Carbapenem-resistant Enterobacteriaceae in Children

United States, 1999-2012

Latania K. Logan; John P. Renschler; Sumanth Gandra; Robert A. Weinstein; Ramanan Laxminarayan


Emerging Infectious Diseases. 2015;21(11):2014-2021. 

In This Article


In our nationally representative sample, we found that CRE in US children showed a major increase during 1999–2012, and the most substantial increases were in children 1–5 years of age, male patients, blood culture isolates, and the ICU setting. However, overall CRE occurrence in children remained low and relatively uncommon compared with ESBL-producing Enterobacteriaceae. The proportion of ESBL-producing Enterobacteriaceae from the same TSN database was much higher than that of CRE (0.47% ESBL vs. 0.08% CRE) in children.[19]

Dissemination of KPC accounts for most of the increasing prevalence of CRE in the United States.[24] However, in the past 5 years, other carbapenemases that are also rapidly spread by mobile genetic elements harboring genes encoding carbapenemases, such as metallo-β-lactamases (MBLs), including New Delhi MBLs, Verona integron-encoded MBLs, and IMPs (active on imipenem), as well as Class D OXA-producing enzymes (such as OXA-48), have also been reported in clinical Enterobacteriaceae isolates from the United States.[8,24] CRE infections have been associated with high rates of illness and death.[25]

Risk factors for CRE are well described in adults and include critical illness, immune compromise, exposure to health care, residence in long-term health care facilities, longer length of stay before infection, and prior exposure to antimicrobial drugs.[13,25,28] However, little is known about the epidemiology of these factors for children,[9] and published data on the prevalence of CRE in children have been scarce. Moreover, the increase in prevalence in children over the past decade has not been well described. Unlike for adults, where increases were greater than for children, we did not find that the increase in CRE in children appeared to be related to residence in long-term care facilities, because only 0.1% of CRE isolates came from this setting.[13] However, long-term care facilities have been described as a potential risk factor for colonization in children,[16] and it is possible that this factor was missed in our study because patient location entered in laboratory information systems might not correspond to the clinical setting in which patients ultimately received care. We observed that CRE are more commonly isolated with hospitalized patients (Table 2).

There are few treatment options for CRE infections. This armamentarium is further reduced for children and pediatric clinical data are lacking.[29] Side effect profiles limit tigecycline use for persons <18 years of age, and the US Food and Drug Administration discourages routine use because of increased risk for death.[30] Several questions remain about optimal pediatric dosing of polymyxins, such as colistin. Oral fosfomycin is available for the treatment of CRE cystitis; however, standard dosing guidelines are available only for older children and adolescents.[29]

Furthermore, CRE are known to harbor additional drug-resistance genes to other antimicrobial drug classes, which may also be carried on mobile genetic elements. K. pneumoniae sequence type 258 strains are KPC-producing clones that harbor Tn4401-bearing plasmids. These clones are highly effective in plasmid transfer across bacteria and are known to carry other plasmid-based antimicrobial drug resistance genes such as those that encode resistance to trimethoprim/sulfamethoxazole, aminoglycosides, and fluoroquinolones.[6] For Enterobacter species, various typing methods have been used to study clonal lineages, including pulse-field gel electrophoresis,[31] repetitive sequence PCR,[32] and, more recently, multilocus sequence typing[33] and partial sequencing of the housekeeping gene hsp60, which suggests that KPC-producing Enterobacter strains are clustered within specific genetic groups.[34]

It has been well documented that carbapenemase-bearing plasmids frequently carry determinants of resistance to multiple drug classes.[1,6,9] Thus, we propose that the high levels of multidrug resistance in carbapenem-resistant K. pneumoniae and E. coli isolates from children and lower levels in Enterobacter species argue in favor of increased prevalence of plasmid-mediated carbapenemase production as the basis for increases in carbapenem resistance in K. pneumoniae and E. coli, and increased prevalence of other mechanisms (e.g., chromosomal AmpC cephalosporinase induction/derepression or porin modification) as the basis in Enterobacter species.

For MDR strains, this resistance could be reflective of dissemination of the sequence type 258 clone. However, the increase in CRE in children might also be caused by additional MDR genetic clusters, because single-center molecular studies of KPC isolates from children have reported that a more polyclonal epidemiology may be responsible for dissemination of KPC in children.[16,35] Among the Enterobacter species, MDR strains were less common when compared with K. pneumoniae and E. coli. Thus, the sensitivity of current surveillance definitions may capture nosocomial ecology and not reflect true carbapenemase production among Enterobacter species.

In addition, S. marcescens (comprising 6.4% of CRE isolates in this study) is known to harbor SME, a serine carbapenemase, as a mechanism of carbapenem resistance.[1,2] Isolates with this phenotype may retain susceptibility to cefepime. Of the S. marcescens in this dataset, 40% were resistant to cefepime.

Although data for infants (children <1 year of age) were only available in the last 2 years of the study (2010–2012), resistance levels in infants were similar to those in other age cohorts, suggesting increases in this age group. The epidemiology of colonization and infection in this age group might differ from that of the overall pediatric population because cases have been described as being caused by vertical transmission or by other risk factors associated with neonatal ICU acquisition; however, data remain limited.[9,36] Available data on colonization with MDR Enterobacteriaceae in pediatric patients suggest that intestinal carriage of these organisms can last for months to years in some children and that this might be associated with reinfection or potential spread to other family members.[37,38]

Our study has major limitations. First, we cannot distinguish between true infection and colonization, especially among non-blood isolates. Second, because of the nature of the TSN data, it is not possible to avoid bias caused by multiple health care visits made by the same patient over the course of an infection because each time a patient is admitted, a new identification number is assigned that is used to tag any specimens obtained during that health care visit. Third, in June 2010, Clinical Laboratory Standards Institute clinical breakpoints for carbapenems against Enterobacteriaceae were decreased. Because MICs were not available, we ran truncated analyses that included all isolates collected before June 2010. All pediatric CRE prevalence trends were still significant. In addition, many clinical laboratories have been slow to adopt these breakpoint revisions. Fourth, because the overall numbers of CRE isolates in the study were small, resistance trends could be potentially affected by an outbreak at 1 or a small number of institutions. Fifth, molecular mechanisms of carbapenem resistance among the isolates could not be determined. Sixth, although we used CDC criteria to define the CRE phenotype, some mechanisms of resistance other than carbapenemase production might account for carbapenem resistance in isolates.

In summary, the prevalence of CRE infections is increasing among children in the United States but CRE remain relatively uncommon. Molecular characterization is necessary to determine specific CRE genotypes associated with this spread. Continued vigilance for CRE and initiation of the CDC 4 core actions to prevent antimicrobial drug resistance[11] should be emphasized for all patient populations, including children.