• PROJECTS

Genetic investigations of Staphylococcus haemolyticus

PI: Pauline Cavanagh
Team: Hermoine Venter, Runa Wolden, Martin Christensen

Infections with S. haemolyticus most often occur in immunosuppressed patient groups such as cancer patients and very premature children. This bacterium can cause serious infections and clinical isolates are often characterized by a high degree of antibiotic resistance. In a comparative analysis of S. haemolyticus full genome sequences from clinical and commensal isolates, we found that genes coding for surface proteins, capsule and a large proportion of antibiotic resistance genes separated the two populations. We have developed molecular tools to look at the effect of individual genes, by doing gene knock-out. We are currently working on projects where we study:1. Significance of various surface proteins for S. haemolyticus virulence2. Significance of different capsule versions for S. haemolyticus virulence3. Significance of different methylation profiles for S. haemolyticus virulence

Selected publications since 2012, please see CRISTIN for the PI´s complete publication list:

• Cavanagh JP, Wolden R, Heise P, Esaiassen E, Klingenberg C, Fredheim EGA. Antimicrobial susceptibility and body site distribution of community isolates of Coagulase Negative Staphylococci. APMIS. 2016; 124: 973-8.
• Pain M, Hjerde E, Klingenberg C, Cavanagh JP. Comparative Genomic Analysis of Staphylococcus haemolyticus Reveals Keys to Hospital Adaptation and pathogenicity. Front Microbiol. 2019 Sep 10; 10:2096. 
• Cavanagh P, Hjerde E, Holden M, Kalkhe T, Klingenberg C, Flægstad T, Bentley S, Parkhill J, Sollid J. Whole genome sequencing reveals clonal expansion of multi-resistant Staphylococcus haemolyticus in European hospitals. J Antimicrob Chemother. 2014; 69: 2920-7.
• Cavanagh JP, Klingenberg C, Hanssen AM, Fredheim EA, Francois P , Schrenzel J, Flægstad T, Sollid JE. Core genome conservation of S. haemolyticus limits sequence based population structure analysis. J Microbiol Methods, 2012; 89: 159-66.
• Cavanagh JP, Pain M, Askarian F, Bruun JA, Urbarova I, Wai SN, Schmidt F, Johannessen M. Comparative exoproteome profiling of an invasive and a commensal Staphylococcus haemolyticus isolate. J Proteomics. 2019 Apr 15;197:106-114.
• Wolden R, Pain M, Karlsson R, Karlsson A, Aarag Fredheim EG, Cavanagh JP.
  Identification of surface proteins in a clinical Staphylococcus haemolyticus isolate by bacterial surface shaving. BMC Microbiol. 2020 Apr 7;20(1):80. 

Characterization and clinical significance of Staphylococcus borealis

PI: Pauline Cavanagh
Team: Claus Klingenberg, Pia Littauer, Hermoine Jean Venter 

In 2020, our research group published the discovery of the new staphylococcal species Staphylococcus borealis. We are currently collecting clinical isolates of S. borealis to investigate the clinical significance of the new bacterial species. Selected publications since 2012, please see CRISTIN for the PI´s complete publication list: ·         Pain M, Wolden R, Jaén-Luchoro D, Salvà-Serra F, Iglesias BP, Karlsson R, Klingenberg C, Cavanagh JP. Staphylococcus borealis sp. nov., isolated from human skin and blood. Int J Syst Evol Microbiol. 2020; 70(12):6067-78.

Antimicrobial effect of bacteriocin produced by S. haemolyticus

PI: Pauline Cavanagh
Team: Hermoine Venter, Runa Wolden, Dzung Diep, NMBU 

Antibiotic-resistant microbes are a global problem that threatens modern medicine as we know it. In this project, we characterize the antimicrobial effect of a bacteriocin produced by S. haemolyticus. We have previously shown that biofilm-producing bacteria are far more resistant to antibiotics than non-biofilm-producing bacteria. We are therefore testing the effect of the bacteriocin against bacteria both in planktonic growth and biofilm. The project is ongoing in collaboration with researchers at NMBU.

Selected publications since 2012, please see CRISTIN for the PI´s complete publication list:

• Kranjec C, Kristensen SS, Bartkiewicz KT, Brønner M, Cavanagh JP, Srikantam A, Mathiesen G, Diep DB. A bacteriocin-based treatment option for Staphylococcus haemolyticus biofilms. Sci Rep. 2021 Jul 6;11(1):13909.
• Wolden R, Ovchinnikov KV, Venter HJ, Oftedal TF, Diep DB, Cavanagh JP. The novel bacteriocin romsacin fromStaphylococcus haemolyticus inhibits Gram-positive WHO priority pathogens. Microbiol Spectr. 2023 Oct 31:e0086923. doi: 10.1128/spectrum.00869-23. Epub ahead of print.

OPTIMIST – Optimizing mastitis identification and treatment

PI: Pauline Cavanagh
Team: Hermoine Jean Venter, Claus Klingenberg, Beate Fossum Løland, Ina Landau Aasen

Mastitis (breast inflammation) is a common complication during breastfeeding, occurring most frequently in the first six to eight weeks postpartum. The term encompasses a spectrum of conditions and a range of symptoms, and there is currently no clinical consensus regarding its aetiology. The main objective of this clinical study is to gather empirical data to provide an evidence-based update to the clinical guidelines for mastitis diagnosis and care. This will provide a foundation for improving the treatment and prevention of mastitis, with better outcomes for mothers and newborns.

The study is ongoing, for more information please visit the website: https://uit.no/project/optimist-studien

Modulation of the host's immune response against coagulase negative staphylococci and other pathogens involved in sepsis among neonates and immunocompromised children 

PIs: Claus Klingenberg, Hildegunn Granslo, Pauline Cavanagh
Team: Tom Eirik Mollnes, Aline Bjerkhaug, Oda Gundersen, Synnøve Holmebukt 
We have, in collaboration with Prof. Mollnes in Bodø for several years conducted studies in a blood model (using umbilical cord blood or blood from adults) to assess the immune response to various microbes and to investigate whether an excessive immune response can be inhibited. In this blood model, we can assess the degree of bacterial virulence and potential new strategies to inhibit the innate immune system, including inhibition of the complement system and Toll-like receptors. New knowledge about the interaction between the microbe and the host is essential for developing methods for the prevention and treatment of infections.

Selected publications since 2012, please see CRISTIN for the PI´s complete publication list:

• Granslo HN, Klingenberg C, Fredheim EA, Acharya G, Mollnes TE, Flægstad T. Staphylococcus epidermidis biofilms induce lower complement activation in neonates compared to adults. Pediatr Res. 2013; 73: 294-300.
• Granslo HN, Fredheim EGA, Esaiassen E, Østrup Jensen P, Mollnes TE, Moser C, Flægstad T, Klingenberg C, Cavanagh JP. The synthetic antimicrobial peptide LTX21 induces inflammatory responses in an in vivo mouse peritonitis model and an ex vivo human whole blood model. APMIS 2019; 127: 475-83
• Bjerkhaug AU, Granslo HN, Cavanagh JP, Høiland I, Ludviksen JK, Lau C, Espevik T, Mollnes TE, Klingenberg C. Dual inhibition of complement C5 and CD14 attenuates inflammation in a cord blood model. Pediatr Res. 2023; 94:512-519.

Composition and change in the intestinal flora in children with HIV after treatment with Azithromycin

PI: Trond Flægstad
Team: Trym Tune Flygel, Erik Hjerde, Pauline Cavanagh, Evgeniya Sovershaeva 
The main aim of the project was to see if azithromycin improves lung function in children with HIV and chronic lung disease. In the study, 346 children aged 6-19 with HIV and chronic lung disease in Zimbabwe and Malawi received weekly azithromycin or placebo for 12 months. In this substudy, we examined the gut flora in children with HIV. Using 16s rRNA sequencing, we investigate whether the intestinal flora changes after using azithromycin and whether any changes are reversed 6 months after the end of treatment. The research project is part of the individually randomized, double-blind, placebo-controlled study "Bronchopulmonary function in response to azithromycin treatment for chronic lung disease in HIV-infected children (BREATHE)". The project is funded by the Research Council of Norway and is an international collaborative project.

Selected publications since 2012, please see CRISTIN for the PI´s complete publication list:

• Flygel TT, Sovershaeva E, Claassen-Weitz S, Hjerde E, Mwaikono KS, Odland JØ, Ferrand RA, Mchugh G, Gutteberg TJ, Nicol MP, Cavanagh JP, Flægstad T; BREATHE Study Team. Composition of Gut Microbiota of Children and Adolescents With Perinatal Human Immunodeficiency Virus Infection Taking Antiretroviral Therapy in Zimbabwe. J Infect Dis. 2020 Jan 14;221(3):483-492. 
• Flygel TT, Hameiri-Bowen D, Simms V, Rowland-Jones S, Ferrand RA, Bandason T, Yindom LM, Odland JØ, Cavanagh JP, Flaegstad T, Sovershaeva E. Exhaled nitric oxide is associated with inflammatory biomarkers and risk of acute respiratory exacerbations in children with HIV-associated chronic lung disease. HIV Med. 2023 Oct 7. doi: 10.1111/hiv.13565. Epub ahead of print. PMID: 37804064.

Epidemiological studies on infections and the use of antibiotics in newborns.

PI: Claus Klingenberg
Team: Zuzana Huncikova, Anlaug Vatne 

For several years, we have worked on various projects where, based on population-based data from the Norwegian Neonatal Medicine Quality Register (NNK), we have studied infections in both full-term and premature babies. We have participated in publications and are planning several new publications in the next 1-2 years with a focus on the use of antibiotics and how infections affect the prognosis of prematurely born children. We collaborate with both national and international researchers in this field.

Selected publications since 2012, please see CRISTIN for the PI´s complete publication list:

• Vatne A, Hapnes N, Stensvold HJ, Dalen I, Guthe HJ, Støen R, Brigtsen AK, Rønnestad AE, Klingenberg C. Early Empirical Antibiotics and Adverse Clinical Outcomes in infants born very preterm: A population-based cohort. J Pediatr. 2023; 253:107-114.
• Huncikova Z, Vatne A, Stensvold HJ, Lang A, Støen R, Brigtsen AK, Salvesen B, Øymar K, Rønnestad AE, Klingenberg C. Late-onset sepsis in very preterm infants in Norway, 2009-2018. Arch Dis Child Fetal Neonatal Ed, 2023;0: F1–F7. doi:10.1136/archdischild-2022-324977
• Mundal HS, Rønnestad A, Klingenberg C, Stensvold HJ, Størdal K. Sepsis and antibiotic use in term and near-term newborns - a nationwide population-based study. Pediatrics. 2021;148: e2021051339.
• Dretvik T, Solevåg AL, Finvåg A, Størdal EH, Størdal K, Klingenberg C. Active antibiotic discontinuation in suspected but not confirmed early-onset neonatal sepsis – a quality-improvement initiative. Acta Paediatr. 2020; 109: 1125-30
• Vatne A, Klingenberg C, Øymar K, Rønnestad A, Manzoni P, Rettedal S. Reduced antibiotic exposure by serial physical examinations in term neonates at risk of early-onset sepsis. Pediatr Infect Dis J. 2020; 39:438-43.
• Achten NB, Klingenberg C, Benitz WE, Stocker M, Schlapbach LJ, Giannoni E, Bokelaar R, Driessen GJA, Brodin P, Uthaya S, van Rossum AMC, Plötz FB. Association of use of the early-onset sepsis calculator with reduction in antibiotic therapy and safety: A systematic review and meta-analysis. JAMA Pediatr. 2019; 173:1032-1040. 
• Fjalstad JW, Stensvold HJ, Bergseng H, Simonsen GS, Rønnestad A, Klingenberg C. Early onset sepsis and antibiotic exposure in term infants: a nationwide population-based study in Norway. Pediatr Infect Dis J. 2016; 35:1-6.

Studies on the effect, side effects and monitoring of aminoglycosides for newborns and older children

PI: Claus Klingenberg
Team: Dagny Hemmingsen, Kasper Øvsthus, Lene Nymo Trulsen 

We have been doing research on aminoglycosides for many years; a group of antibiotics that are ecologically favorable and to a small extent promote the development of resistance. The challenges with this group of antibiotics are uncertainty regarding dosage and possible side effects. We have evaluated a gentamicin dosing regimen in newborns including very thorough assessment of hearing. We have several other ongoing projects in the evaluation of aminoglycosides for newborns and older children.

Selected publications since 2012, please see CRISTIN for the PI´s complete publication list:

• Grodås KTM, Døllner H, Thaulow CM, Knudsen PK, Skeibrok M, Tønnessen A, Klingenberg C. Måling av gentamicin serum konsentrasjon hos barn. Tidsskr Nor Laegeforen 2023 Jan 16;143(1). doi: 10.4045/tidsskr.22.0238.
• Hemmingsen D, Mikalsen C, Hansen AR, Fjalstad JW, Stenklev NC, Klingenberg C. Hearing assessment in schoolchildren after neonatal exposure to a high-dose gentamicin regimen. Pediatrics. 2020 145:e20192373.
• Rypdal V, Jørandli S, Hemmingsen D, Solbu MD, Klingenberg C. Exposure to an Extended-interval High-Dose Gentamicin regimen in the Neonatal period is not associated with long-term Nephrotoxicity. Front Pediatr 30 November 2021, doi: 10.3389/fped.2021.779827

Studies on the effect of probiotic administration to newborns

PI: Claus Klingenberg
Team: Veronika Pettersen, Ahmed Bargheet

We have carried out a national study in which we have looked at the effects of probiotics given to prematurely born children. We are now participating together with a group of Norwegian and Tanzanian researchers in a large study where we are investigating whether probiotics can influence the health of infants in a favorable direction and have a positive effect on the gut microbiome.

Selected publications since 2012, please see CRISTIN for the PI´s complete publication list:

• Bargheet A, Klingenberg C, Esaiassen E, Hjerde E, Cavanagh JP, Bengtsson-Palme J, Pettersen VK. Development of early life gut resistome and mobilome across gestational ages and microbiota-modifying treatments. eBioMedicine 2023; 92:104613
• Kuwelker K, Langeland N, Löhr I, Gidion J, Manyahi J, Moyo S, Blomberg B, Klingenberg C. Use of Probiotics to Reduce Infections and Death and Prevent Colonization with Extended-spectrum beta-lactamase (ESBL) producing bacteria among newborn infants in Tanzania (ProRIDE Trial): study protocol for a randomized controlled clinical trial. Trials, 2021;22:312.
• Esaiassen E, Hjerde E, Cavanagh JP, Pedersen T, Andresen JH, Rettedal SI, Støen R, Nakstad B, Willassen NP, Klingenberg C. Effects of Probiotic Supplementation on the Gut Microbiota and Antibiotic Resistome Development in Preterm Infants. Front Pediatr. 2018 Nov 16;6:347. doi: 10.3389/fped.2018.00347. eCollection 2018

Metabolomics in neonatal infections

PI: Veronika Pettersen, Pauline Cavanagh, Claus Klingenberg

Team: Hildegunn Granslo, Aline Bjerkhaug, Gaute Hovde Bø, Oda Gundersen, Synnøve Holmebukt

Vi gjennomfører, og planlegger, ulike studier der vi gjør analyser på metabolomikk i urin, avføring og blod hos nyfødte og spedbarn barn som behandles med antibiotika eller spedbarn som behandles med probiotika. Metabolomikk i avføring gjøres med tanke på å se hvordan probiotika/antibiotika påvirker metabolske forhold i tarmen. Metabolomikk i urin og blod er med tanke på utvikling av biomarkører for infeksjon og alvorlighetsgrad.

Compositional and metabolic changes of the gut microbiome in childhood cancers 

PI: Veronika Pettersen, 

Team: Hildegunn Granslo, Trond Flægstad

The project is a collaboration between the Paediatric Research group at UiT, Norwegian Childhood Cancer Biobank, and researchers from the Centre for Ecological and Evolutionary Synthesis at the University of Oslo.

The gut microbiome has been implicated as a possible driver and regulator of cancer pathogenesis. Producing small molecules and metabolites that act both locally and systemically, the gut microbiome may promote or suppress cancer generation and progression.

This project explores the gut microbiome in pediatric cancer patients. By using DNA sequencing methods and metabolite profiling, we will characterize features of the gut microbiome associated with cancer diagnoses in children. The goal is to describe microbiome-based markers that discriminate cancer cases from healthy controls and microbial metabolites that can serve as diagnostic biomarkers in therapeutic explorations.

Utvalgte referanser siden 2012, se ellers publikasjoner i CRISTIN til aktuelle PI

• Bjerkhaug AU, Granslo HN, Klingenberg C. Metabolic responses in neonatal sepsis - A systematic review of human metabolomic studies. Acta Paediatr. 2021; 110: 2316-25.

Gut Microbiome-based Biomarkers to Prevent Infections by Antimicrobial Resistant Bacteria in Infancy 

PI: Veronika Pettersen

Team: Claus Klingenberg, Hildegunn Granslo, Pauline Cavanagh

The microbial community living in the human intestine provides first-line defense against enteric pathogens. Exploiting symbiotic bacteria for pathogen suppression is a viable alternative to the use of antibiotics in preventing infections.

This research project leverages two cohort studies of term infants to describe the impact of antibiotics and probiotics on the gut microbiome. The first is a randomized clinical trial co-led by the Paediatric Research group in Tromsø (UiT/UNN), which investigates the effects of probiotic therapy in Tanzanian children and its potential to prevent infections by ESBL-producing Enterobacterales (ProRIDE: Probiotics to Reduce Infections and Death and Prevent Colonization with ESBL- producing bacteria). The second study is a prospective, observational pilot study of infants with suspected symptoms of infection during the 1st week of life leading to antibiotic therapy (IMPALE: Impact of Antibiotics on the Neonatal Metabolome). The aim of both studies is to describe changes in faecal metabolites and microbial composition in association with antibiotic/probiotic use, drug-resistant strain colonization, and a risk of infection.