Antibiotic considerations for necrotizing enterocolitis

Pathogenesis of NEC

Current evidence suggests that tissue injury results from intestinal inflammation caused by disruption of the gut microbiome and an altered immune response. Preterm infants are especially at high risk of dysbiosis given their exposure to antibiotics and their prolonged hospitalization. ^{, ,} Prolonged antibiotic exposure in uninfected preterm infants has been associated with an increased risk of NEC. NEC ultimately results in bacterial overgrowth, mimicking a complicated intra-abdominal infection characterized by bowel inflammation with mucosal edema, ulcerations, hemorrhages and coagulation necrosis, localized or diffused peritonitis, and, in some cases, sepsis and bowel perforation.

Clinical presentation and diagnosis of NEC

Age of onset is typically inversely proportional to gestational age. Although relatively rare, term and near-term infants usually develop NEC in the first week of life and very preterm infants after the third week of life. ^, NEC presents with both digestive and systemic manifestations. Infants generally have abdominal distention and/or tenderness, feeding intolerance, and occult or grossly bloody stools. Nonspecific systemic symptoms include apnea and bradycardia, lethargy, poor perfusion, and respiratory distress. Disease can be mild with only feeding intolerance or sudden and fulminant with multiple organ failure.

Laboratory studies supporting the diagnosis of NEC include abnormal complete blood count with neutropenia or thrombocytopenia, hyponatremia, high C-reactive protein, and metabolic acidosis. Radiological studies are used to confirm the diagnosis of NEC and determine the stage of disease severity according to Bell’s criteria ( Table 12.1 ). Plain abdominal radiography may reveal distended, fixed bowel loops, air fluid levels, pneumatosis intestinalis (intramural gas), portal venous gas, or pneumoperitoneum in the case of intestinal perforation. In recent years, data have accumulated regarding the potential benefits of using abdominal ultrasound in the diagnosis and management of NEC.

Although many pathogens have been associated with NEC, no specific microorganism has consistently been linked to this condition. Blood culture is positive in 7% to 30% of cases, and ≤1% of infants with NEC present with an associated meningitis. More rarely, Candida spp. and viruses (e.g., cytomegalovirus, rotavirus, and norovirus) have also been associated with NEC. For most infants with NEC, however, no microorganism is identified, and a polymicrobial infection with endogenous intestinal flora may be assumed. Therefore, antibiotic empirical therapy should be active against enteric Gram-negative aerobic and facultative anaerobic bacilli such as Enterobacteriaceae (e.g., Escherichia coli , Klebsiella spp.); enteric Gram-positive streptococci (e.g., Streptococcus anginosus ); and, in some situations, obligate anaerobic bacilli (e.g., Clostridium perfringens , Bacteroides fragilis ). C. perfringens seems to be associated with more severe and fulminant NEC presentations. However, it is still unclear whether, in general, anaerobic bacteria play a pathogenic or a protective role in the pathogenesis of NEC. Disruption of the intestinal mucosa with subsequent intramural invasion by anaerobic bacteria causes pneumatosis intestinalis . But, anaerobic bacteria are also known to produce short-chain fatty acids po tentially regulating the intestinal inflammatory response. Moreover, Gram-negative rods, as opposed to anaerobic bacteria, are predominant in stools of very-low-birth-weight (VLBW) infants (birth weight <1500 g) who have developed NEC compared to those who have not.