A systematic review of the epidemiology of carbapenem-resistant Enterobacteriaceae in the United States

The Centers for Disease Control and Prevention (CDC) in the United States has deemed carbapenem-resistant Enterobacteriaceae (CRE) an urgent public health threat that requires immediate and aggressive action [1]. The reason for this urgency is clear: CRE infections are resistant to nearly all antibiotics and are associated with poor clinical outcomes [2].

Carbapenem-resistance in Enterobacteriaceae can result from a variety of mechanisms [3]. In the US, CRE isolates commonly produce carbapenemases; these enzymes are carried on plasmids and can be easily shared with other gram-negative bacteria. The Klebsiella pneumoniae carbapenemase (KPC) was first recognized in North Carolina in 1996 and has since spread around the world [4]. Other examples of carbapenemases include the New Delhi Metallo-β-lactamase (NDM), Verona Integron-encoded Metallo-β-lactamase (VIM), Oxacillinase-48-type carbapenemases (OXA-48), and imipenemase (IMP).

CRE infections are typically seen in patients with prior healthcare exposure, and medical devices are a common risk factor for CRE acquisition [5]. According to 2009–2010 data from the National Healthcare Safety Network (NHSN), 20% of hospitals reporting central line-associated bloodstream infections (CLABSIs) or catheter-associated urinary tract infections (CAUTIs) due to Klebsiella spp. reported at least 1 carbapenem-resistant strain [6]. In 2013, an outbreak of NDM-producing Escherichia coli was associated with duodenoscopes at an Illinois hospital [7].

Despite ongoing control efforts, CRE has become prevalent in several US regions, including Orange County, California and the Chicago metropolitan area [8, 9]. CRE has been endemic in the New York/New Jersey area since the early 2000s [10]. According to the 2013 CDC Antibiotic Resistance Threat Report, there are 9000 healthcare-associated CRE infections every year in the US, resulting in 600 deaths (mortality rate 6.6%) [1]. However, such a low proportion of deaths may be an underestimation due to how infections were defined.

The CDC has published toolkits on preventing the spread of CRE within and between healthcare facilities [3, 11]. While these toolkits have aided efforts at CRE prevention, a better understanding of the epidemiology and burden of CRE is critical to encourage increased investments in the study and prevention of these pathogens. To this end, we conducted a systematic review and evaluation of studies which investigated incidence and outcomes of CRE infection at US sites.

We screened 18,178 unique studies for eligibility (Fig. 1). Nine studies were eligible for inclusion, including 5 multicenter studies reporting the incidence of CRE infections [15‐19] and 4 studies (2 multicenter and 2 single center) evaluating relevant outcomes [20‐23]. Included studies were of moderate-to-high risk of bias according to the Newcastle-Ottawa tool (Table 1). Included studies had low risk of bias when it came to representativeness and ascertainment of CRE infected patients and controls. However, most of the included studies had high risk of bias in terms of adequacy of follow-up, cohort design and analysis, and assessment of outcomes.

Estimating the incidence of CRE is an important step in designing a national public health response to this emerging pathogen [24]. Our review found that the reported incidence of CRE in the US was 0.3–2.93 infections per 100,000 person-years. The incidence of CRE is relatively higher in LTACs compared to acute-care hospitals and community settings. In 1 population-based study, nearly half of CRE isolates produced a carbapenemase. Carbapenemase-producing CRE are of the greatest epidemiologic concern, because these enzymes are typically carried on mobile genetic elements that can be shared with other bacteria [25].

Based on our findings, CRE is still relatively uncommon in the US compared to other antibiotic-resistant pathogens. For example, the estimated incidence of invasive methicillin-resistant Staphylococcus aureus (MRSA) infections in 2011 across the US was 25 per 100,000 persons, or at least 8 times more common than CRE [26]. In the Veterans Health Administration during 2009–2013, the overall incidence of C. difficile was approximately 200 infections per 100,000 patient-years, which was at least 65 times more common than CRE [27]. It is important to note that, even though the current incidence of CRE is low, CRE has been rapidly spreading across the US. Prior to 1996, carbapenemase-producing CRE was not reported in the US, but as of August 2017, this pathogen has been reported in every US state but Idaho [28].

Despite its low incidence, CRE remains a public health threat due to its limited treatment options and worse clinical outcomes [1]. Based on the studies that compared outcomes between CRE and uninfected patients, infection with CRE was associated with a higher risk of being discharged to a LTAC and a higher risk of death within the year after liver transplantation [20, 23]. Studies consistently reported an unadjusted CRE-related mortality rate that was higher than the 6.6% estimate from the CDC [1].

Surprisingly, however, patients with CRE were not always found to have an increased risk for death compared with controls. Studies that compared CRE to uninfected patients reached different conclusions on mortality, albeit using different definitions of mortality [20, 23]. Conflicting results on mortality were also seen in studies that compared CRE to CSE. Two studies found that patients with carbapenem-resistant K. pneumoniae had 2–3 times the odds of in-hospital death as patients with carbapenem-susceptible K. pneumoniae, but a similar difference in mortality was not seen in a study that included all types of Enterobacteriaceae (i.e., CRE compared with CSE). In contrast, evidence from outside the United States shows increased mortality with CRE. A case-control study from Israel found that, after adjusting for severity of illness, patients with infections from carbapenem-resistant K. pneumoniae had 4 times the risk of death as patients infected with carbapenem-susceptible K. pneumoniae [29].

While it seems intuitive that CRE would be associated with worse outcomes, the lack of consistency across the literature raises several important questions about how CRE cases are defined and how CRE outcomes are measured. First, only 2 studies in this systematic literature review restricted cases to patients with CRE-positive cultures from normally sterile body sites. As a result, there is potential that patients colonized with CRE (i.e., a positive culture from a non-sterile site in the absence of signs or symptoms of infection) were included as “infected” cases. Such a misclassification bias could obscure differences in outcomes. As with any bacteria, the body site of infection is a key determinant of outcomes. A CRE bacteremia, for example, would be expected to have a higher mortality rate than a CRE urinary tract infection. In fact, a case-control study from Israel found that carbapenem-resistant K. pneumoniae bacteremia has an attributable mortality of 50%, or 3 times the risk of death compared with non-bacteremic controls [30]. Second, patients with CRE may have a higher risk of death for reasons beyond the infection itself. For example, CRE-positive patients may have a higher burden of comorbidities and, due to these comorbidities, be more acutely ill when they do become infected. These factors were not adequately accounted for in all studies. Third, it is possible that outcomes other than mortality are worse in patients with CRE, but these alternate outcomes have gone unmeasured. For example, none of the studies measured hospital re-admissions and costs.

Another potential explanation for the conflicting mortality results is that the current studies were underpowered to find statistically significant results. Each of the 4 studies that evaluated mortality included fewer than 100 CRE-infected patients. In the future, larger well-designed studies should be performed to assess the association between CRE infection and mortality.

All the studies included in this systematic literature review evaluated outcomes before the Food and Drug Administration’s (FDA) approval of ceftazidime-avibactam and meropenem-vaborbactam. Now that these new and potentially more efficacious agents are available, a re-evaluation of CRE-related outcomes is warranted.

There are several limitations to our meta-analysis. First, definitions of CRE varied across studies. This discrepancy reflects differences in how each study chose to define a CRE case; it also reflects changes in the CDC’s definition for CRE and the CLSI’s breakpoints for carbapenem-resistance. The original CDC definition for CRE did not include ertapenem, which limited its sensitivity for detecting OXA-48-producing CRE. Furthermore, studies that used the pre-2010 CLSI guidelines to define carbapenem-resistance or evaluated just certain species of Enterobacteriaceae may have under-estimated the true incidence of CRE [19, 31]. Thus, we were unable to pool data using meta-analytic techniques. Second, while we excluded studies that used surveillance cultures, clinical cultures reflecting colonization of a non-sterile site were not consistently distinguished from true infections. This may have resulted in an overestimation of the incidence of infection and an underestimation of the risk of mortality. Third, our incidence rates were derived from a limited number of geographic regions and not the entire US. However, 2 studies included multiple states, which should increase the generalizability of our findings. Fourth, outcome studies were limited in both number and quality. For example, 3 of the 4 studies involved ≤2 hospitals, and only 1 adjusted for severity of illness, a key determinant of mortality.

In conclusion, while the incidence of CRE infections in the United States remains low on a national level, the incidence is highest in LTACs. Several studies have measured the incidence of CRE, but the percentage of CRE that results from carbapenemase-production needs to be better defined. Studies assessing outcomes in CRE-infected patients have been small and have reached conflicting results. Future research should measure a variety of clinical outcomes, should be adequately powered and should adequately adjust for confounders to better assess the full burden of CRE. Specifically, outcomes of CRE infections treated with recently FDA-approved antibiotics warrant further evaluation.

Without adequate studies measuring the burden of CRE infections, proper distribution of resources for research and prevention efforts will be impossible, thereby leaving patients vulnerable to this important emerging pathogen.