| 1. |
- Holmbom, Martin, 1984-
(författare)
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Clinical Impact of Bloodstream Infections – Characterization, Risk factors and Outcome
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bloodstream infection (blood poisoning) and antibiotic resistance are increasing worldwide, and already cause the loss of millions of human lives each year. According to the World Health Organisation (WHO), bloodstream infections (BSIs) represent 20% of global mortality on a par with cardiac infarct, stroke, and major trauma. BSI may occur when bacteria from a focus of infection gain access to the circulation (bacteraemia). BSIs are usually divided into two subclasses: community- and hospital-onset infections, since disease this involves different patient groups, types of bacteria, and reasons for infection. Compared to other countries, Sweden has been fortunate in having a relatively low death rate from BSI and low antibiotic resistance. However, as our lifestyle changes, the age of the population increases with more disease as a result, and as the healthcare system responds, death from infection and antibiotic resistance are on the increase. It is important that we recognise ”warning symptoms” if we are to manage BSIs correctly and initiate effective treatment. It is difficult to design individualised empirical treatment, so it is very important to be aware of risk factors for BSI and local resistance patterns, and to have an effective management programme. Bacterial resistance to antibiotics is an increasing problem, especially in bowel organisms that can cause infections that are very difficult to treat. In short, antibiotic resistance arises as a result of evolutionary processes where bacteria protect themselves by developing resistance genes. These genes can be exchanged between similar organisms or transmitted to others that in turn cause resistant infection. The use of antibiotics leads to an evolutionary/selection process leading to resistance in bacteria, both normal and pathogenic, enabling resistant organisms to survive, thrive, and go on to cause infection. Antibiotic resistance is a threat to global health. This thesis aims to increase our awareness of a large group of patients who suffer bloodstream infection. BSIs are increasing globally, and the death toll is high. Antibiotic resistance is an increasing threat to the health of the population, and we are inundated by alarming reports of resistance getting out of control. What is the situation in Sweden, and can we identify risk factors for BSI and mortality? In Study I, our aim was to study the incidence and mortality of BSI in Östergötland. To be able to do this, a large patient population stretching over several years was required. The study design was thus population-based in the form of an observational cohort study where all blood culture results from 2000 to 2013 were analysed, and evaluated from clinical data. A total of 109,938 results were analysed resulting in 11,480 BSIs. We saw that the incidence of BSI increased by 64% (mostly community-onset BSIs). We also saw that mortality increased by 45%. These results illustrate the importance of nationwide cooperation to combat the increasing problem of BSI and its mortality, and the establishment of a nationwide BSI register. The aim of Study II was to assess resistance development in Östergötland and its relationship to mortality. A total of 9,587 microorganisms were analysed between 2008 and 2016. We observed an increase in quinolone resistance (3.7-7.7%) and cephalosporin resistance (2.5-5.2%) amongst Enterobacteriaceae. We then looked at BSIs caused by multiresistant bacteria showing a total of 245 cases (2.6%); an increase of 300%. Despite this, we did not see an increased mortality in this group. There are several possible explanations for the increase in BSI mortality of which antibiotic resistance is a predominant factor globally. We were unable to show this in our study, even so mortality is increasing and is currently at a high level. In Study III we therefore analysed risk factors associated with death during a community-acquired BSI, focusing on preliminary prehospital and hospital management. In a retrospective case-control study on 195 deaths matched 1:1 regarding age, gender, and microorganism, with 195 survivors (controls). Results showed that many patients had contacted the primary healthcare system because of infection before they became severely ill, and that the strongest affectable risk factor for death was delay (>24h) between primary healthcare visit and admission to hospital. This shows the need for increased awareness in society and amongst the medical profession of those patients at risk and symptoms that should raise the alarm, leading to more rapid treatment. In Studies I and II we found an increase in both BSIs and mortality, we also saw an increase in antibiotic resistance and multiresistant bacteria, mainly ESBL-producing E. coli. On the other hand, we did not see any coupling between multiresistance and mortality in this Swedish population. E. coli is a gram-negative bacteria that causes most BSIs. Since E. coli is predominantly a urine tract pathogen, Study IV aimed to study BSIs caused by ESBL-producing E. coli originating from the urinary tract. We studied the prevalence of E. coli clones, resistance genes and risk factors, as well as any signs of increased mortality from ESBL-producing E. coli compared to sensitive E. coli. Our main finding was a surprisingly low mortality from ESBL-producing E. coli (3%). Most patients in the ESBL-producing E. coli group received inadequate antibiotic treatment for at least 48h, but we did not see any sign of increased mortality or risk for serious sepsis with circulatory failure in this group. This finding is interesting and opens up for new studies on virulence factors and immunological factors that govern the immune response to BSI. The implementation of cost-effective monitoring systems including clinical microbiological epidemiology and early identification of BSI, together with information campaigns aimed at the public as well as healthcare personnel regarding patients at risk and symptoms giving cause for alarm, should lead to a radical reduction in morbidity and mortality from BSI. This requires new diagnostic tools to individualise both antibiotic treatment and targeted management based on microorganism virulence factors. Modernisation of the medical journal system with algorithms aimed at early identification of risk patients and automated suggestions for empirical antibiotic treatment based on antibiotic resistance seen in previous cultures and local resistance patterns, would certainly improve management. Furthermore, new immunological tests showing the type of immunological reaction to a serious BSI will lead to individualised immunotherapy that, together with antibiotic treatment, will further improve patient care in this important group.
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| 2. |
- Ekdahl, Christer, 1962-
(författare)
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Infective Endocarditis : aspects of pathophysiology, epidemiology, management and prognosis
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Infective endocarditis (IE) is a rare but complex disease that is fatal if untreated. With a modern combination of antimicrobial therapy and heart valve surgery, mortality is still 10-20 %. The structure of the endocarditis vegetation impedes the penetration of phagocytic cells such as monocytes and granulocytes. This leads to high bacterial counts inside the vegetation and the need for long treatment courses with a combination of intravenously administered bactericidal antibiotics.The aim of this thesis was to study the changes in epidemiology, management, and mortality at our hospital between 1980 and 2001, and to identify prognostic factors associated with mortality. To assess the issue of referral bias, differences between referred episodes and episodes from our local community were studied. Additional aims were to study the occurrence of the pro-chemotactic cytokines IL-8 and TNF-α in heart valves and vegetations during the active phase of IE, and to study the effect of the glycopeptide antibiotic vancomycin in dense staphylococcal cultures in vitro. As it is a rare and complex disease, management of IE is usually complicated for non-specialists. For this reason a computerised decision support system for IE was developed and evaluated.Between 1980 and 2001, the occurrence of Staphylococcus aureus IE and the use of early heart valve surgery increased significantly, regardless of whether the episodes were referred or of local origin. Glycopeptide antibiotics, mainly vancomycin, were used more frequently, especially among referred patients. Referred patients were younger, predominantly male, had more complications, and received surgical treatment more often than patients from our local community. The reason for the lower frequency of female patients in the referral cohort cannot be explained by more comorbidity or fewer complications. The differences between referred and local episodes seen in our study highlight the need for assessment and adjustment for referral bias in IE studies (Paper I).In six patients who needed early heart valve surgery, the largest numbers of IL-8-containing cells, and the greatest amount of inflammation, were seen in patients with short preoperative antimicrobial treatment courses. No such relationships were seen with respect to TNF-α-containing cells. The IL-8-containing cells and the inflammatory cells were predominantly scattered in the heart valve stroma or in the margin of the vegetation (Paper II). The primary effect of IL-8 is to stimulate chemotaxis of polymorphonuclear neutrophil granulocytes. This indicates that there is no deficiency of IL-8 in the area close to the vegetation as a cause of the localised agranulocytosis often present inside the vegetation.Our study revealed a need for computerised decision support systems (DSSs) in the field of IE, but to be used in clinical practice these DSSs need be part of knowledge bases covering larger domains (Paper IV). Some of our initial ideas described in Paper III, especially the use of Internet technology and the combination of rule-based advice and explanatory hypertext, will probably be included in these knowledge bases.In vitro, there is a rapid reduction of free vancomycin in broth containing dense staphylococcal cultures. Consequently, there is a simultaneous increase in broth MICs, particularly in high inocula, which is not caused by a development of resistance (Paper V). These findings need further evaluation in vivo, but indicate that the dosing regimen of vancomycin is of particular importance in staphylococcal infections with dense inocula, e.g. infective endocarditis.Diabetes mellitus and moderate to severe heart failure were independent risk factors for 6-month mortality in left-sided, Duke definite IE episodes, regardless of referral or local origin of the episodes. Early heart valve surgery had a positive impact on the 6-month mortality in the referral cohort of episodes, which may be due to referral bias (Paper VI).
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| 3. |
- Lindqvist, Maria, 1983-
(författare)
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Epidemiological and molecular biological studies of multi-resistant methicillin-susceptible Staphylococcus aureus
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Antibiotic resistance is increasingly recognised as a major problem and threat. During the last decades Gram-positive bacteria in general, and methicillin-resistant Staphylococcus aureus (MRSA) in particular, have been in focus both concerning matters of antibiotic resistance and as pathogens causing health care-associated (nosocomial) infections. In contrast to MRSA, studies on clonal distribution of methicillin-susceptible S. aureus (MSSA) are scarce. However, interest in MSSA has increased since it was shown that MRSA emerges from susceptible backgrounds by acquisition of a staphylococcal cassette chromosome element, carrying the mecA gene encoding methicillin-resistance (SCCmec).In an outbreak investigation of MRSA in Östergötland County, Sweden, in 2005, a high incidence of MSSA isolates with concomitant resistance to erythromycin, clindamycin and tobramycin (ECT-R) was detected. Analysis showed that 91 % of the investigated isolates were genetically related (clonal). The ECT-R clone was divided into four different but closely related patterns with pulsed-field gel electrophoresis (PFGE), and was designated spa type t002. Whole genome sequencing revealed that the ECT-R clone carried a pseudo-SCC element estimated to be 12 kb in size, showing a resemblance of more than 99 % with the SCCmec type II element of MRSA strain N315 (New York/Japan clone). This suggested a probable derivation from a highly successful MRSA strain, which had partially excised its SCCmec. The clonal outbreak was concentrated in eight hospital departments and two primary care centres, all located in the city of Linköping. Despite a high exchange of patients with the hospitals in the neighbouring counties in southeast Sweden (Jönköping- and Kalmar County), the ECT-R clone seemed to be limited to Östergötland County. However, a tobramycin-resistant clone predominated by isolates of spa type t084 was found in all three counties in southeast Sweden, and in particular among newborns, suggesting inter-hospital transmission.The ECT-R clone has survived as an abundant MSSA clone for a decade in Östergötland County, which indicates an insufficiency in the maintenance of basic hygiene guidelines, and that the clone probably possesses mechanisms of virulence and transmission that are yet to be discovered.
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| 4. |
- Zarei, Maryam, et al.
(författare)
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Accuracy of gross tumour volume delineation with [68Ga]-PSMA-PET compared to histopathology for high-risk prostate cancer
- 2024
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Ingår i: Acta Oncologica. - : MJS Publishing, Medical Journals Sweden. - 0284-186X .- 1651-226X. ; 63, s. 503-510
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The delineation of intraprostatic lesions is vital for correct delivery of focal radiotherapy boost in patients with prostate cancer (PC). Errors in the delineation could translate into reduced tumour control and potentially increase the side effects. The purpose of this study is to compare PET-based delineation methods with histopathology.MATERIALS AND METHODS: The study population consisted of 15 patients with confirmed high-risk PC intended for prostatectomy. [68Ga]-PSMA-PET/MR was performed prior to surgery. Prostate lesions identified in histopathology were transferred to the in vivo [68Ga]-PSMA-PET/MR coordinate system. Four radiation oncologists manually delineated intraprostatic lesions based on PET data. Various semi-automatic segmentation methods were employed, including absolute and relative thresholds, adaptive threshold, and multi-level Otsu threshold.RESULTS: The gross tumour volumes (GTVs) delineated by the oncologists showed a moderate level of interobserver agreement with Dice similarity coefficient (DSC) of 0.68. In comparison with histopathology, manual delineations exhibited the highest median DSC and the lowest false discovery rate (FDR) among all approaches. Among semi-automatic approaches, GTVs generated using standardized uptake value (SUV) thresholds above 4 (SUV > 4) demonstrated the highest median DSC (0.41), with 0.51 median lesion coverage ratio, FDR of 0.66 and the 95th percentile of the Hausdorff distance (HD95%) of 8.22 mm.INTERPRETATION: Manual delineations showed a moderate level of interobserver agreement. Compared to histopathology, manual delineations and SUV > 4 exhibited the highest DSC and the lowest HD95% values. The methods that resulted in a high lesion coverage were associated with a large overestimation of the size of the lesions.
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