J. C. Lim1, B. Bell1, G. Jang1, D. Hawkins1, D. Thomas1, S. Papillon1, J. Golden1, J. Wang1, L. Wang2, A. Grishin1, H. R. Ford1 1Children’s Hospital Los Angeles,Pediatric Surgery,Los Angeles, CA, USA 2Children’s Hospital Los Angeles,Pathology,Los Angeles, CA, USA
Introduction:
Necrotizing enterocolitis (NEC) is the most common gastrointestinal surgical emergency among neonates. The precise etiology of NEC is unknown, but risk factors include a susceptible host, enteral feeding, and bacterial colonization. Opportunistic pathogens, such as Cronobacter muytjensii, have been identified in clinical outbreaks and confirmed as disease contributors in experimental models. Current clinical management includes broad-spectrum antibiotics with variable results. We hypothesized that antibiotic prophylaxis targeting opportunistic pathogens would decrease the incidence and severity of NEC.
Methods:
NEC was induced in a neonatal rat model of thrice[CG1] daily formula feeding and hypoxia. The pups were separated into six treatment groups based on formula composition: baseline, early ampicillin (starting day of life #1), late ampicillin (starting day of life #3), C. muytjensii (every feed), early ampicillin with C. muytjensii, and late ampicillin with C. muytjensii. Animals were sacrified on day of life #4. The terminal ileum was histologically scored by H&E stain with scores ≥2 indicative of NEC. The microbiota of the terminal ileum and daily stools were characterized by culture-based 16S rRNA sequencing.
Results:
The baseline group produced an NEC incidence of 29%. The opportunistic pathogen C. muytjensii increased incidence to 69% (p=0.0013 compared to baseline). When early ampicillin was given in the presence of C. muytjensii, NEC incidence decreased to 25%, resembling baseline (p=0.9060 compared to baseline, p=0.0185 to C. muytjensii). In contrast, when late ampicillin was given to rats exposed to C. muytjensii, the incidence remained high at 71% (p=0.0047 compared to baseline, p=0.7701 to C. muyjtensii). Ampicillin alone, regardless of timing, increased NEC: early with 67% incidence and late with 75% incidence.
Microbiota profiling revealed an overall paucity of bacteria in animals with NEC compared to those without NEC. Utilizing the Shannon Index of diversity, no significant trends were found between treatment groups or NEC scores.
Conclusion:
Targeted antibiotic therapy was only effective in the presence of the opportunistic pathogen and only if started early. In the absence of the opportunistic pathogen, the antibiotic treatment was harmful rather than beneficial. Our findings suggest that neonates at risk for NEC should undergo routine surveillance for opportunistic pathogens in their stool followed by targeted antibiotic therapy for these isolates. Further studies are indicated to investigate the similarities between the opportunistic pathogens and empiric antibiotic groups.