BACKGROUND: Infection of the prostate gland following biopsy, usually with Escherichia coli, is a common complication, despite the use of antimicrobial prophylaxis. A fluoroquinolone (FQ) is commonly prescribed as prophylaxis. Worryingly, the rate of fluoroquinolone-resistant (FQ-R) E. coli species has been shown to be increasing. OBJECTIVE: This study aimed to identify risk factors associated with infection after transrectal ultrasound-guided prostate biopsy (TRUS-Bx). METHODS: This was a prospective study on patients undergoing TRUS-Bx in southeast Sweden. Prebiopsy rectal and urine cultures were obtained, and antimicrobial susceptibility and risk-group stratification were determined. Multivariate analyses were performed to identify independent risk factors for post-biopsy urinary tract infection (UTI) and FQ-R E. coli in the rectal flora. RESULTS: In all, 283 patients were included, of whom 18 (6.4%) developed post-TRUS-Bx UTIs. Of these, 10 (3.5%) had an UTI without systemic inflammatory response syndrome (SIRS) and 8 (2.8%) had a UTI with SIRS. Being in the medium- or high-risk groups of infectious complications was not an independent risk factor for UTI with SIRS after TRUS-Bx, but low-level FQ-resistance (minimum inhibitory concentration (MIC): 0.125-0.25 mg/L) or FQ-resistance (MIC > 0.5 mg/L) among E. coli in the faecal flora was. Risk for SIRS increased in parallel with increasing degrees of FQ-resistance. Significant risk factor for harbouring FQ-R E.coli was travelling outside Europe within the previous 12 months. CONCLUSION: The predominant risk factor for UTI with SIRS after TRUS-Bx was FQ-R E. coli among the faecal flora. The difficulty in identifying this type of risk factor demonstrates a need for studies on the development of a general approach either with rectal swab culture for targeted prophylaxis, or prior rectal preparation with a bactericidal agent such as povidone-iodine before TRUS-Bx to reduce the risk of FQ-R E. coli-related infection.

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.  

Infektioner i blodbanan och antibiotikaresistens ökar globalt och leder redan nu till att miljontals människor dör årligen och enligt World Health Organization (WHO) står blodförgiftning för ca 20% av den globala dödligheten vilket kan t.ex. jämföras med akut hjärtinfarkt, akut stroke och allvarliga trauman. Blodförgiftning kan uppstå när bakterier från en infektionshärd når blodbanan och kallas då för bakteriemi. Blodinfektioner undergrupperas ofta till samhällsförvärvade eller sjukhus/sjukvårdsrelaterade infektioner då det ofta rör sig om olika patientgrupper, bakterier och orsak till infektionen. Sverige har i relation till många andra länder varit förskonade med förhållandevis låg dödlighet i blodinfektioner och antibiotikaresistens. Dock i takt med en förändrad livsstil och en population med stigande ålder med fler underliggande sjukdomar och en förändrad sjukvård ökar både dödligheten och antibiotikaresistens i Sverige. Vid blodförgiftning är det viktigt att snabbt identifiera  ”alarmsymptom” för korrekt omhändertagande och effektiva behandlingsåtgärder. Att empiriskt skräddarsy effektiva åtgärder är svårt varför det är viktigt att känna till riskfaktorer för blodinfektioner, lokal antibiotikaresistensproblematik, och identifiera effektiva behandlingsåtgärder. Antibiotikaresistenta bakterier är ett ökat problem och i synnerhet hos tarmbakterier som kan bli mycket svåra att behandla. Förenklat kan man beskriva antibiotikaresistens som en evolutionär process där bakterien skyddar sig själv genom att utveckla resistensgener. Resistensgener kan överföras mellan bakterier som vidare kan orsaka infektion. Vid antibiotikaanvändning utsätts bakterier (även normal bakterieflora) för ett  ”selektions-/ evolutionärt tryck” vilket ger resistenta bakterier en överlevnadsfördel, varpå det kan öka i antal och därmed orsaka infektion. Antibiotikaresistenta bakterier är ett globalt hot mot folkhälsan.   

Denna avhandling har till syfte att synliggöra en stor patientgrupp som drabbas av blodinfektioner. Blodinfektioner ökar globalt med hög dödlighet. Antibiotikaresistens är ett ökat hot mot folkhälsa och larmrapporter om skenande antibiotikaresistens sköljer över oss. Hur ser denna utveckling ut i Sverige och kan vi identifiera riskfaktorer för blodinfektion och dödlighet.    

I Studie I vill vi fram för allt studera förekomst, dödlighet och utveckling av blodinfektioner i Östergötland för att kunna göra det behövs ett stort patientunderlag som sträcker sig över flera år. Vår studiedesign blev därför en populationsbaserad studie i form av en observation kohortstudie där samtliga blododlingar tagna mellan 2000 och 2013 analyserades och värderades utifrån kliniska data. Totalt analyserades 109,983 blododlingar som resulterade i 11,480 blodinfektioner och vi kunde då se att blodinfektionerna har ökat med 64% och det var fram för allt de samhällsförvärvade infektionerna som ökade. Vi kunde även se att dödligheten har ökat (45%) men även samsjukligheten i populationen. Resultatet understryker vikten av nationellt samordnat arbete för att motverka utvecklingen av ökat antal blodinfektioner och dödlighet samt utformning av övervakningsstrategier.   

Målsättningen med Studie II var att undersöka resistensutveckling i Östergötland och relatera till dödlighet. Totalt analyserades 9,587 mikroorganismer mellan 2008-2016 där vi bland annat noterade en ökad resistensutveckling av kinolonresistens (3.7 till 7.7%) och cefalosporinresistens (2.5 till 5.2%) hos Enterobacteriaceae. Vidare undergrupperades blodinfektionerna till de infektioner som orsakades av en multiresistent bakterie, totalt 245 stycken (2.6%). Totalt ökade dessa bakterier med 300%. Trots fler infektioner orsakade av multiresistenta bakterier kunde vi inte se att det hade någon avgörande betydelse för dödligheten.    

Det finns flera möjliga förklaringar till ökad mortalitet vid blodinfektioner, globalt är antibiotikaresistens en drivande faktor vilket vi inte kan se i våra studier, ändock ökar dödligheten och är på en hög nivå. I Studie III vill vi därför studera riskfaktorer kopplat till död vid samtidig blodinfektion, med fokus på den primära handläggningen både utanför och på sjukhus. Vilket undersöktes i en retrospektiv fall-kontroll studie med 195 fall (avlidna) matchade (1:1) avseende ålder, kön och mikroorganismer med 195 kontroller (överlevande). Resultatet visade på att många patienter har en infektionsrelaterad öppenvårdskontakt innan dom blir allvarligt sjuka och att den starkaste riskfaktorn för död var förlängd tid (>24 timmar) från öppenvårdskontakt till inläggning på sjukhus. Resultatet visar ökat behov av kunskap i allmänhet men även inom den medicinska professionen kring riskpatienter och symtom som bör föranleda ett snabbare omhändertagande.   

I Studie I och Studie II beskrivs en ökning av både blodinfektioner och död, vi vet även att antibiotikaresistens och multiresistenta bakterier, fram för allt ESBL E. coli ökar. Dock kunde vi inte se att multiresistens per se leder till ökad dödlighet i en svensk population.  E. coli är en gramnegativ bakterie som är den vanligaste förekommande bakterien vid blodinfektioner. E. coli är en primär urinvägspatogen varför vi i Studie IV vill studera ESBL E. coli med ursprung från urinvägarna. Både avseende förekomst av E. coli klon, resistensgener, riskfaktorer men även studera om det föreligger en ökad dödlighet vid ESBL E. coli infektion jämfört med känsliga E. coli. Huvudfyndet var låg dödlighet vid ESBL E. coli infektion (3%). Majoriteten av patienterna i ESBL E. coli gruppen fick inadekvat antibiotika i nästan två dygn, dock kunde vi inte påvisa någon ökad dödlighet eller risk att utveckla allvarlig blodförgiftning med cirkulationspåverkan i denna grupp. Fyndet är intressant och öppnar upp för nya intressanta studier kring virulensfaktorer och immunologiska faktorer som styr det inflammatoriska svaret.   

Implementering av kostnadseffektiva övervakningssystem med klinisk mikrobiologisk epidemiologi, tidig identifikation av blodinfektioner tillsammans med informationskampanjer till allmänheten och hälso- och sjukvårdspersonal avseende symptom och riskpatienter skulle leda till att vi kan reducera morbiditet och dödlighet vid blodinfektioner. Därutöver behövs nya diagnostiska verktyg både för att skräddarsy antibiotikabehandlingen men även för individualiserad behandling t.ex. genom att målinriktad behandling mot mikroorganismens virulensfaktorer. Vidare kan modernisering av journalsystemen med algoritmer för tidig identifikation av riskpatienter och generering av förslag till empirisk antibiotikabehandling utifrån antibiotikaresistens från tidigare odlingar men även utifrån aktuell resistenssituation lokalt förbättra handläggningen. Adderas därutöver nya immunologiska tester för att påvisa typ av immunologisk reaktion vid allvarlig blodinfektion kan individualiserad immunoterapi tillsammans med antibiotikabehandling ytterligare förbättra vården kring denna patientgrupp.   

Objectives The aim of this study was to identify prehospital and early hospital risk factors associated with 30-day mortality in patients with blood culture-confirmed community-acquired bloodstream infection (CA-BSI) in Sweden.

Methods A retrospective case–control study of 1624 patients with CA-BSI (2015–2016), 195 non-survivors satisfying the inclusion criteria were matched 1:1 with 195 survivors for age, gender and microorganism. All forms of contact with a healthcare provider for symptoms of infection within 7 days prior CA-BSI episode were registered. Logistic regression was used to analyse risk factors for 30-day all-cause mortality.

Results Of the 390 patients, 61% (115 non-survivors and 121 survivors) sought prehospital contact. The median time from first prehospital contact till hospital admission was 13 hours (6–52) for non-survivors and 7 hours (3–24) for survivors (p<0.01). Several risk factors for 30-day all-cause mortality were identified: prehospital delay OR=1.26 (95% CI: 1.07 to 1.47), p<0.01; severity of illness (Sequential Organ Failure Assessment score) OR=1.60 (95% CI: 1.40 to 1.83), p<0.01; comorbidity score (updated Charlson Index) OR=1.13 (95% CI: 1.05 to 1.22), p<0.01 and inadequate empirical antimicrobial therapy OR=3.92 (95% CI: 1.64 to 9.33), p<0.01. In a multivariable model, prehospital delay >24 hours from first contact remained an important risk factor for 30-day all-cause mortality due to CA-BSI OR=6.17 (95% CI: 2.19 to 17.38), p<0.01.

Conclusion Prehospital delay and inappropriate empirical antibiotic therapy were found to be important risk factors for 30-day all-cause mortality associated with CA-BSI. Increased awareness and earlier detection of BSI in prehospital and early hospital care is critical for rapid initiation of adequate management and antibiotic treatment.All data relevant to the study are included in the article or uploaded as supplemental information.

Background: Antimicrobial resistance is an increasing concern in ICUs worldwide. Infection with an antibiotic resistant (ABR) strain of an organism is associated with greater mortality than infection with the non-resistant strain, but there are few data assessing whether being admitted to an intensive care unit (ICU) with high levels of antimicrobial resistance is associated with a worse outcome than being admitted to an ICU with low rates of resistance. The aim of this study was, therefore, to compare the characteristics of infections and antibiotic treatments and patient outcomes in patients admitted to ICUs in countries considered as having high levels of antibiotic resistance and those admitted to ICUs in countries considered as having low levels of antibiotic resistance. Methods: Data from the large, international EPIC II one-day point prevalence study on infections in patients hospitalized in ICUs were used. For the current study, we compared the data obtained from patients from two groups of countries: countries with reported MRSA rates of greater than= 25% (highABR: Greece, Israel, Italy, Malta, Portugal, Spain, and Turkey) and countries with MRSA rates of less than 5% (lowABR: Denmark, Finland, Netherlands, Norway, and Sweden). Results: On the study day, 1187/2204 (53.9%) patients in the HighABR ICUs were infected and 255/558 (45.7%) in the LowABR ICUs (P less than 0.01). Patients in the HighABR ICUs were more severely ill than those in the LowABR ICUs, as reflected by a higher SAPS II score (35.6 vs 32.7, P less than 0.05) and had longer median ICU (12 days vs 5 days) and hospital (24 days vs 16 days) lengths of stay. They also had higher crude ICU (20.0% vs 15.4%) and hospital (27.0% vs 21.5%) mortality rates (both P less than 0.05). However, after multivariable adjustment and matched pair analysis there were no differences in ICU or hospital mortality rates between High or LowABR ICU patients overall or among those with infections. Conclusions: Being hospitalized in an ICU in a region with high levels of antimicrobial resistance is not associated per se with a worse outcome.