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dc.contributor.advisorKlingenberg, Claus
dc.contributor.authorEsaiassen, Eirin
dc.date.accessioned2019-05-21T07:48:04Z
dc.date.available2019-05-21T07:48:04Z
dc.date.issued2018-02-16
dc.description.abstractThe 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.en_US
dc.description.doctoraltypeph.d.en_US
dc.description.popularabstractAntibiotics are the most commonly prescribed drugs in neonatal intensive care units. Changes in the gut flora, often induced by antibiotics, are associated with development of severe gut inflammation in preterm infants. Probiotics are live bacteria associated with health benefits in humans and are associated with reduced risk of gut inflammation in preterm infants. Still, little is known about the impact of probiotics on early development of the gut flora and antibiotic-associated changes in the gut flora in preterm infants receiving probiotics. Furthermore, the potential of these live probiotic bacteria to cause infections is still unknown. The main objective of this thesis was to systematically study the literature on potential side effects of antibiotic therapy in newborn infants, and to study the gut flora in preterm infants receiving probiotic therapy. We also studied the potential of Bifidobacterium, a commonly used group of probiotic bacteria, to cause infections in humans, including preterm infants. In order to do this, we performed literature searches in different databases to find all the evidence of potential side-effects of antibiotic treatment in newborns. To study the effects of probiotics on the preterm infant gut flora, we performed a multi-centre study where six Norwegian hospitals participated. We recruited preterm infants given probiotics and preterm infants not given probiotics. We also recruited a small group of full term vaginally delivered healthy newborns as a control group. Stool samples were collected at 7 days, 28 days and 4 months of age and analysed using advanced techniques. To increase our knowledge about Bifidobacterium, we studied 15 patients where Bifidobacterium had caused a blood stream infection. We found that antibiotic treatment in newborns appears to induce disease-promoting changes in the gut flora, and antibiotics given for longer periods in babies with no bacterial infections are associated with increased risk of serious gut inflammation and/or death. From our literature search, we also found that the use of broad-spectrum antibiotics is associated with increased risk of fungal infections and antibiotic resistance development, the latter also seen in our multi-centre study. In our multi-centre study, preterm infants exposed to probiotics early had high levels of Bifidobacterium compared to preterm infants not given probiotics. This finding suggests that preterm infants given probiotics may need a more gradual increase in probiotic doses to mimic their physiological gut flora development. In infants given probiotics, we found no difference in antibiotic resistance development compared to infants not given probiotics, despite the massive antibiotic exposure in the probiotic-group compared to the other infants. Our findings support the potential of probiotics to reduce the spread of antibacterial resistance and thereby infections caused by antibiotic resistant bacteria. Bifidobacterium has the potential to cause infections in humans with a weakened immune system and may cause blood stream infections. However we could not find any specific disease-causing characteristics in Bifidobacterium similar to those found in more dangerous bacteria.en_US
dc.description.sponsorshipNorthern Norway Regional Health Authorityen_US
dc.identifier.urihttps://hdl.handle.net/10037/15334
dc.language.isoengen_US
dc.publisherUiT The Arctic University of Norwayen_US
dc.publisherUiT Norges arktiske universiteten_US
dc.relation.haspart<p>Paper I: Esaiassen, E., Fjalstad, J.W., Juvet, L.K., van den Anker, J.N. & Klingenberg, C. (2017). Antibiotic exposure in neonates and early adverse outcomes: a systematic review and meta-analysis. <i>Journal of Antimicrobial Chemotherapy, 72</i>, 1858-70. Publisher’s version not available in Munin due to publisher’s restrictions. Publisher’s version available at <a href=https://doi.org/10.1093/jac/dkx088>https://doi.org/10.1093/jac/dkx088</a>. <p>Paper II: Fjalstad, J.W., Esaiassen, E., Juvet, L.K., van den Anker, J.N. & Klingenberg, C. (2017). Antibiotic Therapy in Neonates and Impact on Gut Microbiota and Antibiotic Resistance Development: A Systematic Review. (Accepted manuscript version). Published version in <i>Journal of Antimicrobial Chemotherapy, 73</i>(3), 569–580, available at <a href=https://doi.org/10.1093/jac/dkx426>https://doi.org/10.1093/jac/dkx426</a>. Accepted manuscript version also available at <a href=https://hdl.handle.net/10037/15336>https://hdl.handle.net/10037/15336</a>. <p>Paper III: Esaiassen, E., Hjerde, E., Cavanagh, P., Pedersen, T., Andresen, J., Rettedal, S., … Klingenberg, C. Probiotic Supplementation and Development of Preterm Infant Gut Microbiota and Antibiotic Resistome- An Observational Multi-Center Study. (Manuscript). Published version in <i>Frontiers in Pediatrics, 6</i>, 347, available at <a href=https://hdl.handle.net/10037/14812>https://hdl.handle.net/10037/14812</a>. <p>Paper IV: Esaiassen, E., Hjerde, E., Cavanagh, J.P., Simonsen, G.S., Klingenberg, C. & Norwegian Study Group on Invasive Bifidobacterial Infections. (2017). <i>Bifidobacterium</i> bacteremia: Clinical Characteristics and a Genomic Approach to Assess Pathogenicity. <i>Journal of Clinical Microbiology 55</i>, 2234-48. Publisher’s version not available in Munin due to publisher’s restrictions. Publisher’s version available at <a href=http://doi.org/10.1128/JCM.00150-17> http://doi.org/10.1128/JCM.00150-17</a>.en_US
dc.rights.accessRightsopenAccessen_US
dc.subject.courseIDDOKTOR-003
dc.subjectMedisinske fagen_US
dc.titleAntibiotics and probiotics to neonates-Adverse effects, impact on gut microbiota and antibiotic resistome, and Bifidobacterium pathogenicityen_US
dc.typeDoctoral thesisen_US
dc.typeDoktorgradsavhandlingen_US


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