The effect of therapeutic drug monitoring of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients: the DOLPHIN trial protocol of a multi-centre randomised controlled trial

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

Critically ill patients undergo extensive physiological alterations that will have impact on antibiotic pharmacokinetics. Up to 60% of intensive care unit (ICU) patients meet the pharmacodynamic targets of beta-lactam antibiotics, with only 30% in fluoroquinolones. Not reaching these targets might increase the chance of therapeutic failure, resulting in increased mortality and morbidity, and antibiotic resistance. The DOLPHIN trial was designed to demonstrate the added value of therapeutic drug monitoring (TDM) of beta-lactam and fluoroquinolones in critically ill patients in the ICU.

Methods

A multi-centre, randomised controlled trial (RCT) was designed to assess the efficacy and cost-effectiveness of model-based TDM of beta-lactam and fluoroquinolones. Four hundred fifty patients will be included within 24 months after start of inclusion. Eligible patients will be randomly allocated to either study group: the intervention group (active TDM) or the control group (non-TDM). In the intervention group dose adjustment of the study antibiotics (cefotaxime, ceftazidime, ceftriaxone, cefuroxime, amoxicillin, amoxicillin with clavulanic acid, flucloxacillin, piperacillin with tazobactam, meropenem, and ciprofloxacin) on day 1, 3, and 5 is performed based upon TDM with a Bayesian model. The primary outcome will be ICU length of stay. Other outcomes amongst all survival, disease severity, safety, quality of life after ICU discharge, and cost effectiveness will be included.

Discussion

No trial has investigated the effect of early TDM of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients. The findings from the DOLPHIN trial will possibly lead to new insights in clinical management of critically ill patients receiving antibiotics. In short, to TDM or not to TDM?

Trial registration

EudraCT number: 2017–004677-14. Sponsor protocol name: DOLPHIN. Registered 6 March 2018 . Protocol Version 6, Protocol date: 27 November 2019.

Related collections

Most cited references 28

Record: found
Abstract: found
Article: not found

DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients?

Jason A Roberts, Sanjoy K Paul, Murat Akova … (2014)

Morbidity and mortality for critically ill patients with infections remains a global healthcare problem. We aimed to determine whether β-lactam antibiotic dosing in critically ill patients achieves concentrations associated with maximal activity and whether antibiotic concentrations affect patient outcome. This was a prospective, multinational pharmacokinetic point-prevalence study including 8 β-lactam antibiotics. Two blood samples were taken from each patient during a single dosing interval. The primary pharmacokinetic/pharmacodynamic targets were free antibiotic concentrations above the minimum inhibitory concentration (MIC) of the pathogen at both 50% (50% f T>MIC) and 100% (100% f T>MIC) of the dosing interval. We used skewed logistic regression to describe the effect of antibiotic exposure on patient outcome. We included 384 patients (361 evaluable patients) across 68 hospitals. The median age was 61 (interquartile range [IQR], 48-73) years, the median Acute Physiology and Chronic Health Evaluation II score was 18 (IQR, 14-24), and 65% of patients were male. Of the 248 patients treated for infection, 16% did not achieve 50% f T>MIC and these patients were 32% less likely to have a positive clinical outcome (odds ratio [OR], 0.68; P = .009). Positive clinical outcome was associated with increasing 50% f T>MIC and 100% f T>MIC ratios (OR, 1.02 and 1.56, respectively; P < .03), with significant interaction with sickness severity status. Infected critically ill patients may have adverse outcomes as a result of inadeqaute antibiotic exposure; a paradigm change to more personalized antibiotic dosing may be necessary to improve outcomes for these most seriously ill patients.

0 comments Cited 329 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections.

J Paladino, J Schentag, Karen P. McKinnon (2008)

The objective of this study was to evaluate the relationship of the predicted pharmacodynamic parameters 24-h area under the inhibitory curve (AUIC=area under the concentration-time curve for 24h of dosing/minimum inhibitory concentration (AUC0-24/MIC) and time above the minimum inhibitory concentration (T>MIC) with clinical and microbiological outcomes in patients with bacteraemia and sepsis treated with cefepime or ceftazidime. Pharmacokinetic and pharmacodynamic parameters were derived for 76 of 107 patients enrolled in two prospective, randomised, clinical trials comparing cefepime with ceftazidime for the treatment of sepsis with bacteraemia, lower respiratory tract infection or complicated urinary tract infection. The relationships between the pharmacodynamic parameters and outcomes were examined. Whilst no significant differences in clinical outcomes were observed between cefepime and ceftazidime, there were significant differences in the pharmacodynamic analysis. Patients with an AUIC> or =250 had significantly greater clinical cure (79% vs. 33%; P=0.002) and bacteriological eradication (96% vs. 44%; P MIC of 100% had significantly greater clinical cure (82% vs. 33%; P=0.002) and bacteriological eradication (97% vs. 44%; P MIC of MIC was <100%.

0 comments Cited 146 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Sepsis incidence and outcome: contrasting the intensive care unit with the hospital ward.

R D Luna, Oscar Peñuelas, Federico Gordo … (2007)

To describe the outcome of patients with sepsis according to location on a ward or in an intensive care unit. Prospective multicentered observational study. Three academic hospitals in Madrid, Spain. Consecutive patients with sepsis admitted to participating hospitals from March 1 to June 30, 2003. None. During the study period, 15,852 patients >18 yrs of age were admitted. Sepsis was identified in 702 patients, giving an estimated cumulative incidence rate of 367 cases per 100,000 adult area residents per year and a cumulative incidence rate among patients admitted to the hospital of 4.4%. Most septic patients had a community-acquired infection (71%). Severe sepsis developed in 199 patients (incidence rate, 104 cases per 100,000 adult area residents per year), and 59 patients developed septic shock (incidence rate, 31 cases per 100,000 adult area residents per year). Most of the patients met the criteria for severe sepsis or septic shock on the same day that they would have qualified for the septic status one step down the scale. In the other patients, the median time between sepsis and severe sepsis was 2 days (interquartile range, 2-5) and between severe sepsis and septic shock was 3 days (interquartile range, 1-4). Only 32% of severe sepsis patients received intensive care. The hospital mortality for all septic patients was 12.8%; for severe sepsis, 20.7%; and for septic shock, 45.7%. This study shows the high incidence of sepsis in a general population of patients admitted to hospital. A significant proportion of patients with severe sepsis are not transferred to the intensive care unit.

0 comments Cited 114 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

A. Abdulla:

ORCID: http://orcid.org/0000-0002-2158-6376

a.abdulla@erasmusmc.nl

Journal

Journal ID (nlm-ta): BMC Infect Dis

Journal ID (iso-abbrev): BMC Infect. Dis

Title: BMC Infectious Diseases

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2334

Publication date (Electronic): 17 January 2020

Publication date PMC-release: 17 January 2020

Publication date Collection: 2020

Volume: 20

Electronic Location Identifier: 57

Affiliations

[1 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Hospital Pharmacy, , Erasmus University Medical Center, ; P.O. Box 2040, 3000 CA Rotterdam, the Netherlands

[2 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Intensive Care, , Erasmus University Medical Center, ; Rotterdam, The Netherlands

[3 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Medical Microbiology and Infectious Diseases, , Erasmus University Medical Center, ; Rotterdam, The Netherlands

[4 ]ISNI 0000 0004 0395 6796, GRID grid.414842.f, Department of Medical Microbiology, , Haaglanden Medical Center, ; The Hague, The Netherlands

[5 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Public Health, , Erasmus University Medical Center, ; Rotterdam, The Netherlands

[6 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Internal Medicine, , Erasmus University Medical Center, ; Rotterdam, The Netherlands

Author information

A. Abdulla http://orcid.org/0000-0002-2158-6376

Article

Publisher ID: 4781

DOI: 10.1186/s12879-020-4781-x

PMC ID: 6969462

PubMed ID: 31952493

SO-VID: eaf3424c-716a-4a92-930d-f1d7f1c060ee

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 28 November 2019

Date accepted : 8 January 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001826, ZonMw;

Award ID: 848017008

Funded by: FundRef http://dx.doi.org/10.13039/501100003061, Erasmus Medisch Centrum;

Custom metadata

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: randomised controlled trial,therapeutic drug monitoring,antibiotic,beta-lactam,fluoroquinolones,critically ill patients,length of stay,pharmacokinetics,pharmacodynamics

Data availability:

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: randomised controlled trial, therapeutic drug monitoring, antibiotic, beta-lactam, fluoroquinolones, critically ill patients, length of stay, pharmacokinetics, pharmacodynamics

The effect of therapeutic drug monitoring of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients: the DOLPHIN trial protocol of a multi-centre randomised controlled trial

Read this article at

Abstract

Background

Methods

Discussion

Trial registration

Related collections

Karger: Coronavirus / COVID-19

Most cited references 28

DALI: defining antibiotic levels in intensive care unit patients: are current β-lactam antibiotic doses sufficient for critically ill patients?

Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections.

Sepsis incidence and outcome: contrasting the intensive care unit with the hospital ward.

Author and article information

Contributors

Journal

Affiliations

Author information

Article

History

Funding

Categories

Custom metadata

Comments

Comment on this article

Similar content 522

Cited by 32

Most referenced authors 533