, urinary tract
infection was the most reported manifestation in cases
associated with IMP-type carbapenemase (Supplemental
Table 2).
Antimicrobial susceptibility

Among the 740 cases with pathogen surveillance data,
357 isolates from the same number of cases (357/740,
48.2%) underwent AST at NIID. The species distribution (p = 0.0776) and CgPE proportion (28.2% vs. 26.5%
in pathogen surveillance, p = 0.562) of the 357 isolates
did not differ significantly from those of the 740 isolates
identified during pathogen surveillance.

Figure 1 depicts the susceptibility to ten antimicrobials by species and the presence or absence of the carbapenemase gene. The proportion of multidrug resistance,
defined as resistance to more than two of four commonlyused broad-spectrum antimicrobials other than carbapenems in Japan (cefepime, piperacillin–tazobactam,
levofloxacin, and amikacin), was 29.1% among the 357
CRE isolates, and the proportion was significantly higher
in CgPE cases than in CgNE cases (65.4% vs. 14.8%,
OR = 10.8; 95% CI = 6.33–18.48, p < 0.0001).
K. aerogenes and carbapenemase gene-negative ECC
retained susceptibility to various types of antimicrobials,
where the proportions of resistance to cefepime, piperacillin–tazobactam, levofloxacin, and amikacin were 5.7,
10.0, 0.5, and 0%, respectively, leading to a low proportionof multidrug resistance among all CgNE isolates. Conversely, K. pneumoniae and E. coli displayed no difference in the proportion of multidrug resistance regarding
carbapenemase gene possession (E. coli: 86.7% for CgNE

Ikenoue et al. BMC Infectious Diseases(2024) 24:209

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Table 2 Seven-day mortality risk analysis among CRE cases with pathogen surveillance data (N = 740)
CRE cases with pathogen surveillance data (N = 740)
Univariate analysis
Covariate

OR (95% CI)

Multivariate analysis
PaOR (95% CI)

P

Male

1.72 (0.79–3.75)

0.202

–

–

Age < 18 years

1.92 (0.43–8.51)

0.308

–

–

Age > 64 years

2.43 (0.73–8.06)

0.174

–

–

Urinary tract infection

0.44 (0.18–1.08)

0.087

–

–

Bloodstream infection

2.87 (1.42–5.8)

0.005

4.00 (1.88–8.52)

0.0003

Respiratory tract infection

2.94 (1.45–5.97)

0.005

4.71 (2.17–10.24)< 0.0001

Intra-abdominal infection

1.3 (0.62–2.74)

0.552

–

–

Bone and soft tissue infection

0.71 (0.17–3.03)

1.000

–

–

Escherichia coli

4.12 (1.83–9.27)

0.002

5.17 (2.18–12.24)

0.0002

Klebsiella aerogenes

0.65 (0.29–1.47)

0.346

–

–

Klebsiella pneumoniae

0.75 (0.22–2.52)

1.000

–

–

Enterobacter cloacae complex

0.85 (0.38–1.91)

0.842

–

–

Serratia marcescens

2.62 (0.75–9.14)

0.134

–

–

Carbapenemase gene-positive Enterobacterales

1.62 (0.78–3.37)

0.225

–

–

aOR adjusted odds ratio: OR odds ratio: CI confidence interval

Table 3 Seven-day mortality risk analysis among CgPE cases(N = 196)
Univariate analysis
OR (95% CI)

P

Male

1.05 (0.32–3.44)

1.000

Age < 18 years

2.3 (0.26–20.38)

0.402

Age > 64 years

1.81 (0.22–14.62)

1.000

Urinary tract infection

0.3 (0.06–1.4)

0.133

Bloodstream infection

3.12 (0.95–10.25)

0.061

Respiratory tract infection

2.91 (0.9–9.48)

0.09

Intra-abdominal infection

0.47 (0.06–3.75)

0.695

Bone and soft tissue infection

1.02 (0.8–8.48)

1.000

Escherichia coli

2.21 (0.63–7.75)

0.253

Klebsiella pneumoniae

0.52 (0.11–2.46)

0.519Enterobacter cloacae complex

1.14 (0.33–3.95)

1.000

Serratia marcescens

5.48 (0.53–57.14)

0.225

blaNDM, blaKPC

5.8 (1.36–24.82)

0.036

OR odds ratio, CI confidence interval

vs. 88.2% for CgPE, p = 1.000; K. pneumoniae: 64.7% for
CgNE vs. 46.7% for CgPE, p = 1.000). Furthermore, E.
coli exhibited remarkably high levofloxacin resistance.
CgNE-E. coli and CgPE-E. coli displayed equally highlevels of levofloxacin resistance (86.7 and 88.2%, respectively). Among the carbapenemase types, NDM/KPCtype CgPE exhibited a distinctively higher proportionof multidrug resistance than IMP-type CgPE (100% vs.

62.0%, p = 0.025). All NDM/KPC-type CgPE isolates wereresistant to cefepime, piperacillin–tazobactam, and levofloxacin. By contrast, 89, 27, and 40% of IMP-type CgPE
isolates were resistant to cefepime, piperacillin–tazobactam, and levofloxacin, respectively.
Regarding the mortality risk associated with multidrug
resistance, CRE isolates simultaneously resistant to threebroad-spectrum antimicrobials, namely cefepime, piperacillin–tazobactam, and levofloxacin, carried a higher
risk of 7-day mortality than isolates not resistant to these
antimicrobials (13.8% vs. 3.7%, OR = 4.22. 95% CI = 1.27–
14.03, p = 0.0593). However, the observed difference was
not significant, possibly because of a lack of statisticalpower attributable to the small number of fatal cases.
Comparison of the two CRE criteria groups

To compare the clinical characteristics of CRE cases identified by imipenem resistance and meropenem resistance,
two groups were defined: the “IPM criteria-only group,”
which fulfilled only the IPM criteria and not the MEPM
criteria, and the “MEPM criteria group,” which met
the MEPM criteria regardless of imipenem resistance.
Among the 357 isolates, 315 (88.2%) met the CRE definition based on AST results at the NIID. Among them, 169
isolates (53.7%) were categorised into the IPM criteriaonly group, and 146 (46.3%) belonged to the MEPM criteria group. The majority (71.2% 104/146) of the isolates
in the MEPM criteria group simultaneously fulfilled theIkenoue et al. BMC Infectious Diseases(2024) 24:209

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Fig. 1 Antimicrobial susceptibility patterns of CRE isolates. Proportions of isolates resistant (R), intermediate (I), and susceptible (S) to the indicatedantimicrobials as specified below the graphs, are represented by red, yellow, and blue bars. Antimicrobial abbreviations: FMOX (flomoxef ), CTRX
(ceftriaxone), CFPM (cefepime), P/T (piperacillin/tazobactam), AZT (aztreonam), IPM (imipenem), MEPM (meropenem), LVFX (levofloxacin), AMK(amikacin), TGC (tigecycline)

Table 4 IPM-criteria-only group and MEPM-criteria group: Comparison among the isolates satisfying Japanese CRE criteria at national
central laboratory (N = 315)
N (%)

IPMcriteria-only group
N = 169

MEPM criteria group
N = 146

P-value

IPM criteria fulfilled

169 (100%)

104 (71.2%)–

Klebsiella aerogenes

109 (64.5%)

13 (8.9%)< 0.0001

Enterobacter cloacae complex

55 (32.5%)

40 (27.4%)

0.328

Klebsiella pneumoniae

0 (0%)

40 (27.4%)< 0.0001

Escherichia coli

1 (0.6%)44 (30.1%)< 0.0001

Serratia marcescens

4 (2.4%)9 (6.2%)

0.153

CgPE

0 (0%)

99 (67.8%)< 0.0001

Multidrug resistance

2 (1.2%)96 (65.8%)< 0.0001

7-day-mortality

3 (1.8%)10 (6.9%)

0.0428

US-CDC CRE reporting ­criteriaa fulfilled

46 (27.2%)

146 (100%)< 0.0001

0 (0%)

128 (87.7%)< 0.0001

Meropenem MIC≥4
Imipenem MIC≥441 (24.3%)

85 (58.2%)< 0.0001

Ertapenem MIC≥2

10 (5.9%)

146 (100%)< 0.0001

IPMcriteria-only group = Isolates meeting the criteria only for imipenem MIC≥2 and cefmetazole MIC≥64
MEPM criteria group = Isolates meeting the criteria for meropenem MIC≥2, irrespective of imipenem resistancea

US CDC-CRE criteria definition: (a) Resistant to any carbapenem antimicrobial (i.e., minimum inhibitory concentrations of ≥4 mcg/ml for doripenem, meropenem,
or imipenem OR ≥ 2 mcg/ml for ertapenem); (b) In addition: (i) For bacteria that have intrinsic imipenem nonsusceptibility (i.e., Morganella morganii, Proteus spp.,
Providencia spp.), resistance to carbapenems other than imipenem is required, OR (ii) Documented to produce carbapenemase

Ikenoue et al. BMC Infectious Diseases(2024) 24:209

IPM criteria, indicating resistance to both imipenem andmeropenem (Table 4).
The species distribution differed between the IPM criteria-only and MEPM criteria groups. K. aerogenes comprised more than 60% of isolates in the IPM criteria-onlygroup, whereas E. coli and K. pneumoniae accounted fornearly 60% of isolates in the MEPM criteria group. Notably, CgPE isolates were not found in the IPM criteriaonly group, whereas 67.8% of the isolates in the MEPM
criteria group were CgPE. The proportion of multidrug
resistance was low in the IPMcriteria-only group (1.2%),
91.1% of the isolates in the IPM criteria-only group weresusceptible to all four antimicrobials. Seven-day mortality was also significantly lower among in the IPMcriteriaonly group than in the MEPM criteria group (1.8% vs.
6.9%, p = 0.0428).
In addition, 61.0% (192/315) of the isolates satisfied
the CRE definition of the US CDC. The CRE definition of US CDC had two-fold higher thresholds for the
MICs of meropenem and imipenem than the Japanese
CRE definition. Among isolates in the IPMcriteria-onlygroup, 24.3% fulfilled the US-CDC CRE criteria for imipenem, and 95.1% (39/41) of them remained susceptible to cefepime, piperacillin–tazobactam, levofloxacin,
and amikacin. Meanwhile, all isolates in the MEPM criteria group fulfilled the US CDC CRE criteria. This was
because all 18 isolates in the MEPM criteria group, which
had a meropenem MIC of 2 mg/L, exhibited an MIC of
2 mg/L for ertapenem. One of these 18 isolates was an
IMP-type carbapenemase producer.

Discussion
In Japan, among the reported CRE cases, the dominant
species were K. aerogenes and ECC, followed by K. pneumoniae and E. coli. The proportion of CgPE isolates was
26.5%, and the 7-day mortality was 4.5%. Both of thesefigures were lower than those reported in other countries [4, 14, 15], but they were consistent with previous
domestic studies that used the same CRE definition [16,17]. However, one of these previous studies reported
higher mortality rates than the present study. Specifically,
Oka et al. reported a 28-day mortality rate of 14.6% [17].
This difference might be attributable to the study populations and longer observational periods, as their study was
conducted at university hospitals in which patients withmore complex clinical backgrounds were more prevalent,
whereas our study, which included cases from primary
hospitals.
One of the reasons for prioritizing CPE among CRE
isolates is that CPE is associated with a significantly
higher risk of mortality than infection caused by nonCPE [18, 19]. However, recent studies revealed no significant differences in clinical outcomes between CPE

Page 7 of 10

and non-CPE infections [14, 16, 17, 20, 21]. Our analysis
also did not conclude that CgPE posed a greater risk ofmortality. Conversely, it revealed a higher proportion ofmultidrug resistance among CgPE isolates than in among
CgNE isolates. Furthermore, CRE isolates exhibiting
multidrug resistance carried a notably high risk of 7-day
mortality. These findings that multidrug resistance, rather
than the mere possession of carbapenemase genes, exerts
a stronger impact on clinical outcomes. In other words,
the previously reported causal association between CPE
infection and mortality might be confounded by thepresence of multidrug resistance. Recently, novel antimicrobials targeting CPE have been introduced in clinicalsettings, including new β-lactam–β-lactamase inhibitor
combinations (e.g., imipenem–relebactam and ceftazidime–avibactam) and cefiderocol. These antimicrobials
can alter the clinical outcomes of CRE infections, particularly those caused by CPE.
The significant difference in the proportion of multidrug resistance between CgPE and CgNE isolates inthis study might be attributable to the large proportion(82.4%, 211/256, Fig. 1) of K. aerogenes and ECC isolatesin CgNE. These isolates remained susceptible to various
antimicrobials, thereby reducing the overall proportionof multidrug resistance among CgNE isolates. The reason for high susceptibility to various antimicrobials but
not to imipenem and cefmetazole in K. aerogenes andCgNE-ECC might be explained by the presence of chromosomal AmpC β-lactamase production combined withaltered membrane permeability, which can elevate the
MIC of imipenem even though they are not exogenously
acquired resistance mechanisms but can elevate the MIC
of imipenem [22–24].
In the analysis of mortality risk, cases other than K.
aerogenes and ECC infections, particularly those involving E. coli and K. pneumoniae, accounted for half of thefatal cases and likely influenced the risk analysis. It is
important to recognize that the proportion of multidrug resistance in E. coli and K. pneumoniae did not differ
between CgPE and CgNE. In particular, the proportionof multidrug resistance in E. coli exceeded 85% regardless of the presence or absence of carbapenemase genes.
This could be one of the explanations for the novel finding that E. coli infection itself increased the risk of earlymortality among cases with CRE infection.
Unlike K. aerogenes and ECC, CgNE-E. coli andCgNE-K. pneumoniae typically exhibit elevated MICs
for carbapenems only when they acquire exogenous
β-lactamase genes, such as plasmid-mediated ESBLs andAmpC β-lactamase genes, alongside altered membrane
permeability [25, 26]. This propensity for co-acquiringother exogenous resistance genes, such as aminoglycoside resistance genes, reflects the scenario for CPE, whichIkenoue et al. BMC Infectious Diseases(2024) 24:209

acquires exogenous carbapenemase genes and other
resistance genes and consequently develops multidrug
resistance. In addition, the distinct high rate of resistanceto levofloxacin, one of the commonly used antimicrobials
in Japan [27], observed in E. coli isolates might also contribute to multidrug resistance and higher mortality rates
because of empirical treatment failure.
IMP-type carbapenemase is a domestically prevalent carbapenemase in Japan, whereas NDM/KPC-type
carbapenemase was more associated with cases with ahistory of travel abroad [28]. Within the CgPE cases analyzed, NDM/KPC-CgPE increased the risk of mortality
compared to IMP-type CgPE. This finding might also be
attributable to the higher prevalence of multidrug resistance in NDM/KPC-CgPE than in IMP-type CgPE.
Despite slight variations in mortality data among
domestic studies, the characteristics of CRE cases inJapan, including the high proportion of K. aerogenes and
ECC, relatively lower proportion of CgPE, and the low
mortality, were distinctive. We assumed that these features in Japan might be explained by the specific Japanese
CRE definition, particularly among cases that met only
the IPM criteria, forming the IPMcriteria-only group in
this study. This group comprised 97% K. aerogenes and
ECC isolates, a single E. coli isolate, and no K. pneumoniae isolates, and no isolates were CgPE. Furthermore,this group exhibited a low proportion of multidrug
resistance (1.2%). Of the isolates in the IPMcriteria-onlygroup, which remained susceptible to meropenem, 91%
were also susceptible to cefepime, piperacillin–tazobactam, levofloxacin, and amikacin, meaning that sufficient
treatment options were available, which could explain the
low mortality of 1.8% in this group.
In the IPMcriteria-only group, 24.3% of the patients
exhibited an imipenem MIC of ≥4 mg/L, which aligns
with the cutoff used in the US-CDC CRE criteria [11].
These isolates also remained susceptible to other antimicrobials used to treat CRE infections. Regardless of its
MIC cutoff, imipenem is an inappropriate reference drugfor the definition of CRE surveillance.
This study had several limitations. First, the NESID
does not provide any definition or guideline for the clinical diagnosis of CRE infection, and all diagnoses are
based on the clinician’s discretion. Second, the clinical aspects of the cases, such as underlying diseases andtreatment courses, were unavailable, and such information is crucial for evaluating mortality risks in realworld settings. Furthermore, because the mortality risk
was analyzed under the limitation of surveillance data,
which were collected within 7 days of diagnosis, a longer
observation period would provide a more precise view ofmortality. Third, the number of isolates tested for antimicrobial susceptibility was limited. Finally, the findings ofPage 8 of 10

this study were derived from an analysis of CRE cases inJapan, where IMP-type carbapenemase is dominant. Further study in regions with different dominant carbapenemase gene profiles is required to evaluate the significanceof imipenem resistance in defining CRE.

Conclusion
In summary, in cases in the IPMcriteria-only group, in
which CRE was identified solely based on imipenem
resistance, the isolates were less likely to be CgPE. Furthermore, and more importantly, these isolates were lesslikely to exhibit multidrug resistance, indicating thatexisting antimicrobials are more likely to be effective,
potentially resulting in a lower clinical and public healthburden. To preserve newly developed antimicrobials
such as ceftazidime–avibactam, meropenem–vaborbactam, imipenem–cilastatin–relebactam, and cefiderocoland to efficiently allocate limited healthcare and publichealth resources for infection control, it is recommended
that CRE is defined solely using the MEPM criteria. Thisapproach will help accurately understand the disease burden of CRE infection and the challenges it presents inclinical management and infection control.
Abbreviations
AST	Antimicrobial susceptibility test
CLSI	Clinical and Laboratory Standards Institute
CgNE	Carbapenemase gene-negative Enterobacterales
CgPE	Carbapenemase gene-positive Enterobacterales
CRE	Carbapenem-resistant Enterobacterales
CPE	Carbapenemase-producing Enterobacterales
ECC	Enterobacter cloacae complex
EDTA	Ethylenediaminetetraacetic acid
ESBL	Extended-spectrum β-lactamase
IPM	Imipenem
MEPM	Meropenem
MICs	Minimum inhibitory concentrations
NESID	National Epidemiological Surveillance of Infectious Diseases
PHI	Public Health Institute
US-CDC	Centers for Disease Control and Prevention of United States

Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s12879-​024-​09107-4.
Additional file 1. Supplementary material 1.
Acknowledgements
We greatly appreciate all the clinicians, officers of the local health department,
and members of the Infectious Diseases Surveillance Centre of the National
Institute of Infectious Diseases, Japan, who reported the Carbapenemresistant Enterobacterales cases and managed the surveillance data. We
would also like to thank Komei Shirabe from Yamaguchi Prefectural Institute of
Public Health and Environment and Hiroto Shinomiya from Ehime Prefectural
Institute of Public Health and Environmental Science for contributing to theestablishment of the Antimicrobial-Resistant Bacteria Laboratory Surveillance Network and Kumiko Kai, Shigeru Muramatsu, Eiko Anzai, Satoyo
Wakai, Manami Nakashita, and Aung Min Soe at the Antimicrobial ResistanceIkenoue et al. BMC Infectious Diseases(2024) 24:209

Research Center, National Institute of Infectious Diseases for conducting theantimicrobial susceptibility test of CRE isolates.
Antimicrobial-Resistant Bacteria Research Group of Public Health Insti‑
tutes (AMR-RG-PHI)
Mari ­Matsui3, Satowa S­ uzuki3, Yohei ­Takahashi5, Nozomi K­ amitaka6, Shiho­Takahashi7, Nami ­Kanno8, Takuya ­Ishi9, Ryo S­ himada10, Hiroko ­Takahashi10,
Mayumi ­Ogawa10, Koji ­Kikuchi11, Hiroyuki ­Ueno11, Kentaro ­Tomari11, Junko­Yoshihara12, Naoshi ­Ando13, Takako ­Katakura14, Yuko ­Matsumoto15, Yoko
­Anzawa16, Satoko ­Haruna17, Mikako H­ osoya18, Masanori ­Watahiki19, Mika
­Shiroza20, Koji ­Yokoyama21, Makiko ­Noda22, Ayako ­Furuta22, Ryuji K­ awahara23,
Kaoru ­Umeda23, Takahiro ­Yamaguchi23, Noriko ­Nakanishi24, Kumiko K­ uroda25,
Etsuko ­Saito26, Yumiko ­Inoue27, Yuta ­Kawakami28, Tatsuaki ­Aota29, Kanako­Masuda30, Hitoshi ­Ohtsuka31, Chiemi F­ ukuda32, Kazumi S­ eki32, Yoko ­Iwashita32,
Yukiko ­Asano33, Yuka ­Fukuguchi33, Emi A­ rikawa34, Rika ­Maeda35 & Tsuyoshi­Kudeken36
5
Aomori Prefectural Public Health and Environment Center, Aomori, Japan.
6
Public Health Institute City of Sendai, Sendai, Japan. 7Akita Prefectural
Research Center for Public Health and Environment, Akita, Japan. 8Fukushima
Prefectural Institute for Public Health, Fukushima, Japan. 9Ibaraki Prefectural
Institute of Public Health, Mito, Japan. 10Gunma Prefectural Institute of Public
Health and Environmental Sciences, Maebashi, Japan. 11Saitama City Instituteof Health Science and Research, Saitama, Japan. 12Chiba City Institute of
Health and Environment, Chiba, Japan. 13Chiba Prefectural Institute of Public
Health, Chiba, Japan. 14Yokosuka Institute of public health, Yokosuka, Japan.
15
Yokohama City Institute of Public Health, Yokohama, Japan. 16Kawasaki City
Institute for Public Health, Kawasaki, Japan. 17Funabashi City Institute of Public
Health, Funabashi, Japan. 18Niigata Prefectural Institute of Public Health andEnvironmental Sciences, Niigata, Japan. 19Toyama Institute of Health, Imizu,
Japan. 20Ishikawa Prefectural Institute of Public Health and Environmental
Science, Kanazawa, Japan. 21Fukui Prefectural Institute of Public Health andEnvironmental Science, Fukui, Japan. 22Gifu Prefectural Research Institute for
Health and Environmental Sciences, Kakamigahara, Japan. 23Osaka Instituteof Public Health, Osaka, Japan. 24Department of Infectious Diseases, Kobe
Institute of Health, Kobe, Japan. 25Himeji City Institute of Environment and
Health, Himeji, Japan. 26Hyogo Prefectural Institute of Public Health Science, Kakogawa, Japan. 27Nara Prefecture Institute of Health, Sakurai, Japan.
28
Shimane Prefectural Institute of Public Health and Environmental Science,
Matsue, Japan. 29Hiroshima City Institute of Public Health, Hiroshima, Japan.
30
Hiroshima Prefectural Technology Research Institute Health and Environment Center, Hiroshima, Japan. 31Yamaguchi Prefectural Institute of Public
Health and Environment, Yamaguchi, Japan. 32Kagawa Prefectural ResearchInstitute for Environmental Sciences and Public Health, Takamatsu, Japan.
33
Ehime Prefectural Institute of Public Health and Environmental Science,
Toon, Japan. 34Kitakyushu City Institute of Health and Environmental Sciences,
Kitakyushu, Japan. 35Kumamoto Prefectural Institute of Public-Health andEnvironmental Science, Uto, Japan. 36Okinawa Prefectural Institute of Healthand Environment, Uruma, Japan.
Authors’ contributions
CI analyzed the data and wrote the manuscript. SS conceived the study andwrote the manuscript. MM and YI contributed to the surveillance data management and supervised the antimicrobial susceptibility test. DY conducted
the statistical analysis, and MS contributed to the revision of the manuscript.
Members of AMR-RG-PHI contributed to the collection of isolates and phenotypic and genotypic detection of carbapenemase production.
Funding
This work was supported by a grant for Research on Emerging and Reemerging Infectious Diseases and Immunization from the Japanese Ministry of
Health, Labour and Welfare (19HA1001, 22HA2001) and the Research Programon Emerging and Re-emerging Infectious Diseases of the Japan Agency for
Medical Research and Development (AMED) [grant number JP21fk0108604,
22fk0108604, JP23fk0108604].
Availability of data and materials
NESID reports are available in the public domain on the NIID website (https://​www.​niid.​go.​jp/​niid/​ja/) as the Infectious Diseases Weekly Report and Infectious Agents Surveillance Report.

Page 9 of 10

Declarations
Ethics approval and consent to participate
For the NESID data, informed consent and ethics review were waived basedon Article 3 of Ethical Guidelines for Medical and Health Research Involving
Human Subjects which was issued by Ministry of Education, Culture, Sports,
Science and Technology, Misnistry of Health, Labour and Welfare, and Ministryof Economy, Trade and Indsuty, because it was collected under the Japanese
Infectious Diseases Control Law: Act on the Prevention of Infectious Diseases
and Medical Care for Patients with Infectious Diseases. The NESID datacontains individual-level data but does not include identifiable information.
Collecting and conducting the AST of isolates from reported cases at NIID was
beyond the scope of the national surveillance program and was approvedby the medical research ethics committee of the NIID for the use of humansubjects on December 12, 2021 with reference number 1344.
Consent for publication
Not applicableCompeting interests
The authors declare no competing interests.
Author details
1
Field Epidemiology Training Program, Infectious Diseases SurveillanceCenter, National Institute of Infectious Diseases, Tokyo, Japan. 2 Center for Field
Epidemic Intelligence, Research, and Professional Development, National Institute of Infectious Diseases, Tokyo, Japan. 3 Antimicrobial Resistance ResearchCenter, National Institute of Infectious Diseases, Tokyo, Japan. 4 Center
for Surveillance, Immunization, and Epidemiologic Research, National Instituteof Infectious Diseases, Tokyo, Japan.
Received: 20 October 2023 Accepted: 6 February 2024

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