European Journal of Clinical Pharmacology

https://doi.org/10.1007/s00228-020-03001-z

PHARMACOKINETICS AND DISPOSITION

Ceftriaxone dosing in patients admitted from the emergency

department with sepsis
Aaron J. Heffernan 1,2 & Rebecca A. Curran 3 & Kerina J. Denny 4 & Fekade B. Sime 2,5 & Claire L. Stanford 6 &
Brett McWhinney 7 & Jacobus Ungerer 7,8 & Jason A. Roberts 2,5,9,10,11 & Jeffrey Lipman 5,10,11

Received: 5 April 2020 / Accepted: 16 September 2020

# Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
Purpose Unbound ceftriaxone pharmacokinetics in adult patients have been poorly characterised. The objective of this study is to
determine the ceftriaxone dose that achieves an unbound trough concentration ≥ 0.5 mg/L in > 90% of adult patients receiving
once-daily dosing presenting to the emergency department (ED) with sepsis.
Methods We performed a prospective single-centre pharmacokinetic study. A single unbound plasma ceftriaxone concentration
was obtained from each patient using blood collected as part of routine clinical practice within the first dosing interval. Samples
were analysed using a validated ultra-high pressure liquid chromatography method. Population pharmacokinetic analysis and
Monte Carlo simulations (n = 1000) were performed using Pmetrics for R.
Results A ceftriaxone concentration obtained throughout the first dosing interval was available for fifty adult patients meeting
sepsis criteria. Using this concentration time-curve data, a pharmacokinetic model was developed with acceptable predictive
performance per the visual predictive check. Simulations show that a 1-g once-daily dose is unlikely to achieve the minimum
therapeutic ceftriaxone exposure in > 90% patients with a creatinine clearance ≥ 60 mL/min. However, a 2-g once-daily dose will
provide a therapeutic exposure for target pathogens infecting patients with a creatinine clearance ≤ 140 mL/min.
Conclusions Ceftriaxone administered as a 1-g once-daily dose is unlikely to achieve a therapeutic exposure in > 90% of patients
presenting to the ED with sepsis. Increasing the ceftriaxone dose to 2 g once daily will likely achieve the desired exposure against
target pathogens. Future clinical trials are required to determine any potential clinical benefit of optimised ceftriaxone dosing.

Keywords Ceftriaxone . Sepsis . Pharmacokinetics . Dose

Aaron J. Heffernan and Rebecca A. Curran are joint first authors

* Aaron J. Heffernan 6
Department of Emergency Medicine, Gold Coast University
aaron.heffernan@griffithuni.edu.au Hospital, Southport, Australia
7
Department of Chemical Pathology, Pathology Queensland,
1
School of Medicine, Griffith University, Southport, Australia Herston, Australia
8
2 Faculty of Biomedical Science, University of Queensland, St
Centre for Translational Anti-Infective Pharmacodynamics, School
Lucia, Australia
of Pharmacy, University of Queensland, Woolloongabba, Australia
9
3
Department of Pharmacy, Royal Brisbane and Women’s Hospital,
Department of Pharmacy, Gold Coast University Hospital, Brisbane, Australia
Southport, Australia
10
Department of Intensive Care Medicine, Royal Brisbane and
4
Department of Intensive Care, Gold Coast University Hospital, Women’s Hospital, Brisbane, Australia
Southport, Australia 11
Division of Anaesthesiology Critical Care Emergency and Pain
5
University of Queensland Centre for Clinical Research, Faculty of Medicine, Nîmes University Hospital, University of Montpellier,
Medicine, University of Queensland, Herston, Australia Nîmes, France

Introduction
Ceftriaxone is a clinically important intravenous broad-
spectrum cephalosporin β-lactam antibiotic commonly pre-
scribed in the emergency department (ED) for the manage-
ment of severe pneumonia, urinary tract infections and intra-
abdominal infections [1]. It is clear that prescribing an empiric
antibiotic to which the causative pathogen is sensitive to re-
duces the risk of mortality in patients with sepsis; therefore,
ceftriaxone may be used empirically given its favourable ac-
tivity against pathogens such as Escherichia coli,
Streptococcus pneumoniae, Klebsiella pneumoniae and
Haemophilus influenzae [2]. However, the clinician should
also optimise the antibiotic dose. Administering a dose that
achieves a cephalosporin concentration exceeding the patho-
gen minimum inhibitory concentration (MIC) throughout the
dosing interval (% fT>MIC) is associated with an approximate
threefold increase in clinical cure rates and an approximate
twofold increase in bacterial eradication rates compared with
patients not meeting this target exposure [3, 4]. These are
important considerations as antibiotics prescribed in the ED
are likely to be continued on admission to hospital; therefore,
the selection of an appropriate antibiotic given at the optimal
dose in the ED is highly likely to contribute to positive patient
outcomes [5, 6].
Prescribing the ceftriaxone dosing regimen that achieves
optimal exposure in patients with sepsis is challenging due
to the underlying pathophysiological changes that occur.
These can include the following: fluid shifts from third spac-
ing, augmented renal clearance (creatinine clearance ≥ 130
mL/min/1.73 m2), altered hepatic/biliary elimination and
hypoalbuminaemia increasing the unbound ceftriaxone frac-
tion of this highly protein-bound (> 90%) antibiotic [7, 8].
Some of these physiological changes may be exacerbated by
fluid resuscitation, which may further dilute albumin and con-
tribute to an increased volume that the antibiotic must distrib-
ute into [7]. Moreover, these physiological changes are likely
to be pronounced on presentation to ED, early in the course of
sepsis. Previous studies in critically ill patients admitted to the
intensive care unit (ICU) highlight that 1-g or 2-g once-daily
dosing regimens are unlikely to achieve the optimal exposure
associated with improved clinical outcomes, a 100% fT>MIC
[9–12]. However, as patients with sepsis may not be confined
to the intensive care unit, ceftriaxone dose optimisation for
other patients who present to the ED should also be reviewed
to potentially improve patient outcomes [13, 14]. However,
many guidelines provide a wide dosing range, from 1 g once-
daily to 2 g twice-daily [1, 15–17]. This may prompt clinicians
to use a lower dose, which remains in accordance with man-
ufacturer’s recommendations [18]. Importantly, there is con-
flicting evidence for a higher dosing regimen. One small study
of patients in Japan with community-acquired pneumonia re-
ceiving a 1-g once-daily dose compared with propensity-
Eur J Clin Pharmacol
matched patients receiving 2 g once-daily showed no signifi-
cant difference in clinical cure rates [19]. In contrast, pharma-
cokinetic studies in patients with sepsis admitted to the inten-
sive care unit show that a 1 g twice-daily dose likely achieves
the therapeutic target ceftriaxone exposure [20].
In the absence of robust clinical evidence directly compar-
ing ceftriaxone dosing regimens with patient-centered out-
comes, an approach that aims to determine the likely optimal
dose based on pharmacokinetic principles may be beneficial.
This research therefore aims to determine if a 1 g once-
daily ceftriaxone dose achieves recommended therapeutic tar-
get of an unbound trough concentration exceeding 0.5 mg/L
for > 90% of adult patients with sepsis not admitted to the
intensive care unit.
Methods
Setting
This single-centre prospective observational pharmacokinetic
study was conducted within a tertiary hospital in South-East
Queensland. Waiver of informed consent was granted by the
Gold Coast University Hospital Ethics Committee HREC/18/
QGC/100.
Study population
Adult patients (age ≥ 18 years) admitted to hospital via the ED
for ≥ 24 h receiving ceftriaxone 1 g intravenously once-daily
for the treatment of sepsis were eligible for inclusion in the
study. Sepsis was defined as having a presumed or microbio-
logical confirmed infection with a Systemic Inflammatory
Response Score (SIRS) ≥ 2 of a temperature ≥ 38 or ≤ 36
°C, a heart rate ≥ 90 beats per minute, respiratory rate ≥ 20
per minute or a white cell count ≥ 12 × 109 cells/L; or a Quick
Sequential Organ Failure Assessment (qSOFA) Score ≥ 2 of a
systolic blood pressure ≤ 90 mmHg, Glasgow Coma Scale ≤
14 or a respiratory rate ≥ 22 per minute [21]. The following
patients were excluded: pregnant, receiving either intermittent
or continuous dialysis, received a ceftriaxone dosing regimen
other than 1 g once-daily, or required intensive care unit ad-
mission. Patients admitted to ICU were excluded as most
would receive a 1 g twice-daily dose, consistent with current
evidence in the ICU population, and the primary aim of this
study was to enable a robust evaluation of the 1-g once-daily
dosing regimen that may be used on general wards. Clinical
and anthropometric data including the patient’s age (years),
weight (kg), height (cm), systolic blood pressure (mmHg),
heart rate (beats per minute), temperature (°C), respiratory rate
(per minute), Glasgow Coma Scale, suspected infection
source, microbiological results, liver transaminases (aspartate
aminotransferase, alanine aminotransferase, gamma-glutamyl
Eur J Clin Pharmacol
transferase, alkaline phosphatase [U/L]), albumin (g/L), lac-
tate (mmol/L), unconjugated and conjugated bilirubin
(μmol/L) and creatinine (μmol/L) were extracted from the
patient’s medical record where available. Suspected infection
source was per the treating clinician’s working diagnosis. A
sample size of 50 patients has previously been shown to ade-
quately describe the population mean area under the
concentration-time curve [22].
Sample handing, storage and measurement
Blood specimens taken in an ethylenediaminetetraacetic acid
(EDTA)–containing vial as part of routine clinical practice
were used to determine the ceftriaxone concentration. Only
one sample was taken per patient at variable times throughout
the first ceftriaxone dosing interval. Samples were centrifuged
at 3000 rpm for 10 min and stored at − 80 °C until analysis.
Analysis was conducted using a previously validated and pub-
lished methodology [23] with the following modifications.
Briefly, unbound ceftriaxone was separated from plasma
using an Amicon Ultra Centrifugal 30-kDa filter. Unbound
ceftriaxone plasma concentrations were quantified using an
Ultra Performance Liquid Chromatography (UPLC) coupled
with QDa Mass Detection (Waters Corporation, Milford, MA,
USA). The lower limit of quantification was 0.1 mg/L and
imprecision was < 10% at all concentrations tested (0.1–50
mg/L). No bias has been identified compared with target total
ceftriaxone concentrations. Our assay is approved as an
in vitro diagnostic product with the appropriate certified ref-
erence material used to calibrate our method.
Population pharmacokinetic modelling
Unbound ceftriaxone concentrations were analysed using
Pmetrics version 1.5.0 software package for R, which allows
for non-parametric parameter estimation thereby making no
assumption of the underlying parameter estimate data distri-
bution [24]. Parametric approaches may underestimate the
population inter-individual parameter variance when com-
pared with a non-parametric approach that has been shown
to appropriately describe extreme parameter estimates [25].
A one-compartment pharmacokinetic model was assessed.
Both the additive and multiplicative error models incorporat-
ing a linear residual error estimate within Pmetrics were tested
and optimised using an iterative process based on model di-
agnostics. Diagnostic plots, including the observed vs. pre-
dicted concentrations, residuals vs. predicted concentrations
and vs. time; as well as statistical comparison tests including
the Akaike Information Criterion (AIC), Bayesian
Information Criterion (BIC) and log-likelihood ratio (LLR)
were considered to compare different models.
Patient variables were selected a priori for potential inclu-
sion in the model to account for inter-patient variability based
on physiological plausibility. Variables assessed against the
volume of distribution and clearance included age (years), sex,
weight (kg), height (cm), creatinine clearance (determined
using the Cockcroft-Gault equation using total body weight)
expressed as mL/min [26], lactate (mmol/L), albumin (g/L),
conjugated and unconjugated bilirubin (μmol/L), and liver
transaminases (aspartate aminotransferase, alanine amino-
transferase, gamma-glutamyl transferase, alkaline phospha-
tase [U/L]). The incorporation of different patient variables
into the model that reduced the LLR, AIC, or BIC and/or
improving the goodness-of-fit plots was included.
Probability of target attainment and fractional target
attainment
Monte Carlo simulations (n = 1000) were performed using
ceftriaxone doses of 1 or 2 g administered once- or twice-
daily in patients with a creatinine clearance ranging from 20
to 140 mL/min. The probability of these regimens achieving a
target unbound ceftriaxone concentration (probability of tar-
get attainment; PTA) exceeding the bacterial MIC throughout
the dosing interval (fT>MIC 100%) for MICs ranging from
0.032 to 1 mg/L was determined. Given that many microbio-
logical laboratories do not report a specific MIC, target expo-
sures for this study were a free minimum concentration (fCmin)
≥ 0.5 mg/L based on the current European Committee of
Antimicrobial Susceptibility Testing (EUCAST) breakpoints
[27].
The fractional target attainment (FTA) represents the prob-
ability that patients would achieve the antibiotic therapeutic
target against a specific pathogen assuming a wild-type distri-
bution of susceptible MICs. The FTA, assuming an unbound
ceftriaxone target of fT>MIC 100%, was calculated for the
above ceftriaxone dosing regimens for susceptible
S. pneumoniae, H. influenzae, E. coli, and K. pneumoniae
isolates using the MIC distribution obtained from the
EUCAST database (available from www.eucast.org).
Dosing regimens were considered successful if the PTA
was ≥ 90% of the simulated patient population.
Results
Study population
Ceftriaxone concentrations were available for 50 patients
(Table 1). These patients had a mean age of 69 years (standard
deviation 15.6 years), with mild-moderate renal impairment
(eGFR 63.48 [standard deviation 23.6] mL/min/1.73 m2).
Patients are presented to the ED with predominantly respira-
tory tract infections (86%). Two isolates had an MIC avail-
able. One S. pneumoniae and one H. influenzae had MICs of
0.016 and 0.032 mg/L respectively.
 Eur J Clin Pharmacol

Table 1 Patient demographic details value (63 mL/min) (Eq. 1). Incorporating TVNR with TVR
Median (IQR) or N (%) reduced the LLR, AIC, and BIC by 6, 3.6, and 2 respectively.
as appropriate The linear adjustment of TVR with creatinine normalised to
63 mL/min reduced the LLR, AIC, and BIC each by 25.5. The
Age, years 73 (58.25–80.75) final model was adequately fit as described by the visual pre-
Weight, kg 72.4 (59.26–81.38) dictive check (Fig. 1) and a population- and individual-
Lactate, mmol/L 1.7 (1.2–2.6) predicted model R2 of 0.47 and 0.99 respectively. Other pa-
Albumin, g/L 34 (31–37) tient covariates (age, weight, albumin, lactate, liver transami-
Creatinine, μmol/L 82.5 (63.25–114.75) nases, unconjugated bilirubin, and conjugated bilirubin) did
Creatinine clearance, mL/min 62.39 (39.15–82.64) not improve the model performance. Final model parameter
Conjugated bilirubin, μmol/L 4 (4–6) estimates are described in Table 2. The moderate-high coeffi-
Unconjugated bilirubin, μmol/L 14 (8–20) cient of variation (CV%) may suggest, at least in part, poor
Alkaline phosphatase, U/L 78 (68–104.5) model precision for the parameter estimates, and also impor-
Gamma-glutamyl transferase, U/L 28 (16–70.75) tantly, reflecting the pharmacokinetic variability of unbound
Aspartate aminotransferase, U/L 21 (16.25–38.75) ceftriaxone in this patient cohort. Furthermore, the TVNR
Alanine aminotransferase, U/L 19 (11–33.5) estimates are skewed as indicated by the difference between
qSOFA Score the mean and median values. The cause of this is likely related
0, n (%) 11 (22) to the heterogeneous patient population included in the study.
1, n (%) 28 (56)
≥ 2, n (%) 11 (22) 
CrCl
SIRS Score Ceftriaxone Clearance ¼ TVNR þ TVR  Þ ð1Þ
1, n (%) 4 (8)
63
2, n (%) 15 (30)
3, n (%) 22 (15)
4, n (%) 9 (18) Dosing simulations
Infection source
Gastrointestinal (%) 3 (6) The PTA for common ceftriaxone dosing regimens is present-
Respiratory (%) 43 (86) ed in Fig. 2. The probability of attaining a therapeutic expo-
Urinary tract (%) 3 (6) sure (100% fT>MIC) within the first 24 h of therapy in ≥ 90%
Unknown (%) 1 (2) of patients receiving a 1 g once-daily dose is only likely for
Causative Pathogen patients with an impaired renal function (CrCL ≤ 60 mL/min)
(total n, susceptible n) for an isolate with an MIC ≥ 0.25 mg/L. Patients with a CrCl
S. pneumoniae 2, 2 between 60 and 120 mL/min require a minimum of a 2 g once-
H. influenzae 2, 1 daily dose for optimal activity against susceptible bacteria per
C. perfringens 1, 0 current EUCAST clinical breakpoints [27]. When considering
Influenza A 2, NA
E. coli 2, 2
S. aureus 3, 3
Parainfluenzae 3 1, NA

IQR, interquartile range; N, number

Pharmacokinetic model

The unbound ceftriaxone concentration time profile was ade-

quately described using a one-compartment model with linear
elimination incorporating an additive error model where error
= (standard deviation2 + 0.32)0.5 and the standard deviation is
Fig. 1 Observed unbound ceftriaxone concentration time data and visual
0.1 + 0.012. The model fit was improved by including a typ- predictive check of the final model. Blue lines represent the model
ical population value for non-renal clearance (TVNR) and the predicted 5th and 95th centiles. Red lines represent the model predicted
typical value for renal clearance (TVR) incorporating creati- 25th and 75th quartiles. Filled dots represent observed patient unbound
ceftriaxone concentrations.
nine clearance (CrCl) normalised to the population median
Eur J Clin Pharmacol

Table 2 Ceftriaxone pharmacokinetic model parameter estimates Discussion

Parameter Mean (SD) Median CV%
The present study has demonstrated that a 1 g once-daily dose
TVNR (L/h) 4.27 (4.77) 1.66 111.66 is unlikely to achieve a therapeutic ceftriaxone exposure in
TVR (L/h) 4.83 (3.69) 4.70 76.43 patients presenting to the ED with a creatinine clearance ≥
Vd (L) 116.21 (62.22) 99.87 53.54 60 mL/min, infected with a susceptible pathogen with an
MIC ≥ 0.25 mg/L. Overall, a 2 g once-daily dose is likely to
TVNR, non-renal ceftriaxone clearance; TVR, renal ceftriaxone clearance;
be optimal in most adult patients admitted to the hospital from
Vd, volume of distribution
the ED with sepsis. The use of a once-daily dose is also con-
venient and may limit the potential for a delayed second anti-
biotic dose that can occur between patient transfers from the
the FTA for specific bacterial species, a 1 g once-daily ceftri- ED to another team [28].
axone dose is adequate for H. influenzae for patients with any A recent study by Bos and colleagues conducted in adult
renal function, including augmented renal clearance (Table 3). patients with sepsis from Africa who were not admitted to the
In contrast, a 1 g once-daily dose is insufficient for patients ICU showed that a dose of 2 g twice-daily may be required to
with a CrCl ≥ 120 mL/min against K. pneumoniae, E. coli, and achieve the same therapeutic exposure (100% fT>MIC with an
S. pneumoniae. Increasing the ceftriaxone dose to 2 g once- isolate MIC of 0.5 mg/L) as targeted in our study [29].
daily will reliably achieve a fT>MIC of 100% for ≥ 90% of all Furthermore, the mean unbound volume of distribution and
isolates, even in patients with augmented renal clearance clearance identified by Bos et al. was 48 L and 11 L/h com-
(Table 3). pared with our values of 116.87 L and 9.1 L/h respectively.

Table 3 Fractional target attainment for different ceftriaxone dosing regimens and bacterial species

Dosing regimen and CrCL (mL/min) Fractional target attainment (%) for 100% fT>MIC by bacterial species

E. coli H. influenzae K. pneumoniae S. pneumoniae

1 g once-daily
20 100 99 99 98
40 98 99 97 96
60 97 97 97 94
80 97 96 96 92
100 95 95 93 89
120 93 93 90 85
140 89 90 85 81
1 g twice-daily
20 100 100 100 100
40 100 100 100 100
60 100 100 100 100
80 100 100 99 99
100 100 100 99 99
120 98 99 98 98
140 98 99 98 97
2 g once-daily
20 100 100 100 100
40 100 100 100 100
60 100 100 100 100
80 100 100 99 99
100 100 100 99 99
120 98 99 98 98
140 98 99 98 97
2 g twice-daily
20 100 100 100 100
40 100 100 100 100
60 100 100 100 100
80 100 100 100 100
100 100 100 99 99
120 99 99 99 99
140 98 99 98 98
 Eur J Clin Pharmacol

Although the ceftriaxone model included total and unbound
concentrations from an intensive sampling strategy in the
study conducted by Bos et al., the key difference between
studies is the patient cohort. Bos et al. primarily included a
younger patient cohort (median age 35 years, range 18–76)
with a lower albumin (median 29 g/L, range 11-44) who were
also seemingly of a much lower weight (mean BMI 18.9 kg/
m2) compared with our study [29]. Moreover, both our study
and the study conducted by Bos et al., like most pharmacoki-
netic studies, only modelled plasma ceftriaxone concentra-
tions and not the antibiotic concentration at the site of
infection.
In the case of patients with pneumonia, infection often
involves the epithelial lining fluid (ELF) [30, 31]. There is
no currently available data regarding ceftriaxone ELF concen-
trations, which may be as low as 20% that of concurrent plas-
ma concentrations in the case of many other β-lactam antibi-
otics [31]. Although there is limited data regarding target site
antibiotic concentrations and outcomes, current evidence
would suggest that optimising the antibiotic concentration at
the site of infection would improve bactericidal activity
[30–32]. This may be an important consideration given the
low FTA in plasma samples for the current 1 g once-daily
ceftriaxone dosing, particularly for patients with
S. pneumoniae (Table 3).
Other ceftriaxone pharmacokinetic studies have been con-
ducted in critically ill patients admitted to ICU which are
likely to be a more seriously affected cohort than studied here.
Joynt et al. [20] described a two-compartment pharmacokinet-
ic model for ceftriaxone in patients admitted to the ICU, with a
Vd of the central compartment of 6 L and a clearance of 9.2 h;
however, this represents the total, not the unbound ceftriax-
one. In contrast, our unbound ceftriaxone mean Vd was
116.87 L with a total average clearance of 9.1 L/h, which is
related to the different (total or unbound) concentrations
assayed. A separate pharmacokinetic study, also conducted
in ICU patients [33], identified an unbound total volume of
distribution of 87.5 L and unbound clearance of 10.61 L/h,
which is similar to that identified in our study. Therefore, the
differences in dosing recommendations between studies (the
current study 2 g once-daily compared with 1–2 g twice-daily
recommended by Ollivier et al.) likely pertain to the lower
albumin concentrations in patients admitted to the ICU and
potential augmented renal clearance observed in such patients
[33]. It has been previously demonstrated that ceftriaxone un-
dergoes biliary (non-renal) elimination [34]. This would likely
account for our observation that the pharmacokinetic model
was improved by incorporating a non-renal clearance
parameter.
Despite the potential benefits of dose optimisation, the con-
cern of clinicians may be that increasing the dose from the
manufacturer recommendation of 1 g once daily may both
increase the potential for dose-related adverse events. Data
regarding ceftriaxone adverse events is lacking, but this risk
is likely low even with doses exceeding 4 g/day in patients
without renal dysfunction [33]. In a small study, the absolute

a Ceftriaxone 1 g once-daily b Ceftriaxone 1 g twice-daily

1.0 1.0
CrCl 20 mL/min CrCl 20 mL/min
Probability of Success

Probability of Success

0.9 0.9
0.8 CrCl 40 mL/min 0.8 CrCl 40 mL/min
0.7 0.7
CrCl 60 mL/min CrCl 60 mL/min
0.6 0.6
0.5 CrCl 80 mL/min 0.5 CrCl 80 mL/min
0.4 CrCl 100 mL/min 0.4 CrCl 100 mL/min
0.3 0.3
CrCl 120 mL/min CrCl 120 mL/min
0.2 0.2
0.1 CrCl 140 mL/min 0.1 CrCl 140 mL/min
0.0 0.0
0.032 0.064 0.125 0.25 0.5 1 0.032 0.064 0.125 0.25 0.5 1
Pathogen MIC (mg/L) Pathogen MIC (mg/L)

c Ceftriaxone 2 g once-daily
d Ceftriaxone 2 g twice-daily
1.0 1.0
CrCl 20 mL/min CrCl 20 mL/min
Probability of Success

Probability of Success

0.9 0.9
0.8 CrCl 40 mL/min 0.8 CrCl 40 mL/min
0.7 0.7
CrCl 60 mL/min CrCl 60 mL/min
0.6 0.6
0.5 CrCl 80 mL/min 0.5 CrCl 80 mL/min
0.4 CrCl 100 mL/min 0.4 CrCl 100 mL/min
0.3 0.3
CrCl 120 mL/min CrCl 120 mL/min
0.2 0.2
0.1 CrCl 140 mL/min 0.1 CrCl 140 mL/min
0.0 0.0
0.032 0.064 0.125 0.25 0.5 1 0.032 0.064 0.125 0.25 0.5 1
Pathogen MIC (mg/L) Pathogen MIC (mg/L)

Fig. 2 Probability of target attainment (unbound ceftriaxone concentration 100% fT>MIC) for ceftriaxone administered as a 1 g once-daily dose (a), 1 g
twice-daily dose (b), 2 g once-daily dose (c), and 2 g twice-daily dose (d)
Eur J Clin Pharmacol
risk of a suspected ceftriaxone adverse reaction was 8.7%,
which was associated with total trough concentrations ≥ 100
mg/L, greatly exceeding the target exposure used for dosing
simulations in our study [35]. Together, the low risk of dose-
related adverse events and the potential benefits may promote
the adoption of a convenient 2 g once-daily or 1 g twice-daily
dosing regimen in most patients with sepsis.
Limitations
Our study is not without limitations. First, a sparse sampling
strategy was used that may result in imprecise parameter esti-
mates within a specific patient’s dosing interval. Nonetheless, the
data presented herein are similar to previous studies conducted in
intensive care unit patients receiving a 2 g once-daily dose [20].
Second, samples were not taken on different days of therapy to
assess temporal changes in ceftriaxone pharmacokinetics. This is
particularly relevant given that patient’s physiology may fluctu-
ate with time and biological markers, such as creatinine, and may
not reflect the current physiological state. Third, only the un-
bound ceftriaxone concentration was assayed and as such we
were unable to account for changes in ceftriaxone binding that
is highly likely to influence the extent of tissue distribution and
vary with albumin concentration. Fourth, the small sample size
including predominantly older patients may not generalise to a
younger patient cohort. Fifth, the MIC distribution for the FTA
was obtained from the EUCAST database, which may reflect a
different pathogen MIC distribution depending on the geograph-
ical location. Sixth, as only patients receiving a 1 g once-daily
ceftriaxone dose were included, future studies are required to
determine if the recommended 2 g once-daily dose is able to
achieve the desired targets as demonstrated in our simulations.
Seventh, sepsis was defined using the SIRS criteria, which does
not reflect the latest Sepsis-3 guidelines [21]; nonetheless, we
have shown in this ill patient cohort that a dose of 2 g once-
daily is the minimum dose that is likely to achieve target expo-
sures. Last, patient-centered outcomes such as mortality or tox-
icity were not assessed in this study—an important focus for
future studies assessing different dosing regimens.
Conclusions
In conclusion, based on the potential benefits of optimised
ceftriaxone dosing and the limited risk of adverse events, we
would recommend the routine use of a 2 g once-daily dose of
ceftriaxone for the management of adult patients with sepsis.
Future studies should be conducted determining if there is a
clinical benefit for the use of a higher daily dose of 1 g twice-
daily or 2 g once-daily as compared with a 1 g once-daily
regimen.
Acknowledgements Aaron J. Heffernan would like to acknowledge
funding from a Griffith School of Medicine Research Higher degree
scholarship; Fekade B. Sime acknowledges funding from the University
of Queensland Post-Doctoral Fellowship (W. T. Allen Bequest);and
Jason Roberts would like to acknowledge funding for a National Health
and Medical Research Council (NHMRC) Centre of Research Excellence
(APP1099452), an NHMRC Project Grant (APP1062040) and a
Practitioner Fellowship (APP1117065).
Authors’ contributions AJH—study design, data collection, data
curation, data analysis, and writing—original draft
RAC—study design, data collection, writing—original draft, review,
and editing
KJD—study design, data analysis, writing, review, and editing
FBS—data analysis, writing, review, and editing
CLS—study design, writing, review, and editing
BMcW—study design, sample analysis, writing, review, and editing
JU—study design, sample analysis, writing, review, and editing
JAR—study design, data analysis, writing, review, and editing
JL—study design, project administration, funding acquisition, writing,
review, and editing
Data availability Data will not be shared per specific ethics requirements.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict o
interest.
Ethics statement Waiver of informed consent was granted by the Gold
Coast University Hospital Ethics Committee HREC/18/QGC/100.
Code availability R code and model files will be available on specific
reasonable request.
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