The continued emergence and spread of CRE worldwide are important concerns among clinicians, infection prevention experts, and public health agencies. Internationally, MBL-type carbapenemases in particular have been of concern for some time, while KPC-producing isolates have been a far greater problem in the United States to date. This report describes three cases of probable domestically acquired IMP-producing Enterobacteriaceae
and adds to reports of likely internationally acquired MBLs that have already been recognized in the United States (7
). Although the ultimate contribution of MBL-producing isolates to the prevalence of CRE remains to be determined, this potential increase in mechanisms highlights the need for vigorous infection prevention efforts aimed at preventing transmission.
The recent heightened attention to CRE is largely due to the emergence of the New Delhi metallo-β-lactamase, an MBL that has been strongly associated with travel and receipt of medical care on the Indian subcontinent. This has been the case among U.S. NDM-producing isolates as well; five of six patients from whom NDM-producing CRE were identified by U.S. public health agencies had a history of recent receipt of medical care in India or Pakistan (7
; also A. Kallen, unpublished data). Similarly, the two VIM-producing CRE identified in the United States were isolated from patients who had been recently hospitalized in Greece or Italy, countries in which these organisms have been reported (26
). In contrast, the IMP-producing K. pneumoniae
described here were from pediatric patients who had no travel history and, in the case of patient 1, had never been outside the hospital prior to CRE isolation.
IMP was originally identified in a Japanese P. aeruginosa
isolate collected in 1988 that was resistant to imipenem and was named for this phenotype (active on imipenem) (43
was located on a plasmid that readily transferred among P. aeruginosa
strains, and within 5 years of that first report, blaIMP
was found among Enterobacteriaceae
in other Japanese hospitals in association with class 3 integrons (1
). IMP variants have now been identified among multiple species of Gram-negative bacteria around the world (42
) but have been reported infrequently in the United States and only among Pseudomonas
). This is the first report of this enzyme from U.S. Enterobacteriaceae
; however, outbreaks caused by IMP-producing Pseudomonas
have been reported from both Canada and Mexico in association with class 1 integrons (15
PFGE analysis demonstrated that all three IMP-producing K. pneumoniae isolates were related to each other but not to a contemporary carbapenemase-negative isolate from the same institution or to other carbapenemase-producing isolates in the CDC database. All three IMP-producing isolates harbored a common plasmid that carried blaIMP on an XmnI fragment of approximately 3.5 kb. These results and the fact that IMP-producing Enterobacteriaceae have not been previously recognized in the United States suggest a common source for these organisms. As the common link between these patients was their overlapping stays in the NICU, it is possible that transmission occurred there and that at least two of the patients remained colonized for months afterward. In the case of patient 2, IMP-producing K. pneumoniae was detected in a clinical culture collected 3 months later, and patient 3's isolate was detected as an incidental finding 5 months after his discharge. The original source and potential route of transmission of this IMP-producing K. pneumoniae isolate for these three patients are not known. It is possible that these strains are circulating widely in the community and that all three patients acquired CRE from independent sources. At least two, and possibly all three, of these cases represent asymptomatic colonization with CRE rather than true infection. It is also possible that they represent cross-transmission (e.g., by health care personnel hands) or a common environmental source. Since surveillance cultures were not obtained to identify additional cases of CRE carriage, the true extent of colonization with IMP-producing K. pneumoniae in this NICU cannot be known.
Each of the CRE described here was recognized by routine antimicrobial susceptibility testing performed in the hospital laboratory as resistant to the third-generation cephalosporins and carbapenems according to the revised (lowered) CLSI guidance for carbapenems (12
), but the isolates were unusual in being susceptible to aztreonam. This antimicrobial susceptibility pattern is characteristic of MBL-producing organisms although it is not frequently encountered since most MBL-producing organisms also carry multiple other resistance mechanisms. The isolates described here are also unusual because although they carry an MBL, they remain susceptible to fluoroquinolones, trimethoprim-sulfamethoxazole, and tetracyclines. Although one isolate demonstrated intermediate susceptibility to minocycline, we believe this was likely due to variability in the test rather than acquired resistance. One of these three isolates consistently yielded an imipenem MIC within the susceptible range although it was nonsusceptible to doripenem, ertapenem, and meropenem.
The IMP-producing K. pneumoniae
isolates yielded variable results with the phenotypic tests used to detect the presence of MBLs. All three were clearly positive for carbapenemase production with the MHT, but the direct MBL test, the Etest MBL, and the broth microdilution MBL screen yielded equivocal results. Two isolates demonstrated a decrease of only one doubling dilution with the broth microdilution MBL screen, which is within the acceptable variation for broth microdilution testing and would not be a reliable indicator of MBL production. Interestingly, the IMP-containing E. coli
transformants were readily detected with the broth MBL screen, suggesting that some factor present in the parent strain interfered with this assay. The Etest MBL demonstrated only a subtle deformation of the ellipse in both the K. pneumoniae
parent and E. coli
transformant strains. Variability in the performance of phenotypic tests for detection of MBLs and difficulty with their interpretation has been described previously (29
), and our results demonstrate the need to include multiple methods to ensure reliable detection of MBLs. In this case, the pattern of nonsusceptibility to all β-lactam agents except aztreonam was an important indicator of MBL presence.
At the time the first isolate was recovered (November 2009), it would have been characterized as susceptible to ertapenem, imipenem, and meropenem and nonsusceptible only to doripenem (11
). Since all three patients had been discharged to their homes by the time that CRE colonization was recognized, infection prevention staff at the facility elected to perform laboratory-based surveillance for organisms with the same antimicrobial susceptibility pattern rather than active surveillance of the NICU in which these patients resided. However, consideration should be given to performing point prevalence surveys and/or active surveillance testing when novel cases of CRE infection or colonization are recognized in a health care facility (8
). The emergence of this new mechanism of carbapenem resistance among Enterobacteriaceae
in the United States has the potential to add to the growing burden of CRE. CRE present treatment dilemmas and are associated with high rates of mortality (31
). This is particularly concerning in light of a 2009 Infectious Diseases Society of America (IDSA) report highlighting the fact that there were no antimicrobials in advanced development with activity against these organisms (3
). In order to slow the emergence of these strains, aggressive infection prevention practices aimed at preventing infections with—and transmission of—these organisms should be employed. Current prevention recommendations for acute-care facilities are available from CDC (8
). Foremost among these recommendations is recognizing when CRE are present in facilities so that infected or colonized patients can be put in contact precautions, and patient contacts can be screened for evidence of transmission.
In summary, this is the first published report of IMP-producing Enterobacteriaceae in the United States. The isolates appear to have been acquired domestically although the mechanism of transmission to these three patients is not known. The emergence of this and other metallo-β-lactamases (i.e., VIM and NDM) among Enterobacteriaceae in the United States has the potential to add to the already substantial burden of CRE due to the emergence and spread of KPC-producing strains. CRE are an important public health problem; in order to limit their impact, implementation of recommended interventions to prevent transmission of these organisms should be a priority for institutions where these organisms are identified.