The topic of This Month Vol.35 No.12(No.418)

Carbapenem-resistant Enterobacteriaceae Infection, Japan

(IASR 35: 281-282, December 2014)

Carbapenem-resistant Enterobacteriaceae (CRE) is a group of Enterobacteriaceae, such as Escherichia coli and Klebsiella pneumoniae that are resistant to both carbapenems and broad-spectrum β-lactams.  CREs cause respiratory tract infections such as pneumonia, urinary tract infections, surgical site infections, catheter-related bacteremia, sepsis and meningitis. While more common among immune compromised patients, postoperative patients or patients treated with antimicrobials for an extended period of time, CREs may also cause infection in otherwise healthy patients.  CREs are often the cause of nosocomial infections.

So far in Japan, the prevalence of CRE has been relatively low.  For example, in 2013, meropenem-resistant isolates occupied less than 1% of the various representative Enterobacteriaceae bacteria isolates (Table 1).  Meanwhile, in many other countries, the proportion of carbapenem resistance is increasing, and in the United States, 10.4% of the isolates belonging to the genus Klebsiella were carbapenem-resistant [MMWR, 62(9): 165-170, 2013].  The World Health Organization (WHO) considers strengthening the surveillance of antimicrobial resistance as a critical priority for member states (WHO, Antimicrobial resistance: global report on surveillance 2014,

Carbapenem resistance mechanisms
Mechanism of carbapenem resistance includes production of various carbapenemases, production of AmpC type or extended-spectrum β-lactamases combined with mutation(s) resulting in the decreased permeability of the cellular membrane (see p. 283 of this issue).  Carbapenemase-producing bacteria are clinically important as they are often resistant not only to broad-spectrum β-lactams but also to other classes of antimicrobials (see p. 284 of this issue).

Carbapenemase producers isolated in Japan are mostly of IMP genotype (see p. 285 of this issue), which can be easily detected by the sodium mercaptoacetic acid (SMA) disk method widely used in medical facilities in Japan.  Isolates abroad, however, carry carbapenemases of NDM, KPC, or OXA-48 genotypes, whose detection requires use of methods other than SMA disk method (see p. 285 of this issue).  As nosocomial infections due to CRE are more frequent abroad, patients who were treated in foreign medical facilities should be investigated for possible carriage of CREs so as to prevent the spread from such imported cases in Japan (see p. 287 of this issue, IASR 35: 200-201, 2014, IASR 34: 237-238, 2013 and IASR 34: 238-239, 2013).

National Epidemiological Surveillance of Infectious Diseases–reporting criteria and current trends
CRE infection is a category V infectious disease under the Infectious Diseases Control Law.  Physicians who make the diagnosis of CRE infection must notify all cases (see for reporting criteria).  Only infections determined to be caused by CRE are notifiable; asymptomatic CRE carriers are not.  For determining carbapenem resistance, resistance to meropenem or resistance to both imipenem and cefmetazole are methods currently used (Table 2).  Among them, use of meropenem is most recommended on account of its sensitivity and specificity (IASR 35: 156-157, 2014).  Imipenem resistance was included in the reporting criteria because imipenem has been widely used as an indicator in the clinical setting.  However, in order to exclude those that are resistant to imipenem but susceptible to other cephem antimicrobials and do not produce carbapenemase (e.g. Genus Proteus), reporting is limited to those resistant to both imipenem and cefmetazole.

Since compulsory reporting of all cases started in week 38 (19 September 2014), 113 CRE infection cases were notified through week 44, among whom 66 were male and 47 female (see p. 288 of this issue).  The age of the patients ranged from 0 year to 97 years; among them 88 (78% of all the cases) were aged 65 years or above (Figure).  CRE was isolated from 47 (42%) aseptic specimens, such as blood, ascites, and cerebrospinal fluid; the isolation was most frequent from blood (n=27).

Among 113 cases, 109 cases were reported as domestically acquired and one case abroad.  Twenty three cases were considered as healthcare-associated infections, such as infection due to medical devices or surgical site infections.  Among 113 cases diagnosed as CRE infection, 31 cases were based on resistance to meropenem, 41 cases by resistance to both imipenem and cefmetazole and 39 cases based on both methods.

Half of the reported CRE cases were infections by Enterobacter spp. (Table 3).  Most carbapenem resistance of Enterobacter spp. was not due to production of carbapenemases but rather due to production of class C β-lactamase associated with reduced cellular membrane permeability.  The current practice of notifying carbapenemase non-producing bacteria resistant to broad-spectrum β-lactams is being reviewed with regards to implications for public health.

Horizontal gene transfer and nosocomial infection
In most cases, the carbapenemase gene is found on plasmids.  It is transmitted to other bacteria belonging to Enterobacteriaceae by conjugation or other horizontal gene transfer mechanisms.  Some Enterobacteriaceae bacteria possessing carbapenemase gene may be phenotypically susceptible to carbapenems.  Such bacteria may become carbapenem-resistant through elevated expression of the drug resistance gene(s) or through cellular membrane change and capable of transmitting the resistance gene(s) to other bacteria of other species.  As such events may go unnoticed, such possibilities should be kept in mind for surveillance.  In fact, dissemination of the carbapenem resistance gene to multiple bacteria species in the clinical setting has already been reported (see pp. 289 & 290 of this issue).

Asymptomatic CRE carriers are not rare.  Although they are not notifiable, if they are hospitalized and a nosocomial outbreak is suspected, such carriers should be reported to health centers according to the notice issued by the Director of Guidance of Medical Service Division, Health Policy Bureau, Ministry of Health, Labour and Welfare (17 June 2011: Isei-shi-hatsu 0617 No.1), and necessary measures taken promptly with assistance of an existing local network of medical institutions.  Though this notice will be updated soon, the requirements for notification will remain unchanged.  If genotyping or further analysis of resistance gene(s) is deemed necessary for infection control purposes, research institutes, including the National Institute of Infectious Diseases, should be consulted.


Copyright 1998 National Institute of Infectious Diseases, Japan