Carbapenem-resistant Enterobacteriaceae in Children

United States, 1999-2012

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

Disclosures

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

In This Article

Results

Of the 438,600 isolates from children corresponding to pathogens of interest during 1999–2012, a total of 316,253 (72.1%) met the inclusion criteria that they had been tested against ≥1 third-generation cephalosporin and ≥1 carbapenem of those considered for the CRE phenotype. Of these 316,253 isolates analyzed, 266 (0.08%) met the CRE criteria (Table 1). The median age of children for all analyzed isolates was 8 years; 120,500 (38.1%) of the isolates were from children 1–5 years of age, 100,198 (31.7%) were from children 6–12 years of age, and 95,555 (30.2%) were from children 13–17 years of age. When we considered only CRE isolates, the age distribution was skewed toward younger patients (median age 4 years), and 145 (54.5%) of isolates were from children 1–5 years of age.

For all analyzed isolates from children, 255,181 (80.7%) were from female patients, and for the subset of CRE isolates, 154 (57.9%) were from female patients (Table 1). When we categorized all isolates by organism, isolate source, and health care setting, we found that most (239,274 [75.7%]) were E. coli, from urinary sources (265,690 [84%]), and from the outpatient setting (245,257 [77.6%]) (Table 1). However, among CRE isolates, the largest number of isolates were Enterobacter species (98 [36.8%]), from urinary sources (85 [31.9%]), and from the inpatient non-ICU setting (116 [43.6%]) (Table 1). Of the 6 geographic regions in the dataset, the largest number of isolates was from the West (78,795 [24.9%]), and for CRE isolates, the highest number of isolates was from the Northeast (63 [23.7%]) (Table 1).

When analyzing for linear and quadratic trends during 1999–2012, we found a significant increase (p<0.0001) in the frequency of CRE isolates (Figure 1). From the 1999–2000 period until the 2011–2012 period, the frequency of CRE isolates (across all of the included Enterobacteriaceae) increased from 0% to 0.47%. The greatest increases were seen among Enterobacter species (from 0.0% in 1999–2000 to 5.2% in 2011–2012) (online Technical Appendix Table 1, https://wwwnc.cdc.gov/EID/article/21/11/15-0548-Techapp1.pdf). Likewise, there was a major increase in CRE across the ICU, inpatient non-ICU, and outpatient health care settings; the greatest increase was seen among ICU isolates (from 0.0% in 1999–2000 to 4.5% in 2011–2012) (Figure 2).

Figure 1.

National trends in prevalence of carbapenem-resistant Enterobacteriaceae (CRE) isolates from children, The Surveillance Network-USA database, 1999–2012. Markers show the percentage of isolates that belonged to the resistance phenotype for each 2-year period. Data for patients <1 year of age were not available for all years and were excluded from this analysis. The All Organisms trend encompasses Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, E. aerogenes, Citrobacter freundii, C. koseri, and Serratia marcescens. Each trend had a significant positive quadratic term: All Organisms (p = 1.3 × 10–40), E. aerogenes and E. cloacae (p = 1.4 × 10–29), K. pneumoniae (p = 6.6 × 10–11), and E. coli (p = 2.4 × 10–11). Trends for C. freundii and C. koseri, S. marcescens, and P. mirabilis are not shown but they all had significant positive quadratic terms (p = 0.0006; p = 0.002; and p = 1.0 × 10–7).

Figure 2.

Prevalence of carbapenem-resistant Enterobacteriaceae (CRE) isolates from children by health care setting, The Surveillance Network-USA database, 1999–2012. Health care setting was determined by patient location at the time a microbiological sample was collected. Data for patients <1 year of age were not available for all years and were excluded from this analysis. There was a significant positive quadratic trend for intensive care unit (ICU) (p = 1.1 × 10–18), outpatient (p = 8.6 × 10–26), and inpatient non-ICU (p = 5.0 × 10–11). There was no significant trend for the nursing home setting, which made up 0.34% of total isolates (Table 1).

The frequency of CRE among analyzed isolates throughout the study period was also highest among male patients, children 1–5 years of age, and blood cultures (online Technical Appendix Figures 1–3). Blood and lower respiratory tract cultures showed large increases of CRE over time, increasing from 0% in 1999–2000 to 3.2% and 2.3% in 2011–2012, respectively (online Technical Appendix Figure 2).

Regional data are shown in Figure 3. Before 2007, the frequency of CRE was consistently low across all regions (<0.1%). In the last 2-year period (2011–2012), all regions except East North Central reached CRE prevalences >0.1%; South Central had the highest prevalence of 1.1%.

Figure 3.

Regional trends in the prevalence of carbapenem-resistant Enterobacteriaceae (CRE) isolates from children, The Surveillance Network-USA database, 1999–2012. A) Percentage of isolates with CRE phenotype, 1999–2006 (0%). The 6 regions shown correspond to the 4 US Census regions (West, Northeast, South, Midwest). However, the Midwest and South regions, respectively, were split into East and West North Central and South Central and South Atlantic. Isolates from Alaska and Hawaii are included in the West region. B–D) Percentage of isolates with CRE phenotype, by 2-year period, 2007–2012. There was a significant positive quadratic trend for West (p = 4.1 × 10–15), South Atlantic (p = 9.4 × 10–12), East North Central (p = 0.0002), South Central (p = 5.2 × 10–17), and West North Central (p = 7.2 × 10–8). There was a significant linear trend for North East (p = 5.8 × 10–8). Data for patients <1 year of age were not available for all years and were excluded from this analysis.

When we compared CRE counts between inpatient and outpatient settings across species, 64% (171/266) of CRE isolates were obtained from hospitalized patients (Table 2). CRE isolates were frequently resistant to additional antimicrobial drugs: 142 (54%) were resistant to trimethoprim/sulfamethoxazole, 139 (52.3%) were resistant to ≥1 aminoglycoside, 122 (48.2%) were resistant to ciprofloxacin, and 127 (48.3%) were multidrug resistant (nonsusceptible to ≥3 antimicrobial drug classes) (Table 3). CRE isolates retained the lowest phenotypic resistance to amikacin (21.3%). However, CRE isolate data did not contain information on susceptibility to other CRE treatment options, including colistin, tigecycline, polymyxin B, and fosfomycin.[22] When the distribution of MDR isolates among CRE isolates was considered by species, we found that MDR strains were more common in K. pneumoniae (89.2%) and E. coli (50.9%) and less common in Enterobacter species (20.4%) (Table 4).

CRE trends were not analyzed for isolates from children <1 year of age because of lack of data before 2010. However, data for this age group collected during 2010–2012 demonstrated resistance levels consistent with those seen in other age cohorts (online Technical Appendix Table 2). Of the 8,319 isolates, 70 (0.8%) met CRE criteria. E. aerogenes and E. cloacae isolates represented the largest group of CRE isolates (41 [58.6%]) compared with other organisms, as did male patients (42 [60%]) compared with female patients and isolates from urinary sources (32 [45.7%]) compared with other sources.

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