We know that prolonged antibiotic use in preterm babies increase their chance of later developing NEC. The assumption being that the disturbance of the intestinal flora leads to the increase in susceptibility. Here is some more direct evidence to support that assumption.
There were 74 babies under 33 weeks studied, who had their microbiomic analysis performed weekly, 3 times. They divided the babies into those who had antibiotics for 0 days, 1-4 days, or 5-7 days.
All of the antibiotic use was empiric, defined as treatment based solely on clinical suspicion of infection without a positive culture result.
RESULTS: Infants who received 5-7 days of empiric antimicrobial agents in the first week had increased relative abundance of Enterobacter (P = .016) and lower bacterial diversity in the second and third weeks of life. Infants receiving early antibiotics also experienced more cases of necrotizing enterocolitis, sepsis, or death than those not exposed to antibiotics.
The table 2 in that article requires a bit of explanation, it took me a while to realize that the row labelled ‘cases’ means those babies who had the combined outcome of death, NEC or sepsis.
The message to me is clear, prematurity is not in itself a septic event. You don’t have to have antibiotics just because you are admitted to an NICU! If you do have an indication for expectant antibiotic therapy, they should be stopped if the cultures are negative unless you have a very good reason.
Of course the other method is that all babies develop a microbiome, we can wreck it by giving antibiotics, and we can nudge it in the right direction by administering probiotics.
Neonatal Research 
Dear Dr Barrington: Thanks for this post. The biggest driver of antibiotics usage in our practice is elevated CRPs in culture negative scenarios with or without antenatal sepsis risk factors. How do you deal with this situation, since blood culture has a low yield in light of maternal intrapartum antibiotic therapy? Are you selective about obtaining CRPs? How do you interpret them?
Personally I never ask for a CRP in this situation. CRPs can be elevated by so many things, and are so non-specific, that in a baby with risk factors I will take a culture and start antibiotics, and almost always stop them at 36 to 48 hours if the cultures are negative. In the rare situation when the mother was treated with antibiotics before delivery and the baby has clinical signs of sepsis and the cultures are negative and I think that maybe the baby had low grade sepsis and the cultures are negative because of maternal antibiotics having crossed the placenta I might continue the antibiotics for 5 days, but that happens maybe once a year! Maternal chorioamnionitis, without any sign of infection in the baby, leads to increased CRP in the infant, but I have no reason to believe that the infant is better off with antibiotic treatment in this situation.
We are all comfortable in stopping antibiotics in term infants exposed to maternal chorioamnionitis if 48 hr blood culture is negative. I wonder what is the consensus for the same in premature infants especially in ELBW infants. It is very common to give 7 days antibiotics even if the blood culture is negative at 48 hours with benign initial inflammatory markers
I rarely prolong antibiotics in this situation, if the blood culture is negative, even if there is a history of clear chorio (which is often a diagnostic dilemma in itself) I stop the antibiotics unless there is a clinical progression which is consistent with sepsis.
As I said in the post, I think you need to have a very good reason for putting the baby at risk by continuing their antibiotics.