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Carbapenemase-producing Enterobacterales (CPEs) are one of the top priority antimicrobial-resistant pathogens. Among CPEs, those producing acquired metallo-β-lactamases (MBLs) are considered particularly problematic as few agents are active against them. Imipenemase (IMP) is the most frequently encountered acquired MBL in Japan, but comprehensive assessment of clinical and microbiological features of IMP-producing Enterobacterales infection remains scarce. Here, we retrospectively evaluated 62 patients who were hospitalized at a university hospital in Japan and had IMP-producing Enterobacterales from a clinical culture. The isolates were either Enterobacter cloacae complex or Klebsiella pneumoniae , and most of them were isolated from sputum. The majority of K. pneumoniae, but not E. cloacae complex isolates, were susceptible to aztreonam. Sequence type (ST) 78 and ST517 were prevalent for E. cloacae complex and K. pneumoniae , respectively, and all isolates carried bla IMP-1 . Twenty-four of the patients were deemed infected with IMP-producing Enterobacterales . Among the infected patients, therapy varied and largely consisted of conventional β-lactam agents, fluoroquinolones, or combinations. Three (13%), five (21%), and nine (38%) of them died by days 14, 30, and 90, respectively. While incremental mortality over 90 days was observed in association with underlying comorbidities, active conventional treatment options were available for most patients with IMP-producing Enterobacterales infections, distinguishing them from more multidrug-resistant CPE infections associated with globally common MBLs, such as New Delhi metallo-β-lactamase (NDM) and Verona integron-encoded metallo-β-lactamase (VIM)., Competing Interests: The authors declare no conflict of interest.

Although recent propagation of carbapenemase-producing Enterobacterales (CPE) has become a problem worldwide, the picture of CPE infection in Japan has not fully been elucidated. In this study, we examined clinical and microbiological characteristics of invasive CPE infection occurring at 8 hospitals in Minami Ibaraki Area between July 2001 to June 2017. Of 7294 Enterobacterales strains isolated from independent cases of bacteremia and/or meningitis, 10 (0.14%) were CPE (8 Enterobacter cloacae-complex, 1 Escherichia coli, and 1 Edwardsiella tarda）, all of which had the bla IMP-1 gene and susceptible to gentamicin and trimethoprim/sulfamethoxazole. These strains were isolated from 7 adult and 2 infant bacteremia (1 infant patient developed CPE bacteremia twice) after 2007. The most common portal of entry was intravenous catheters. All of the adult patients were recovered, while the infant patients eventually died. Genomic analyses showed that the 8 E. cloacae-complex strains were classified into 5 groups, each of which was exclusively detected in specific facilities at intervals of up to 3 years, suggesting persistent colonization in the facilities. This study showed that invasive CPE infection in the area was rare, caused by IMP-1-type CPE having susceptibility to various antibiotics, and nonfatal among adult patients.

Background: Information about the clinical and microbiological characteristics of IMP-producing Enterobacterales has been limited. Here, we describe an institutional outbreak of IMP-producing Enterobacter cloacae complex (ECC) involving multiple clades of ECC sequence type (ST) 78 strains., Methods: Antimicrobial susceptibility testing, whole-genome sequencing, and conjugation experiments of 18 IMP-producing ECC strains isolated during four-year study period were performed. Species and subspecies were determined by average nucleotide identity analysis and clonal relatedness of the isolates was analyzed with multilocus sequence typing and core-genome single nucleotide polymorphism (SNP) analysis. Relevant clinical information was extracted from medical records., Results: Fourteen of 18 IMP-producing ECC isolates were determined as Enterobacter hormaechei ST78. Sixteen isolates, including 13 isolates belonging to ST78, carried bla IMP-1 in In316-like class 1 integron and also carried IncHI2 plasmids. Conjugation experiments were successful for 12 isolates carrying bla IMP-1 on IncHI2 plasmids and for an isolate carrying bla IMP-11 on an IncL/M plasmid. Although isolation of ST78 strains was clustered in a 14-months period suggesting nosocomial transmission, these strains were subdivided into three clades by SNP analysis: clade A (n = 10), clade B (n = 1), clade C (n = 3). A part of clonal relatedness was unexpected by the epidemiological information at the time of isolation of the strains. Most of the IMP-producing ECC strains were susceptible to non-β-lactam antibiotics and had relatively low minimum inhibitory concentrations to carbapenems (≤4 μg/mL). Five of six infections caused by IMP-producing ECC were treated successfully., Conclusions: Whole-genome sequencing analysis revealed the outbreak was caused by three different clades of ST78 strains, where patients had favorable treatment outcome of the infections compared with that caused by Enterobacterales producing other carbapenemases, possibly due to their non-multidrug-resistant phenotype.

Background: To clarify the molecular epidemiology of carbapenem-resistant Enterobacter cloacae complex (CREC) and the risk factors for acquisition of carbapenemase-producing E. cloacae complex (CPEC)., Methods: Using clinical CREC isolates detected in a Japanese university hospital over 4 years, carbapenemase production was screened with phenotypic methods. Carbapenemase genes were analysed by PCR and sequencing. Molecular epidemiological analyses were conducted with repetitive extragenic palindromic (REP)-PCR and multilocus sequence typing (MLST). CRECs were identified to the subspecies level by hsp60 sequencing. Whole-genome sequencing of plasmids was conducted. A case-control study was performed to identify risk factors for acquisition of CPEC among patients with CREC., Results: Thirty-nine CRECs including 20 CPECs carrying bla IMP-1 were identified. Patients with CPEC had longer hospital stay before detection (26.5 days vs. 12 days, p  = 0.008), a urinary catheter (odds ratio [OR], 5.36; 95% confidence interval [CI], 1.14-30.9; p  = 0.023), or intubation (OR, 7.53; 95% CI, 1.47-53.8; p  = 0.008) compared to patients without CPEC. Four genetically closely related CPEC clusters were observed, which showed that three of four CPEC clusters corresponded to E. asburiae (ST 53), E. hormaechei subsp. steigerwaltii (ST 113 and ST 1047) and E. cloacae subsp. cloacae (ST 513) by MLST and hsp60 sequencing. Seven representative plasmids shared structures with class I integron containing bla IMP-1 and IncHI2A replicon type., Conclusions: A longer hospital stay, presence of a urinary catheter, and intubation are risk factors for CPEC acquisition. In addition to horizontal transmission of genetically indistinguishable CPECs, IncHI2A plasmid carrying bla IMP-1 appeared to be transferred among genetically different ECs., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

A carbapenem-resistant and colistin-heteroresistant clinical isolate of Enterobacter cloacae was obtained from an inpatient in Okinawa, Japan. The minimum inhibitory concentrations of both imipenem and meropenem were 32 μg/mL. The isolate showed heteroresistance to colistin using the Etest method and resistance to colistin using the broth microdilution method. It had a disrupted ompC and a mutation in the promoter region of bla ACT-2 , but did not harbor any genes encoding carbapenemase. The disruption of ompC and the mutation in bla ACT-2 was associated with the carbapenem resistance of this isolate. This isolate also had mutations in pmrAB and phoPQ encoding two-component regulatory systems, which may be associated with colistin heteroresistance., (Copyright © 2018. Published by Elsevier Ltd.)

The isolation of a carbapenem-resistant Enterobacter cloacae strain harboring the IMI-1 variant of bla IMI-1 carbapenemase points to the worldwide emergence of multidrug resistant bacteria as a potential source of health care infections. In this report, we describe the first isolation of E. cloacae with bla IMI-1 carbapenemase isolated from a Japanese patient in September 2016. The isolate was resistant to carbapenems, levofloxacin, and aminoglycosides, and heteroresistant to colistin but sensitive to fourth-generation cephalosporins. All microbiology laboratories worldwide should be made aware of these bla IMI-1 -producing subtypes with unusual antibiotic susceptibility profiles., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

We report three cases of IMP-type metallo-β-lactamase-producing Enterobacter cloacae bloodstream infection, which showed minimum inhibitory concentration values for imipenem with 2 μg/ml in all isolates. Although carbapenems were initiated empirically in all cases, two of three cases died. The Clinical and Laboratory Standards Institute lowered the breakpoints of carbapenems for Enterobacteriaceae in 2010. However, the previous breakpoints are still used in many clinical laboratories, which can result in failure to detect carbapenem-resistant Enterobacteriaceae. Therefore, lower breakpoints of carbapenems should be used in clinical settings, and alternative tests for detecting metallo-β-lactamase such as polymerase chain reaction and immunochromatographic assays may contribute to better detection of carbapenem-resistant isolates.

We analyzed the antibiotic resistant genes, metallo-beta-lactamase and extended-spectrum beta-lactamase (ESBL), in highly resistant Enterobacter cloacae isolated at Showa University Hospital from April to June 2008. Thirty eight strains of E. cloacae were isolated. Of these strains, 35 demonstrating resistant to either cefotaxime (Minimum inhibitory concentration: MIC > or = 32 microg/ml), ceftadizime (MIC > or = 16 microg/ml), or aztreonam (MIC > or = 16 microg/ml) were selected for the analysis. The strains were subjected to a Double-disk synergy test (DDST) using sodium mercaptoacetic acid (SMA) and ceftadizime. As a result, 7 strains showed an enlargement of inhibition zone diameter by SMA. Among 7 SMA responded strains, 6 strains carried the bla(IMP-1) or bla(IMP-11) gene. There were 2 strains sensitive to imipenem (MIC < 1 microg/ml) in SMA responded strains, and one carried bla(IMP-11) gene. ESBL genes were detected in 5 strains, bla(CTX-M3) gene from 3 strains, and bla(CTX-M14) gene from 2 strains. All of the ESBL harboring strains showed an enlargement of inhibition zone diameter in DDST using clavulanic acid and ceftadizime, cefotaxime, aztreonam or cefepime. Among 35 strains, one strain carried both bla(IMP-1) and bla(CTX-M3) genes. In addition to the AmpC beta-lactamase, increase of the E. cloacae strains carrying these resistant genes cause the complex antibiotic resistant patterns. Especially, strains carrying bla(IMP) gene, which exhibit low imipenem MIC value may be induced to be resistant strains under the existence of imipenem. Analysis of resistant genes would be a beneficial for the measure the spread of drug-resistant E. cloacae.

Routine surveillance in a cardiovascular ward showed that the incidence of Enterobacter cloacae isolated from sputum and oropharyngeal cultures in June 2004 increased to 27.6% (8/29) compared to 5.5% (12/219) from the rest of the hospital during the same period (OR=13.2; 95% CI 2.97-58.7; P<0.05). While an increase in E. cloacae pneumonia was not verified, an investigation was undertaken by the infection control team to prevent an outbreak. The estimate of relative risk for E. cloacae infection was based on a case-control study which measured exposure to intubation, history of a stay in the intensive care unit (ICU) and oral care between patients with E. cloacae and those negative for E. cloacae. An odds ratio of 13.2 suggested cross-contamination via the transoesophageal echocardiography (TOE) probe in the ICU prior to transfer to the cardiovascular ward. Pulsed-field gel electrophoresis and antibiogram patterns were also consistent with this hypothesis. Intervention was undertaken in the form of enforcing the disinfection of TOE probes using a 0.55% phtharal solution and the use of a single-use sheath to protect the probe from recontamination. Following intervention, the incidence rate returned to previous levels. This report illustrates the limitations in the effectiveness of current nosocomial surveillance strategies due to the retrospective nature of analysis. Improved surveillance methods such as data-mining tools specifically applicable to the institution, patient population, region and country are needed to increase the sensitivity of detecting unrecognized outbreaks, including cross-contamination.