Incidence and Outcomes of Infections Caused by Multidrug-Resistant Enterobacteriaceae in Children, 2007–2015

Incidence and Outcomes of Infections Caused by Multidrug-Resistant Enterobacteriaceae in... Abstract Background The escalating incidence of invasive disease caused by multidrug-resistant Gram-negative enteric Enterobacteriaceae (MDR-GNE) is a global concern. Scant published studies in which the epidemiology of these infections in children is described exist; previous studies focused mainly on adults, described circumscribed populations, or lacked clinical detail. The objective of this study was to examine and describe the incidence, risk factors, and outcomes associated with MDR-GNE infection in children. Methods In this cohort study, we used data from 48 children’s hospitals maintained by the Pediatric Health Information System. We documented the proportion of MDR-GNE diagnoses among children’s hospital patients aged 0 to <18 years who were diagnosed with an Enterobacteriaceae-associated infection between January 1, 2007, and March 31, 2015, and we analyzed the association between MDR-GNE infection and hospital length of stay and death before discharge. Results During the study period, 107610 discharges included a diagnosis code for Enterobacteriaceae infection, 724 (0.7%) of which included MDR-GNE infection. The incidence of MDR-GNE, and the proportion of infections with Enterobacteriaceae organisms that were MDR-GNE increased over the study period; from 0.2% in 2007 to 1.5% by 2015 (test for trend < .001). Almost one-quarter (23%) of the infections in children hospitalized for MDR-GNE were nosocomial. Increased odds of MDR-GNE infection were associated with older age and comorbid illnesses. Lengths of stay in patients with MDR-GNE infection were increased 20% (95% confidence interval, 9.9%–30.5%; P < .001) over those without MDR-GNE infection; the increased odds for death did not reach statistical significance (1.46 [95% confidence interval, 0.98–2.18]; P = .06). Results were robust to sensitivity analyses. Conclusions The incidence of pediatric MDR-GNE infection increased during 2007–2015. MDR-GNE infection was associated with increased length of stay, and we found a trend toward increased risk of death. Infections with Gram-negative enteric bacilli are becoming increasingly difficult to treat; considering the global burden of these antimicrobial-resistant organisms, interventions to curtail or even reverse this trend are needed urgently. Escalating antibiotic resistance limits treatment options, worsens clinical outcomes, and is an evolving global public health crisis. The development of new wider-spectrum antibacterial drugs, especially those appropriate for children, remains relatively stagnant [1–7]. Since the introduction of effective vaccination against Streptococcus pneumonia and Haemophilus influenza type B and an increase in the prevalence of chronic complex medical conditions, Gram-negative enteric bacteria are responsible for an increasing proportion of serious bacterial infections in children [8, 9]. The Enterobacteriaceae are a large family of Gram-negative enteric bacilli. The US Centers for Disease Control and Prevention called attention to the rising incidence of infections caused by Enterobacteriaceae that are resistant to almost all β-lactam antibiotics, termed here multidrug-resistant Gram-negative Enterobacteriaceae (MDR-GNE) [10]. These organisms include bacteria that express any one of a family of β-lactamases that hydrolyze the antibiotic β-lactam ring and confer resistance to penicillins, cephalosporins (including third-generation cephalosporins), and monobactams [11]. Genetic material that confers multiple resistance mechanisms can be spread among bacteria and even among species via mobile genetic elements such as plasmids, which then can be transmitted between patients and to family and community members [4, 12, 13]. MDR-GNE infection is increasingly prevalent worldwide, especially in less-developed countries, where antibiotics are often available over the counter. Between 2008 and 2010, 11.4% of Gram-negative bacilli associated with pediatric intra-abdominal infections worldwide were caused by MDR-GNE (2.5%, 8.8%, and 27% in Europe, Latin America, and Asia and the Pacific, respectively) [4, 14–18]. Factors typically reported to be associated with a higher risk of MDR-GNE infection are younger age, female sex, recent antibiotic exposure (particularly to fluoroquinolones), recent steroid exposure, and comorbid conditions, especially neurologic conditions [4, 11, 18–23]. Children are at increased risk from adverse outcomes related to MDR-GNE infection, because only a limited number of broad-spectrum antibiotics have been approved for pediatric use [11]. Data describing MDR-GNE infections in US children are limited. Several reports described outbreaks of MDR-GNE in non-US settings and/or in a single US state or city [20–27]. Infection outbreaks usually have occurred in intensive care units (ICUs); more recently, community-acquired infections have become increasingly prevalent [4, 18, 20, 21, 23, 27, 28]. Results of studies using US surveillance data suggest that the incidence of MDR-GNE infection is rising, but these studies included few clinical data [28, 29]. The objectives of this study were to characterize the current epidemiology of infection with MDR-GNE in hospitalized US children and to assess the relationships between infection and resulting length of stay and death. METHODS Population Data for this multicenter retrospective cohort study were obtained from the Pediatric Health Information System (PHIS), an administrative database that contains inpatient, emergency department, ambulatory surgery, and observation encounter-level data from 48 children’s hospitals in the United States and is affiliated with the Children’s Hospital Association (Overland Park, KS). Discharge/encounter data are deidentified at the time of submission and include demographics, up to 41 diagnoses per encounter, and resource utilization (eg, drugs, disposition, devices, laboratory testing, procedures). Data are updated quarterly and are subjected to a number of quality, reliability, and validity checks by the Children’s Hospital Association, Truven Health Analytics (Ann Arbor, MI), and participating hospitals before being included in the database [30]. Not all hospitals joined the PHIS at the same time, and so the first year of available data varies among them. Data on inpatient and observation hospitalizations between January 1, 2007, and March 31, 2015, from 48 PHIS hospitals were included in this analysis. The organisms of concern were the Enterobacteriaceae. Using demographic data and International Classification of Diseases, Ninth Revision (ICD-9), codes, we identified patients aged 0 to <18 years with a primary or secondary discharge diagnosis corresponding to a specific Enterobacteriaceae bacterium (Table 1). ICD-9 codes have been shown to have good accuracy for identifying hospitalizations that include similar diagnoses (eg, hospitalizations related to urinary tract infection [31]). Discharges with multiple ICD-9 codes for Enterobacteriaceae were counted only once. Table 1. ICD-9 Diagnosis Codes for Enterobacteriaceae ICD-9 Diagnosis Code  Diagnosis  No. of Dischargesa  002.0  Typhoid fever  370  003.0  Salmonella gastroenteritis  4171  003.1  Salmonella septicemia  361  003.20  Localized Salmonella infection, unspecified  4  003.21  Salmonella meningitis  101  003.22  Salmonella pneumonia  3  003.23  Salmonella arthritis  23  003.24  Salmonella osteomyelitis  141  003.29  Other localized Salmonella infection  39  003.8  Other specified Salmonella infection  212  003.9  Salmonella infection, unspecified  835  004.0  Shigella dysenteriae  75  004.1  Shigella flexneri  121  004.2  Shigella boydii  2  004.3  Shigella sonnei  665  004.8  Other specified Shigella infection  259  004.9  Shigellosis, unspecified  792  008.00  Intestinal infection due to unspecified Escherichia coli  503  008.01  Intestinal infection due to enteropathogenic Escherichia coli  31  008.02  Intestinal infection due to enterotoxigenic Escherichia coli  18  008.03  Intestinal infection due to enteroinvasive Escherichia coli  9  008.04  Intestinal infection due to enterohemorrhagic Escherichia coli  636  008.09  Intestinal infection due to other intestinal Escherichia coli infection  280  008.3  Intestinal infection due to Proteus (mirabilis) (morganii)  29  008.44  Intestinal infection due to Yersinia enterocolitica  173  038.42  Septicemia due to Escherichia coli  3973  038.44  Septicemia due to Serratia  624  041.3  Klebsiella pneumoniae infection in conditions classified elsewhere and of unspecified site  18888  041.4  Escherichia coli infection in conditions classified elsewhere and of unspecified site  40532  041.41  Shiga toxin-producing Escherichia coli (STEC) O157  353  041.42  Other specified Shiga toxin-producing Escherichia coli (STEC)  15  041.43  Shiga toxin-producing Escherichia coli (STEC), unspecified  90  041.49  Other and unspecified Escherichia coli  30905  041.6  Proteus (mirabilis) (morganii) infection in conditions classified elsewhere and of unspecified site  4598  482.0  Pneumonia due to Klebsiella pneumoniae  1632  482.82  Pneumonia due to Escherichia coli  736  ICD-9 Diagnosis Code  Diagnosis  No. of Dischargesa  002.0  Typhoid fever  370  003.0  Salmonella gastroenteritis  4171  003.1  Salmonella septicemia  361  003.20  Localized Salmonella infection, unspecified  4  003.21  Salmonella meningitis  101  003.22  Salmonella pneumonia  3  003.23  Salmonella arthritis  23  003.24  Salmonella osteomyelitis  141  003.29  Other localized Salmonella infection  39  003.8  Other specified Salmonella infection  212  003.9  Salmonella infection, unspecified  835  004.0  Shigella dysenteriae  75  004.1  Shigella flexneri  121  004.2  Shigella boydii  2  004.3  Shigella sonnei  665  004.8  Other specified Shigella infection  259  004.9  Shigellosis, unspecified  792  008.00  Intestinal infection due to unspecified Escherichia coli  503  008.01  Intestinal infection due to enteropathogenic Escherichia coli  31  008.02  Intestinal infection due to enterotoxigenic Escherichia coli  18  008.03  Intestinal infection due to enteroinvasive Escherichia coli  9  008.04  Intestinal infection due to enterohemorrhagic Escherichia coli  636  008.09  Intestinal infection due to other intestinal Escherichia coli infection  280  008.3  Intestinal infection due to Proteus (mirabilis) (morganii)  29  008.44  Intestinal infection due to Yersinia enterocolitica  173  038.42  Septicemia due to Escherichia coli  3973  038.44  Septicemia due to Serratia  624  041.3  Klebsiella pneumoniae infection in conditions classified elsewhere and of unspecified site  18888  041.4  Escherichia coli infection in conditions classified elsewhere and of unspecified site  40532  041.41  Shiga toxin-producing Escherichia coli (STEC) O157  353  041.42  Other specified Shiga toxin-producing Escherichia coli (STEC)  15  041.43  Shiga toxin-producing Escherichia coli (STEC), unspecified  90  041.49  Other and unspecified Escherichia coli  30905  041.6  Proteus (mirabilis) (morganii) infection in conditions classified elsewhere and of unspecified site  4598  482.0  Pneumonia due to Klebsiella pneumoniae  1632  482.82  Pneumonia due to Escherichia coli  736  Abbreviation: ICD-9, International Classification of Diseases, Ninth Revision. aDischarged patients could have more than 1 Enterobacteriaceae diagnosis. View Large Outcome and Exposure Variables Exposure We were interested in Enterobacteriaceae that were resistant to third-generation cephalosporins, including MDR organisms that expressed extended-spectrum β-lactamases (ESBLs) and resistance conferred by other mechanisms (eg, carbapenemases, AmpC cephalosporinases) [11, 32]. As we were unable to measure this directly, as a surrogate for overall nonspecific antimicrobial resistance in Enterobacteriaceae, we defined MDR-GNE as the subset of these Enterobacteriaceae discharges that also included the ICD-9 codes: V09.81 “Infection with microorganisms with resistance to multiple drugs” or V09.91 “Infection with drug-resistant microorganisms, unspecified, with multiple drug resistance” (Table 2). Table 2. ICD-9 Diagnosis Codes for Multidrug-Resistant Enterobacteriaceae ICD-9 Diagnosis Code  Diagnosis  V09.81  Infection with microorganisms resistant to other specified drugs with resistance to multiple drugs  V09.91  Infection with drug-resistant microorganisms unspecified with multiple drug resistance  ICD-9 Diagnosis Code  Diagnosis  V09.81  Infection with microorganisms resistant to other specified drugs with resistance to multiple drugs  V09.91  Infection with drug-resistant microorganisms unspecified with multiple drug resistance  Abbreviation: ICD-9, International Classification of Diseases, Ninth Revision. View Large We assessed the accuracy of our MDR-GNE diagnosis codes in 2 ways. To assess their positive predictive value, for all discharges we identified with an MDR-GNE diagnosis in 2011, 2 investigators independently reviewed all of the discharge diagnoses associated with that encounter and their timing (whether present on admission). Potential discrepancies were discussed with 2 coding specialists from our institution and resolved between the 2 investigators. We also compared our results to publicly available 2007–2012 data from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project Kids’ Inpatient Database (HCUP-KID). The KID samples data from US hospitals to provide national estimates of hospital use by US children. We used HCUPnet [33], the HCUP online query system, to identify in the KID discharges from children’s hospitals with the same ICD-9 diagnosis codes we used to query the PHIS database for Enterobacteriaceae organisms. We then queried HCUPnet for the V09.81 and V09.91 codes for MDR infection. The unit of analysis for this database is the diagnosis code, not discharges; thus, the same discharge can be included more than once in the query, depending on the number of identified diagnosis codes. Therefore, discharges with MDR Enterobacteriaceae should have been identified at least twice, once with an Enterobacteriaceae code and again with either V09.81 or V09.91. Accordingly, we estimated the proportion of MDR Enterobacteriaceae as follows: % MDR-GNE = (MDR Enterobacteriaceae)/(Enterobacteriaceae – MDR Enterobacteriaceae). Outcomes Primary outcomes were length of stay, measured in days, and death before discharge. Our secondary outcome was either death or discharge to hospice care. Covariates Covariates included age (age in years and age category), sex, race, ethnicity, discharge year, insurance payer, the presence of a comorbidity, pediatric or neonatal ICU stay, and US geographic region (Northeast, South, Midwest, or West). Interaction terms between discharge year, age, and race were considered. Race was dichotomized as black versus nonblack, and insurance payer was dichotomized as commercial versus public and other, which included Medicaid, Tricare, uninsured, and unknown [34]. Individual comorbidities are defined in the PHIS as described previously [35]; each comorbidity was considered separately, and all of them were considered together as “any comorbidity,” designating whether any one of the comorbidity flags was present. ANALYSIS Individual characteristics were summarized using means, medians, and percentages for categorical and continuous variables, as appropriate. We compared characteristics of children with versus those without MDR-GNE infection by using bivariate analyses using the χ2 test or nonparametric tests, as noted. Approximate χ2 tests based on the score statistic were used to test adjusted and unadjusted linear trends of odds. All regression models adjusted for clustering according to hospital and used robust standard errors. Multivariable 0-truncated negative binomial regression was used to model the length-of-stay outcome and to calculate incidence rate ratios (IRRs) [36]. Binary logistic regression was used to model the odds of death and death-or-hospice outcomes. Model fit was evaluated by using the Wald test, Akaike information criterion, and Bayesian information criterion. Analyses were performed using Stata SE 12.1 (StataCorp LP, College Station, TX). Sensitivity Analyses The PHIS uses encrypted patient identifiers; to assess for bias caused by clustering according to patient, we repeated the primary analyses using only each patient’s first discharge during the study period. Multivariable analysis was also repeated, stratifying according to whether patients had an ICU stay during that admission. To assess the effect of missing data on the mortality outcome, we used chained equations to impute the data and create 9 imputed data sets; multiple-imputation multivariable analysis was repeated to assess the principal outcome using all 10 data sets [37]. We also repeated the multivariable analysis using conditional fixed-effects regression to obtain within-practice estimates of the effect of MDR-GNE on the primary death outcome. RESULTS Our cohort included a total of 107610 hospital discharges, including 94258 different patients, with a diagnosis of Enterobacteriaceae infection in the PHIS database during the study period. Table 3 lists the characteristics of patients included in this cohort. The mean age was 4.1 years (median, 1 year [IQR, 0–17 years]). Of all the hospitalizations, 724 (0.7%) were associated with MDR-GNE. Although the number of discharges with Enterobacteriaceae-associated infection remained relatively stable between 2007 and 2015, the proportion of those with MDR-GNE infection rose from 0.2% in January 2007 to 1.5% by March 2015 (P < .001, test for trend) (Figure 1). This trend of increasing odds of MDR-GNE across study years was robust to adjustments for age, total parenteral nutrition (TPN), surgery and surgical complications, mechanical ventilation, malignancy, and metabolic, hematologic, respiratory, gastrointestinal, and cardiac conditions (P < .001). MDR-GNE infections were more prevalent in the western United States and were similar among the remaining US geographic regions (P < .001). Over the course of the study period, MDR-GNE infections were increasingly more likely to be associated with hospitalizations including an ICU stay; this trend persisted after adjusting for age and insurance payer (commercial vs public or uninsured, P = .03) (Figure 2). Table 3. Characteristics of Hospitalized Patients Characteristic  Total  MDR-GNE  No MDR-GNE  P  Total no.  107610  724  106886    Sex (n [% of column total])        .77   Male  45074 (41.9)  294 (40.6)  44780     Female  62531  430  62101     Information missing  5  0  5    Age (y)           Mean (SD)  4.1 (5.5)  5.3 (5.8)  4.1 (5.5)  <.001   Median (IQR)  1 (0–17)  3 (0–17)  1 (0–17)  <.001  Age category (n [% of column total])        <.001   <1 y  49398 (45.9)  239 (33.0)  49159 (46.0)     1 to <6 y  25653 (23.8)  205 (28.3)  25448 (23.8)     6 to <12 y  15411 (14.3)  127 (17.5)  15284 (14.3)     12 to 18 y  17148 (15.9)  153 (21.1)  16995 (15.9)    Race (n [% of column total])        <.001   Black  15026 (14.0)  57 (7.9)  14969 (14.0)     White  52162 (48.5)  351 (48.5)  51811 (48.5)     Other or >1 race  20839 (19.4)  245 (33.8)  20594 (19.3)     Information missing  19583 (18.2)  71 (9.8)  19512 (18.2)    Payer (n [% of column total])        .24a   Public (Medicare, Medicaid, Tricare, other government)  58729  408 (56.3)  58321 (54.6)     Commercial  29178  237 (32.7)  28941 (27.1)     Self-pay  1507  13 (1.8)  1494 (1.4)     Charity, other  2423  23 (3.2)  2400 (2.2)     Information missing  15773  43 (5.9)  15730 (14.7)    Region (n [% of column total])        <.001   Midwest  25689  128 (17.7)  25561 (23.9)     Northeast  13503  70 (9.7)  13433 (12.6)     South  42370  216 (29.8)  42154 (39.4)     West  26043  310 (42.8)  25733 (24.1)     Information missing  5  0  5 (<1%)    Mortality (n [% of column total])        <.001b   Death before discharge  1882 (0.7)  21 (2.9)  1861 (1.7)     Death or hospice  2048 (1.9)  22 (3.0)  2026 (1.9)     Other  90.295  655  89640     Information missing  15268  47  15221    Year (n [% of column total])        <.001   2007  12200  29 (4.0)  12171 (11.4)     2008  12565  39 (5.4)  12526 (11.7)     2009  13020  51 (7.0)  12969 (12.1)     2010  13143  73 (10.1)  13070 (12.2)     2011  13086  83 (11.5)  13003 (12.2)     2012  13214  110 (15.2)  13104 (12.3)     2013  13339  118 (16.3)  13221 (12.4)     2014  13891  176 (24.3)  13715 (12.8)     2015  3092  45 (6.2)  3047 (2.8)    Length of stay (days)           Mean (SD)  17.4 (39.4)  21.4 (43.4)  17.3 (39.4)  .006   Median (IQR)  4 (1919)  7 (1218)  4 (1919)  <.001  Comorbidity flags (n [% of column total])           ICU stay  19255 (17.9)  149 (20.6)  19106 (17.9)  .058   Neonatal ICU stay  9104 (8.5)  52 (7.2)  9052 (8.5)  .215   Technology dependent  25737 (23.9)  240 (33.1)  25497 (23.8)  <.001    Information missing  5869  45  5824     Cardiovascular  13562 (12.6)  101 (13.9)  13461 (12.6)  .273    Information missing  5  0  5     Neuromuscular  16176 (15.0)  174 (24.0)  16002 (15.0)  <.001    Information missing  5  0  5     Respiratory  8.903 (8.3)  71 (9.8)  8.832 (8.3)  .133    Information missing  5  0  5     Renal  17180 (16.0)  214 (29.6)  16996 (15.9)      Information missing  0  0  5     Gastrointestinal  20850 (19.4)  180 (24.9)  20.670 (19.3)  <.001    Information missing  5  5  0     Hematologic/oncologic  6866 (6.4)  77 (10.6)  6789 (6.3)  <.001    Information missing  5  0  5     Malignancy  6734  74 (10.2)  6660 (6.20)  <.001    Information missing  5  0  5     Metabolic  7172 (6.7)  84 (11.6)  7088 (6.6)  <.001    Information missing  0  0  0     Congenital/genetic  10484 (9.7)  78 (10.8)  10406 (9.7)  .348    Information missing  5  0  5     Transplant  3379 (3.14)  43 (5.9)  3336 (3.1)  <.001    Information missing  5869  45  5824    Total parenteral nutrition (n [% of column total])  18979 (17.6)  125 (17.3)  18854 (17.6)  .792  Surgery (n [% of column total])  23902 (22.2)  210 (29.0)  23692 (22.2)  <.001   Any flag  63274 (58.8)  506 (69.9)  62768 (58.7)  <.001  Characteristic  Total  MDR-GNE  No MDR-GNE  P  Total no.  107610  724  106886    Sex (n [% of column total])        .77   Male  45074 (41.9)  294 (40.6)  44780     Female  62531  430  62101     Information missing  5  0  5    Age (y)           Mean (SD)  4.1 (5.5)  5.3 (5.8)  4.1 (5.5)  <.001   Median (IQR)  1 (0–17)  3 (0–17)  1 (0–17)  <.001  Age category (n [% of column total])        <.001   <1 y  49398 (45.9)  239 (33.0)  49159 (46.0)     1 to <6 y  25653 (23.8)  205 (28.3)  25448 (23.8)     6 to <12 y  15411 (14.3)  127 (17.5)  15284 (14.3)     12 to 18 y  17148 (15.9)  153 (21.1)  16995 (15.9)    Race (n [% of column total])        <.001   Black  15026 (14.0)  57 (7.9)  14969 (14.0)     White  52162 (48.5)  351 (48.5)  51811 (48.5)     Other or >1 race  20839 (19.4)  245 (33.8)  20594 (19.3)     Information missing  19583 (18.2)  71 (9.8)  19512 (18.2)    Payer (n [% of column total])        .24a   Public (Medicare, Medicaid, Tricare, other government)  58729  408 (56.3)  58321 (54.6)     Commercial  29178  237 (32.7)  28941 (27.1)     Self-pay  1507  13 (1.8)  1494 (1.4)     Charity, other  2423  23 (3.2)  2400 (2.2)     Information missing  15773  43 (5.9)  15730 (14.7)    Region (n [% of column total])        <.001   Midwest  25689  128 (17.7)  25561 (23.9)     Northeast  13503  70 (9.7)  13433 (12.6)     South  42370  216 (29.8)  42154 (39.4)     West  26043  310 (42.8)  25733 (24.1)     Information missing  5  0  5 (<1%)    Mortality (n [% of column total])        <.001b   Death before discharge  1882 (0.7)  21 (2.9)  1861 (1.7)     Death or hospice  2048 (1.9)  22 (3.0)  2026 (1.9)     Other  90.295  655  89640     Information missing  15268  47  15221    Year (n [% of column total])        <.001   2007  12200  29 (4.0)  12171 (11.4)     2008  12565  39 (5.4)  12526 (11.7)     2009  13020  51 (7.0)  12969 (12.1)     2010  13143  73 (10.1)  13070 (12.2)     2011  13086  83 (11.5)  13003 (12.2)     2012  13214  110 (15.2)  13104 (12.3)     2013  13339  118 (16.3)  13221 (12.4)     2014  13891  176 (24.3)  13715 (12.8)     2015  3092  45 (6.2)  3047 (2.8)    Length of stay (days)           Mean (SD)  17.4 (39.4)  21.4 (43.4)  17.3 (39.4)  .006   Median (IQR)  4 (1919)  7 (1218)  4 (1919)  <.001  Comorbidity flags (n [% of column total])           ICU stay  19255 (17.9)  149 (20.6)  19106 (17.9)  .058   Neonatal ICU stay  9104 (8.5)  52 (7.2)  9052 (8.5)  .215   Technology dependent  25737 (23.9)  240 (33.1)  25497 (23.8)  <.001    Information missing  5869  45  5824     Cardiovascular  13562 (12.6)  101 (13.9)  13461 (12.6)  .273    Information missing  5  0  5     Neuromuscular  16176 (15.0)  174 (24.0)  16002 (15.0)  <.001    Information missing  5  0  5     Respiratory  8.903 (8.3)  71 (9.8)  8.832 (8.3)  .133    Information missing  5  0  5     Renal  17180 (16.0)  214 (29.6)  16996 (15.9)      Information missing  0  0  5     Gastrointestinal  20850 (19.4)  180 (24.9)  20.670 (19.3)  <.001    Information missing  5  5  0     Hematologic/oncologic  6866 (6.4)  77 (10.6)  6789 (6.3)  <.001    Information missing  5  0  5     Malignancy  6734  74 (10.2)  6660 (6.20)  <.001    Information missing  5  0  5     Metabolic  7172 (6.7)  84 (11.6)  7088 (6.6)  <.001    Information missing  0  0  0     Congenital/genetic  10484 (9.7)  78 (10.8)  10406 (9.7)  .348    Information missing  5  0  5     Transplant  3379 (3.14)  43 (5.9)  3336 (3.1)  <.001    Information missing  5869  45  5824    Total parenteral nutrition (n [% of column total])  18979 (17.6)  125 (17.3)  18854 (17.6)  .792  Surgery (n [% of column total])  23902 (22.2)  210 (29.0)  23692 (22.2)  <.001   Any flag  63274 (58.8)  506 (69.9)  62768 (58.7)  <.001  Abbreviations: ICU, intensive care unit; IQR, interquartile range; MDR-GNE, multidrug-resistant Enterobacteriaceae; SD, standard deviation. aPublic or uninsured versus other. bFor death. View Large Figure 1. View largeDownload slide Multidrug-resistant Enterobacteriaceae according to year. Shown are the percentages of discharges with a diagnosis of multidrug-resistant Enterobacteriaceae infection. Figure 1. View largeDownload slide Multidrug-resistant Enterobacteriaceae according to year. Shown are the percentages of discharges with a diagnosis of multidrug-resistant Enterobacteriaceae infection. Figure 2. View largeDownload slide Multidrug-resistant Gram-negative Enterobacteriaceae (MDR-GNE) and intensive care unit (ICU) stays according to year. Shown are the percentages of discharges with MDR-GNE infection that included an ICU stay. Figure 2. View largeDownload slide Multidrug-resistant Gram-negative Enterobacteriaceae (MDR-GNE) and intensive care unit (ICU) stays according to year. Shown are the percentages of discharges with MDR-GNE infection that included an ICU stay. Sixty-three percent of our cohort overall, and 76% of those with MDR-GNE infection, had an Enterobacteriaceae-associated infection documented on admission; infection timing could not be determined for 26% of overall admissions or 10% of admissions with MDR-GNE infection. For 685 of the 724 MDR-GNE-associated discharges with only 1 documented Enterobacteriaceae infection, 525 (77%) were present on admission; for the remaining 39 discharges with more than 1 documented Enterobacteriaceae infection, at least 26 (67%) were all present on admission, which suggests that at least 551 (76%) of the MDR-GNE infections were present on admission. The timing of MDR-GNE infection could not be determined using PHIS discharge data when Enterobacteriaceae infection diagnoses were recorded with discordant onsets. Of the 107610 discharges in the study period, 27875 (26%) were missing information on diagnosis timing. In unadjusted analysis, without including covariates (Table 3), black patients had lower odds of MDR-GNE infection than did white patients (odds ratio [OR], 0.75 [95% confidence interval (CI), 0.576–0.99]; P = .49); patients of other or mixed races had higher odds than did white patients (OR, 1.57 [95% CI, 1.29–1.91]; P < .001). The multivariable model adjusted for age; sex; discharge year; black race; insurance payer; any ICU stay; intravenous nutrition; operating room use; mechanical ventilation; malignancy, metabolic, respiratory, cardiovascular, hematologic/oncologic, and gastrointestinal comorbidities; and clustering according to hospital; in this adjusted model, the lower odds for black patients was no longer statistically significant (OR, 0.77 [95% CI, 0.58–1.03]; P = .08) but remained so for patients of other or mixed races (OR, 1.73 [1.42–2.10]; P < .001). In the adjusted model, MDR-GNE infection was also associated with older age (P < .001), TPN (P = .002), and surgery (P = .027) comorbidity flags but not with sex, metabolic or gastrointestinal comorbidities, or public insurance (P = .80, .06, .22, and .14, respectively). Validation of MDR-GNE Coding Of 84 discharges with an ICD-9 code indicating an MDR-GNE diagnosis in 2011, 5 were of indeterminate accuracy: 1 included both E coli infection and streptococcal septicemia (unspecified type); 1 included Klebsiella, E coli, and Haemophilus influenza (unspecified type) infections; 1 included E coli, streptococcal, and H influenza infections; 1 included E coli and Pseudomonas infections; and 1 included both Klebsiella and Pseudomonas infections. Even if all 5 of these diagnoses were incorrect, our positive predictive value would be 79/84 (at least 94%). Comparison With HCUP KID Data The HCUP-KID–estimated proportions of MDR-GNE–related infections were 0.8% in 2006 and 1.7% in 2012 for all children’s hospitals and 0.8% in 2006 and 1.9% in 2012 for freestanding children’s hospitals. Length of Stay The length-of-stay distribution was skewed to the right (median, 4 days [IQR, 2–23]). In an unadjusted analysis, the mean length of stay for patients hospitalized with an MDR-GNE–related diagnosis was 21.4 days versus 17.3 days for patients without an MDR-GNE–related diagnosis (median, 7 vs 4 days, respectively; P < .001, Wilcoxon rank-sum test) (Table 4 and Figure 3). Table 4. Regression Model Results for Patients With Versus Those Without Multidrug-Resistant Enterobacteriaceae Parameter  Unadjusted IRR  Adjusted IRR  95% CI  P  Length of stay, daysa           Primary analysis  1.23  1.20  1.10–1.30  <.001   ICU stay            No  1.38  1.21  1.08–1.36  .001    Yes  1.11  1.21  1.11–1.31  <.001   First discharge only  1.31  1.22  1.09–1.36  <.001  Mortality (OR)           Death before dischargeb    Primary analysis  1.54  1.46  0.98–2.18  .06    Multiple imputation  1.54  1.46  0.98–2.18  .06    First admission only  1.56  1.45  0.93–2.26  .10    Conditional on practice  1.54  1.50  0.90–2.48  .12   Death or discharge to hospicec    Primary analysis  1.42  1.35  0.89–2.06  .16    Multiple imputation  1.42  1.35  0.89–2.06  .16    First admission only  1.47  1.39  0.88–2.19  .16  Parameter  Unadjusted IRR  Adjusted IRR  95% CI  P  Length of stay, daysa           Primary analysis  1.23  1.20  1.10–1.30  <.001   ICU stay            No  1.38  1.21  1.08–1.36  .001    Yes  1.11  1.21  1.11–1.31  <.001   First discharge only  1.31  1.22  1.09–1.36  <.001  Mortality (OR)           Death before dischargeb    Primary analysis  1.54  1.46  0.98–2.18  .06    Multiple imputation  1.54  1.46  0.98–2.18  .06    First admission only  1.56  1.45  0.93–2.26  .10    Conditional on practice  1.54  1.50  0.90–2.48  .12   Death or discharge to hospicec    Primary analysis  1.42  1.35  0.89–2.06  .16    Multiple imputation  1.42  1.35  0.89–2.06  .16    First admission only  1.47  1.39  0.88–2.19  .16  Abbreviations: CI, confidence interval; ICU, intensive care unit; IRR, incidence rate ratio; OR, odds ratio. aMultivariable models for length of stay adjusted for age; sex; discharge year; black race; insurance payer; any ICU stay; intravenous nutrition; operating room use; mechanical ventilation; malignancy; metabolic, respiratory, cardiovascular, hematologic/oncologic, and gastrointestinal comorbidities; and clustering according to hospital. bMultivariable models for death included discharge year; insurance payer; any ICU stay; any comorbidity flag; intravenous nutrition; operating room use; mechanical ventilation; malignancy; metabolic, respiratory, cardiovascular, hematologic/oncologic, and gastrointestinal comorbidities; interaction between any comorbidity and discharge year; and clustering according to hospital. cMultivariable models for death or discharge to hospice included discharge year; intravenous nutrition; operating room use; mechanical ventilation; any comorbidity flag; malignancy; metabolic, respiratory, cardiovascular, hematologic/oncologic, and gastrointestinal comorbidities; and clustering according to hospital. View Large Figure 3. View largeDownload slide Lengths of stay for pediatric patients with multidrug-resistant Enterobacteriaceae infection (MDR-GNE), unadjusted. Figure 3. View largeDownload slide Lengths of stay for pediatric patients with multidrug-resistant Enterobacteriaceae infection (MDR-GNE), unadjusted. In unadjusted 0-truncated negative binomial regression analysis, the IRR for length of stay for patients with versus those without MDR-GNE infection was 1.235, which indicates that patients with MDR-GNE infection had a 23.5% increased length of stay compared with patients without MDR-GNE infection (Table 4). The fully adjusted final multivariable model included age; black race; any chronic condition; TPN; surgery; mechanical ventilation; malignancy; neonatal ICU stay; and metabolic, hematologic, respiratory, gastrointestinal, and cardiac conditions; patients with MDR-GNE infection had a 19.8% increased mean length of stay (95% CI, 9.9%–30.5%; P < .001). This increased length of stay depending on MDR-GNE status was unchanged across the study years (<1% change in IRR; P = .81 for the interaction term). Black patients had an 11.2% higher mean length of stay compared with nonblack patients. Patients with any ICU stay experienced, on average, a slightly lower impact of MDR-GNE infection on their length of stay than patients without an ICU stay when we adjusted for all other covariates (20.7% [95% CI, 11.6–30.6] increased length of stay for ICU patients vs 21.5% [95% CI, 8.4–36.3] increased length of stay for those without an ICU stay); this interaction did not reach statistical significance. Results of analysis using only each patient’s first admission during the study period were essentially the same; patients with MDR-GNE infection experienced an increased mean length of stay of 21.8% (95% CI, 9.4–35.7; P < .001). Death Before Discharge As shown in Table 3, 1882 patients died before discharge, and 2048 either died or were discharged to hospice care; disposition data for 14.2% of the discharges were missing. Patients who were diagnosed with an MDR-GNE infection had a higher crude risk of death before discharge compared with those without MDR-GNE infection (2.9% vs 1.7%; P < .001) (Table 3). In the regression models, adjusted only for clustering according to hospital, the OR for death for patients with versus those without MDR-GNE infection was 1.54 (95% CI, 0.99–2.4; P = .058). The multivariable fully adjusted model included age; year; TPN; surgery and surgical complications; mechanical ventilation; any ICU stay; insurance payer; malignancy; hematologic, metabolic, respiratory, cardiovascular, and gastrointestinal conditions; and the interaction between any chronic condition and year; the OR for death before discharge in a comparison of patients with versus those without MDR-GNE infection was 1.46 (95% CI, 0.98–2.18; P = .06). Results from the sensitivity analysis, the multiple-imputation analysis, and an analysis using only the first discharge of each patient were essentially unchanged from the primary analysis (Table 4). The adjusted OR for the composite variable death or discharge to hospice was similar to that for death before discharge at 1.35 (0.89–2.06; P = .16). Results from the multiple imputation analysis, in which we used only the first discharge of each patient and conditional within-practice analysis, were unchanged from the primary analysis (Table 4). DISCUSSION To the extent of our knowledge, this study was the first to examine the epidemiology of MDR-GNE infection across US children’s hospitals. We found that the incidence of infection with MDR-GNE has increased over the past 8 years from 0.2% in 2007 to 1.5% by March 2015; the rise has been even faster for patients admitted to an ICU. Few previous study reports have described the changing epidemiology of pediatric MDR-GNE infection in the United States. Logan et al [28], who used US surveillance data, characterized Enterobacteriaceae isolates from 368398 children older than 1 year and found an increasing incidence of MDR-GNE between 1999 and 2011. In 2011, 2% and 0.5% of Enterobacteriaceae isolates expressed third-generation cephalosporin resistance and ESBL-related resistance, respectively. Although the PHIS did not provide culture data and so we cannot report patterns or mechanisms of resistance to specific antibiotics, our MDR-GNE definition should identify organisms relatively comparable to their organisms of interest, so it is reassuring that their estimates are similar to our findings. KID data estimated 0.8% of Enterobacteriaceae infections to be MDR-GNE for all children’s hospitals and freestanding children’s hospitals in 2006 and 1.7% and 1.9% for all children’s hospitals and freestanding children’s hospitals, respectively, in 2012. Our MDR-GNE rates were 0.2% in 2007 and 0.8% in 2012, relatively consistent with the KID results, considering the different unit of analysis in the HCUPnet. The HCUPnet provides only aggregate data, has limited demographic and clinical information, and uses diagnosis code as the unit of analysis; thus, discharges including multiple queried diagnosis codes (ie, multiple Enterobacteriaceae infections) are counted more than once, and admission rates can be overestimated. In addition, the cohort of HCUPnet discharges coded with our multidrug-resistance codes can include some patients infected with organisms that were not Enterobacteriaceae. We found that older children, children with comorbidities, and those in the western United States were more likely to be infected with MDR-GNE, but we found no differences based on sex or insurance coverage. We found inconsistent risks based on race (lower risks of MDR-GNE infection for white and black children than for those of other races and those of mixed race). Reasons underlying these disparities are unknown. Consistent with our results, Logan et al [28] reported that children with underlying comorbidities had the highest proportion of MDR-GNE isolates; their findings that younger children, girls, and children in the central United States were also at higher risk differed from our results. MDR-GNE infections are associated with poor outcomes in adults yet this has been inconsistently shown in children [20, 23, 26, 38]. We found that MDR-GNE infections were associated with longer lengths of stay and a trend toward a higher mortality rate. Point estimates and CIs of unadjusted versus adjusted models were similar for both mortality outcomes, death before discharge and death or discharge to hospice. Our results suggest that if there is an increased risk of death for patients with MDR-GNE infection, the difference is too small to be detected, even with our large sample size. This study had limitations. Our organisms of interest were those in the bacterial family Enterobacteriaceae associated with pediatric bacterial infections in the United States for which there were specific ICD-9 codes [11]. The results do not generalize to children in other countries or to those with an infection caused by other organisms. The results do not necessarily generalize to pediatric discharges from hospitals other than children’s hospitals. Although the PHIS data have certain limitations, they offer researchers an opportunity to examine a rare but concerning diagnosis of interest across a large number of US children’s hospitals. We believe that there are no previous studies that used the codes we used to identify MDR-GNE; however, we found that these codes had a high positive predictive value for identifying admissions of pediatric patients with an infection associated with MDR Enterobacteriaceae. There was no way for us to directly identify third-generation cephalosporin resistance or specific mechanisms of resistance (eg, ESBLs, carbapenemases, AmpC cephalosporinases). Gauging the sensitivity of these codes was beyond the scope of this study. It is conceivable that, over the course of the study period, the increasing rate of MDR-GNE infection reflected increasing sensitivity of diagnosing and coding for these infections and/or that discharges including more severe outcomes might have been more likely to have been identified as MDR-GNE related; similar limitations afflict any observational study in which claims data are used. The PHIS does not include culture data, and we did not have the resources to obtain culture data from PHIS hospitals; thus, isolate resistance patterns and mechanisms of resistance are not included here. To our knowledge, timing of infection in the PHIS has not been validated; this variable was missing for more than one-quarter of our diagnoses, and for children with more than 1 Enterobacteriaceae diagnosis, we could not always ascertain the timing of the particular MDR-GNE infection. We also were not able to determine whether the patients had unrecorded risk factors (eg, chronic health conditions and social determinants of health) before admission that put them at higher risk of infection with antibiotic-resistant bacteria. This information could be difficult to tease out; we would not want to treat variables as confounders if they are truly mediators, and we would not necessarily want to adjust for them if they could be in the causal chain between MDR-GNE infection and the outcome. Our similar results using only the first admission of each child are reassuring in that results are not necessarily different for children with multiple admissions. The high proportion of community-acquired infections needs to be confirmed using other data sources. It would be ideal to have preadmission data on antibiotic exposure, which might put a child at greater risk of a resistant infection. The missing disposition data could have biased our results; it is reassuring that our results were robust to reanalysis using imputed data. Sicker patients are likely to receive more antibiotics, to be at risk of colonization and infection with resistant organisms, to experience longer hospitalizations, and to have adverse outcomes. To the extent that they were measured, our models adjusted for confounding by comorbidities; however, future studies will need to address residual confounding, the underlying causal relationships, and their directionality among these clinical variables. In conclusion, we found that infections with MDR-GNE have increased by more than 700% between 2007 and 2015 for pediatric patients admitted to children’s hospitals and are associated with an increased length of stay and a trend toward a higher mortality rate. Previously described as mostly nosocomial, most MDR-GNE infections in this recent cohort were present on admission. Hospital surveillance cultures, strict cohorting, limited use of third-generation cephalosporins, and restricted agricultural antibiotic use have been recommended for reducing MDR-GNE colonization and related infection [11]. The march of escalating antibiotic resistance seems inexorable; however, thoughtful and thorough efforts to reverse this trend can be successful [2, 39, 40]. Considering the global skyrocketing incidence of MDR-GNE infection, we must be vigilant and do everything possible to curtail, or even reverse, this process. Notes Financial support. This work was supported by the National Institute for Allergy and Infectious Diseases at the National Institutes of Health (grant K23AI097284). Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Choffnes E Relman DA Mack A. Antibiotic resistance: implications for global health and novel intervention strategies: workshop summary . In: Forum on Microbial Threats. Washington, DC: Institute of Medicine; 2010. 2. Baym M Stone LK Kishony R . Multidrug evolutionary strategies to reverse antibiotic resistance. Science  2016; 351: aad3292. Google Scholar CrossRef Search ADS PubMed  3. Metlay JP Hofmann J Cetron MS et al.   . Impact of penicillin susceptibility on medical outcomes for adult patients with bacteremic pneumococcal pneumonia. Clin Infect Dis  2000; 30: 520– 8. 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Aarestrup FM Seyfarth AM Emborg HD et al.   . Effect of abolishment of the use of antimicrobial agents for growth promotion on occurrence of antimicrobial resistance in fecal enterococci from food animals in Denmark. Antimicrob Agents Chemother  2001; 45: 2054– 9. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of the Pediatric Infectious Diseases Society Oxford University Press

Incidence and Outcomes of Infections Caused by Multidrug-Resistant Enterobacteriaceae in Children, 2007–2015

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Pediatric Infectious Diseases Society
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© The Author(s) 2017. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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2048-7193
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2048-7207
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10.1093/jpids/piw093
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Abstract

Abstract Background The escalating incidence of invasive disease caused by multidrug-resistant Gram-negative enteric Enterobacteriaceae (MDR-GNE) is a global concern. Scant published studies in which the epidemiology of these infections in children is described exist; previous studies focused mainly on adults, described circumscribed populations, or lacked clinical detail. The objective of this study was to examine and describe the incidence, risk factors, and outcomes associated with MDR-GNE infection in children. Methods In this cohort study, we used data from 48 children’s hospitals maintained by the Pediatric Health Information System. We documented the proportion of MDR-GNE diagnoses among children’s hospital patients aged 0 to <18 years who were diagnosed with an Enterobacteriaceae-associated infection between January 1, 2007, and March 31, 2015, and we analyzed the association between MDR-GNE infection and hospital length of stay and death before discharge. Results During the study period, 107610 discharges included a diagnosis code for Enterobacteriaceae infection, 724 (0.7%) of which included MDR-GNE infection. The incidence of MDR-GNE, and the proportion of infections with Enterobacteriaceae organisms that were MDR-GNE increased over the study period; from 0.2% in 2007 to 1.5% by 2015 (test for trend < .001). Almost one-quarter (23%) of the infections in children hospitalized for MDR-GNE were nosocomial. Increased odds of MDR-GNE infection were associated with older age and comorbid illnesses. Lengths of stay in patients with MDR-GNE infection were increased 20% (95% confidence interval, 9.9%–30.5%; P < .001) over those without MDR-GNE infection; the increased odds for death did not reach statistical significance (1.46 [95% confidence interval, 0.98–2.18]; P = .06). Results were robust to sensitivity analyses. Conclusions The incidence of pediatric MDR-GNE infection increased during 2007–2015. MDR-GNE infection was associated with increased length of stay, and we found a trend toward increased risk of death. Infections with Gram-negative enteric bacilli are becoming increasingly difficult to treat; considering the global burden of these antimicrobial-resistant organisms, interventions to curtail or even reverse this trend are needed urgently. Escalating antibiotic resistance limits treatment options, worsens clinical outcomes, and is an evolving global public health crisis. The development of new wider-spectrum antibacterial drugs, especially those appropriate for children, remains relatively stagnant [1–7]. Since the introduction of effective vaccination against Streptococcus pneumonia and Haemophilus influenza type B and an increase in the prevalence of chronic complex medical conditions, Gram-negative enteric bacteria are responsible for an increasing proportion of serious bacterial infections in children [8, 9]. The Enterobacteriaceae are a large family of Gram-negative enteric bacilli. The US Centers for Disease Control and Prevention called attention to the rising incidence of infections caused by Enterobacteriaceae that are resistant to almost all β-lactam antibiotics, termed here multidrug-resistant Gram-negative Enterobacteriaceae (MDR-GNE) [10]. These organisms include bacteria that express any one of a family of β-lactamases that hydrolyze the antibiotic β-lactam ring and confer resistance to penicillins, cephalosporins (including third-generation cephalosporins), and monobactams [11]. Genetic material that confers multiple resistance mechanisms can be spread among bacteria and even among species via mobile genetic elements such as plasmids, which then can be transmitted between patients and to family and community members [4, 12, 13]. MDR-GNE infection is increasingly prevalent worldwide, especially in less-developed countries, where antibiotics are often available over the counter. Between 2008 and 2010, 11.4% of Gram-negative bacilli associated with pediatric intra-abdominal infections worldwide were caused by MDR-GNE (2.5%, 8.8%, and 27% in Europe, Latin America, and Asia and the Pacific, respectively) [4, 14–18]. Factors typically reported to be associated with a higher risk of MDR-GNE infection are younger age, female sex, recent antibiotic exposure (particularly to fluoroquinolones), recent steroid exposure, and comorbid conditions, especially neurologic conditions [4, 11, 18–23]. Children are at increased risk from adverse outcomes related to MDR-GNE infection, because only a limited number of broad-spectrum antibiotics have been approved for pediatric use [11]. Data describing MDR-GNE infections in US children are limited. Several reports described outbreaks of MDR-GNE in non-US settings and/or in a single US state or city [20–27]. Infection outbreaks usually have occurred in intensive care units (ICUs); more recently, community-acquired infections have become increasingly prevalent [4, 18, 20, 21, 23, 27, 28]. Results of studies using US surveillance data suggest that the incidence of MDR-GNE infection is rising, but these studies included few clinical data [28, 29]. The objectives of this study were to characterize the current epidemiology of infection with MDR-GNE in hospitalized US children and to assess the relationships between infection and resulting length of stay and death. METHODS Population Data for this multicenter retrospective cohort study were obtained from the Pediatric Health Information System (PHIS), an administrative database that contains inpatient, emergency department, ambulatory surgery, and observation encounter-level data from 48 children’s hospitals in the United States and is affiliated with the Children’s Hospital Association (Overland Park, KS). Discharge/encounter data are deidentified at the time of submission and include demographics, up to 41 diagnoses per encounter, and resource utilization (eg, drugs, disposition, devices, laboratory testing, procedures). Data are updated quarterly and are subjected to a number of quality, reliability, and validity checks by the Children’s Hospital Association, Truven Health Analytics (Ann Arbor, MI), and participating hospitals before being included in the database [30]. Not all hospitals joined the PHIS at the same time, and so the first year of available data varies among them. Data on inpatient and observation hospitalizations between January 1, 2007, and March 31, 2015, from 48 PHIS hospitals were included in this analysis. The organisms of concern were the Enterobacteriaceae. Using demographic data and International Classification of Diseases, Ninth Revision (ICD-9), codes, we identified patients aged 0 to <18 years with a primary or secondary discharge diagnosis corresponding to a specific Enterobacteriaceae bacterium (Table 1). ICD-9 codes have been shown to have good accuracy for identifying hospitalizations that include similar diagnoses (eg, hospitalizations related to urinary tract infection [31]). Discharges with multiple ICD-9 codes for Enterobacteriaceae were counted only once. Table 1. ICD-9 Diagnosis Codes for Enterobacteriaceae ICD-9 Diagnosis Code  Diagnosis  No. of Dischargesa  002.0  Typhoid fever  370  003.0  Salmonella gastroenteritis  4171  003.1  Salmonella septicemia  361  003.20  Localized Salmonella infection, unspecified  4  003.21  Salmonella meningitis  101  003.22  Salmonella pneumonia  3  003.23  Salmonella arthritis  23  003.24  Salmonella osteomyelitis  141  003.29  Other localized Salmonella infection  39  003.8  Other specified Salmonella infection  212  003.9  Salmonella infection, unspecified  835  004.0  Shigella dysenteriae  75  004.1  Shigella flexneri  121  004.2  Shigella boydii  2  004.3  Shigella sonnei  665  004.8  Other specified Shigella infection  259  004.9  Shigellosis, unspecified  792  008.00  Intestinal infection due to unspecified Escherichia coli  503  008.01  Intestinal infection due to enteropathogenic Escherichia coli  31  008.02  Intestinal infection due to enterotoxigenic Escherichia coli  18  008.03  Intestinal infection due to enteroinvasive Escherichia coli  9  008.04  Intestinal infection due to enterohemorrhagic Escherichia coli  636  008.09  Intestinal infection due to other intestinal Escherichia coli infection  280  008.3  Intestinal infection due to Proteus (mirabilis) (morganii)  29  008.44  Intestinal infection due to Yersinia enterocolitica  173  038.42  Septicemia due to Escherichia coli  3973  038.44  Septicemia due to Serratia  624  041.3  Klebsiella pneumoniae infection in conditions classified elsewhere and of unspecified site  18888  041.4  Escherichia coli infection in conditions classified elsewhere and of unspecified site  40532  041.41  Shiga toxin-producing Escherichia coli (STEC) O157  353  041.42  Other specified Shiga toxin-producing Escherichia coli (STEC)  15  041.43  Shiga toxin-producing Escherichia coli (STEC), unspecified  90  041.49  Other and unspecified Escherichia coli  30905  041.6  Proteus (mirabilis) (morganii) infection in conditions classified elsewhere and of unspecified site  4598  482.0  Pneumonia due to Klebsiella pneumoniae  1632  482.82  Pneumonia due to Escherichia coli  736  ICD-9 Diagnosis Code  Diagnosis  No. of Dischargesa  002.0  Typhoid fever  370  003.0  Salmonella gastroenteritis  4171  003.1  Salmonella septicemia  361  003.20  Localized Salmonella infection, unspecified  4  003.21  Salmonella meningitis  101  003.22  Salmonella pneumonia  3  003.23  Salmonella arthritis  23  003.24  Salmonella osteomyelitis  141  003.29  Other localized Salmonella infection  39  003.8  Other specified Salmonella infection  212  003.9  Salmonella infection, unspecified  835  004.0  Shigella dysenteriae  75  004.1  Shigella flexneri  121  004.2  Shigella boydii  2  004.3  Shigella sonnei  665  004.8  Other specified Shigella infection  259  004.9  Shigellosis, unspecified  792  008.00  Intestinal infection due to unspecified Escherichia coli  503  008.01  Intestinal infection due to enteropathogenic Escherichia coli  31  008.02  Intestinal infection due to enterotoxigenic Escherichia coli  18  008.03  Intestinal infection due to enteroinvasive Escherichia coli  9  008.04  Intestinal infection due to enterohemorrhagic Escherichia coli  636  008.09  Intestinal infection due to other intestinal Escherichia coli infection  280  008.3  Intestinal infection due to Proteus (mirabilis) (morganii)  29  008.44  Intestinal infection due to Yersinia enterocolitica  173  038.42  Septicemia due to Escherichia coli  3973  038.44  Septicemia due to Serratia  624  041.3  Klebsiella pneumoniae infection in conditions classified elsewhere and of unspecified site  18888  041.4  Escherichia coli infection in conditions classified elsewhere and of unspecified site  40532  041.41  Shiga toxin-producing Escherichia coli (STEC) O157  353  041.42  Other specified Shiga toxin-producing Escherichia coli (STEC)  15  041.43  Shiga toxin-producing Escherichia coli (STEC), unspecified  90  041.49  Other and unspecified Escherichia coli  30905  041.6  Proteus (mirabilis) (morganii) infection in conditions classified elsewhere and of unspecified site  4598  482.0  Pneumonia due to Klebsiella pneumoniae  1632  482.82  Pneumonia due to Escherichia coli  736  Abbreviation: ICD-9, International Classification of Diseases, Ninth Revision. aDischarged patients could have more than 1 Enterobacteriaceae diagnosis. View Large Outcome and Exposure Variables Exposure We were interested in Enterobacteriaceae that were resistant to third-generation cephalosporins, including MDR organisms that expressed extended-spectrum β-lactamases (ESBLs) and resistance conferred by other mechanisms (eg, carbapenemases, AmpC cephalosporinases) [11, 32]. As we were unable to measure this directly, as a surrogate for overall nonspecific antimicrobial resistance in Enterobacteriaceae, we defined MDR-GNE as the subset of these Enterobacteriaceae discharges that also included the ICD-9 codes: V09.81 “Infection with microorganisms with resistance to multiple drugs” or V09.91 “Infection with drug-resistant microorganisms, unspecified, with multiple drug resistance” (Table 2). Table 2. ICD-9 Diagnosis Codes for Multidrug-Resistant Enterobacteriaceae ICD-9 Diagnosis Code  Diagnosis  V09.81  Infection with microorganisms resistant to other specified drugs with resistance to multiple drugs  V09.91  Infection with drug-resistant microorganisms unspecified with multiple drug resistance  ICD-9 Diagnosis Code  Diagnosis  V09.81  Infection with microorganisms resistant to other specified drugs with resistance to multiple drugs  V09.91  Infection with drug-resistant microorganisms unspecified with multiple drug resistance  Abbreviation: ICD-9, International Classification of Diseases, Ninth Revision. View Large We assessed the accuracy of our MDR-GNE diagnosis codes in 2 ways. To assess their positive predictive value, for all discharges we identified with an MDR-GNE diagnosis in 2011, 2 investigators independently reviewed all of the discharge diagnoses associated with that encounter and their timing (whether present on admission). Potential discrepancies were discussed with 2 coding specialists from our institution and resolved between the 2 investigators. We also compared our results to publicly available 2007–2012 data from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project Kids’ Inpatient Database (HCUP-KID). The KID samples data from US hospitals to provide national estimates of hospital use by US children. We used HCUPnet [33], the HCUP online query system, to identify in the KID discharges from children’s hospitals with the same ICD-9 diagnosis codes we used to query the PHIS database for Enterobacteriaceae organisms. We then queried HCUPnet for the V09.81 and V09.91 codes for MDR infection. The unit of analysis for this database is the diagnosis code, not discharges; thus, the same discharge can be included more than once in the query, depending on the number of identified diagnosis codes. Therefore, discharges with MDR Enterobacteriaceae should have been identified at least twice, once with an Enterobacteriaceae code and again with either V09.81 or V09.91. Accordingly, we estimated the proportion of MDR Enterobacteriaceae as follows: % MDR-GNE = (MDR Enterobacteriaceae)/(Enterobacteriaceae – MDR Enterobacteriaceae). Outcomes Primary outcomes were length of stay, measured in days, and death before discharge. Our secondary outcome was either death or discharge to hospice care. Covariates Covariates included age (age in years and age category), sex, race, ethnicity, discharge year, insurance payer, the presence of a comorbidity, pediatric or neonatal ICU stay, and US geographic region (Northeast, South, Midwest, or West). Interaction terms between discharge year, age, and race were considered. Race was dichotomized as black versus nonblack, and insurance payer was dichotomized as commercial versus public and other, which included Medicaid, Tricare, uninsured, and unknown [34]. Individual comorbidities are defined in the PHIS as described previously [35]; each comorbidity was considered separately, and all of them were considered together as “any comorbidity,” designating whether any one of the comorbidity flags was present. ANALYSIS Individual characteristics were summarized using means, medians, and percentages for categorical and continuous variables, as appropriate. We compared characteristics of children with versus those without MDR-GNE infection by using bivariate analyses using the χ2 test or nonparametric tests, as noted. Approximate χ2 tests based on the score statistic were used to test adjusted and unadjusted linear trends of odds. All regression models adjusted for clustering according to hospital and used robust standard errors. Multivariable 0-truncated negative binomial regression was used to model the length-of-stay outcome and to calculate incidence rate ratios (IRRs) [36]. Binary logistic regression was used to model the odds of death and death-or-hospice outcomes. Model fit was evaluated by using the Wald test, Akaike information criterion, and Bayesian information criterion. Analyses were performed using Stata SE 12.1 (StataCorp LP, College Station, TX). Sensitivity Analyses The PHIS uses encrypted patient identifiers; to assess for bias caused by clustering according to patient, we repeated the primary analyses using only each patient’s first discharge during the study period. Multivariable analysis was also repeated, stratifying according to whether patients had an ICU stay during that admission. To assess the effect of missing data on the mortality outcome, we used chained equations to impute the data and create 9 imputed data sets; multiple-imputation multivariable analysis was repeated to assess the principal outcome using all 10 data sets [37]. We also repeated the multivariable analysis using conditional fixed-effects regression to obtain within-practice estimates of the effect of MDR-GNE on the primary death outcome. RESULTS Our cohort included a total of 107610 hospital discharges, including 94258 different patients, with a diagnosis of Enterobacteriaceae infection in the PHIS database during the study period. Table 3 lists the characteristics of patients included in this cohort. The mean age was 4.1 years (median, 1 year [IQR, 0–17 years]). Of all the hospitalizations, 724 (0.7%) were associated with MDR-GNE. Although the number of discharges with Enterobacteriaceae-associated infection remained relatively stable between 2007 and 2015, the proportion of those with MDR-GNE infection rose from 0.2% in January 2007 to 1.5% by March 2015 (P < .001, test for trend) (Figure 1). This trend of increasing odds of MDR-GNE across study years was robust to adjustments for age, total parenteral nutrition (TPN), surgery and surgical complications, mechanical ventilation, malignancy, and metabolic, hematologic, respiratory, gastrointestinal, and cardiac conditions (P < .001). MDR-GNE infections were more prevalent in the western United States and were similar among the remaining US geographic regions (P < .001). Over the course of the study period, MDR-GNE infections were increasingly more likely to be associated with hospitalizations including an ICU stay; this trend persisted after adjusting for age and insurance payer (commercial vs public or uninsured, P = .03) (Figure 2). Table 3. Characteristics of Hospitalized Patients Characteristic  Total  MDR-GNE  No MDR-GNE  P  Total no.  107610  724  106886    Sex (n [% of column total])        .77   Male  45074 (41.9)  294 (40.6)  44780     Female  62531  430  62101     Information missing  5  0  5    Age (y)           Mean (SD)  4.1 (5.5)  5.3 (5.8)  4.1 (5.5)  <.001   Median (IQR)  1 (0–17)  3 (0–17)  1 (0–17)  <.001  Age category (n [% of column total])        <.001   <1 y  49398 (45.9)  239 (33.0)  49159 (46.0)     1 to <6 y  25653 (23.8)  205 (28.3)  25448 (23.8)     6 to <12 y  15411 (14.3)  127 (17.5)  15284 (14.3)     12 to 18 y  17148 (15.9)  153 (21.1)  16995 (15.9)    Race (n [% of column total])        <.001   Black  15026 (14.0)  57 (7.9)  14969 (14.0)     White  52162 (48.5)  351 (48.5)  51811 (48.5)     Other or >1 race  20839 (19.4)  245 (33.8)  20594 (19.3)     Information missing  19583 (18.2)  71 (9.8)  19512 (18.2)    Payer (n [% of column total])        .24a   Public (Medicare, Medicaid, Tricare, other government)  58729  408 (56.3)  58321 (54.6)     Commercial  29178  237 (32.7)  28941 (27.1)     Self-pay  1507  13 (1.8)  1494 (1.4)     Charity, other  2423  23 (3.2)  2400 (2.2)     Information missing  15773  43 (5.9)  15730 (14.7)    Region (n [% of column total])        <.001   Midwest  25689  128 (17.7)  25561 (23.9)     Northeast  13503  70 (9.7)  13433 (12.6)     South  42370  216 (29.8)  42154 (39.4)     West  26043  310 (42.8)  25733 (24.1)     Information missing  5  0  5 (<1%)    Mortality (n [% of column total])        <.001b   Death before discharge  1882 (0.7)  21 (2.9)  1861 (1.7)     Death or hospice  2048 (1.9)  22 (3.0)  2026 (1.9)     Other  90.295  655  89640     Information missing  15268  47  15221    Year (n [% of column total])        <.001   2007  12200  29 (4.0)  12171 (11.4)     2008  12565  39 (5.4)  12526 (11.7)     2009  13020  51 (7.0)  12969 (12.1)     2010  13143  73 (10.1)  13070 (12.2)     2011  13086  83 (11.5)  13003 (12.2)     2012  13214  110 (15.2)  13104 (12.3)     2013  13339  118 (16.3)  13221 (12.4)     2014  13891  176 (24.3)  13715 (12.8)     2015  3092  45 (6.2)  3047 (2.8)    Length of stay (days)           Mean (SD)  17.4 (39.4)  21.4 (43.4)  17.3 (39.4)  .006   Median (IQR)  4 (1919)  7 (1218)  4 (1919)  <.001  Comorbidity flags (n [% of column total])           ICU stay  19255 (17.9)  149 (20.6)  19106 (17.9)  .058   Neonatal ICU stay  9104 (8.5)  52 (7.2)  9052 (8.5)  .215   Technology dependent  25737 (23.9)  240 (33.1)  25497 (23.8)  <.001    Information missing  5869  45  5824     Cardiovascular  13562 (12.6)  101 (13.9)  13461 (12.6)  .273    Information missing  5  0  5     Neuromuscular  16176 (15.0)  174 (24.0)  16002 (15.0)  <.001    Information missing  5  0  5     Respiratory  8.903 (8.3)  71 (9.8)  8.832 (8.3)  .133    Information missing  5  0  5     Renal  17180 (16.0)  214 (29.6)  16996 (15.9)      Information missing  0  0  5     Gastrointestinal  20850 (19.4)  180 (24.9)  20.670 (19.3)  <.001    Information missing  5  5  0     Hematologic/oncologic  6866 (6.4)  77 (10.6)  6789 (6.3)  <.001    Information missing  5  0  5     Malignancy  6734  74 (10.2)  6660 (6.20)  <.001    Information missing  5  0  5     Metabolic  7172 (6.7)  84 (11.6)  7088 (6.6)  <.001    Information missing  0  0  0     Congenital/genetic  10484 (9.7)  78 (10.8)  10406 (9.7)  .348    Information missing  5  0  5     Transplant  3379 (3.14)  43 (5.9)  3336 (3.1)  <.001    Information missing  5869  45  5824    Total parenteral nutrition (n [% of column total])  18979 (17.6)  125 (17.3)  18854 (17.6)  .792  Surgery (n [% of column total])  23902 (22.2)  210 (29.0)  23692 (22.2)  <.001   Any flag  63274 (58.8)  506 (69.9)  62768 (58.7)  <.001  Characteristic  Total  MDR-GNE  No MDR-GNE  P  Total no.  107610  724  106886    Sex (n [% of column total])        .77   Male  45074 (41.9)  294 (40.6)  44780     Female  62531  430  62101     Information missing  5  0  5    Age (y)           Mean (SD)  4.1 (5.5)  5.3 (5.8)  4.1 (5.5)  <.001   Median (IQR)  1 (0–17)  3 (0–17)  1 (0–17)  <.001  Age category (n [% of column total])        <.001   <1 y  49398 (45.9)  239 (33.0)  49159 (46.0)     1 to <6 y  25653 (23.8)  205 (28.3)  25448 (23.8)     6 to <12 y  15411 (14.3)  127 (17.5)  15284 (14.3)     12 to 18 y  17148 (15.9)  153 (21.1)  16995 (15.9)    Race (n [% of column total])        <.001   Black  15026 (14.0)  57 (7.9)  14969 (14.0)     White  52162 (48.5)  351 (48.5)  51811 (48.5)     Other or >1 race  20839 (19.4)  245 (33.8)  20594 (19.3)     Information missing  19583 (18.2)  71 (9.8)  19512 (18.2)    Payer (n [% of column total])        .24a   Public (Medicare, Medicaid, Tricare, other government)  58729  408 (56.3)  58321 (54.6)     Commercial  29178  237 (32.7)  28941 (27.1)     Self-pay  1507  13 (1.8)  1494 (1.4)     Charity, other  2423  23 (3.2)  2400 (2.2)     Information missing  15773  43 (5.9)  15730 (14.7)    Region (n [% of column total])        <.001   Midwest  25689  128 (17.7)  25561 (23.9)     Northeast  13503  70 (9.7)  13433 (12.6)     South  42370  216 (29.8)  42154 (39.4)     West  26043  310 (42.8)  25733 (24.1)     Information missing  5  0  5 (<1%)    Mortality (n [% of column total])        <.001b   Death before discharge  1882 (0.7)  21 (2.9)  1861 (1.7)     Death or hospice  2048 (1.9)  22 (3.0)  2026 (1.9)     Other  90.295  655  89640     Information missing  15268  47  15221    Year (n [% of column total])        <.001   2007  12200  29 (4.0)  12171 (11.4)     2008  12565  39 (5.4)  12526 (11.7)     2009  13020  51 (7.0)  12969 (12.1)     2010  13143  73 (10.1)  13070 (12.2)     2011  13086  83 (11.5)  13003 (12.2)     2012  13214  110 (15.2)  13104 (12.3)     2013  13339  118 (16.3)  13221 (12.4)     2014  13891  176 (24.3)  13715 (12.8)     2015  3092  45 (6.2)  3047 (2.8)    Length of stay (days)           Mean (SD)  17.4 (39.4)  21.4 (43.4)  17.3 (39.4)  .006   Median (IQR)  4 (1919)  7 (1218)  4 (1919)  <.001  Comorbidity flags (n [% of column total])           ICU stay  19255 (17.9)  149 (20.6)  19106 (17.9)  .058   Neonatal ICU stay  9104 (8.5)  52 (7.2)  9052 (8.5)  .215   Technology dependent  25737 (23.9)  240 (33.1)  25497 (23.8)  <.001    Information missing  5869  45  5824     Cardiovascular  13562 (12.6)  101 (13.9)  13461 (12.6)  .273    Information missing  5  0  5     Neuromuscular  16176 (15.0)  174 (24.0)  16002 (15.0)  <.001    Information missing  5  0  5     Respiratory  8.903 (8.3)  71 (9.8)  8.832 (8.3)  .133    Information missing  5  0  5     Renal  17180 (16.0)  214 (29.6)  16996 (15.9)      Information missing  0  0  5     Gastrointestinal  20850 (19.4)  180 (24.9)  20.670 (19.3)  <.001    Information missing  5  5  0     Hematologic/oncologic  6866 (6.4)  77 (10.6)  6789 (6.3)  <.001    Information missing  5  0  5     Malignancy  6734  74 (10.2)  6660 (6.20)  <.001    Information missing  5  0  5     Metabolic  7172 (6.7)  84 (11.6)  7088 (6.6)  <.001    Information missing  0  0  0     Congenital/genetic  10484 (9.7)  78 (10.8)  10406 (9.7)  .348    Information missing  5  0  5     Transplant  3379 (3.14)  43 (5.9)  3336 (3.1)  <.001    Information missing  5869  45  5824    Total parenteral nutrition (n [% of column total])  18979 (17.6)  125 (17.3)  18854 (17.6)  .792  Surgery (n [% of column total])  23902 (22.2)  210 (29.0)  23692 (22.2)  <.001   Any flag  63274 (58.8)  506 (69.9)  62768 (58.7)  <.001  Abbreviations: ICU, intensive care unit; IQR, interquartile range; MDR-GNE, multidrug-resistant Enterobacteriaceae; SD, standard deviation. aPublic or uninsured versus other. bFor death. View Large Figure 1. View largeDownload slide Multidrug-resistant Enterobacteriaceae according to year. Shown are the percentages of discharges with a diagnosis of multidrug-resistant Enterobacteriaceae infection. Figure 1. View largeDownload slide Multidrug-resistant Enterobacteriaceae according to year. Shown are the percentages of discharges with a diagnosis of multidrug-resistant Enterobacteriaceae infection. Figure 2. View largeDownload slide Multidrug-resistant Gram-negative Enterobacteriaceae (MDR-GNE) and intensive care unit (ICU) stays according to year. Shown are the percentages of discharges with MDR-GNE infection that included an ICU stay. Figure 2. View largeDownload slide Multidrug-resistant Gram-negative Enterobacteriaceae (MDR-GNE) and intensive care unit (ICU) stays according to year. Shown are the percentages of discharges with MDR-GNE infection that included an ICU stay. Sixty-three percent of our cohort overall, and 76% of those with MDR-GNE infection, had an Enterobacteriaceae-associated infection documented on admission; infection timing could not be determined for 26% of overall admissions or 10% of admissions with MDR-GNE infection. For 685 of the 724 MDR-GNE-associated discharges with only 1 documented Enterobacteriaceae infection, 525 (77%) were present on admission; for the remaining 39 discharges with more than 1 documented Enterobacteriaceae infection, at least 26 (67%) were all present on admission, which suggests that at least 551 (76%) of the MDR-GNE infections were present on admission. The timing of MDR-GNE infection could not be determined using PHIS discharge data when Enterobacteriaceae infection diagnoses were recorded with discordant onsets. Of the 107610 discharges in the study period, 27875 (26%) were missing information on diagnosis timing. In unadjusted analysis, without including covariates (Table 3), black patients had lower odds of MDR-GNE infection than did white patients (odds ratio [OR], 0.75 [95% confidence interval (CI), 0.576–0.99]; P = .49); patients of other or mixed races had higher odds than did white patients (OR, 1.57 [95% CI, 1.29–1.91]; P < .001). The multivariable model adjusted for age; sex; discharge year; black race; insurance payer; any ICU stay; intravenous nutrition; operating room use; mechanical ventilation; malignancy, metabolic, respiratory, cardiovascular, hematologic/oncologic, and gastrointestinal comorbidities; and clustering according to hospital; in this adjusted model, the lower odds for black patients was no longer statistically significant (OR, 0.77 [95% CI, 0.58–1.03]; P = .08) but remained so for patients of other or mixed races (OR, 1.73 [1.42–2.10]; P < .001). In the adjusted model, MDR-GNE infection was also associated with older age (P < .001), TPN (P = .002), and surgery (P = .027) comorbidity flags but not with sex, metabolic or gastrointestinal comorbidities, or public insurance (P = .80, .06, .22, and .14, respectively). Validation of MDR-GNE Coding Of 84 discharges with an ICD-9 code indicating an MDR-GNE diagnosis in 2011, 5 were of indeterminate accuracy: 1 included both E coli infection and streptococcal septicemia (unspecified type); 1 included Klebsiella, E coli, and Haemophilus influenza (unspecified type) infections; 1 included E coli, streptococcal, and H influenza infections; 1 included E coli and Pseudomonas infections; and 1 included both Klebsiella and Pseudomonas infections. Even if all 5 of these diagnoses were incorrect, our positive predictive value would be 79/84 (at least 94%). Comparison With HCUP KID Data The HCUP-KID–estimated proportions of MDR-GNE–related infections were 0.8% in 2006 and 1.7% in 2012 for all children’s hospitals and 0.8% in 2006 and 1.9% in 2012 for freestanding children’s hospitals. Length of Stay The length-of-stay distribution was skewed to the right (median, 4 days [IQR, 2–23]). In an unadjusted analysis, the mean length of stay for patients hospitalized with an MDR-GNE–related diagnosis was 21.4 days versus 17.3 days for patients without an MDR-GNE–related diagnosis (median, 7 vs 4 days, respectively; P < .001, Wilcoxon rank-sum test) (Table 4 and Figure 3). Table 4. Regression Model Results for Patients With Versus Those Without Multidrug-Resistant Enterobacteriaceae Parameter  Unadjusted IRR  Adjusted IRR  95% CI  P  Length of stay, daysa           Primary analysis  1.23  1.20  1.10–1.30  <.001   ICU stay            No  1.38  1.21  1.08–1.36  .001    Yes  1.11  1.21  1.11–1.31  <.001   First discharge only  1.31  1.22  1.09–1.36  <.001  Mortality (OR)           Death before dischargeb    Primary analysis  1.54  1.46  0.98–2.18  .06    Multiple imputation  1.54  1.46  0.98–2.18  .06    First admission only  1.56  1.45  0.93–2.26  .10    Conditional on practice  1.54  1.50  0.90–2.48  .12   Death or discharge to hospicec    Primary analysis  1.42  1.35  0.89–2.06  .16    Multiple imputation  1.42  1.35  0.89–2.06  .16    First admission only  1.47  1.39  0.88–2.19  .16  Parameter  Unadjusted IRR  Adjusted IRR  95% CI  P  Length of stay, daysa           Primary analysis  1.23  1.20  1.10–1.30  <.001   ICU stay            No  1.38  1.21  1.08–1.36  .001    Yes  1.11  1.21  1.11–1.31  <.001   First discharge only  1.31  1.22  1.09–1.36  <.001  Mortality (OR)           Death before dischargeb    Primary analysis  1.54  1.46  0.98–2.18  .06    Multiple imputation  1.54  1.46  0.98–2.18  .06    First admission only  1.56  1.45  0.93–2.26  .10    Conditional on practice  1.54  1.50  0.90–2.48  .12   Death or discharge to hospicec    Primary analysis  1.42  1.35  0.89–2.06  .16    Multiple imputation  1.42  1.35  0.89–2.06  .16    First admission only  1.47  1.39  0.88–2.19  .16  Abbreviations: CI, confidence interval; ICU, intensive care unit; IRR, incidence rate ratio; OR, odds ratio. aMultivariable models for length of stay adjusted for age; sex; discharge year; black race; insurance payer; any ICU stay; intravenous nutrition; operating room use; mechanical ventilation; malignancy; metabolic, respiratory, cardiovascular, hematologic/oncologic, and gastrointestinal comorbidities; and clustering according to hospital. bMultivariable models for death included discharge year; insurance payer; any ICU stay; any comorbidity flag; intravenous nutrition; operating room use; mechanical ventilation; malignancy; metabolic, respiratory, cardiovascular, hematologic/oncologic, and gastrointestinal comorbidities; interaction between any comorbidity and discharge year; and clustering according to hospital. cMultivariable models for death or discharge to hospice included discharge year; intravenous nutrition; operating room use; mechanical ventilation; any comorbidity flag; malignancy; metabolic, respiratory, cardiovascular, hematologic/oncologic, and gastrointestinal comorbidities; and clustering according to hospital. View Large Figure 3. View largeDownload slide Lengths of stay for pediatric patients with multidrug-resistant Enterobacteriaceae infection (MDR-GNE), unadjusted. Figure 3. View largeDownload slide Lengths of stay for pediatric patients with multidrug-resistant Enterobacteriaceae infection (MDR-GNE), unadjusted. In unadjusted 0-truncated negative binomial regression analysis, the IRR for length of stay for patients with versus those without MDR-GNE infection was 1.235, which indicates that patients with MDR-GNE infection had a 23.5% increased length of stay compared with patients without MDR-GNE infection (Table 4). The fully adjusted final multivariable model included age; black race; any chronic condition; TPN; surgery; mechanical ventilation; malignancy; neonatal ICU stay; and metabolic, hematologic, respiratory, gastrointestinal, and cardiac conditions; patients with MDR-GNE infection had a 19.8% increased mean length of stay (95% CI, 9.9%–30.5%; P < .001). This increased length of stay depending on MDR-GNE status was unchanged across the study years (<1% change in IRR; P = .81 for the interaction term). Black patients had an 11.2% higher mean length of stay compared with nonblack patients. Patients with any ICU stay experienced, on average, a slightly lower impact of MDR-GNE infection on their length of stay than patients without an ICU stay when we adjusted for all other covariates (20.7% [95% CI, 11.6–30.6] increased length of stay for ICU patients vs 21.5% [95% CI, 8.4–36.3] increased length of stay for those without an ICU stay); this interaction did not reach statistical significance. Results of analysis using only each patient’s first admission during the study period were essentially the same; patients with MDR-GNE infection experienced an increased mean length of stay of 21.8% (95% CI, 9.4–35.7; P < .001). Death Before Discharge As shown in Table 3, 1882 patients died before discharge, and 2048 either died or were discharged to hospice care; disposition data for 14.2% of the discharges were missing. Patients who were diagnosed with an MDR-GNE infection had a higher crude risk of death before discharge compared with those without MDR-GNE infection (2.9% vs 1.7%; P < .001) (Table 3). In the regression models, adjusted only for clustering according to hospital, the OR for death for patients with versus those without MDR-GNE infection was 1.54 (95% CI, 0.99–2.4; P = .058). The multivariable fully adjusted model included age; year; TPN; surgery and surgical complications; mechanical ventilation; any ICU stay; insurance payer; malignancy; hematologic, metabolic, respiratory, cardiovascular, and gastrointestinal conditions; and the interaction between any chronic condition and year; the OR for death before discharge in a comparison of patients with versus those without MDR-GNE infection was 1.46 (95% CI, 0.98–2.18; P = .06). Results from the sensitivity analysis, the multiple-imputation analysis, and an analysis using only the first discharge of each patient were essentially unchanged from the primary analysis (Table 4). The adjusted OR for the composite variable death or discharge to hospice was similar to that for death before discharge at 1.35 (0.89–2.06; P = .16). Results from the multiple imputation analysis, in which we used only the first discharge of each patient and conditional within-practice analysis, were unchanged from the primary analysis (Table 4). DISCUSSION To the extent of our knowledge, this study was the first to examine the epidemiology of MDR-GNE infection across US children’s hospitals. We found that the incidence of infection with MDR-GNE has increased over the past 8 years from 0.2% in 2007 to 1.5% by March 2015; the rise has been even faster for patients admitted to an ICU. Few previous study reports have described the changing epidemiology of pediatric MDR-GNE infection in the United States. Logan et al [28], who used US surveillance data, characterized Enterobacteriaceae isolates from 368398 children older than 1 year and found an increasing incidence of MDR-GNE between 1999 and 2011. In 2011, 2% and 0.5% of Enterobacteriaceae isolates expressed third-generation cephalosporin resistance and ESBL-related resistance, respectively. Although the PHIS did not provide culture data and so we cannot report patterns or mechanisms of resistance to specific antibiotics, our MDR-GNE definition should identify organisms relatively comparable to their organisms of interest, so it is reassuring that their estimates are similar to our findings. KID data estimated 0.8% of Enterobacteriaceae infections to be MDR-GNE for all children’s hospitals and freestanding children’s hospitals in 2006 and 1.7% and 1.9% for all children’s hospitals and freestanding children’s hospitals, respectively, in 2012. Our MDR-GNE rates were 0.2% in 2007 and 0.8% in 2012, relatively consistent with the KID results, considering the different unit of analysis in the HCUPnet. The HCUPnet provides only aggregate data, has limited demographic and clinical information, and uses diagnosis code as the unit of analysis; thus, discharges including multiple queried diagnosis codes (ie, multiple Enterobacteriaceae infections) are counted more than once, and admission rates can be overestimated. In addition, the cohort of HCUPnet discharges coded with our multidrug-resistance codes can include some patients infected with organisms that were not Enterobacteriaceae. We found that older children, children with comorbidities, and those in the western United States were more likely to be infected with MDR-GNE, but we found no differences based on sex or insurance coverage. We found inconsistent risks based on race (lower risks of MDR-GNE infection for white and black children than for those of other races and those of mixed race). Reasons underlying these disparities are unknown. Consistent with our results, Logan et al [28] reported that children with underlying comorbidities had the highest proportion of MDR-GNE isolates; their findings that younger children, girls, and children in the central United States were also at higher risk differed from our results. MDR-GNE infections are associated with poor outcomes in adults yet this has been inconsistently shown in children [20, 23, 26, 38]. We found that MDR-GNE infections were associated with longer lengths of stay and a trend toward a higher mortality rate. Point estimates and CIs of unadjusted versus adjusted models were similar for both mortality outcomes, death before discharge and death or discharge to hospice. Our results suggest that if there is an increased risk of death for patients with MDR-GNE infection, the difference is too small to be detected, even with our large sample size. This study had limitations. Our organisms of interest were those in the bacterial family Enterobacteriaceae associated with pediatric bacterial infections in the United States for which there were specific ICD-9 codes [11]. The results do not generalize to children in other countries or to those with an infection caused by other organisms. The results do not necessarily generalize to pediatric discharges from hospitals other than children’s hospitals. Although the PHIS data have certain limitations, they offer researchers an opportunity to examine a rare but concerning diagnosis of interest across a large number of US children’s hospitals. We believe that there are no previous studies that used the codes we used to identify MDR-GNE; however, we found that these codes had a high positive predictive value for identifying admissions of pediatric patients with an infection associated with MDR Enterobacteriaceae. There was no way for us to directly identify third-generation cephalosporin resistance or specific mechanisms of resistance (eg, ESBLs, carbapenemases, AmpC cephalosporinases). Gauging the sensitivity of these codes was beyond the scope of this study. It is conceivable that, over the course of the study period, the increasing rate of MDR-GNE infection reflected increasing sensitivity of diagnosing and coding for these infections and/or that discharges including more severe outcomes might have been more likely to have been identified as MDR-GNE related; similar limitations afflict any observational study in which claims data are used. The PHIS does not include culture data, and we did not have the resources to obtain culture data from PHIS hospitals; thus, isolate resistance patterns and mechanisms of resistance are not included here. To our knowledge, timing of infection in the PHIS has not been validated; this variable was missing for more than one-quarter of our diagnoses, and for children with more than 1 Enterobacteriaceae diagnosis, we could not always ascertain the timing of the particular MDR-GNE infection. We also were not able to determine whether the patients had unrecorded risk factors (eg, chronic health conditions and social determinants of health) before admission that put them at higher risk of infection with antibiotic-resistant bacteria. This information could be difficult to tease out; we would not want to treat variables as confounders if they are truly mediators, and we would not necessarily want to adjust for them if they could be in the causal chain between MDR-GNE infection and the outcome. Our similar results using only the first admission of each child are reassuring in that results are not necessarily different for children with multiple admissions. The high proportion of community-acquired infections needs to be confirmed using other data sources. It would be ideal to have preadmission data on antibiotic exposure, which might put a child at greater risk of a resistant infection. The missing disposition data could have biased our results; it is reassuring that our results were robust to reanalysis using imputed data. Sicker patients are likely to receive more antibiotics, to be at risk of colonization and infection with resistant organisms, to experience longer hospitalizations, and to have adverse outcomes. To the extent that they were measured, our models adjusted for confounding by comorbidities; however, future studies will need to address residual confounding, the underlying causal relationships, and their directionality among these clinical variables. In conclusion, we found that infections with MDR-GNE have increased by more than 700% between 2007 and 2015 for pediatric patients admitted to children’s hospitals and are associated with an increased length of stay and a trend toward a higher mortality rate. Previously described as mostly nosocomial, most MDR-GNE infections in this recent cohort were present on admission. Hospital surveillance cultures, strict cohorting, limited use of third-generation cephalosporins, and restricted agricultural antibiotic use have been recommended for reducing MDR-GNE colonization and related infection [11]. The march of escalating antibiotic resistance seems inexorable; however, thoughtful and thorough efforts to reverse this trend can be successful [2, 39, 40]. Considering the global skyrocketing incidence of MDR-GNE infection, we must be vigilant and do everything possible to curtail, or even reverse, this process. Notes Financial support. This work was supported by the National Institute for Allergy and Infectious Diseases at the National Institutes of Health (grant K23AI097284). Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Choffnes E Relman DA Mack A. Antibiotic resistance: implications for global health and novel intervention strategies: workshop summary . In: Forum on Microbial Threats. Washington, DC: Institute of Medicine; 2010. 2. Baym M Stone LK Kishony R . Multidrug evolutionary strategies to reverse antibiotic resistance. Science  2016; 351: aad3292. Google Scholar CrossRef Search ADS PubMed  3. Metlay JP Hofmann J Cetron MS et al.   . Impact of penicillin susceptibility on medical outcomes for adult patients with bacteremic pneumococcal pneumonia. Clin Infect Dis  2000; 30: 520– 8. 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Journal of the Pediatric Infectious Diseases SocietyOxford University Press

Published: Mar 1, 2018

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