| 1. |
- Davidsson, Sabina, 1972-
(author)
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Infection induced chronic inflammation and it's association with prostate cancer initiation and progression
- 2013
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Doctoral thesis (other academic/artistic)abstract
- An association between cancer development and inflammation has long been suggested. Approximately 20% of all human cancers in adults are assumed to result from chronic inflammation. The aim of this thesis was to investigate if infection-induced chronic inflammation plays a role in prostate carcinogenesis.Our results revealed a greater infiltration of the bacterium Propionibacterium acnes in the prostate tissue obtained from men with prostate cancer compared to men without any histological evidence of the disease. These findings indicate that prostate cancer could potentially be included in the list of cancers with an infectious etiology.Further, we investigated whether chronic inflammation has a role in disease progression. Our results demonstrated that men with lethal prostate cancer had pronounced infiltration of immune cells with suppressive function of the anti-tumor immune response compared to men with a more indolent prostate cancer.Confirmation of our results may open up avenues for targeted prostate cancer treatment by offering men with chronic inflammation alternative therapies such as anti-inflammatory drugs. If the involvement of P. acnes in prostate cancer development is replicated in other studies, vaccination therapies may be feasible. To further individualize prostate cancer therapy, bolstering the anti-tumor immune response in order to reduce tumor progression may be determined to be advantageous for some patients.
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| 2. |
- Asfaw Idosa, Berhane, 1977-
(author)
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Inflammasome polymorphisms and the Inflammatory Response to Bacterial Infections
- 2016
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Doctoral thesis (other academic/artistic)abstract
- NLRP3 inflammasome; a key component of the innate immune system, can be activated by a number of pathogens and other threats of the body. Activation of the NLRP3 inflammasome triggers caspase-1 mediated maturationof IL-1β and IL-18. Polymorphisms Q705K and C10X are two gene variants of the NLRP3 inflammasome that combined or per se have been associated with higher risk and severity of chronic inflammation and excessive production of IL-1β. Host genetic factors have been found an important determinants of susceptibility of infectious diseases and disease outcome. The aims of this thesis were to investigate the association between polymorphisms Q705K and C10X with bacterial infections and the inflammatory response, moreover to determine the inflammasome activation state in healthy carriers of these polymorphisms. The data of the thesis show higher levels of IL-1β and IL-33 in healthy carriers of combined polymorphisms of Q705K and C10X as compared to non-carrier controls. This may provide individuals with combined polymorphisms a more robust innate immune response against pathogens, but could also lead to the onset of chronic inflammation, and excessive inflammation during acute infection. In addition, individuals with C10X polymorphism per se showed association with the presence of bacteremia as compared withhealthy blood donors. No association was found in severely ill patients with negative blood culture bottle. In addition, the results show that LOS of N. meningitidis is responsible for the priming and activating steps of the inflammasome. The non-LOS components were found to contribute to the priming step. A higher inflammatory response to N. meningitidis was found in individuals who were non-carriers of the polymorphisms than individuals with the Q705K and C10X per se or combined regardless of the strain of bacteria. Taken together, the gene variations of the NLRP3 inflammasome are of importance in explaining inter-individual variation in susceptibility to infectious diseases.
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| 3. |
- Khan, Faisal Ahmad, 1986-
(author)
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Carbapenemase-Producing Enterobacteriaceae in Wastewater-Associated Aquatic Environments
- 2020
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Doctoral thesis (other academic/artistic)abstract
- The emergence of carbapenem resistance due to the carbapenem-hydrolyzing enzymes (carbapenemases) in Enterobacteriaceae has led to limited therapeutic options. The increased resistance to these “last-resort” antibiotics is fueled by overuse and misuse of antibiotics in human medicine and agriculture. According to the One-Health concept, the microbiomes of humans, animals and natural environments are interconnected reservoirs of antibiotic resistance genes (ARGs) and changes in one compartment will affect the other compartments. Thus, the environmental waters exposed to the pathogens, ARGs and other contaminants of human origin can play a significant role in the spread of resistance. The study aimed to characterize carbapenemase-producing Enterobacteriaceae (CPE) and ARGs in wastewaters and associated river and lake waters in Örebro, Sweden. The study also analyzed de novo development of resistance in Klebsiella oxytoca during long-term growth in river water and the effect of temperature on the emergence of resistance. OXA-48-producing Escherichia coli (ST131) and VIM-1-producing K.oxytoca (ST172) were repeatedly detected in the wastewaters and associated river, suggesting that these isolates were persistently present in these environments. Furthermore, K. oxytoca ST172 isolated from the river was genetically similar to two isolates previously recovered from patients in a local hospital, which shows the possibility of transmission of CPE from hospital to aquatic environments. A high diversity of ARGs was detected in these environments especially in hospital wastewater where ten different carbapenemase genes were detected. These results emphasized that the effective treatment of wastewaters must be ensured to reduce or eliminate the spread of antibiotic resistance. Increased resistance to meropenem (up to 8-fold) and ceftazidime (>10-fold) was observed in K. oxytoca after exposure to both river and tap water after 600 generations and resistance emerged earlier when the bacteria was grown at the higher temperature. The exposure to contaminants and increased environmental temperature may induce similar changes in the environmental microbiome, generating novel resistant variants at accelerated rates that may pose a significant threat to human health.
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| 4. |
- Månsson, Emeli, 1978-
(author)
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Molecular epidemiology of Staphylococcus epidermidis in prosthetic joint infections
- 2019
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Doctoral thesis (other academic/artistic)abstract
- Staphylococcus epidermidis is ubiquitous in the human microbiota, but also an important pathogen in healthcare-associated infections, such as prosthetic joint infections (PJIs). In this thesis, aspects of the molecular epidemiology of S. epidermidis in PJIs were investigated with the aim of improving our understanding of the pre- and perioperative measures required to reduce the incidence of S. epidermidis PJIs.In Paper I, S. epidermidis retrieved from air sampling in the operating field during arthroplasty was characterized by multilocus sequence typing and antibiotic susceptibility testing. No isolates belonging to sequence types (STs) 2 and 215, previously associated with PJIs, were found in the air of the operating field. During air sampling, several Staphylococcus pettenkoferi isolates were identified, and as a spin-off of Paper I, the genomic relatedness of these isolates to S. pettenkoferi isolates from blood cultures was described in Paper II.In Paper III, genetic traits distinguishing S. epidermidis isolated from PJIs were determined using genome-wide association study accounting for population effects after whole-genome sequencing (WGS) of a population- based 10-year collection of S. epidermidis isolates from PJIs and of nasal isolates retrieved from patients scheduled for arthroplasty. Genes associated with antimicrobial agents used for prophylaxis in arthroplasty, i.e., beta-lactam antibiotics, aminoglycosides, and chlorhexidine, were associated with PJI origin. S. epidermidis from PJIs were dominated by the ST2a, ST2b, ST5, and ST215 lineages.In Paper IV, selective agar plates were used to investigate colonization with methicillin resistant S. epidermidis (MRSE) in patients scheduled for arthroplasty. MRSE were further characterized by WGS. A subset of patients was found to harbour PJI-associated S. epidermidis lineages in their microbiota before hospitalization, but no isolates belonging to the ST2a lineage nor any rifampicin-resistant isolates were retrieved.
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| 5. |
- Sahdo, Berolla, 1984-
(author)
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Inflammasomes : defense guardians in host-microbe defence
- 2013
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Doctoral thesis (other academic/artistic)abstract
- The inflammasomes are emerging as key regulators of the innate immune response as they response to cellular infection, tissue damage and/or stress. Activated inflammasomes provide a signalling platform for caspase-1 activation which subsequently processes the maturation of interleukin (IL)-1β and IL-18, and in addition promotes cell death, named pyroptosis. These effector mechanisms of the inflammasome constitute an important part of the innate immune response in host-defence.The aims of this thesis were to elucidate if the inflammasome is activated by specific pathogens, and if genetic variations lead to susceptibility to severe inflammatory diseases, such as blood stream infections. We found that the commensal pathogens Staphylococcus aureus and Propionibacterium acnes induce caspase-1 activation, the latter being a stronger activator. The data also propose that it is rather the bacterial ligands than the secreted toxins of P. acnes that induce inflammasome activation. Even though the S. aureus PVL-toxin induces a caspase-1 activation, involvement of other virulence factors are of importance. Upon S. aureus and P. acnes stimulation, inter-individual variations were found, implying that the characteristics of the host innate immune system, rather than the properties of the bacteria, are decisive for the inflammatory response. Indeed, healthy individuals with the combined polymorphisms of the NLRP3 inflammasome (C10X/Q705K) have higher levels of spontaneous IL-1β, and most intriguingly C10X polymorphism showed a strong correlation with patients with bacteremia.In conclusion, these studies suggest that different pathogens activate the inflammasomes to various degrees. The genetics of the host innate immune system, rather than the properties of the bacteria, define the inflammatory response against these bacteria, and specific genetic variations such as C10X polymorphism can increase the susceptibility for disease development.
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| 6. |
- Sahlberg Bang, Charlotte, 1967-
(author)
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Carbon monoxide and nitric oxide as antimicrobial agents : focus on ESBL-producing uropathogenic E.coli
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Urinary tract infections (UTI) are common in humans and most often caused by uropathogenic Escherichia coli (E. coli). Extended-spectrum beta-lactamase (ESBL)-producing E. coli are increasing worldwide and they are frequently multidrug-resistant with limited treatment options. The overall aim of this thesis was to study the role of the host-derived factors nitric oxide (NO) and carbon monoxide (CO) as antimicrobial agents against ESBL-producing uropathogenic strains of E. coli (UPEC).The NO-donor DETA/NO caused a temporary growth inhibition in ESBL-producing UPEC. The antibacterial effect of DETA/NO was improved when DETA/NO was combined with miconazole, a pharmacological inhibitor of NO-protective mechanisms. Combination treatment with DETA/NO, miconazole and polymyxin B nonapeptid prolonged the bacteriostatic effect in the majority of examined isolates. The CO-donor CORM-2 showed a pronounced antibacterial effect in ESBL-producing UPEC with a fast bactericidal effect. Moreover, CORM-2 was shown to reduce the bacterial viability of ESBL-producing UPEC grown under biofilm-like conditions and to decrease the bacterial colonization of human bladder epithelial cells. A microarray analysis was performed to define transcriptomic targets of CORM-2 after a single exposure and after repeated exposure to CORM-2. Many processes were affected by CORM-2, including a downregulation in energy metabolism and biosynthesis pathways and upregulation of the SOS response and DNA repair. Repeated exposure to CORM-2 did not change the gene expression patterns or fold changes and the growth inhibitory response to CORM-2 was not altered after repeated exposure.In conclusion, NO- and CO-donors have antibacterial effects against ESBL-producing UPEC and may be interesting candidates for development of new antibiotics to treat UTI caused by multidrug-resistant uropathogens.
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| 7. |
- Sid Ahmed, Mazen, 1970-
(author)
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Molecular Epidemiology and Mechanisms of Antibiotic Resistance in Clinical Isolates of Pseudomonas aeruginosa from Qatar
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Inappropriate and excessive use of antibiotics promotes antimicrobial resistance (AMR), particularly in Gram-negative bacteria (GNB). There is a noticeable increase in nosocomial infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa, which is associated with significant morbidity, mortality, and an increase in cost management. Although this is a global problem, there is a lack of sufficient data on regional differences that can contribute towards effective AMR management. This thesis presents a study of MDR-P. aeruginosa at five different hospitals in Qatar conducted prospectively between October 2014 - September 2017. The aim was to study the epidemiology, microbiological and clinical characteristics of MDR-P. aeruginosa infections as well as investigate the activity of new antibiotic combinations against these bacteria. The prevalence of MDR-P. aeruginosa isolates in the first year was 8.1% (205/2533), isolated from different clinical specimens, but the majority were from respiratory infections (44.9%, n=92). Most cases were exposed to antibiotics during the 90 days prior to isolation (85.4%, n=177), and the resistance to cefepime, ciprofloxacin, piperacillin/tazobactam, meropenem was >90%. To compare pre- and post-Antimicrobial Stewardship Program, there was a significant reduction in antibiotic consumption by 30.4% of total inpatient antibiotic prescriptions (p=0.008) and the prevalence of MDR-P. aeruginosa significantly declined from 9% to 5.4% (p=0.019). The in vitro investigation of ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (C/T) against MDR-P. aeruginosa isolates, showed promising results with susceptibility of 68.8% (n=141/205) and 62.9% (n=129/205), respectively, which was higher than other antipseudomonal agents except colistin. Seventy-five isolates that were sequenced belonged to 29 different sequence types, with ST235 being predominant at 21.3% (16/75). Among the 42 isolates that were resistant to CZA and/or C/T, the most prevalent genes were blaOXA-488 and blaVEB-9 detected in 45.2% (19/42) of isolates. Spearman’s analysis showed that resistance to CZA and C/T were positively correlated with the presence of blaOXA-10, blaPDC-2a, blaVIM-2, and blaVEB-9 , respectively. The study highlights potential key mechanisms that could explain the resistance of MDR-P. aeruginosa to the new antibiotic combinations.
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| 8. |
- Wildeman, Peter, 1975-
(author)
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Prosthetic Joint Infection of the Hip : Cause and Effect
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Every year, 18 000 patients in Sweden and more than 1 million worldwide undergo total hip arthroplasty (THA). The operation is of great benefit to patients, but is associated with several complications. Prosthetic joint infections (PJIs) are among the most common complications, and can be devastating in terms of suffering for the patient and cost for the healthcare provider. The aim of this thesis was to investigate different aspects of PJIs in order to gain a better understanding of the causes and effects of infection. Four studies were conducted covering genomic analysis of the causative organism, identification of risk factors for failure of treatment, evaluation of a national infection control program aimed at reducing the burden of infections (PRISS: Prosthesis-related infections shall be stopped), and examination of the long-term impact of a PJI on the patient’s health through patient-reported measurement questionnaires.The main findings were as follows. Commensal bacteria such as Cutibacterium avidum have the potential to cause PJIs, and should be specially accounted for when performing hip surgery with an anterior approach. S. aureus is both a commensal and a pathogen with invasive capacity, and the commensal strains do not differ from the PJI strains regarding prevalence of virulence genes and clonal complexes. The genomic traits of pathogens had no impact on treatment success or eradication of infection in S. aureus PJIs The long-term effects of a PJI in the hip include increased mortality, lower quality of life, and decreased hip function. The incidence of PJIs was higher following the PRISS project. Increasing risk factors contributing to PJI explain the increasing incidence of PJI after primary THA.In conclusion, PJIs of the hip have multifactorial causes which are difficult to reduce, and long-term effects are severe.
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| 9. |
- Ahlstrand, Erik, 1974-
(author)
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Coagulase-negative staphylococci in hematological malignancy
- 2013
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Doctoral thesis (other academic/artistic)abstract
- Bacterial infections are common in hematological malignancy. Coagulase-negative staphylococci (CoNS) are among the most prevalent causes of bacteremia in patients with hematological malignancies.In this thesis, different aspects of CoNS in hematological malignancy have been studied in four papers:In paper 1, CoNS blood culture isolates from patients with hematological malignancies treated at the University Hospital of Örebro from 1980 to 2009 were revaluated for the presence of reduced sensitivity to glycopeptides. A high incidence of heterogeneous-intermediate glycopeptide resistance was observed and there was a trend towards increasing incidence of this phenotype over time.In paper 2, the colonization pattern of CoNS among patients undergoing intensive chemotherapy for hematological malignancy was investigated. A successive homogenization and an accumulation of CoNS phenotypes mutually present in a majority of included patients were demonstrated.In paper 3, a PCR method to determine the clinical significance of positive blood cultures of the CoNS species Staphylococcus epidermidis was evaluated. The test failed to discriminate bloodstream infection from blood culture contamination.Finally, in paper 4, the long-term molecular epidemiology of S. epidermidis blood culture isolates from patients with hematological malignancies was studied with multilocus sequence typing. A predominance of sequence type 2 was demonstrated during the entire 30 year study period.In conclusion, the results are consistent with that CoNS have established as important pathogens by its capacity to colonize the human skin, its ability to reside and spread in the hospital environment and its rapid adaptation to stressors such as antimicrobials.
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| 10. |
- Fagerström, Anna, 1980-
(author)
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Long-term molecular epidemiology of extended-spectrum β-lactamase producing Escherichia coli in a low-endemic setting
- 2020
-
Doctoral thesis (other academic/artistic)abstract
- Escherichia coli is a commensal inhabitant in the gastro-intestinal tract of humans and animals but it is also the most common bacterial species causing urinary tract infection, which ranges in severity from distal cystitis to urosepsis and septic shock. During the past decades, the prevalence of antibiotic resistant E. coli has increased worldwide. Extended-spectrum β-lactamases (ESBL) causes resistance to β-lactam antibiotics, the most widely used class of antibiotics. The genes encoding ESBL, bla, are usually carried on conjugative plasmids, which can be transferred between different bacterial lineages and different species. These plasmids frequently also carry resistance genes to additional antibiotic classes, and ESBL-producing E. coli are therefore often multidrug-resistant. The aim of this thesis was to describe the long-term molecular epidemiology of ESBL-producing E. coli in Örebro County during the time when they first started to emerge. In addition, potential transmission to the environment was investigated by performing a comparative analysis on ESBL-producing E. coli isolated from patients and from the aquatic environment in Örebro city. In general, the E. coli population was genetically diverse, but the pandemic lineage ST131, first identified in 2004, appears to have been responsible for the dramatic increase of CTX-M-15-producing E.coli observed during the late 2000s. CTX-M-15 was the most prevalent ESBL-type followed by CTX-M-14 and these genes were mainly found on plasmids belonging to the IncF or IncI1 families. Continuous horizontal transmission of IncI1 ST31 and ST37 plasmids between diverse E. coli lineages have also contributed to the dissemination of blaCTX-M-15 in Örebro County. Extended spectrum β-lactamase-producing E. coli were found to be common in the aquatic environment in Örebro city and E. coli lineages genetically similar to those causing infections in humans were present in environmental waters indicating that transmission of ESBL-producing E. colifrom humans to the aquatic environment likely has occurred.
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| 11. |
- Falk-Brynhildsen, Karin, 1959-
(author)
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The effect of peroperative skin preparation on bacterial growth during cardiac surgery
- 2013
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Doctoral thesis (other academic/artistic)abstract
- Routine products are used and procedures are followed in order to prevent and minimize the bacterial contamination of the surgical wound, and thus reduce the risk of postoperative wound infections. The overall aim of this thesis was to investigate the effect of different preoperative skin preparation before cardiac surgery.In study I, 10 healthy volunteers were compared in time to recolonization of the skin and bacterial growth with or without plastic adhesive drape. Bacterial samples were taken as paired samples on both side of the sternum. Plastic drape on disinfected skin seems to hasten recolonization compared with bare skin.In study II, 135 cardiac surgery patients were comparing plastic adhesive drape versus bare skin on the chest regarding intra-operative bacterial growth. Plastic adhesive drape did not reduce the bacterial recolonization or wound contamination, P. acnes colonizes males more often than females and P. acnes is not affected by disinfection with 0.5% chlorhexidine in ethanol.Study III, compared the leg harvesting site with or without microbal skin sealant in 135 CABG patients regarding intraoperative bacterial growth and postoperative wound infection. Almost no bacterial growth was found during surgery regardless of the use of microbial skin sealant and bare skin. A high incidence of postoperative wound infections (16.8%) in 2 month follow up was present and SSI was largely caused by S. aureus, i.e. other bacterial species than observed intraoperative.Study IV, a descriptive study using phenotypic and genotypic methods investigate susceptibility to chlorhexidine among S. epidermidis indicating that S. epidermidis isolates following preoperative skin disinfection are sensitive tochlorhexidine.
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| 12. |
- Rasmussen, Gunlög, 1973-
(author)
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Staphylococcus aureus bacteremia, molecular epidemiology and host immune response
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Staphylococcus aureus is a major pathogen responsible for a considerable disease burden worldwide. It may cause a wide array of infections, from superficial skin infections to invasive bacteremia and complications such as infective endocarditis (IE) and osteomyelitis. This thesis aimed to investigate aspects of the molecular epidemiology of S. aureus and host immune response in relation to disease manifestation, severity, and over time during S. aureus bacteremia (SAB).Genotypic characteristics in isolates causing colonization, bacteremia, and bacteremia with IE were studied. The S. aureus population was genetically diverse and certain clones with their set of often lineage-specific virulence genes were associated with invasive disease. Characterization of the long-term molecular epidemiology of MSSA bacteremia showed an increased prevalence of CC5 and CC15, while CC8, CC25 and CC30 declined. Antibiotic resistance pattern was favorable and unaffected.Further, different aspects of host immune response were explored in patients with SAB during the acute phase of bacteremia. When investigating the NLRP3 inflammasome signaling, induced caspase-1 activity was found, with a great inter-individual variation between patients, and subsequent release of IL-18, indicating inflammasome activity. Finally, the dynamics of MHC class II related genes HLA-DRA and CD74 were analyzed as markers of immunosuppression. Patients with complicated SAB had significantly lower HLA-DRA expression than patients with uncomplicated bacteremia, demonstrating an association between complicated SAB and impaired immune function.In conclusion, the S. aureus genotype, as well as host factors reflected by inter-individual variations in inflammasome signaling and immune function, may all contribute to disease manifestation and outcome during SAB. An ability to measure the immune response early and continuously during the hospital stay and course of bacteremia could offer a way to tailor patient management and treatment in an individualized way.
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| 13. |
- Sagerfors, Susanna, 1977-
(author)
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Infectious keratitis : causative microorganisms and how to detect them
- 2021
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Doctoral thesis (other academic/artistic)abstract
- First, to describe the microbial spectrum in infectious keratitis by both a culture and a targeted sequencing approach; second, to describe the clinical and genetic characteristics of Corynebacterium macginleyi; and third, to study different aspects of the corneal culture process by comparing two instruments used for sampling and two sampling and inoculation strategies. The five studies in this thesis made use of two retrospective study populations and one prospective study population.In the retrospective population the microbial spectrum by corneal culture was explored, Gram-positive bacteria, mainly coagulase-negative staphylococci, Staphylococcus aureus, and Corynebacterium spp. were commonly isolated. In the prospective study population, culture detected 13 different bacterial genera, while targeted sequencing identified a total of 168 different bacterial genera, with individual samples having a median of 13 (7–28) genera. Culture and sequencing showed an 82% agreement on the bacterial genera detected by culture. Genome sequencing and analysis of C. macginleyi revealed two different clades of which the minor clade (n=7), not previously described, exhibited a more complicated disease course. Cotton tipped applicators generated a significantly higher rate (44%) of positive corneal cultures on solid media than knife blades (31%). Direct transferal of multiple corneal samples to culture media generated a significantly higher rate of positive corneal cultures (61%) than indirect transferal through a single transport medium (44%).In conclusion, the microbial spectrum in a Swedish population is similar to previously described in Europe, and C. macginleyi may be considered a corneal pathogen. Targeted sequencing may gain clinical application if further developed. The findings of this thesis indicate that a cotton tipped applicator may be sufficient for corneal sampling for direct inoculation, and the corneal culture procedure can be simplified from seven samplings on four different media to three samplings on two media.
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| 14. |
- Samuelsson, Annika, 1964-
(author)
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The faecal flora : a source of healthcare-associated infections and antibiotic resistance
- 2013
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Doctoral thesis (other academic/artistic)abstract
- Healthcare-associated infections (HAI) are important causes of mortality and morbidity, and antibiotic treatment is often necessary. Development and availability of new antibiotics are closely followed by development of resistance among microorganisms. During antibiotic therapy, a fraction of the antibiotic given is found in the gut. The human gut is an important reservoir of bacteria. Microorganisms residing or passing the gut is referred to as the gut flora or microbiota. The results of this thesis showed spread of Enterococcus spp between patients on a general intensive care unit, causing septicaemia. After improved hygiene, reorganisation of rooms and thorough cleaning of the unit, together with revision of antibiotic strategy, the incidence of septicaemia with Enterococcus spp fell. Investigation of patients treated for acute intra-abdominal infections showed a shift in the aerobic faecal flora from antibiotic-susceptible Enterobacteriaceae spp towards Enterococcus faecium, yeasts and species of Enterobacteriaceae more resistant to antibiotics, after antibiotic treatment and hospital care. Investigation of recurrent outbreaks of Serratia marcescens sepsis in patients admitted to a neonatal intensive care unit showed different clones with each outbreak. Multiple hygiene interventions and revision of antibiotic strategy subsequently obviated recurrent outbreaks of sepsis, but spread of S. marcescens was not reduced until compliance with basic hygiene guidelines remained stable above 80%. We also found that low gestational age at birth, ventilator treatment and central venous or umbilical catheters are independent risk factors for late onset sepsis. Investigation of the faecal microbiota in patients with acute appendicitis or diverticulitis revealed that disturbance of the faecal microbiota already existed on admission, with higher numbers of Enterobacteriaceae and less Bacteroides, Faecalibacterium, Ruminococcus and Prevotella prior to antibiotic treatment and hospitalisation, than the control population. After treatment and hospitalisation diversity increased significantly in the diverticulitis group, approaching the healthy controls in composition.
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| 15. |
- Scheer, Vendela, 1967-
(author)
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Perioperative Strategies to Prevent Surgical Site Infection After Shoulder Surgery
- 2022
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Doctoral thesis (other academic/artistic)abstract
- In Sweden, about 18 000 patients undergo shoulder surgery each year. The current surgical site infection (SSI) rate after planned shoulder surgery is 0,3-5 %, which means that approximately 300 people are affected each year in Sweden. Treatment of deep SSIs always involves at least one reoperation followed by long-lasting treatment with antibiotics. In addition to pain and reduced mobility, an SSI can also have a negative effect on mental health. It is not possible to pinpoint exactly what causes an SSI. However, in today´s modern operating theatres with ultra clean air, tightly woven gowns, and surgical practice that strictly adheres to aseptic guidelines, SSIs after orthopaedic surgery are predominately caused by bacteria from the patient’s skin.The aim of this thesis was to evaluate perioperative strategies to prevent surgical site infection after shoulder surgery, focusing on bacterial burden on the skin. Cutibacterium acnes (C. acnes), a skin commensal, thrives in the sebaceous glands and causes most infections after shoulder surgery. Despite strict standardised preoperative preparation with 0.5% chlorhexidine solution in 70% ethanol, studies have shown that C. acnes are only partially eradicated. Topical treatment with benzoyl peroxide (BPO) over several months has been used to treat acne vulgaris for more than 50 years.In two randomised studies, we compared prophylactic topical treatment with BPO (applied five times over a period of 48 hours before surgery), with a control group with no BPO treatment. In the BPO group, the burden of C. acnes prior to incision and at the end of the surgery decreased significantly.When studying the effects of skin preparation, the technique and method used to capture the microbiome while maintaining the skin’s barrier, is crucial. In a pilot study, we developed a novel Pencil Eraser Swab-technique (PES) and compared this with two established swab techniques. The PES-technique was found to be significantly better, both in terms of sensitivity in detecting C. acnes and in quantification of viable bacteria.Following closure of a surgical incision, the wound is re-epithelialised within 24-72 hours. Choice of dressing is usually a question of personal preference and tradition rather than evidence based. The degree of colonisation of bacteria beneath wound dressings with different occlusive properties is not known. To investigate this, we compared three wound dressings of varying permeability on healthy skin. After 48 hours we found that recolonisation of bacteria was significantly higher beneath the semipermeable and occlusive wound dressings, than beneath the airy (gauze) dressing.Perioperative reduction of the bacterial burden on the skin is important in the fight against surgical site infection. A reliable technique to capture bacteria is essential when evaluating different methods.
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| 16. |
- Tevell, Staffan, 1975-
(author)
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Staphylococcal prosthetic joint infections : similar, but still different
- 2019
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Doctoral thesis (other academic/artistic)abstract
- Staphylococci constitute a major part of our commensal flora but are also the most common bacteria causing prosthetic joint infections (PJIs), a dreaded complication of arthroplasty surgery. However, not all staphylococci are the same. The virulent Staphylococcus aureus has the ability to cause severe disease such as bacteremia and infective endocarditis in previously healthy people, while the coagulase-negative staphylococci Staphylococcus epidermidis and Staphylococcus capitis rarely act as pathogens unless the patient is immunocompromised or has an implanted medical device, such as a prosthetic joint. This thesis accordingly explores similarities and differences between these three staphylococci in PJIs.S. capitis can cause early postinterventional and chronic PJIs, a finding that has not previously been described. Furthermore, its nosocomial NRCS-A outbreak sublineage, recently observed in neonatal intensive care units, is also present in adult PJIs. When comparing nasal and PJI isolates, the patterns differed between staphylococcal species. In S. capitis, the commensal and infecting strains were separated phylogenetically, while they clustered together for S. aureus. This may indicate diverse reservoirs and acquisition routes in PJIs caused by different staphylococcal species.Outcomes in early postinterventional PJIs were similar in S. capitis and S. aureus infections, with 70–80% achieving clinical cure. In S. aureus infections, no virulence genes were significantly associated with outcome. Although multidrug resistance (MDR) was rare in S. aureus, inability to use biofilm-active antibiotics was a risk factor for failure. However, in S. epidermidis and in the NRCS-A sublineage of S. capitis, MDR and glycopeptide heteroresistance were widespread, highlighting the challenge of antibiotic resistance in the treatment of PJIs.
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| 17. |
- Thunberg, Ulrica, 1967-
(author)
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Aspects of Staphylococcus aureus in Chronic Rhinosinusitis
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Chronic rhinosinusitis (CRS) affects about 10% of the European population, and is considered a great scourge. Its cause is not clear. Findings of Staphylococcus aureus in the maxillary sinus are common in CRS patients, but are usually regarded as insignificant due to the bacterium’s attribute as a commensal elsewhere. S. aureus has the ability to cause both mild disease and serious conditions, due to its wide armoury of secreted components such as staphylococcal enterotoxins and cell-surface-associated virulence components. This thesis focuses on the clinical features and importance of S. aureus in CRS, including a long-term perspective on the disease, through studying a cohort of CRS patients. S. aureus was found to be highly prevalent in the maxillary sinus and nares of CRS patients, which might indicate an impact on the disease. A sheltered sampling technique for maxillary sinus culture reduced the contamination rate but did not significantly improve the diagnostic reliability. Whole genome sequencing showed that 95% of paired S. aureus isolates collected simultaneously from the nares and maxillary sinus were from identical lineages, indicating colonization of the maxillary sinus from the nares as one joint milieu. A decade-long persistence of S. aureus in the nares and maxillary sinus was established in 20% of CRS patients. The vast majority of S. aureus isolates were susceptible to all tested antibiotics, including the strains that had persisted for a decade. No significant differences in the prevalence of gene determinants were seen for selected virulence factors and MSCRAMMs in S. aureus isolates sampled from CRS patients and healthy controls. The overall alterations of anti-staphylococcal antibodies over time showed great variability and minor support for an impact of S. aureus on CRS. At the long-term follow-up, symptoms were generally reduced and VAS quality of life in terms of fatigue was improved. The subgroup of CRS patients without nasal polyposis had a greater chance of symptom relief than their counterparts with nasal polyposis in this longterm perspective. There was no correlation between severity of symptoms for CRS patients and S. aureus growth in the maxillary sinus to support a role for S. aureus in CRS.
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| 18. |
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| 19. |
- Wistrand, Camilla, 1970-
(author)
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Swedish operating room nurses preventive interventions to reduce bacterial growth, surgical site infections, and increase comfort in patients undergoing surgery
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Surgical site infection is a major postoperative complication that causes patient suffering and is costly for society. The general aim of this thesis was to test and describe interventions performed by operating room (OR) nurses to prevent bacterial growth in surgical patients, with the intent to prevent surgical site infections (SSIs) whilst increase patients comfort.In studies I and II, 220 pacemaker patients were tested to compare pre-heated skin disinfection with room-temperature skin disinfection regard-ing bacterial growth, skin temperature and patient experience. Preheated skin disinfection was not less effective compared to room-temperature skin disinfection in reducing bacterial growth after skin disinfection and there were no differences regarding SSIs three month postoperatively. Preheated skin disinfection reduces skin heat loss and was perceived as more pleas-ant compared to room-temperature skin disinfection.In study III, 12 OR nurses were examined regarding bacterial growth on their hands and at the sterile glove cuff end after surgical hand disinfec-tion and again after wearing sterile surgical gloves during surgery. They were compared with a control group of 13 non-health care workers. OR nurses’ hands had higher amounts of bacterial growth at two of three culture sites after surgical hand disinfection compared with the control group, and the bacterial growth increased in both groups with time during surgery. There seems to be a risk of bacterial growth at the glove cuff end during surgery, involving the same type of bacteria as isolated from the hands.In study IV, 890 OR nurses answered an online questionnaire describ-ing OR nurses interventions guided by national guidelines to reduce SSIs, such as preparation of the patient skin, patient temperature, and OR ma-terials used. The proportion of the OR nurses who complied with the national guidelines preventive interventions was high: skin disinfection solution (93.5%), drapes (97.4%) and gowns (83.8%), and double gloves (73%). However, when guidelines were lacking the interventions differed.
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| 20. |
- Berglund, Carolina, 1980-
(author)
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Molecular epidemiology of methicillin-resistant staphylococcus aureus : epidemiological aspects of MRSA and the dissemination in the community and in hospitals
- 2008
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Doctoral thesis (other academic/artistic)abstract
- Methicillin-resistenta Staphylococcus aureus (MRSA) som bär på genen mecA, har förekommit och spridit sig över hela världen, främst i sjukhusmiljö, och orsakat utbrott av vårdrelaterade (så kallade nosokomiala) infektioner. Dessa infektioner kan inte behandlas med stafylokock-penicilliner och MRSA-bakterierna är ofta resistenta även mot flera andra grupper av antibiotika vilket medför att infektionerna ofta är påtagligt svårbehandlade. Under senare år har emellertid allt fler fall beskrivits av samhällsförvärvad MRSA infektion, det vill säga uppträdande av MRSA hos personer som tidigare ej har haft kontakt med sjukhusvård eller behandlats med antibiotika. Det har länge varit oklart om de samhällsförvärvade MRSA [community-acquired (CA-MRSA)] representerar spridning av bakterier från sjukhusmiljön ut till samhället eller om dessa MRSA är spontant uppträdande. Många av dessa stammar har dessutom visat sig bära på sjukdomsrelaterade gener som vanligen inte återfinns hos S. aureus, t.ex. Panton Valentine leukocidin (PVL) som associeras med hudinfektioner och allvarlig lunginflammation med hög dödlighet hos unga och annars friska individer. Denna avhandling beskriver den molekylära epidemiologin hos MRSA med fokus på samhällsförvärvade MRSA som utgjorde mer än hälften av samtliga fall av MRSA i Örebro län och som dessutom ofta producerade PVL toxinet, vars funktion vidare analyserades i detalj. Undersökning av ursprung och släktskap hos samtliga MRSA som isolerats i Örebro län, samt karaktärisering av det genetiskt element som kallas staphylococcal cassette chromosome mec (SCCmec) vilket innehåller genen mecA och ibland även andra resistensgener, visade att CA-MRSA inte är relaterade till de nosokomiala MRSA, och att dessa har uppstått oberoende av varandra. Flertalet MRSA visade sig dessutom bära på SCCmec, och resistensmekanismer, som tidigare inte beskrivits. Troligen har dessa MRSA uppstått genom ett genetiskt utbyte av SCCmec mellan methicillin-resistenta koagulas-negativa stafylokocker (MR-KNS), som utgör huvudparten av normalfloran på huden, och methicillin-känsliga S. aureus som därvid erhåller genen mecA och resistensmekanismer mot samtliga stafylokockantibiotika. I den här avhandlingen framläggs bevis för att ett sådant genetiskt utbyte har skett på Barnkliniken på Universitetssjukhuset i Örebro i slutet på 1990-talet, vilket resulterade i uppkomsten av en ny klon av MRSA som därefter orsakade ett allvarligt utbrott. Kartläggning av DNA-sekvensen hos flertalet unika SCCmec från svenska MRSA gav dessutom en bättre förståelse för hur resistens uppkommer och sprider sig, samt mekanismerna bakom detta. Dessa nya kunskaper kan bidra till en förbättrad diagnostik av MRSA. Detta är framför allt av stor betydelse eftersom nya effektiva kloner av MRSA verkar kunna uppstå ute i samhället med potential att orsaka svårbehandlade infektioner men även att sprida sig bland den friska befolkningen.
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| 21. |
- Cajander, Sara, 1980-
(author)
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Dynamics of Human Leukocyte Antigen-D Related expression in bacteremic sepsis
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Monocytic human leukocyte antigen-D related (mHLA-DR) expression determined by flow cytometry has been suggested as a biomarker of sepsisinduced immunosuppression.In order to facilitate use of HLA-DR in clinical practice, a quantitative real-time PCR technique measuring HLA-DR at the transcription level was developed and evalutated. Levels of HLA-DR mRNA correlated to mHLADR expression and were robustly measured, with high reproducibility, during the course of infection. Dynamics of mHLA-DR expression was studied during the first weeks of bloodstream infection (BSI) and was found to be dependent on the bacterial etiology of BSI. Moreover, mHLA-DR was shown to be inversely related to markers of inflammation. In patients with unfavourable outcome, sustained high C-reactive protein level and high neutrophil count were demonstrated along with low mHLA-DR expression and low lymphocyte count. This supports the theory of sustained inflammation in sepsis-induced immunosuppression. The association between mHLA-DR and bacterial etiology may be linked to the clinical trajectory via differences in ability to cause intractable infection. Staphylococcus aureus was the dominating etiology among cases with unfavourable outcome. With focus on patients with S. aureus BSI, those with complicated S. aureus BSI were found to have lower HLA-DR mRNA expression during the first week than those with uncomplicated S. aureus BSI. If these results can be confirmed in a larger cohort, HLA-DR measurement could possibly become an additional tool for early identification of patients who require further investigation to clear infectious foci and achieve source control.In conclusion, PCR-based measurement of HLA-DR is a promising method for measurements of the immune state in BSI, but needs further evaluation in the intensive care unit setting to define the predictive and prognostic value for deleterious immunosuppression. The etiology of infection should be taken into consideration in future studies of translational immunology in sepsis.
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| 22. |
- Luhr, Robert, et al.
(author)
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Trends in sepsis mortality over time in randomised sepsis trials : a systematic literature review and meta-analysis of mortality in the control arm, 2002-2016
- 2019
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In: Critical Care. - : BMC. - 1364-8535 .- 1466-609X. ; 23
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Research review (peer-reviewed)abstract
- Background: Epidemiologic data have shown an increasing incidence and declining mortality rate in sepsis. However, confounding effects due to differences in disease classification might have contributed to these trends.To assess if a declining mortality over time could be supported by data derived from high-quality prospective studies, we performed a meta-analysis using data from randomised controlled trials (RCTs) on sepsis. The primary aim was to assess whether the mortality in sepsis trials has changed over time. The secondary aim was to investigate how many of the included trials could show efficacy of the studied intervention regarding 28-day mortality.Methods: We searched PubMed for RCTs enrolling patients with severe sepsis and septic shock, published between 2002 and 2016. The included trials were assessed for quality and sorted by date of first inclusion. A meta-analysis was performed to synthesise data from the individual sepsis trials.Results: Of 418 eligible articles, 44 RCTs on sepsis were included in the analysis, enrolling 13,315 patients in the usual care arm between 1991 and 2013. In this time period, mortality decreased by 0.42% annually (p=0.04) to give a total decline of 9.24%. In subgroup analyses with adjustments for APACHE II, SAPS II and SOFA scores, the observed time trend was not significant (p=0.45, 0.23 and 0.98 respectively). Only four of the included trials showed any efficacy with regard to mortality.Conclusions: Data from RCTs show a declining trend in 28-day mortality in severe sepsis and septic shock patients during the years from 1991 to 2013. However, when controlling for severity at study inclusion, there was no significant change in mortality over time. The number of trials presenting new treatment options was low.Trial registration: PROSPERO CRD42018091100. Registered 27 August 2018.
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| 23. |
- Thunberg, Ulrica, 1967-, et al.
(author)
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Anti-Staphylococcal humoral immune response in patients with chronic rhinosinusitis
- 2019
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In: Rhinology Online. - : European Rhinologic Society. - 2589-5613. ; 2, s. 50-58
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Journal article (peer-reviewed)abstract
- Background: Staphylococcus aureus (S. aureus) can behave both as a harmless commensal and as a pathogen. Its significance in the pathogenesis of chronic rhinosinusitis (CRS) is not yet fully understood. This study aimed to determine serum antibody re-sponses to specific staphylococcal antigens in patients with CRS and healthy controls, and to investigate the correlation between specific antibody response and severity of symptoms.Methodology: Serum samples from 39 patients with CRS and 56 healthy controls were analysed using a protein microarray to investigate the antibody response to S. aureus specific antigens, with a focus on immunoglobulin G (IgG) directed toward stap-hylococcal components accessible to the immune system. Holm-Bonferroni corrections were applied in all analyses. Information about growth of S. aureus in nares and maxillary sinus was taken from a previous study based on the same individuals. Clinical symptoms were assessed using a scoring system.Results: IgG antibody levels toward staphylococcal TSST-1 and LukF-PV were significantly higher in the CRS patient group com-pared to healthy controls, and levels of anti-TSST-1 antibodies were significantly higher in the CRS patient group with S. aureus in maxillary sinus than in controls. There were no correlations between the severity of symptoms and levels of serum anti-staphylo-coccal IgG antibody levels for LukF-PV and TSST-1.Conclusions: TSST-1 and LukF-PV could be interesting markers for future studies of the pathogenesis of CRS.
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| 24. |
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| 25. |
- Thunberg, Ulrica, et al.
(author)
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Long-Term Sinonasal Carriage of Staphylococcus aureus and Anti-Staphylococcal Humoral Immune Response in Patients with Chronic Rhinosinusitis
- 2021
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In: Microorganisms. - : MDPI. - 2076-2607. ; 9:2
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Journal article (peer-reviewed)abstract
- We investigated Staphylococcus aureus diversity, genetic factors, and humoral immune responses against antigens via genome analysis of S. aureus isolates from chronic rhinosinusitis (CRS) patients in a long-term follow-up. Of the 42 patients who provided S. aureus isolates and serum for a previous study, 34 could be included for follow-up after a decade. Clinical examinations were performed and bacterial samples were collected from the maxillary sinus and nares. S. aureus isolates were characterized by whole-genome sequencing, and specific anti-staphylococcal IgG in serum was determined using protein arrays. S. aureus was detected in the nares and/or maxillary sinus at both initial inclusion and follow-up in 15 of the 34 respondents (44%). Three of these (20%) had S. aureus isolates from the same genetic lineage as at inclusion. A low number of single-nucleotide polymorphisms (SNPs) were identified when comparing isolates from nares and maxillary sinus collected at the same time point. The overall change of antibody responses to staphylococcal antigens over time showed great variability, and no correlation was found between the presence of genes encoding antigens and the corresponding anti-staphylococcal IgG in serum; thus our findings did not support a role, in CRS, of the specific S. aureus antigens investigated.
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| 26. |
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| 27. |
- Widerström, Micael, 1958-
(author)
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Molecular epidemiology of coagulase-negative staphylococci in hospitals and in the community
- 2010
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Doctoral thesis (other academic/artistic)abstract
- Background Coagulase-negative staphylococci (CoNS) and in particular Staphylococcus epidermidis have emerged as major pathogens primarily causing nosocomial infections in patients with indwelling medical devices. These infections are often caused by multidrug-resistant strains of S. epidermidis (MDRSE). Other clinical entities due to CoNS are lower urinary tract infections (UTI) in women and native valve endocarditis. The purpose of this work was to investigate the frequency of antibiotic resistance and the molecular epidemiology of both hospital and community-associated isolates of S. epidermidis in order to examine if certain clones are related to MDRSE infections. Furthermore, we aimed to explore if specific clones of S. saprophyticus are associated with UTI in women. Methods A total of 359 hospital-associated methicillin-resistant isolates of CoNS obtained from 11 hospitals in northern Europe and 223 community-associated staphylococcal isolates were examined. Furthermore, 126 isolates of S. saprophyticus isolated from women with uncomplicated UTI from five different locations in northern Europe were analyzed. Pulsed-field gel electrophoresis (PFGE) was used for genotyping. Additionally, some of the S. epidermidis isolates were analyzed with multilocus sequence typing (MLST). Antibiotic susceptibility was determined for all isolates by the disc diffusion test. Results 293 of the 359 (82%) hospital-associated and 124 of the 223 (56%) community-associated isolates belonged to the species S. epidermidis. Among the hospital-associated S. epidermidis isolates, two dominating PFGE types (type A and B) were distinguished, comprising 78 (27%) and 51 (17%) isolates, respectively. Type A, which was detected in a Norwegian and eight Swedish hospitals, corresponded with a novel sequence type (ST215). Type B was discovered in a German, a Danish and seven Swedish hospitals and corresponded with ST2. In contrast, community-associated isolates of S. epidermidis were genetically extremely diverse with no predominating genotype, and showed a low rate of antibiotic resistance; only two (1.6%) methicillin-resistant strains were detected. Among 126 analyzed isolates of S. saprophyticus, 47 different PFGE profiles were identified. Several clusters of genetically highly related isolates were detected among isolates obtained from different locations and periods of time. Conclusion We have demonstrated the occurrence, persistence and potential dissemination of two multidrug-resistant S. epidermidis (MDRSE) genotypes, including a novel sequence type (ST215), within hospitals in northern Europe. Community-associated isolates of S. epidermidis showed a low rate of methicillin-resistance and were genetically heterogeneous. These results indicate that MDRSE by large are confined to the hospital setting in our region. Moreover, although the S. saprophyticus population was quite heterogeneous, indistinguishable isolates of S. saprophyticus causing lower UTI in women were identified in different countries 11 years apart, indicating the persistence and geographical spread of some clones of S. saprophyticus.
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