Evaluering av immunmarkörer och antibiotikabehandling av IVA vårdade sepsispatienter.
Evaluering av immunmarkörer och antibiotikabehandling av IVA vårdade sepsispatienter.
Project number : 241381
Created by: Jan Källman, 2018-01-11
Last revised by: Jan Källman, 2019-11-04
Project created in: FoU Region Örebro län

PublishedPublished
2019-11-04
Rekrytering/datainsamling pågår

Titel och sammanfattning

Populärvetenskaplig sammanfattning

Tidig diagnos och insättning av adekvat behandling vid sepsis är associerad med förbättrat kliniskt utfall. Tidig upptäckt av aktuell patogen ökar chansen att påbörja en riktad behandling och minskar felaktig användning av antibiotika.

Gold-standard för diagnostik av bakteriella infektioner i blodet (sepsis) är blododling. Den är associerad med hög specificitet men låg sensitivitet och lång tidsåtgång innan svar.  Studier har visat att 25-50 % av alla patienter med misstänkt septisk chock på IVA har negativa blododlingar trots en i övrigt förenlig bild med diagnosen.  Tidigare studier har visat att farmakokinetiken för beta-laktamantibiotika varierar stort mellan olika IVA- patienter samt att det kan variera  hos samma patient. Vid septisk chock förändras kärlens permeabilitet som ett led i en omfattande inflammatorisk kaskad. Det leder till att distributionsvolymen är större än normalt. .

Nyare metoder med Polymerase Chain reaction (PCR) har utvecklats. Dessa kan upptäcka mikroorganismer i låga kvantiteter, ger möjlighet till snabba svar men är otillräckligt utvärderade. Denna metod ger möjlighet att mäta bakteriellt-DNA i blodet hos patienter med sepsis och är förhoppningsvis en lovande metod för att utvärdera behandlingseffekten av givet antibiotika.

Infektionskliniken, ANIVA-kliniken och laboratoriemedicinska kliniken, planerar nu en prospektiv observationsstudie på patienter med kliniska tecken på sepsis som inläggs på Intensivvårdsavdelningen, USÖ.

Sammanfattning på engelska

Septic syndrome caused by bloodstream infections represents a major healthcare problem worldwide and is the leading cause of mortality in the non-cardiac intensive care unit(ICU). Despite ongoing research efforts in sepsis, the mortality remain high.
In severe sepsis, the time to adequate antibiotic therapy has been clearly linked to survival. An indiscriminate use of antibiotics inevitably leads to bacterial resistance and unacceptable adverse events. Thus, there is a great and unmet medical need to develop novel diagnostic instruments that could inform the clinician about who would need antibiotics and who would not benefit from it.
Early identification of the causal microorganism and the inflammatory status of the patients would improve decisions about treatments and reduce administration of antibiotics.

Today the gold-standard for diagnosis of bloodstream infections (BSI) is bloodculture followed by identification of species and resistance pattern by standard laboratory procedures. This procedure is associated with a high specifity but also with a low sensitivity. Probable reasons for a negative blood culture despite a strong clinical suspicion, could be insufficient bloodvolume in the culture bottles or antibiotic treatment prior to bloodsampling with a subsequent failure of the bacteria to grow in the bottles.

In recent years Polymerase Chain reaction (PCR) has been proposed as a method to determine bacterial DNA based on amplification of specific subunits (16S and 18S) of bacterial ribosomal RNA. PCR require very small amount of DNA. Another advantage is the possibility to determine bacterial species from non-viable bacteria by multiplex PCRs. However most of those multiplex PCRs have shown a limited sensitivity even though they also found clinical relevant pathogens that are missing by the blood culturing . Another limitation is that multiplex-PCR only detects around 95% of all sepsis-causing pathogens. In a recent published study the author conclude that a tested multiplex PCR “on whole blood specimens in adjunct to current culture-based methods provides a clinical add-on value”. The future role of PCR and other molecular techniques in a clinical setting need further evaluation.

A new method that could improve the diagnostics of sepsis and also have the possibility to follow the bacterial DNA load during antibiotic treatment is Droplet Digital PCR; ddPCR. This ddPCR enable an absolute quantification of the sepsis causing pathogen targeting 16S rDNA, a gene that is present in many copies per pathogen.
To further be able to identify the sepsis causing pathogen a shotgun metagenomics approach can be used were all DNA in a sample (both bacterial and human) is massively parallel sequenced using Next Generation Sequencing (NGS) and the sepsis causing pathogen can be both detected and quantified trough advanced bioinformatic data analysis.

During the septic course the patient go from vasodilation to vascular leakage and finally a hypotension. This together with added i.v fluid treatment will increase the distribution volume with a altered pharmakokinetic state for added antibiotics. Furthermore, most ICU patients has a decreased kidney function. Therefore it´s hard to anticipate the optimal antibiotic dose for the septic patient.

Aim of the study

Examine if there is a relation between clearence of bacterial DNA and clinical outcome in the ICU setting ( ICU mortality, time in the ICU, change in SOFA score).
Secondly to study if there is a correlation between concentration of beta-laktam antibiotics ( e.g penicillin) and clearence of bacterial DNA.

Method

This is a prospective observational study.

Patient setting
Inclusion: Suspected community aquired sepsis in patients at the emergency care unit and infectious departments at the university hospital Örebro with a need of intensive care treatment at the ICU. After admittance to the ICU, inclusion will be performed within one hour. Clinical assessment is performed at inclusion and every twentyfour hours with SOFA score, cystatin C, kreatinin, fluid balance. Sampling will be permitted according to schedule. CRP, monocytes,leukocytes and lymphocytes is collected according to standard clinical procedure.

Patients with a positive blood culture is enrolled in the study group. Analysis will be performed, after informed consence from patient or ancesters within two weeks after inclusion. Patients with negative bloodculture will be the control group after informed consence from patient or ancesters.
Exclusion: Plasmapheres. Dismissed to another department within 48 hours.
Studystart: In total, 60 patients are included, divided to 30 patients in the study group and 30 patients in the control group. Analysis will be performed with: ddPCR of 16S, determination of antibiotic concentration and shotgun metagenomic determination

Projektspecifik information

Ämnesord

checked Anestesi och intensivvård
checked Infektionsmedicin
checked Klinisk laboratoriemedicin


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Studietyp

Observationsstudie

Randomiserad studie

Nej

Diagnoskod för huvuddiagnos

A30-A49 Andra bakteriesjukdomar

Multicenterstudie

Nej

Etikprövningsmyndighetens diarienummer

2018/121

ClinicalTrials.gov

Ansökan pågår

Biobanksavtal

Ansökan pågår

Inklusionsstatus

 Planerat antalAntal tillfrågadeScreen-failureAntal randominserade
n=60   

Vetenskaplig sammanfattning

vg se engelsk sammanfattning

Involverade parter

Arbetsplats

Added workplaces

Regioner - Region Örebro Län - Hälso- och sjukvård - Område medicin och rehabilitering - Infektionskliniken workplace verified by Region Örebro län on 2018-06-14
Regioner - Region Örebro Län - Hälso- och sjukvård - Område thorax kärl diagnostik - Laboratoriemedicinska kliniken workplace verified by Region Örebro län on 2018-06-14
Regioner - Region Örebro Län - Hälso- och sjukvård - Område opererande och onkologi - Anestesi- och intensivvårdskliniken workplace verified by Region Örebro län on 2018-06-14

Projektägare är huvudprövare eller ansvarig forskare

checked Ja


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Medarbetare i projektet

johanna savilampi
specialistläkare, Anestesi- och intensivvårdskliniken

Roll i projektet

checked Medarbetare
Karolina Prytz
Specialistläkare, Barn - och ungdomskliniken

Roll i projektet

checked Medarbetare
Martin Sundqvist
Leg. läkare, Laboratoriemedicinska kliniken

Roll i projektet

checked Medarbetare
Paula Mölling
Molekylärbiolog, docent, Laboratoriemedicinska kliniken

Roll i projektet

checked Medarbetare
Hans Hjelmqvist
Professor/Överläkare, Medicinska vetenskaper, Anestesi- och intensivvårdskliniken

Roll i projektet

checked Medarbetare

Evaluering av immunmarkörer och antibiotikabehandling av IVA vårdade sepsispatienter., from FoU Region Örebro län
http://www.researchweb.org/is/en/fourol/project/241381