Resistance Determinants and Factors associated with Multi-drug Resistant Enterobacteriaceae in Children

Background: National studies have found an increase in multi-drug resistant (MDR) Enterobacteriaceae (Ent) infections in children over the last decade; however, there is a paucity of literature on the antibiotic resistance determinants associated with these increases, and, regarding the children most impacted by these dangerous pathogens. Objectives: 1) To determine the genetic basis of extended-spectrum beta-lactam (ESBL), carbapenem, and fluoroquinolone resistance (FQR) phenotypes in Enterobacteriaceae isolates from children cared for by multiple centers in the Chicago area; 2) To identify which exposures and host factors serve as predictors of infection within dominant genotypes of resistant Enterobacteriaceae recovered from children from multiple centers. Methods: Objective 1: A retrospective cohort study of 276 GNB isolates from unique patients, phenotypically identified as beta-lactamases producers, was performed. Isolates from 5 Chicago hospitals were recovered from children ages 0-18 years hospitalized between 2011- 2015. DNA microarray (Check-Points™) was used to query the genetic background associated with beta-lactam resistance. Determinants of quinolone resistance (e.g., QRDR and PMFQR) were investigated. Objective 2: A case-control study of children cared for by 3 Chicago area hospitals during 2011-14 was performed. Cases were 53 children diagnosed with PMFQR containing beta-lactam resistant isolates. Controls were 131 children with antibiotic susceptible Ent infections matched by hospital, age and source. Demographics; comorbidities; device, antibiotic, and healthcare exposures; and the impact of location of patient residence were evaluated. Race categories were white, black, Hispanic, and other. Multivariable logistic regression was used to explore associations between predictors and PMFQR infection. Data were analyzed in SAS 9.4. Results: Median age was 4.8 years, 59% were female, and 46% were outpatients. Most isolates (69%) were from urine. E. coli (62%) was most frequently recovered; and of 272 bla genes detected, the most common was blaCTX-M-1 (49%); 1.9% were CRE (4- blaKPC and 1- blaIMP-13). PMFQR was found in 56/82 (66%) and associated with QRDR mutations in 84% of cases. Overall, pAmpC were found in 12% (34/276). The blaKPC harboring K. pneumoniae were mainly non-ST258 strains, which differs from adults. Children with PMFQR Ent infections were more likely to be diagnosed in an outpatient clinic (OR 33.1; CI 7.1, 154.7) and of race “other” (OR 6.5; CI 1.9, 22.2). Residents of Southwest Chicago were 5 times more likely to have a PMFQR Ent infection than those residing in other regions (OR 5.3; CI 1.8, 15.2); while residence in Central Chicago was associated with a 97% decreased risk (OR 0.03; CI 0.002, 0.3). Significant differences in other demographics; comorbidities; invasive devices; antibiotic use; or recent healthcare were not found. Conclusions: Complex bla genotypes were responsible for the beta-lactam resistant phenotypes in children. Transmissible plasmid mediated resistance may be the underlying reason for this emerging health threat. Regional differences associated with PMFQR Ent are observed. Environmental influences may contribute to acquisition of MDR organisms showing FQR. A significant number of PMFQR strains are found in the community, which may reflect linkage to blaCTX-M harboring plasmids which are endemic in some communities.