Fleuren et al.

Critical Care (2019) 23:185

https://doi.org/10.1186/s13054-019-2438-1

RESEARCH Open Access

Clinically relevant pharmacokinetic

knowledge on antibiotic dosing among
intensive care professionals is insufficient:
a cross-sectional study
Lucas M. Fleuren1* , Luca F. Roggeveen1, Tingjie Guo1, Petr Waldauf2, Peter H. J. van der Voort3, Rob J. Bosman3,
Eleonora L. Swart4, Armand R. J. Girbes1 and Paul W. G. Elbers1

Abstract
Background: Antibiotic exposure in intensive care patients with sepsis is frequently inadequate and is associated
with poorer outcomes. Antibiotic dosing is challenging in the intensive care, as critically ill patients have altered and
fluctuating antibiotic pharmacokinetics that make current one-size-fits-all regimens unsatisfactory. Real-time bedside
dosing software is not available yet, and therapeutic drug monitoring is typically used for few antibiotic classes and
only allows for delayed dosing adaptation. Thus, adequate and timely antibiotic dosing continues to rely largely on the
level of pharmacokinetic expertise in the ICU. Therefore, we set out to assess the level of knowledge on antibiotic
pharmacokinetics among these intensive care professionals.
Methods: In May 2018, we carried out a cross-sectional study by sending out an online survey on antibiotic dosing to
more than 20,000 intensive care professionals. Questions were designed to cover relevant topics in pharmacokinetics
related to intensive care antibiotic dosing. The preliminary pass mark was set by members of the examination committee
for the European Diploma of Intensive Care using a modified Angoff approach. The final pass mark was corrected for
clinical relevance as assessed for each question by international experts on pharmacokinetics.
Results: A total of 1448 respondents completed the survey. Most of the respondents were intensivists (927 respondents,
64%) from 97 countries. Nearly all questions were considered clinically relevant by pharmacokinetic experts. The pass
mark corrected for clinical relevance was 52.8 out of 93.7 points. Pass rates were 42.5% for intensivists, 36.1% for fellows,
24.8% for residents, and 5.8% for nurses. Scores without correction for clinical relevance were worse, indicating that
respondents perform better on more relevant topics. Correct answers and concise clinical background are provided.
Conclusions: Clinically relevant pharmacokinetic knowledge on antibiotic dosing among intensive care professionals is
insufficient. This should be addressed given the importance of adequate antibiotic exposure in critically ill patients with
sepsis. Solutions include improved education, intensified pharmacy support, therapeutic drug monitoring, or the use of
real-time bedside dosing software. Questions may provide useful for teaching purposes.
Keywords: Antibiotics, Intensive care, Pharmacokinetics, Drug dosing

* Correspondence: [email protected]
1
Department of Intensive Care Medicine, Research VUmc Intensive Care
(REVIVE), Amsterdam Medical Data Science (AMDS), Amsterdam
Cardiovascular Sciences (ACS), Amsterdam Infection and Immunity Institute
(AI&II), Amsterdam UMC, Location VUmc, Vrije Universiteit Amsterdam,
Amsterdam, The Netherlands
Full list of author information is available at the end of the article

© The Author(s). 2019 Open Access This 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.
Fleuren et al. Critical Care (2019) 23:185 Page 2 of 9

Background Therefore, we encourage readers to take the questionnaire

Sepsis and septic shock remain one of the deadliest diseases themselves.
in intensive care units worldwide [1, 2] and are estimated to
contribute to more than one third of all hospital deaths [3]. Methods
Despite the magnitude of the sepsis burden, efforts to de- In May 2018, we set up a cross-sectional study by sending
velop new treatments have been largely unsuccessful [4, 5]. out a questionnaire testing the level of knowledge on phar-
Therefore, sepsis management continues to rely on source macometric principles governing antibiotic dosing in the crit-
control, supportive measures, and adequate antibiotic treat- ically ill by electronic mail. Approximately 20,000 healthcare
ment. This includes adequate antibiotic dosing to prevent professionals in the field of intensive care medicine were
toxicity and inadequate exposure. approached using the professional networks of the authors
Despite the importance of antibiotic dosing, antibiotic and the database of the international fluid academy (iFAD)
exposure is well known to be frequently inadequate in inten- days meeting. iFAD comprises of an international collabor-
sive care patients [6–8]. The DALI study showed that less ation group with the aim of improving outcomes in the crit-
than 50% of patients treated for infection with β-lactam anti- ically ill through fluid management, organ support, and
biotics achieved their preferred pharmacokinetic target [8]. monitoring. Attendees include nurses and critical care
Similar observations have been reported in other studies for specialists.
beta-lactam antibiotics [9, 10], as well as for fluoroquinolones
[11, 12]. More importantly, the DALI study showed aberrant Population
serum concentrations were associated with poorer outcome Target populations for the questionnaires were intensivists,
in clinical patients [8]. The rationale that underdosing leads residents, fellows, and intensive care nurses. No patients
to ineffective pathogen eradication seems probable for other were involved in this study. For the purpose of this study,
antibiotics as well. intensivist was defined as a medical specialist in critical care
Admittedly, adequate antibiotic dosing for critically ill pa- medicine. Fellows were defined as physicians with a dedi-
tients is challenging. Intensive care patients have markedly cated program towards national or international accredit-
altered and variable pharmacokinetic parameters for antibi- ation as an intensivist. Residents were defined as all other
otics as compared to healthy individuals or less severely ill junior physicians working in intensive care medicine. As
patients. Organ dysfunction, abnormal fluid balances, altered considerable differences in medical postgraduate programs
hemodynamics, and organ replacement therapy can severely exist among countries, respondents themselves were asked
impact dosing requirements [13]. However, guidelines fail to to select the category most appropriate to them [18–21].
provide recommendations on dose adaptation or dose
personalization in these patients [14]. Therefore, prescribing Privacy and consent
antibiotics routinely follows a one-size-fits-all principle. Only individuals who consented to receive electronic mail
Therapeutic drug monitoring may provide guidance, but is related to intensive care medicine were approached. Re-
usually only provided for aminoglycosides [15] and the glyco- cipients were asked to further disseminate the question-
peptide vancomycin [16], but not for other antibiotics. In naire in their professional network at their own discretion
addition, this guidance requires drug sampling and can to yield more responses. All intensive care professionals
therefore not be used at the start of antibiotic treatment, that chose to respond provided written informed consent
paradoxically when adequate dosing may be most important. for use of their data, in compliance with the General Data
Fully automated systems that provide real-time bedside ad- Protection Regulation [22]. Participation was anonymous,
vice and are integrated with the electronic patient record and internet protocol addresses were not stored. We did
could be a solution, but require further development and collect additional data including date, time, and duration
clinical validation [17]. of questionnaire completion, age, years of work experi-
As a consequence, adequate pharmacokinetic knowledge ence, hospital, and country. For privacy reasons, data on
remains pivotal to optimize antibiotic dosing at the bedside age and work experience were collected in discretized
of the critically ill. It is currently not known whether the level form using brackets and participants were not obliged to
of knowledge on pharmacometric principles among intensive provide information on hospital and country.
care professionals is sufficient. Our hypothesis was that there
is room for improvement given the signals of frequent inad- Questions
equate antibiotic exposure in the critically ill. To test our hy- All questions were specifically developed for this question-
pothesis, we set out to assess the level of clinically relevant naire and designed to cover the clinically relevant topics re-
knowledge on pharmacokinetic principles governing anti- lated to antibiotic pharmacokinetics in the setting of
biotic dosing in the setting of intensive care medicine using intensive care medicine. The core competencies defined by
an expert-validated questionnaire. As a corollary, this ques- the Competency-Based Training in Intensive Care Medicine
tionnaire may serve as a validated educational tool. in Europe (CoBaTrICE) collaboration provided a reference
Fleuren et al. Critical Care (2019) 23:185 Page 3 of 9

standard for these topics [23]. This yielded 12 questions, Assessment of clinical relevance
which can be found in Table 1 together with the answer key. As an additional step, we asked pharmacokinetic experts to
The relationship between the questions and the CoBaTrICE rate our questions on clinical relevance. A PubMed
collaboration and a review by Roberts et al. [13] can be found ReMiner-search was conducted to identify the top 10 publish-
in the Additional file 1. Underlying principles and concise ing experts in intensive care pharmacokinetics [29]. Titles
background for these questions can be found in Box 1. The and abstracts were searched (“antibiotics,” “intensive care,”
maximum number of possible answers varied, and questions “pharmacokinetics”) and sorted per author, which resulted in
with multiple answers were allowed. No open questions were a list of top publishing institutions. Among these, one author
used for ease of automated scoring. Participants were asked from each institution was selected, which yielded six authors.
to refrain from using other resources to fill out the questions The scores for these six experts were averaged and served as
and were asked not to discuss questions with colleagues that a correction factor for the Angoff scores. The average of all
had not yet participated in the survey. The questionnaire clinically relevance-corrected Angoff scores for each question
contained a control question to verify whether additional formed the pass mark for the survey. All analyses were per-
sources such as colleagues, textbooks, or the Internet were formed using Python (Python Software Foundation. Python
used. Language Reference, version 3.6.4).

Modified Angoff scoring Results

Questions answered correctly resulted in 10 points; subques- A total of 1448 respondents completed the survey. Character-
tions yielded part of the points amounting to a total of 10. istics of the respondents are shown in Table 1. Most of the re-
To set the pass mark for the designed questions, we used a spondents were intensivists (n = 927, 64%); the majority of
modified Angoff approach [24]. In this approach, subject whom were between 40 and 50 years of age (n = 383, 41%).
matter experts each attribute a minimally competent candi- Most of the fellows (n = 117, 69%) were in their thirties,
date (MCC) score to each of the questions. This score repre- compared to 31% of intensivists. Experience in the practice of
sents the percentage of borderline candidates (i.e., those intensive care medicine varied widely, with nurses and inten-
candidates that the subject matter expert expects to just have sivists having worked in their profession the longest. The lar-
passed the exam) that would answer these individual ques- gest group has worked in the ICU between 10 and 20 years
tions correctly. This score was corrected for guessing and ad- (27% and 34% of nurses and intensivists respectively). Re-
justed to acknowledge a theoretical maximum score using spondents from 97 different countries completed the survey,
the formula: corrected score = subject matter expert score × with the majority of those countries being located in Europe
(90 − score expected by guessing) + score expected by guess- (74%). Even though completion of country of residence was
ing. Finally, the corrected scores for individual questions are not mandatory, it was provided in 1400 responses (97%).
averaged to yield the exam Angoff score. The score has been The Angoff pass mark was 70.8 out of 120 points (59.0%
used extensively in medical education with good reliability threshold). The final pass mark, adjusted for clinical rele-
[25–27]. It has been shown that a second round of vancy, was 52.8 out of 93.7 points (56.4% threshold).
decision-making adds little to precision; this step was there- Overall, 513 respondents (35.4%) passed with the final
fore omitted [28]. We chose members of the examination pass mark. Pass rates differed per job category; results are
committee of the European Society of Intensive Care Medi- shown in Fig. 1a. Intensivists scored best (42.5%), followed
cine as our subject matter experts. Nine of these independ- by fellows (36.1%), residents (24.7%) and nurses (5.8%).
ently scored our questions. They are all experienced Without correcting for clinical relevance, respondents
intensivists and responsible for the European Diploma in In- scored lower (nurses 3.9%, residents 19.2%, fellows 20.1%,
tensive Care (EDIC) exams. In addition, they have ample ex- intensivists 30.1%). Two-hundred and ninety-seven re-
perience in Angoff scoring. Therefore, our final pass mark spondents (21%) reported consulting books (50%), the
can be seen as the level of knowledge that is expected from Internet (88%), and colleagues (49%). Test results from
intensivists in independent practice. the 297 respondents that used additional resources are

Table 1 Characteristics of the respondents

Nurse Resident Fellow Intensivist Total
Respondents (#) 154 198 169 927 1448
Age (mean, yrs) 41.1 33.1 38.3 44.6 42
Work Experience (mean, yrs) 10.7 2.9 5.3 11.1 9.3
Time to completion (mean, min) 14.9 12.3 13.2 13.8 13.6
From European countries (#) 147 192 165 896 1400
yrs years, min minutes
Fleuren et al. Critical Care (2019) 23:185 Page 4 of 9

Fig. 1 Scores of respondents. All results are percentages of respondents who passed based on the final pass mark adjusted for clinical relevance. a Survey
results per job-title. b Intensivists’ scores per age bin. c Intensivists’ scores per years of experience, binned. d Results for respondents using additional resources
to answer the questions

shown in Fig. 1d. For fellows and intensivists, this led to All survey questions with their model answers are shown
an increase of more than 20% of respondents achieving in Table 2. Angoff scores, clinical relevance, and pass rates are
the pass mark; for nurses and residents, absolute pass shown for each question. Overall, clinical relevance is high for
rates improved by 226% and 59%, respectively. Results all questions, except for questions 10 (56/100) and 12 (49/
from intensivists were stratified by age and years of ICU 100) on calculating half-lives. Angoff scores for some ques-
experience (results shown in Fig. 1b, c). No clear trend in tions were below 60/100, indicating questions were hard.
the age group was observed, although intensivists with less Both questions that have low clinical relevance also showed
than 1 year of experience tended to score lower. Percent- low Angoff scores. Intensivists’ pass rates per question range
age scores per country can be found in Additional file 1. from 14.6 to 98.1%. Questions pertaining to Vancomycin ex-
Only countries with at least three respondents are shown cretion and antibiotic dosing in renal dysfunction showed
(51 out of 97, 52.6%). high pass rates (90% and ≥ 90% for meropenem,
Fleuren et al. Critical Care (2019) 23:185 Page 5 of 9

Table 2 Questions and model answers with their respective Angoff scores and clinical relevance
Question Answer Angoff scorea Clinical relevancea Pass intensivists (%)
1 Are these antibiotics lipophilic or hydrophilic?
Vancomycin Hydrophilic 64 74 60.2
Ceftriaxone Hydrophilic 64 74 44.6
Meropenem Hydrophilic 64 74 49.1
Ciprofloxacin Lipophilic 64 74 37.2
2 Which antibiotic is barely protein-bound? Meropenem 42 71 14.6
3 For which antibiotic, using continuous infusion, Meropenem 49 83 18.3
is a loading dose least (!) important
4 In case of severe renal dysfunction, how should
the maintenance dose be adapted for these
antibiotics?
Vancomycin Lower the doseb 74 94 98.2
Ceftriaxone Lower the doseb 68 94 96.0
Meropenem Lower the doseb 72 94 90.0
Ciprofloxacin Lower the doseb 70 94 70.4
5 In case of severe renal dysfunction, how should the
initial dose be adapted for these antibiotics?
Vancomycin No adaptation 75 93 65.5
Ceftriaxone No adaptation 72 93 85.0
Meropenem No adaptation 74 93 64.1
Ciprofloxacin No adaptation 74 93 66.9
6 Which treatment goal is most relevant for these
antibiotics?
Vancomycin AUC0–24/MIC 57 87 31.8
Ceftriaxone T > MIC 60 87 45.2
Meropenem T > MIC 60 87 49.9
Ciprofloxacin AUC0-24/MIC 54 87 31.6
7 How are these antibiotics cleared?
Vancomycin Mostly renally 64 89 90.0
Ceftriaxone Both renally and via liver/bile/feces 59 89 31.0
Meropenem Mostly renally 60 89 48.8
Ciprofloxacin Both renally and via liver/bile/feces 60 89 30.7
8 What are risk factors for augmented renal clearance?
Cardiac arrest False 66 87 82.1
Prolonged ICU admittance False 65 87 73.3
Advanced age False 65 87 78.8
Multi-trauma True 65 87 47.6
Limited comorbidity True 65 87 33.1
9 How do these parameters change in the initial phase
of septic shock following adequate volume
resuscitation?
Volume of distribution Increases 61 85 87.1
Clearance Increases 61 85 35.5
10 The volume of distribution of an antibiotic is 100 L. About 7 h 50 56 41.6
Clearance is 10 L/h. What is the half-life?
11 What happens to half-life if …
Clearance increases Decreases 64 70 88.9
Clearance decreases Increases 65 70 89.8
Volume of distribution increases Increases 63 70 40.5
Volume of distribution decreases Decreases 63 70 39.4
12 The half-life of an antibiotic is 3 h. When is steady state 13–17 h 49 49 38.8
reached approximately following start of continuous
infusion?
a
Score out of 100
b
Multiple answers can be correct; see Box 1
Fleuren et al. Critical Care (2019) 23:185 Page 6 of 9

ciprofloxacin, and ceftriaxone, respectively). Box 1 shows recommendation at the bed side in real time [33, 34]. Other
concise explanations for all questions. than therapeutic drug monitoring, these models could pro-
vide dosing advice based on the large amount of routinely
Discussion collected clinical parameters rather than based on antibiotic
This is the first study to show that clinically relevant pharma- samples alone. Advantages of these systems include immedi-
cokinetic knowledge on antibiotic dosing among international ate availability of dosing recommendations, i.e., even before
intensive care professionals is insufficient. More than half of the first dose, and the continuous correction of these recom-
intensivists failed the test, while fellows, resident, and nurses mendations at the touch of a button, based on a changing
had even lower scores. Thus, we have identified a major physiology in the critically ill. Evidently, safety and efficacy
knowledge gap. Given the pivotal importance of adequate should be of unconditional importance when designing and
antibiotic dosing, this should be addressed. implementing these systems. Therefore, such systems are
The importance of pharmacokinetic principles to guide currently still under investigation [17].
antibiotic dosing in critically ill patient is well recognized This study has several strengths. First, all questions were
given the markedly altered and often changing pharmacokin- based on the Cobatrice framework, which ensures close ad-
etics in the critically ill [6, 8]. In particular, the DALI study herence to validated training and examination goals for
showed that low antibiotic serum concentrations are associ- intensivists. Second, the number of respondents was high
ated with worse outcome in ICU patients [8]. Therefore, it is and their background was heterogeneous, which extends the
surprising that pharmacokinetic education does not have a results to an international audience of ICU professionals.
prominent role in medical education, even though clinical Third, the pass mark and clinical relevance were assessed by
educational tools are readily available [30]. The lack of phar- members of the ESICM examination committee and
macokinetic expertise among intensive care professionals has world-renowned experts on pharmacokinetics, which assures
likely contributed to the tolerance of standard dosing regi- test validity. Scores were adjusted for clinical relevance as an
mens for many antibiotics, even in the setting of intensive extra step after Angoff scoring. The two questions that were
care medicine. This one-size-fits-all principle is also reflected rated hard (i.e., lower Angoff scores) concomitantly had
in most national and international guidelines which fail to lower clinical relevance scoring, which was therefore adjusted
recommend individualized dosing strategies. for in the final scores.
Education such as antimicrobial stewardship is a potential This study also has some limitations. Firstly, although the
solution to improve pharmacokinetic expertise among inten- number of responses is high, the response rate is low. We
sive care professionals in order to optimize antibiotic dosing. asked people to disperse the survey to colleagues to increase
However, large improvements in pharmacometric knowledge the number of respondents, which also clouds the response
among intensive care professionals may not prove realistic. rate. We risk that only people who felt comfortable with the
Causes include increasing workload in clinic [31] and the questions completed the survey. This would imply, however,
growing body of medical literature to stay up to date with that our score is an overestimation. Although we asked
[32]. An alternative solution could therefore be the extended people to refrain from using other resources to answer the
use of therapeutic drug monitoring and increased support by questions, 21% sought help, which would also contribute to
clinical pharmacists and microbiologists. For vancomycin the overestimation of their personal knowledge on the sub-
and the aminoglycosides, therapeutic drug monitoring has ject. Additionally, the number of respondents per country
shown to increase efficacy and limit the occurrence of might not be a representative sample of that country. We
nephrotoxicity [15, 16]. Studies on therapeutic drug monitor- therefore refrain from drawing conclusions on a per country
ing for the beta lactams are ongoing. basis. The sample from multiple countries, however, implies
Automated pharmacokinetic modeling systems are another trends are similar in an international population. Lastly,
viable solution to tackle inadequate antibiotic exposure in definitions of intensive care units vary worldwide due to
the setting of intensive care medicine. The advent of elec- available resources and historical trends. Concomitantly,
tronic health record systems in most ICUs in resource-rich definitions of job titles in the ICU differ per region or even
settings allows for continuous data feeds into integrated within countries [20, 21]. We assumed, however, that the
pharmacometric software, resulting in individual dosing title intensivist is reserved globally for doctors taking care

Table 3 Properties of antibiotics. Results from multiple online resources [35, 36]
VD (L) Lipo-/hydrophilic T1/2 (h) Protein binding Renal clearance Treatment goal
Vancomycin 32–68 Hydrophilic 5–11 55% 75–90% AUC0–24/MIC
Ceftriaxone 7–12 Hydrophilic 8 85–95% 60% T > MIC
Meropenem 11–27 Hydrophilic 1 2% 50–75% T > MIC
Ciprofloxacin 150–225 Lipophilic 4–7 20–40% 75% AUC0–24/MIC
Fleuren et al. Critical Care (2019) 23:185 Page 7 of 9

of patients threatened in their vital parameters, including

Elimination—routes and dosage adaptations (Q3, 5, 7,
sepsis and septic shock.
8, 9, 10, 11, 12)

Antibiotic elimination is mostly renal and to a lesser extent

Conclusion
In conclusion, we showed that clinically relevant pharmaco- through hepatic routes, depending on antibiotic class. Hepatic
kinetic knowledge on antibiotic dosing among intensive care elimination is generally related to cardiac output, which may be
professionals is insufficient. This should be addressed, as sub- increased in sepsis. Likewise, augmented renal clearance may
optimal dosing strategies are associated with poorer out- occur in the very early phase of critical illness, while impaired renal
comes. Options include extended use of therapeutic drug function is common at later stages [38, 39]. Risk factors for
monitoring and pharmacist support as well as automated augmented renal clearance include young age, multi-trauma, and
pharmacokinetics systems that provide dosing advice at the
limited comorbidity, which could reflect the ability to recruit renal
bedside in real time.
reserve [38, 39]. The time to reach steady state depends on half-
life and thus is related to VD and CL. Steady state is reached after 4
Box 1. Pharmacokinetic background
to 5 half-lives. This implies that for antibiotics with a long half-life,
Pharmacokinetics (the ancient Greek kinetikos meaning “putting time to target concentration may be too long, necessitating a
in motion”) deals with drug movement into (absorption), within loading dose. This loading dose depends on VD only and not on
(distribution), and out of (metabolism and excretion) the body. CL or rate of elimination. Therefore, in the setting of decreased
All of these are subject to major alterations in critically ill clearance, e.g., because of renal failure, the loading dose should
patients, necessitating adaptations in antibiotic dosing. The still be given in full. This can be thought of as the full VD needed
following brief educational overview addresses relevant to be filled to quickly attain target concentration. An antibiotic
pharmacokinetic changes and provides explanations for the with a low volume of distribution and short half-life such as mero-
answers to our test questions. Changes in absorption are penem will therefore quickly reach steady-state target concentra-
omitted here as antibiotics should always be given intravenously tion and requires no or low loading doses.
in critically ill patients (100% absorption).
Treatment goals and dosing (Q4, 6)
Distribution—antibiotic properties in the ICU (Q1, 2, 9, 11)
Pre-clinical and clinical studies have identified pharmacokinetic
The apparent volume of distribution (VD) of an antibiotic represents treatment goals for antibiotics (Table 1). Depending on antibiotic
the necessary theoretical volume that contains the amount of class, these may be concentration (Cmax/MIC) or time (T > MIC)
administered drug to maintain the observed plasma concentration. dependent, or a combination of both (AUC0–24/MIC) [13]. In case
VD is derived by the amount of drug in the body/concentration of reduced clearance, e.g., because of renal failure, time-
measured in plasma. Size of antibiotic molecules, protein binding, dependent treatment goals require prolongation of the dosing
and preference for aqueous (hydrophilic) or lipid (lipophilic) interval as maximum concentration—Cmax—and T > MIC will re-
environments are properties of an antibiotic and influence antibiotic main unchanged. For AUC/MIC targets, the goal is to maintain
distribution and thus VD (see Table 3). Additionally, in critically ill AUC, possible through both a decrease in the maintenance dose
septic patients, capillary leak, fluid resuscitation, and inotrope and elongation of the interval. The smallest decrease in AUC is ob-
administration may decrease antibiotic concentrations and therefore served with a lowering of the dose and is therefore preferred. For
increase VD. VD is related to elimination, as increases in VD indicate a some antibiotics, a decrease in renal clearance leads to an increase
decrease in elimination rate or an increase in half-life, as half-life is of hepatic clearance (ceftriaxone) in healthy subject, but this effect
defined as t1/2 = 0.693 × VD/CL. An increase in VD may be thought was not observed in a critically ill population [40].
of as a lower plasma concentration presenting to the kidneys, clear-
ing the plasma from the drug. Additional file

Metabolism—enzymatic function in the critically ill Additional file 1: Result per country for intensivists (percentages and
absolute numbers). (DOC 434 kb)
The liver metabolizes drugs through phase I (oxidation—CYP
enzymes) and phase II (conjugation) reactions. During sepsis,
Acknowledgements
hepatic dysfunction, hypo- and hyperthermia, and altered hepatic We would like to thank all participating members of the examination
blood flow, among others, may influence drug metabolism [37]. committee of the European Society of Intensive Care Medicine for setting
the pass mark. We would like to thank the following internationally
The effect on antibiotic levels has not been completely elucidated. renowned experts on pharmacokinetics for contributing to assessment of
Fleuren et al. Critical Care (2019) 23:185 Page 8 of 9

clinical relevance of our test: J. Lipman, MD, PhD, J. Rello, MD, PhD, A.A. Udy, Med [Internet]. 2014 Apr 24 [cited 2018 Dec 5];370(17):1583–93. Available
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The dataset that was used and analyzed for this study is available from the et al. Is prolonged infusion of piperacillin/tazobactam and meropenem in
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