Antibiotics and probiotics to neonates-Adverse effects, impact on gut microbiota and antibiotic resistome, and Bifidobacterium pathogenicity

The main objective of this thesis was to systematically review potential side effects of antibiotic therapy in neonates and to study the gut microbiota composition of preterm infants receiving probiotic prophylaxis. This thesis includes two systemic reviews, a prospective longitudinal multi-centre trial investigating the gut microbiota in preterm infants receiving probiotics compared to preterm infants not receiving probiotics and a retrospective cohort study investigating the pathogenic potential of Bifidobacterium. Results from our systematic reviews show that antibiotic exposure appears to induce disease-promoting alterations in the gut microbiota and antibiotics given for longer periods in babies with negative cultures is associated with increased risk of NEC and/or death in preterm infants. Our findings also suggests that use of broad-spectrum antibiotics, particularly third generation cephalosporins or carbapenems, is associated with increased risk of invasive fungal infections and higher abundance of antibiotic resistance development, the latter also seen in the clinical trial. In our multicentre study, we found high abundance of Bifidobacterium in probiotic supplemented infants at one week of age suggesting that a more gradual increase in probiotic supplementation may replicate the physiological gut microbiota development of the preterm infant. In probiotic supplemented infants, we found no difference in the abundance of antibiotic resistance genes compared to other infants, despite the massive antibiotic exposure in the probiotic group compared to the other non-supplemented infants. Our findings support the potential of probiotics to provide colonisation resistance to reduce spread of antibacterial resistance and thereby infections caused by antibiotic resistant pathogens. Bifidobacterium has an invasive potential in the immunocompromised host and may cause a sepsis-like picture, but we could not delineate specific pathogenic traits characterising invasive isolates.