Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000167460
Ethics application status
Approved
Date submitted
7/01/2016
Date registered
10/02/2016
Date last updated
10/10/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
Antibiotic Concentration in Critically ill intensive care unit (ICU) patients in Sweden
Scientific title
Antibiotic Concentration in Critically ill ICU-patients in Sweden (ACCIS)
Secondary ID [1] 288252 0
None
Universal Trial Number (UTN)
Trial acronym
ACCIS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Sepsis 297184 0
Septic shock 297185 0
Critical illness 297186 0
Condition category
Condition code
Infection 297405 297405 0 0
Other infectious diseases

Intervention/exposure
Study type
Observational
Patient registry
True
Target follow-up duration
3
Target follow-up type
Days
Description of intervention(s) / exposure
Concentrations of cefotaxime, piperacillin-tazobactam, meropenem, ciprofloxacin, gentamicin, tobramycin, amikacin and vancomycin in the plasma will be assessed upon start of antibiotic therapy, in intensive care patients with suspected or verified infection. Blood samples will be taken twice daily for 3 days. Clinical data with impact on pharmacokinetics as well as microbiological results will be collected.
Intervention code [1] 293538 0
Not applicable
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 296955 0
To assess if antibiotic concentrations in plasma are lower than those recommended in current international guidelines.
Timepoint [1] 296955 0
Days 1-3 of antibiotic therapy.
Secondary outcome [1] 319763 0
To assess if antibiotic concentrations in plasma are higher than those recommended in current international guidelines.
Timepoint [1] 319763 0
Days 1-3 of antibiotic therapy.
Secondary outcome [2] 319764 0
To find mechanistic explanations to variations in plasma antibiotic concentration in this group such as variations in renal function (eGFR), liver function (INR), plasma protein levels (plasma albumin), continuous renal replacement therapy (dose) etc.
Timepoint [2] 319764 0
Days 1-3 antibiotic therapy.
Secondary outcome [3] 319765 0
To relate plasma antibiotic concentration to the MIC values of the isolated bacteria from each patient with positive cultures.
Timepoint [3] 319765 0
Days 1-3 of antibiotic therapy.

Eligibility
Key inclusion criteria
Intensive care patient with any severe suspected or verified infection requiring initiation of new antibiotic treatment.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Intermittent hemodialysis
Known pregnancy
Limitations of care

Study design
Purpose
Natural history
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Descriptive statistics

To show that 10% of the patients have lower plasma antibiotic concentration than current recommendations, at least 16 patients will have to be included for each 8 studied antibiotic agent for an alpha error of 0.05 and beta error of 0.8. Due to the risk of missing data, uneven distribution between groups etc we aim at including 150 patients i.e. 10% more than the sample size suggests.
To counteract uneven distribution between groups, an interim analysis will be performed after the inclusion of 75 patients to ensure that the distribution of patients is similar for the eight antibiotics studied. Inclusion for antibiotics with 16 or more patients included will be terminated.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
18/01/2016
Date of last participant enrolment
Anticipated
Actual
5/07/2017
Date of last data collection
Anticipated
Actual
3/09/2017
Sample size
Target
150
Accrual to date
Final
158
Recruitment outside Australia
Country [1] 7498 0
Sweden
State/province [1] 7498 0

Funding & Sponsors
Funding source category [1] 292631 0
Other Collaborative groups
Name [1] 292631 0
Uppsala-Orebro Regional Research Council
Country [1] 292631 0
Sweden
Funding source category [2] 292632 0
Hospital
Name [2] 292632 0
Uppsala university hospital research fund
Country [2] 292632 0
Sweden
Primary sponsor type
University
Name
Uppsala university
Address
Department of Surgical Sciences
Anaesthesiology and Intensive Care
Uppsala University
Akademiska sjukhuset
751 85 Uppsala
Sweden
Country
Sweden
Secondary sponsor category [1] 291349 0
Hospital
Name [1] 291349 0
Uppsala university hospital
Address [1] 291349 0
Akademiska sjukhuset
751 85 Uppsala
Sweden
Country [1] 291349 0
Sweden
Other collaborator category [1] 278754 0
Hospital
Name [1] 278754 0
Karlstad county hospital
Address [1] 278754 0
Centralsjukhuset i Karlstad
Rosenborgsgatan
652 30 Karlstad
Sweden
Country [1] 278754 0
Sweden
Other collaborator category [2] 278755 0
Hospital
Name [2] 278755 0
Eskilstuna county hospital
Address [2] 278755 0
Malarsjukhuset
Kungsvagen 34
633 49 Eskilstuna
Sweden
Country [2] 278755 0
Sweden
Other collaborator category [3] 278756 0
Hospital
Name [3] 278756 0
Vasteras county hospital
Address [3] 278756 0
Vastmanlands sjukhus Vasteras
721 89 Vasteras
Sweden
Country [3] 278756 0
Sweden
Other collaborator category [4] 278757 0
Hospital
Name [4] 278757 0
Gavle county hospital
Address [4] 278757 0
Gavle sjukhus
Lasarettsvagen 5
803 24 Gavle
Sweden
Country [4] 278757 0
Sweden
Other collaborator category [5] 278758 0
Hospital
Name [5] 278758 0
Karolinska University Hospital Huddinge
Address [5] 278758 0
Karolinska Universitetssjukhuset Huddinge
Halsovagen, Flemingsberg
141 86 Stockholm
Sweden
Country [5] 278758 0
Sweden

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294113 0
The Regional Ethical Review Board, Uppsala
Ethics committee address [1] 294113 0
Drottninggatan 4
753 09 Uppsala
Sweden
Ethics committee country [1] 294113 0
Sweden
Date submitted for ethics approval [1] 294113 0
26/03/2015
Approval date [1] 294113 0
03/09/2015
Ethics approval number [1] 294113 0
Dnr 2015/135

Summary
Brief summary
Background
Antibiotic therapy has the major impact on morbidity and mortality in severe sepsis and septic shock (Kumar, Roberts et al. 2006; Bagshaw, Lapinsky et al. 2009). Rapid killing of bacteria is considered important to limit the infection and systemic inflammatory response. Pharmacokinetic data for most antibiotics are obtained in healthy human volunteers. Hence, it is unclear if adequate antibiotic concentrations in plasma are achieved in critically ill patients with infections, especially on the first day of treatment when benefits of adequate dosed antibiotics are greatest. This is unfortunate, since the outcome in ICU patients depends on early, accurate and adequately dosed antibiotic treatment. Underdosing antibiotics leads to the no or limited effect against infectious agents with the risk of lack of infection control as well as risk of emergence of multi-resistant strains. Overdosing antibiotics increases the risk of toxicity without providing additional benefit.
There are several reasons for variations in drug concentration in ICU. Large changes in total body water may be seen due to intravenous fluids given during resuscitation (Liu, Thompson et al. 2011). Moreover, changes are seen in plasma protein levels (Investigators, Finfer et al. 2011) permeability between the different compartments, liver function, (Macnab, Macrae et al. 1986) renal function (White, Hassoun et al. 2013) and renal tubular function (Wen, Peng et al. 2011). In addition, critically ill patients treated with continuous renal replacement therapy (CRRT) in severe renal impairment that alters the excretion of the drugs with predominantly renal clearance (Lau, Kronfol et al. 1987).
Thus, to date it is unknown what proportion of the ICU patients have adequate plasma concentrations of antibiotics, whether antibiotic concentrations change during the first days and if the pharmacokinetics of these drugs is affected by the critical illness and / or intensive care.
Hypothesis
Plasma concentrations of antibiotics in ICU patients during the first 72 hours after initiation of treatment are too low to provide adequately dosed antibacterial therapy.
Method
In a prospective multicenter study, concentrations of cefotaxime, piperacillin-tazobactam, meropenem, ciprofloxacin, gentamicin, tobramycin, amikacin and vancomycin in the plasma will be measured twice daily for 3 days after the initiation of treatment in intensive care patients with suspected infection. Participating centers are: the general ICU, the cardiothoracic ICU and the burns ICU at Uppsala university hospital, and general ICUs at County hospitals in Eskilstuna, Vasteras, Karlstad, and Gavle, as well as the general ICU at Karolinska University Hospital Huddinge. Demographic, clinical, laboratory and microbiological data will be collected. Antibiotic concentrations in each patient with positive cultures will be compared with the MIC for the isolated bacteria from the same patient.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 62522 0
A/Prof Miklos Lipcsey
Address 62522 0
Department of Surgical Sciences
Anaesthesiology and Intensive Care
Uppsala University Hospital
Akademiska sjukhuset
751 85 Uppsala
Sweden
Country 62522 0
Sweden
Phone 62522 0
+46 - 18 - 611 96 60
Fax 62522 0
Email 62522 0
[email protected]
Contact person for public queries
Name 62523 0
A/Prof Miklos Lipcsey
Address 62523 0
Department of Surgical Sciences
Anaesthesiology and Intensive Care
Uppsala University Hospital
Akademiska sjukhuset
751 85 Uppsala
Sweden
Country 62523 0
Sweden
Phone 62523 0
+46 - 18 - 611 96 60
Fax 62523 0
Email 62523 0
[email protected]
Contact person for scientific queries
Name 62524 0
A/Prof Miklos Lipcsey
Address 62524 0
Department of Surgical Sciences
Anaesthesiology and Intensive Care
Uppsala University Hospital
Akademiska sjukhuset
751 85 Uppsala
Sweden
Country 62524 0
Sweden
Phone 62524 0
+46 - 18 - 611 96 60
Fax 62524 0
Email 62524 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseSwedish multicentre study of target attainments with beta-lactams in the ICU: which MIC parameter should be used?.2023https://dx.doi.org/10.1093/jac/dkad327
EmbasePopulation pharmacokinetics of cefotaxime in intensive care patients.2022https://dx.doi.org/10.1007/s00228-021-03218-6
EmbaseLow attainment to PK/PD-targets for beta-lactams in a multi-center study on the first 72 h of treatment in ICU patients.2022https://dx.doi.org/10.1038/s41598-022-25967-9
N.B. These documents automatically identified may not have been verified by the study sponsor.