Antibiotic Therapy for Neonatal Sepsis - Studies on epidemiology, gentamicin safety, and early adverse effects of antibiotics

Paper 1, 2, 3 & 4 are not available in Munin. Paper 1: Fjalstad, J.W., Stensvold, H.J., Bergseng, H., Simonsen, G.S., Salvesen, B., Rønnestad, A.E. & Klingenberg, C. (2016). Early-onset Sepsis and Antibiotic Exposure in Term Infants: A Nationwide Population-based Study in Norway. Available in The Pediatric Infectious Disease Journal, 35(1), 1-6. Paper 2: Fjalstad, J.W., Laukli, W., van den Anker, J.N. & Klingenberg, C.(2013). High-dose gentamicin in newborn infants: is it safe? Available in European journal of pediatrics (2014),173, 489-495. Paper 3: 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. Available in Journal of Antimicrobial Chemotherapy, 72(7), 1858-70. Paper 4: 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. Available in Journal of Antimicrobial Chemoterapy (2018), 73(3), 569-580. Objectives: The overall aim of this thesis was to investigate different aspects of antibiotic therapy for neonatal sepsis. Material and Methods: The epidemiology of early onset sepsis (EOS) and systemic antibiotic exposure in the first week of life was studied in a nationwide population-based study from the Norwegian Neonatal Network between 2009-2011. A high-dose extended-interval gentamicin regimen was studied in the neonatal unit in Tromsø from 2004-2012. Early adverse effects of antibiotic therapy were studied in a systematic review. We included observational studies and randomized controlled trials that provided data on different categories of antibiotic therapy and either the risk of necrotizing enterocolitis, invasive fungal infection, death, antibiotic resistance development, or changes in the gut microbiota. Results: There were 0.54 cases of culture-confirmed EOS per 1000 live-born term infants with a mortality rate of 1%. Intravenous antibiotics were administered to 2.3% of all live-born term infants in Norway, and half of them were not diagnosed with an infection. In the neonatal unit in Tromsø, gentamicin trough concentrations were above the threshold of 2 mg/L in 6% of cases. Only 1% of these infants suffered from permanent hearing loss. In our systematic reviews, prolonged antibiotic exposure was significantly associated with necrotizing enterocolitis and/or death in preterm infants and reduced gut microbial diversity in all infants. Broad-spectrum antibiotic treatment increased the risk of invasive fungal infection. All categories of antibiotic exposure were associated with an increased risk of antibiotic resistance development. Main Conclusions: The incidence of culture-confirmed EOS in Norway was in line with previous international reports, and the mortality was very low. A large proportion of infants were treated with antibiotics without an infection. The extended-interval high-dose gentamicin regimen studied in this thesis seems safe. Neonatal antibiotic treatment was associated with several adverse effects

Genetic parameters for Photobacterium damselae subsp. piscicida resistance, immunological markers and body weight in gilthead seabream (Sparus aurata)

A challenge test for Photobacterium damselae subsp. piscicida (Phdp) resistance was carried out in two juvenile populations of gilthead seabream (Sparus aurata L.): F2_ATL and F0_MED. At 250 days post-hatching (dph), a fish plasma sample was collected to measure humoral immune markers (peroxidase activity, bactericidal activity, and IgM immunoglobulin levels), and at 272 dph fish were weighed and inoculated with bacteria Phdp. From that time onwards, surviving fish were recorded for nine days, and days to death was registered. Heritabilities for body weight and Phdp survival were moderate, although for days to death the heritability was low. Regarding humoral immune markers, for peroxidase activity it was moderate, and for IgM levels and for bactericidal activity it was low. Genetic correlations for body weight with Phdp survival and days to death were high and positive, while with peroxidase activity and IgM levels they tended to be positive, although these estimates were not accurate. Regarding genetic correlations between Phdp survival and humoral immune markers, they were very high, positive with peroxidase activity, and negative with IgM levels and bactericidal activity. Some humoral immune markers, particularly peroxidase activity, along with performance traits such as body weight and absence of deformities, are proposed to be included in a selective breeding program to raise fish that are capable of coping with diseasesVersión del editor2,04

Antibiotic Therapy for Neonatal Sepsis - Studies on epidemiology, gentamicin safety, and early adverse effects of antibiotics

Objectives: The overall aim of this thesis was to investigate different aspects of antibiotic therapy for neonatal sepsis. Material and Methods: The epidemiology of early onset sepsis (EOS) and systemic antibiotic exposure in the first week of life was studied in a nationwide population-based study from the Norwegian Neonatal Network between 2009-2011. A high-dose extended-interval gentamicin regimen was studied in the neonatal unit in Tromsø from 2004-2012. Early adverse effects of antibiotic therapy were studied in a systematic review. We included observational studies and randomized controlled trials that provided data on different categories of antibiotic therapy and either the risk of necrotizing enterocolitis, invasive fungal infection, death, antibiotic resistance development, or changes in the gut microbiota. Results: There were 0.54 cases of culture-confirmed EOS per 1000 live-born term infants with a mortality rate of 1%. Intravenous antibiotics were administered to 2.3% of all live-born term infants in Norway, and half of them were not diagnosed with an infection. In the neonatal unit in Tromsø, gentamicin trough concentrations were above the threshold of 2 mg/L in 6% of cases. Only 1% of these infants suffered from permanent hearing loss. In our systematic reviews, prolonged antibiotic exposure was significantly associated with necrotizing enterocolitis and/or death in preterm infants and reduced gut microbial diversity in all infants. Broad-spectrum antibiotic treatment increased the risk of invasive fungal infection. All categories of antibiotic exposure were associated with an increased risk of antibiotic resistance development. Main Conclusions: The incidence of culture-confirmed EOS in Norway was in line with previous international reports, and the mortality was very low. A large proportion of infants were treated with antibiotics without an infection. The extended-interval high-dose gentamicin regimen studied in this thesis seems safe. Neonatal antibiotic treatment was associated with several adverse effects

Abrupt changes in sea ice and dynamics of Dansgaard-Oeschger events

Changes in sea ice are proposed as an important component in Dansgaard-Oeschger events; the abrupt climate change events that occurred repeatedly during the last ice age. Paleoclimatic reconstructions suggest an expansion of sea ice in the Nordic Seas during the cold stadial periods of the Dansgaard-Oeschger cycles. However, as the present configuration of the Nordic Seas does not allow for an extensive sea-ice cover in this region, the hydrography must have been different during glacial times. In fact, reconstructions show that the Nordic Seas hydrography during cold stadial periods was similar to the stratification of the Arctic Ocean today. However, the dynamic impacts of changing freshwater input and Atlantic water temperature on the Arctic stratification and sea ice are unclear. This study aims to assess the potential for Arctic-like stratification in the Nordic Seas during the last glacial period and the dynamics behind Dansgaard-Oeschger events, using models and theory. The results are presented in three papers. In the first paper, we develop a simple conceptual two-layer ocean model including sea ice representing the Nordic Seas during stadial times. Here, we find that a sea-ice cover is sensitive to changes in freshwater input, subsurface temperature, and the representation of vertical mixing. Abrupt changes in sea ice can occur with small changes to surface freshwater supply or Atlantic water temperatures. In the second paper we apply a three-dimensional eddy resolving numerical model to the same problem and find further support for the conclusions from Paper I; the stability of a sea-ice cover in the Nordic Seas is dependent on the background climate and large changes in stratification and sea ice occur with small changes in forcing. In addition, additional results presented in this dissertation (Sec. 6.2.1) show self-sustained oscillations in sea-ice cover without a change in forcing. From Paper II we learn that an extensive sea-ice cover and an Arctic-like stratification with a fresh surface layer and a halocline can exist in the Nordic Seas without an external freshwater supply. Under sufficient cold conditions, a halocline capped by sea ice emerges spontaneously due to redistribution of freshwater through sea-ice formation and melt. We find that an extensive sea-ice cover slows down the local overturning in the Nordic Seas; decreases the heat import to the basin; warms intermediate waters, and cools deep waters. In Paper III, the importance of background climate is further stressed. In this study, we move away from studying an Arctic-like stratification, and focus on sea-surface temperature variability in the region of the Nordic Seas and North Atlantic. We compile all available planktic foraminifera records from the North Atlantic with a sea-surface temperature reconstruction from the Dansgaard-Oeschger events. These are then combined with fully coupled climate model simulations using a proxy surrogate reconstruction method. The resulting spatial sea-surface temperature patterns agree over a number of different general circulation models and simulations. However, forced runs from glacial times are needed to capture the amplitude of the temperature variability as seen in the proxy records. We suggest that sea-ice changes are important in extending the oceanic temperature signals to land. Combined, the three papers argue for an important role of the Nordic Seas during Dansgaard-Oeschger events, consistent with paleoclimatic reconstructions. Our results are also relevant for understanding potential future changes in Arctic sea-ice cover, and we argue that changes in Atlantic water temperature are of large importance

Neonatal sepsis and the adverse effect of antibiotic treatment - a systematic review

Abstract Objective: Antibiotic treatment in the neonatal period can be life-saving, but overuse is frequent. Recently studies have shown adverse effects from neonatal antibiotic treatment. This study aims to systematically review the litterature on the relationship between neonatal antibiotic treatment and changes in gut microbiota, the risk of necrotizing enterocolitis (NEC), and the risk of fungemia. Methods: We performed a systematic search in the Pubmed, Embase, and Medline databases up to December 2014. We included studies that assessed the effect of neonatal antibiotic treatment on the following outcomes; (1) change in gut microbiota, (2) NEC, and (3) fungemia. Abstracts were considered for eligibility by two researchers. Results: We included 14 studies in the microbiota category, twelve in the NEC category, and eleven in the fungemia category. The studies used very different designs and often had small study samples. Neonatal antibiotic treatment appeared to decrease gut microbiota diversity and the total bacteriall count, but findings were inconclusive on different bacteria. Neonatal antibiotic treatment, particularly prolonged treatment, appeared to increase the risk of NEC. Antibiotic treatment appeared protective of NEC in sepsis patients. Broad-spectrum antibiotic treatment appeared to increase the risk of fungemia. Conclusions: Neonatal antibiotic treatment appears to have an effect on gut microbiota, the risk of NEC, and the risk of fungemia. However, the methodological quality was poor in many studies, and more studies, preferably prospective with large study populations, are needed

The interaction between sea ice and salinity-dominated ocean circulation: implications for halocline stability and rapid changes of sea ice cover

Changes in the sea ice cover of the Nordic Seas have been proposed to play a key role for the dramatic temperature excursions associated with the Dansgaard–Oeschger events during the last glacial. In this study, we develop a simple conceptual model to examine how interactions between sea ice and oceanic heat and freshwater transports affect the stability of an upper-ocean halocline in a semi-enclosed basin. The model represents a sea ice covered and salinity stratified Nordic Seas, and consists of a sea ice component and a two-layer ocean. The sea ice thickness depends on the atmospheric energy fluxes as well as the ocean heat flux. We introduce a thickness-dependent sea ice export. Whether sea ice stabilizes or destabilizes against a freshwater perturbation is shown to depend on the representation of the diapycnal flow. In a system where the diapycnal flow increases with density differences, the sea ice acts as a positive feedback on a freshwater perturbation. If the diapycnal flow decreases with density differences, the sea ice acts as a negative feedback. However, both representations lead to a circulation that breaks down when the freshwater input at the surface is small. As a consequence, we get rapid changes in sea ice. In addition to low freshwater forcing, increasing deep-ocean temperatures promote instability and the disappearance of sea ice. Generally, the unstable state is reached before the vertical density difference disappears, and the temperature of the deep ocean do not need to increase as much as previously thought to provoke abrupt changes in sea ice

Large changes in sea ice triggered by small changes in Atlantic water temperature

The sensitivity of sea ice to the temperature of inflowing Atlantic water across the Greenland–Scotland Ridge is investigated using an eddy-resolving configuration of the Massachusetts Institute of Technology General Circulation Model with idealized topography. During the last glacial period, when climate on Greenland is known to have been extremely unstable, sea ice is thought to have covered the Nordic seas. The dramatic excursions in climate during this period, seen as large abrupt warming events on Greenland and known as Dansgaard–Oeschger (DO) events, are proposed to have been caused by a rapid retreat of Nordic seas sea ice. Here, we show that a full sea ice cover and Arctic-like stratification can exist in the Nordic seas given a sufficiently cold Atlantic inflow and corresponding low transport of heat across the Greenland–Scotland Ridge. Once sea ice is established, continued sea ice formation and melt efficiently freshens the surface ocean and makes the deeper layers more saline. This creates a strong salinity stratification in the Nordic seas, similar to today’s Arctic Ocean, with a cold fresh surface layer protecting the overlying sea ice from the warm Atlantic water below. There is a nonlinear response in Nordic seas sea ice to Atlantic water temperature with simulated large abrupt changes in sea ice given small changes in inflowing temperature. This suggests that the DO events were more likely to have occurred during periods of reduced warm Atlantic water inflow to the Nordic seas

Transient Increase in Arctic Deep-Water Formation and Ocean Circulation under Sea Ice Retreat

Abstract While a rapid sea ice retreat in the Arctic has become ubiquitous, the potential weakening of the Atlantic meridional overturning circulation (AMOC) in response to global warming is still under debate. As deep mixing occurs in the open ocean close to the sea ice edge, the strength and vertical extent of the AMOC is likely to respond to ongoing and future sea ice retreat. Here, we investigate the link between changes in Arctic sea ice cover and AMOC strength in a long simulation with the EC-Earth–Parallel Ice Sheet Model (PISM) climate model under the emission scenario RCP8.5. The extended duration of the experiment (years 1850–2300) captures the disappearance of summer sea ice in 2060 and the removal of winter sea ice in 2165. By introducing a new metric, the Arctic meridional overturning circulation (ArMOC), we document changes beyond the Greenland–Scotland ridge and into the central Arctic. We find an ArMOC strengthening as the areas of deep mixing move north, following the retreating winter sea ice edge into the Nansen Basin. At the same time, mixing in the Labrador and Greenland Seas reduces and the AMOC weakens. As the winter sea ice edge retreats farther into the regions with high surface freshwater content in the central Arctic Basin, the mixing becomes shallower and the ArMOC weakens. Our results suggest that the location of deep-water formation plays a decisive role in the structure and strength of the ArMOC; however, the intermittent strengthening of the ArMOC and convection north of the Greenland–Scotland ridge cannot compensate for the progressive weakening of the AMOC