J Antimicrob Chemother

doi:10.1093/jac/dky553

Tolerability of high-dose ceftriaxone in CNS infections: a prospective

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multicentre cohort study
Paul Le Turnier 1*, Dominique Navas2,3, Denis Garot4, Thomas Guimard5, Louis Bernard6, Pierre Tattevin7,
Yves Marie Vandamme8, Jérôme Hoff9, Anne Chiffoleau10, Martin Dary11, Laurene Leclair-Visonneau12,
Matthieu Grégoire2,13, Morgane Pere14, David Boutoille1,2, Véronique Sébille14, Eric Dailly2,13
and Nathalie Asseray1 on behalf of the High-Dose Ceftriaxone CNS Infections Study Group†

1
Department of Infectious Diseases, Nantes University Hospital and CIC 1413, INSERM, Nantes, France; 2EA 3826, University of Nantes,
Nantes, France; 3Pharmacy Department, Nantes University Hospital, Nantes, France; 4Intensive Care Unit, Anaesthesia and Critical
Care Department, Tours University Hospital, Tours, France; 5Infectious Diseases Department, La Roche sur Yon Hospital, La Roche sur
Yon, France; 6Infectious Diseases Department, Tours University Hospital, Tours, France; 7Infectious Diseases Department, Rennes
University Hospital, Rennes, France; 8Infectious Diseases Department, Angers University Hospital, Angers, France; 9Intensive Care Unit,
Anaesthesia and Critical Care Department, Saint Nazaire Hospital, Saint Nazaire, France; 10Pharmacovigilance, Research Board, Nantes
University Hospital, Nantes, France; 11Emergency Department, Nantes University Hospital, Nantes, France; 12Neurology and
Neurophysiology Department, Nantes University Hospital, Nantes, France; 13Clinical Pharmacology Department, Nantes University
Hospital, Nantes, France; 14Biostatistics Unit, Research Board, Nantes University Hospital, Nantes, France

*Corresponding author. Infectious Diseases Department, Nantes University Hospital, Hotel Dieu, Place Alexis Ricordeau, 44093 Nantes cedex, France.
Fax: !33-2-40-08-33-30; E-mail: paul.leturnier@gmail.com orcid.org/0000-0002-6164-311X
†Members are listed in the Acknowledgements section.

Received 21 August 2018; returned 2 October 2018; revised 14 November 2018; accepted 28 November 2018

Background: Ceftriaxone is widely used to treat community-acquired CNS bacterial infections. French guidelines
for meningitis in adults promote 75–100 mg/kg/day ceftriaxone without an upper limit for dosage, yet little is
known about the pharmacology and tolerability of such regimens.
Patients and methods: A multicentre prospective cohort study was conducted in adult patients to assess the
adverse drug reactions (ADRs) of high-dose ceftriaxone (i.e. daily dosage 4 g or 75 mg/kg) in CNS infections
and to analyse their related factors. Drug causality was systematically assessed by an expert committee who
reviewed the medical charts of all included patients.
Results: A total of 196 patients were enrolled over a 31 month period. Median dosage and duration of ceftriax-
one were 96.4 mg/kg/day (7 g/day) and 8 days, respectively. Nineteen ceftriaxone-related ADRs (mainly neuro-
logical) occurred in 17 patients (8.7%), with only one case of treatment discontinuation (biliary pseudolithiasis).
In univariate analysis, older age, male gender, renal impairment and high trough ceftriaxone plasma concentra-
tion were associated with ceftriaxone-related ADRs.
Conclusions: High-dose ceftriaxone for CNS infection administered as recommended by French guidelines in
adults was well tolerated overall, suggesting these recommendations could be applied and generalized. In
patients with advanced age or renal insufficiency, prescription should be done with caution and therapeutic drug
monitoring could be useful.

Introduction administration.2,3 In accordance with the regulatory framework,

CNS bacterial infections, mainly represented by community-
acquired bacterial meningitis (CABM), are usually considered as se-
vere and difficult-to-treat infections. Because of the low diffusion
of antibiotics into CSF and cerebral parenchyma, recommenda-
tions are to use high dosages of antibiotics.1 Cephalosporins are
widely used in this therapeutic indication, especially
ceftriaxone because of its antibacterial spectrum and ease of
ESCMID and IDSA guidelines for bacterial meningitis in adults rec-
ommend a ceftriaxone dosage limited to 4 g/day as a single or
double injection with no body weight adjustment.4,5 In 2008, the
French guidelines for bacterial meningitis treatment in adults rec-
ommended the administration of monotherapy of a high dose of
either cefotaxime or ceftriaxone (except in the case of suspected
neurolisteriosis), adjusted to body weight.6 Specifically, 75 to

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Le Turnier et al.
100 mg/kg ceftriaxone (in one or two injections per day) was rec-
ommended without an upper limit or adjustment for renal func-
tion. Such a dosage was proposed to provide adequate coverage
of all strains of Streptococcus pneumoniae encountered in bacter-
ial meningitis.
However, the pharmacological properties of ceftriaxone treat-
ment above 4 g/day are unknown. Besides, the toxicity of such
high-dose ceftriaxone regimens is unknown despite several
reports of toxicity related to high doses.7,8
This study aimed to assess the toxicity of a high-dose regimen
of ceftriaxone (i.e. daily dosage 4 g or 75 mg/kg/day) adminis-
tered for CNS infection in an adult population, through screening
and characterizing of ceftriaxone-related adverse drug reactions
(ADRs). Secondarily, associated factors were analysed.
Patients and methods
Ethics
This study was approved by the Western Protection Committee (ref 2012/
12) and regulatory authorities according to French rules and research clinic-
al practice. The study has been registered both by the French Agency for
Drug Safety (ANSM) and the US FDA (registration available on
ClinicalTrials.gov under identifier NCT01745679). All included patients or
legal representatives gave their written consent for their participation.
Study design and data collection
This was an open-label, multicentre, prospective pharmacoepidemiological
cohort study conducted between December 2012 and July 2015 in six
French hospitals located in western France (Nantes University Hospital,
Angers University Hospital, Saint Nazaire Hospital, Tours University Hospital,
La Roche sur Yon Hospital and Rennes University Hospital). Adult inpatients
(aged 18 years) were enrolled when treated for a community- or
hospital-acquired CNS infection (suspected or proven) with intravenous ad-
ministration of ceftriaxone at a dosage of 4 g/day or 75 mg/kg/day as
recommended by the French guidelines. Patients enrolled in a clinical trial
with a blinded medication were excluded. Initial therapeutic indication for
ceftriaxone was classified as community-acquired meningitis, post-
operative meningitis or cerebral abscess and empyema. Patients were
included within the first 5 days of ceftriaxone therapy. Changes in ceftriax-
one regimen were collected in terms of dosing frequency and dosage (total
daily dose). An electroencephalogram (EEG) was performed at baseline for
each included patient. Data were prospectively collected from the initiation
of ceftriaxone therapy until its discontinuation. Anonymized case report
forms (CRFs) were used for data collection on patients’ history, clinical signs
and laboratory findings at admission, imaging, clinical course, co-
administered drugs, ceftriaxone dosage and dosing frequency, ceftriaxone
plasma concentrations, adverse events including suspected ADRs, cause of
ceftriaxone discontinuation and outcome.
Investigators had to perform all required additional investigations for
complete documentation in cases of AEv occurrence, paying special atten-
tion to ceftriaxone-related ADRs. A second EEG was systematically done in
cases of neurological adverse events.
Expert committee and drug causality assessment
method
The expert committee included a physician specialized in infectious dis-
eases, an emergency physician, a clinical pharmacist and a pharmacovigi-
lance specialist. The committee was independent from investigators. The
role of the expert committee was to retrospectively review all included
cases to obtain a final diagnosis at the end of study.
2 of 8
The role of the expert committee was also to analyse each overall clinic-
al course through a systematic review of completed CRFs to detect any ad-
verse events. They had access to overall data of the study via electronic-
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CRFs (including associated medication). When necessary, the experts could
ask for complementary medical information from the investigators.
Among the adverse events, the expert committee especially assessed
the ceftriaxone-related ADRs based on a two-step method. First, the expert
committee used the WHO-UMC classification to screen ADRs.9 Screened
ADRs were then selected as ceftriaxone-related if a causal relationship was
a reasonable possibility as recommended by the EMA.10
All neurological alterations reported by the investigator were assessed
by the expert committee as mentioned above. Liver toxicity was defined as
cholestatic or cytolytic alterations identified with routine blood monitoring.
Renal toxicity was defined as elevation of blood urea and/or creatinine lev-
els. Neutropenia was defined as a neutrophil polynuclear count ,0.5%109/L
and thrombocytopenia was defined by a platelet count ,150%109/L.
The severity of ADRs was graded according to the common terminology
criteria for adverse events (CTCAE) scale available at the time of protocol
drafting.11
The safety data were transmitted to the authorities and the Ethics
Committee according to French and European regulatory frameworks.
Sample collection and determination of ceftriaxone
plasma concentration
Total and free plasma concentrations of ceftriaxone were measured at
steady-state (i.e. after at least 48 h of ceftriaxone treatment) within 2 h
prior to the next intravenous administration, corresponding to a trough con-
centration.12 Total plasma ceftriaxone concentrations were determined by
HPLC with UV detection in two reference centres of the study (Rennes and
Nantes).13 Free plasma concentration was considered since ceftriaxone is a
high plasma protein-binding drug and free concentration is responsible for
tissue diffusion. Free plasma concentrations of ceftriaxone were obtained
according to a previously validated method using the Amicon Ultra 0.5 mL
30 000 molecular weight cut-off centrifugal filter device (Millipore, Cork,
Ireland) after centrifugation at 37 C from the plasma used to measure total
plasma concentrations.14 A second measure, dedicated to an ancillary
population pharmacokinetic (PK) analysis was performed at any time during
the ceftriaxone treatment.15 The consistency of results between the
pharmacology departments of Nantes and Rennes University Hospitals was
verified by exchanging samples between both departments. Both pharma-
cology departments are subject to external quality controls by an organiza-
tion that complies with ISO 15189 (ASQUALAB, Paris) on a 2 monthly basis.
Statistical analyses
Quantitative data are expressed as median and IQR and qualitative data
are expressed as percentages. Patients with ceftriaxone-related ADRs were
compared with the rest of the cohort to identify factors associated with cef-
triaxone toxicity. First, clinically pertinent variables were tested in univariate
analysis. These variables were: age, gender, BMI 25 kg/m2, pre-existing
neurological condition, baseline MDRD-calculated renal clearance at admis-
sion (where MDRD stands for Modification of Diet in Renal Disease Study
Equation), mental status alteration at hospital admission associated with
CNS infection, ICU admission, corticosteroid therapy, ceftriaxone initial daily
dosage and trough plasma concentrations of total and free ceftriaxone. All
variables were analysed using the v2 test or Fisher’s exact test as appropri-
ate. Since an association between ceftriaxone total plasma concentration
and ADR occurrence was observed in univariate analysis, a receiver operat-
ing characteristic (ROC) curve analysis was performed to assess the diag-
nostic performance of plasma levels and determine a threshold.
Subsequently, a multivariate logistic regression analysis was performed.
Variables associated with ceftriaxone-related ADR occurrence, with a P
value 0.20 in univariate analysis, were tested in the multivariate model
Tolerability of high-dose ceftriaxone in CNS infections
with a forward step-by-step approach. All statistical tests were two-tailed
and a P value of ,0.05 was taken to indicate statistical significance. All
analyses were performed using SAS software (version 9.4).
Results
Description of the study population
During the 31 months of enrolment, 198 patients were enrolled, 2
being secondarily excluded (Figure 1). Proven or suspected diagno-
sis leading to administration of high-dose ceftriaxone therapy was
CABM in most cases (73.0%, n " 143), cerebral abscess or empy-
ema in 13.8% (n " 27) and post-operative meningitis in 13.3%
(n " 26) of cases (Figure 1). Median age was 59 years (IQR 40–68).
The male-to-female ratio was 1.6. At the initiation of ceftriaxone
therapy, 61.2% (120/196) of patients had a neurological complica-
tion associated with the CNS infection: mental status alteration in
53.3% (104/195), seizure in 8.3% (16/193), focal neurological signs
(including cranial-nerve palsy) in 8.7% (17/196) and visual impair-
ment in 2.0% (4/196). At the end of study, the final diagnosis
retained by the expert committee was CABM in 55.6% (n " 109),
cerebral abscess or empyema in 12.8% (n " 25), post-operative
meningitis in 12.8% (n " 25), viral meningitis in 7.7% (n " 15) and
other diagnoses in 11.2% (n " 22) of the cases. In the subgroup of
patients initially suspected to have CABM, dexamethasone was
administered in 72.3% (99/137, missing data in 6 cases). Among
the 109 patients diagnosed with CABM at the end of the study, the
most frequent causative bacteria were S. pneumoniae (29.4%,
n " 32), Neisseria meningitidis (17.4%, n " 19), other streptococci
(10.1%, n " 11) and Haemophilus influenzae (8.3%, n " 9). Among
the 32 patients suffering from pneumococcal meningitis, 25 iso-
lates of S. pneumoniae were identified and tested for antibiotic
susceptibility. S. pneumoniae was susceptible to amoxicillin
(MIC  0.5 mg/L) in 23 cases and resistant (MIC . 0.5 mg/L) in 2
cases. Ceftriaxone susceptibility was reported for 22 S. pneumoniae
strains: 21 were susceptible (MIC  0.5 mg/L) and 1 showed
R
decreased susceptibility (MIC " 1 mg/L, EtestV). During the study
seven patients died (3.6% of study population); among them, six
had CABM ascertained by experts (5.5% of CABM) and one had
cerebral empyema.
The median ceftriaxone initial dosage was 96.4 mg/kg/day (IQR
81.6–103.9), corresponding to a median of 7 g/day (IQR 6–8). The
median duration of treatment was 8 days (IQR 5–12).
Two-thirds of the patients (n " 131) were treated with the same
ceftriaxone regimen (dosing frequency and dosage) during the
whole study period. The dosing frequency was modified in 27 cases:
9 patients received more injections (usually changing from one to
two) and 18 received fewer injections per day (usually changing
from two to one). Among patients with at least one dosage change
(n " 66), ceftriaxone dosage was increased for 34 patients (51.5%).
The median delay between ceftriaxone initiation and dosage
change was 1 day (IQR 1–3). Total ceftriaxone plasma concentra-
tions were measured in 189 patients (Figure 1). A ceftriaxone trough
plasma concentration at steady-state was available in 164 cases
for total ceftriaxone and in 126 cases for free ceftriaxone.
Description of the ceftriaxone-related ADRs
A ceftriaxone-related ADR was notified by the investigators in five
(2.6%) patients. After the expert committee analysis, the number
JAC
of patients experiencing ceftriaxone-related ADRs increased to 17,
corresponding to 8.7% (95% CI 5.1%–13.4%) of the study popula-
tion. Two patients had 2 ADRs, thus 19 different ADRs were
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reported in total (detailed in Table 1). Neurotoxicity (n " 7) was the
most frequently reported ADR. The neurotoxicity was initially
reported by the investigators as a ceftriaxone-related ADR in only
one case. In other cases, neurological symptoms were attributed
to CNS infection by the investigators. The median delay between
ceftriaxone initiation and onset of neurotoxicity symptoms was
5 days (IQR 3.5–6). Neurotoxicity symptoms lasted for a median of
5.5 days (IQR 3.5–9.25; missing data for one case). In one case, an
elevation of liver enzymes was noted by the investigator and consid-
ered as ceftriaxone-related hepatic toxicity, which led to its discon-
tinuation. Antibiotic therapy was switched to co-trimoxazole and the
patient’s condition improved. On assessment by the expert commit-
tee, this case was classified as ceftriaxone-related biliary pseudoli-
thiasis. No ceftriaxone-related deaths occurred during the study.
Factors associated with the occurrence of ceftriaxone-
related ADRs
Table 2 presents the baseline characteristics and therapeutic data
in patients with and without ceftriaxone-related ADRs. The univari-
ate analysis (see Table 3) revealed that older age (OR 1.06, 95% CI
1.02–1.10, P " 0.004) and male gender (OR 5.05, 95% CI 1.12–
22.74, P " 0.035) were risk factors for ceftriaxone-related ADRs.
Higher renal clearance was a protective factor (OR 0.98, 95% CI
0.97–1.00, P " 0.010). Despite a visible trend, receiving an initial
ceftriaxone daily dosage of 8 g was not significantly associated
with ADR occurrence (OR 2.54, 95% CI 0.9–7.18, P " 0.078).
However, among the eight patients initially receiving 10 g/day,
five (62.5%) developed a ceftriaxone-related ADR. An association
between the plasma concentration of ceftriaxone and
ceftriaxone-related ADRs was noted and further evaluated
through ROC analysis (Figure S1, available as Supplementary data
at JAC Online). Having a total ceftriaxone trough plasma concen-
tration above 100 mg/L was associated with the occurrence of
ceftriaxone-related ADRs (OR 4.06, 95% CI 1.31–12.60, P " 0.02).
This toxicity threshold had a sensitivity of 40% and a specificity of
85%. The multivariate analysis was limited by the small number of
patients with ceftriaxone-related ADRs and demonstrated only
age (increment of 1 year) and male gender as risk factors, with ORs
of 1.06 (95% CI 1.02–1.10) and 5.71 (95% CI 1.23–26.50),
respectively.
Discussion
In this study, high-dose ceftriaxone administered for CNS infection
was well tolerated overall and ceftriaxone-related ADRs were in-
frequent and mostly harmless.
In recent large cohort studies of bacterial meningitis or reviews
on CNS infections, no mention of cephalosporin toxicity is made,
despite elevated dosages, notably for ceftriaxone.2,3 A dosage of
ceftriaxone not exceeding 4 g/day has been advised by European
and US infectious diseases societies for the treatment of bacterial
meningitis. However, in 2008, French guidelines recommended
ceftriaxone posology of 75 to 100 mg/kg/day for acute bacterial
meningitis, depending on suspected bacteria and susceptibility
test results.6 In 2008, among the S. pneumoniae isolated from
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Le Turnier et al.

Enrolled patients
n = 198

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Excluded patients, n = 2
• 1 consent withdrawal
• 1 CRO treatment <24 h

Analysed patients
n = 196

Acute CABM Cerebral abscess/empyema Post-operative meningitis*

n = 143 n = 27 n = 26

CRO plasma concentration

n = 189

Steady-state trough concentration

total CRO n =164, free CRO n = 126

Figure 1. Flow chart of the study patients with initial therapeutic indication for ceftriaxone and details of plasma sampling for ceftriaxone dosage.
The asterisk indicates that this was an external ventricular drain-associated infection in four cases. CRO, ceftriaxone.

invasive infections in adults (bacteraemia and meningitis), the
French National Reference Centre for S. pneumoniae found a high
level of penicillin resistance (about 30% with MIC . 0.06 mg/L) but
susceptibility to injectable cephalosporins. Indeed, the intermedi-
ate (0.5 , MIC 2 mg/L)/resistant (MIC . 2 mg/L) S. pneumoniae
strains represented 9.3%/0.2% and 1.9%/0%, respectively, for
cefotaxime and ceftriaxone.16 Since then, reports have shown a
decrease in the penicillin resistance level (close to 20% in the last
few years) and maintenance of an even higher level of susceptibil-
ity to injectable cephalosporins.17 To our knowledge, no study has
specifically assessed ceftriaxone-related ADRs, when administered
at a dosage higher than 4 g/day, or factors associated with the oc-
currence of ADRs, including ceftriaxone plasma concentration. A
specific workflow was set up in this study to detect all ceftriaxone-
related ADRs. The low incidence observed, despite the very high
dosages, is reassuring and consistent with previous reports in
patients receiving ceftriaxone at 4 g per day. In a study of 45
patients with amyotrophic lateral sclerosis receiving ceftriaxone
therapy at a daily dose of 2 to 4 g, adverse events were noted in
11% of patients (n " 5) without assessment of drug causality and
only two treatment discontinuations occurred because of possible
toxicity in the group of patients receiving 4 g/day (one case of pul-
monary oedema and one of cholelithiasis).18 Other reports of
ceftriaxone-related toxicity in the literature concern patients
receiving lower daily dosages than in our study and reflect an over-
all limited toxicity.19,20 Herein, the only report of treatment discon-
tinuation was due to biliary pseudolithiasis with sludge formation.
Biliary toxicity is a well-known complication of high-dose ceftriax-
one treatment. In a recent retrospective study, a high dosage (4
versus 2 g) of ceftriaxone was a risk factor for hepatic toxicity.7
However, in the majority of cases sludge formation is a self-
resolving asymptomatic condition and in symptomatic cases cef-
triaxone cessation is sufficient to reverse it.21
Neurological toxicity, although the most frequent ADR in our
study, was reported in only seven cases. Its incidence appeared to
be relatively low considering the pre-existing neurological condi-
tion (CNS infection in this case), which is a recognized risk factor for
b-lactam toxicity.8 The delay between ceftriaxone initiation and
onset of neurotoxicity symptoms observed here was consistent
with previous reports of cephalosporin neurotoxicity.22 Other
ceftriaxone-related ADRs reported in the present study, such as
renal and haematological alterations and Clostridioides
(Clostridium) difficile infection, have also been previously
reported.18,23–25
Patients suffering from ceftriaxone-related ADRs were signifi-
cantly older than others. ADRs are more frequently reported in the
elderly population for multiple reasons.26 Above all, this population
is particularly susceptible to antibiotic-related neurotoxicity be-
cause of multifactorial cerebral frailty.8,27,28 This population is also
subject to drug overdosage due to impaired renal function. The in-
fluence of age on b-lactam-induced hepatic toxicity and the occur-
rence of C. difficile infection has also been reported.29,30
The influence of male gender on ceftriaxone tolerability was
unexpected. Nevertheless, the gender effect in the course of CNS
infection has already been described.31 There is no clear explan-
ation for these gender-based differences.
The link between ceftriaxone dosage and ceftriaxone-related
ADRs has been rarely studied. In experimental models, an associ-
ation between high doses of b-lactams and neurotoxicity, espe-
cially seizures, has been clearly demonstrated.27 However,
ceftriaxone is not usually considered as a major cause of neurotox-
icity compared with other b-lactams such as penicillin, imipenem
or cefazolin.32,33 A daily dosage not to exceed would have been

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Tolerability of high-dose ceftriaxone in CNS infections JAC
Table 1. Details of ceftriaxone-related ADRs (n " 19) in 17 patients

Severity

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Delay after graded by ADR attributed
Type of ceftriaxone experts on to ceftriaxone
ceftriaxone- Patient initiation Duration CTCAE treatment by
related ADRa number Symptoms (days) (days) scaleb Evolution investigators

Neurological toxicity 1 hallucination 6 1 2 RWS yes

2 seizure 3 4 4 (context of death no
septic
multiorgan
failure)
3a visual hallucination 10 unknown 2 improving at no
the end of
the study
4 confusion 2 10 2 RWS no
5 somnolence 6 7 2 RWS no
6 hallucination and confusion 4 3 3 RWS no
7 confusion 5 10 3 RWS no
Liver toxicity 8 hepatic cytolysisc, no US 1 unknown 2 unknown no
9 hepatic cholestasis and 5 3 2 RWS yes
cytolysisc, no US
10 hepatic cytolysis 5% 2 8 2 RWS yes and led
normal valuec, to ceftriaxone
biliary sludge discontinuation
and liver steatosis on
hepatic US
11 hepatic cytolysisc, no US 2 unknown 2 unknown no
Renal toxicity 12 renal failure (creatinine 2 5 3 RWS no
level 5%baseline)c, no US
13 renal failure (creatinine 4 unknown 2 improving at no
level 3%baseline)c, no US the end of
the study
Infection 14 C. difficile infection, 8 4 2 RWS no
non-severe form
15 C. difficile infection, 3 10 2 RWS no
non-severe form
Haematological toxicity 16a thrombocytopeniac 7 7 3 RWS yes
17 neutropeniac 20 28 3 RWS yes

RWS, resolved without sequelae; US, ultrasonography.

a
Two patients developed other ceftriaxone-related ADRs: oral mycosis (patient 3) and skin rash (patient 16).
b
Grades 1, 2, 3 and 4 correspond to mild, moderate, severe and life-threatening severity, respectively.
c
Seen in blood test.

convenient for physicians but could not be determined from the
results of this study. Nevertheless, when administering very high
dosages (i.e. 8 g/day) to patients with CNS infection, physicians
should carefully monitor the signs of toxicity, especially neurologic-
al ones. In this situation, therapeutic drug monitoring could help
the physician’s decision to lower the dosage, basing the possible
toxicity threshold at 100 mg/L.
The low frequency and limited severity of ceftriaxone-
related ADRs justified the choice of a highly specific concentra-
tion threshold. The objective was to avoid the risk of
over-reducing the dosage of ceftriaxone, which could
potentially endanger the therapeutic success in cases of
reduced susceptibility to ceftriaxone. In this study, susceptibility
data for S. pneumoniae revealed a low b-lactam resistance level
in accordance with the latest epidemiology of b-lactam suscep-
tibility in S. pneumoniae strains responsible for meningitis in
France.17 Indeed, between 2001 and 2015, the French National
Reference Centre for S. pneumoniae reported a decrease for
amoxicillin and cefotaxime non-susceptibility from 29% to 9%,
and from 14% to 3%, respectively. This shift towards greater b-
lactam susceptibility in S. pneumoniae may raise questions
about the current utility of using such high ceftriaxone dosages.

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Le Turnier et al.

Table 2. Characteristics and ceftriaxone concentrations of the study population

Patients with no Patients with

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ceftriaxone-related ceftriaxone-related All patients
Variables ADRs (n " 179) ADRs (n " 17) (n " 196)

Baseline characteristics
age, years 58 (40–68) 76 (59–80) 59 (40–68)
male gender 107 (59.8) 15 (88.2) 122 (62.2)
BMI, kg/m2 24.5 (21.8–29.1) 28.0 (24.7–32.7) 24.7 (21.8–29.2)
weight, kg 73 (62.0–84.0) 88 (73.0–95.9) 74 (62.0–85.0)
MDRD renal clearance, mL/min 98.3 (77.1–125.6) 84.2 (43.5–103.7) 97.4 (76.5–124.3)
(n " 176/179) (n " 193/196)
pre-existing neurological history 55 (30.7) 5 (29.4) 60 (30.6)
mental status alteration at hospital admission 92 (51.7) (n " 178/179) 12 (70.6) 104 (53.3) (n " 195/196)
Patient’s management and therapeutics
ICU admission 78 (43.8) (n " 178/179) 7 (41.2) 85 (43.6) (n " 195/196)
initial daily dosage of ceftriaxone
g 6.5 (6.0–8.0) 8.0 (7.0–10.0) 7.0 (6.0–8.0)
minimum–maximum, g 4–12 6–12 4–12
8 g/day 75 (41.9) 11 (64.7) 86 (43.9)
10 g/day 3 (1.7) 5 (29.4) 8 (4.1)
Daily dosing frequency of ceftriaxone
once 59 (33.0) 2 (11.8) 61 (31.1)
twice 106 (59.2) 14 (82.4) 120 (61.2)
three times or more 14 (7.8) 1 (5.9) 15 (7.7)
Duration of treatment with ceftriaxone, days 8 (4–12) 9 (6–14) 8 (5–12)
Corticosteroid therapy 63 (37.7) (n " 167/179) 8 (57.1) (n " 14/17) 71 (39.2) (n " 181/196)
Trough ceftriaxone plasma concentration
total, mg/L 52.60 (32.40–80.10) 70.00 (57.20–202.5) 56.85 (33.20–82.15)
(n " 149/179) (n " 15/17) (n " 164/196)
free, mg/L 3.30 (1.56–6.25) 13.32 (5.28–42.21) 3.95 (1.74–6.76)
(n " 115/179) (n " 11/17) (n " 126/196)

Data are expressed as median (IQR) or n (%). In cases of missing data, n/N is indicated.

However, considering the low frequency of ceftriaxone-related Conclusions

ADRs with a dosage above 4 g/day, limiting the dosage to 4 g/
day owing to the risk of ADRs does not seem necessary.
This study has some limitations. The small number of patients
who experienced ceftriaxone-related ADRs could have underpow-
ered the analysis of risk factors. The factors associated with
ceftriaxone-related ADRs in multivariate analysis, namely age and
gender, are determinants of a reduced glomerular filtration rate,
which could be a confounding factor, as suggested by the univari-
ate analysis. Similarly, in the elderly, the neurological toxicity may
be related to a higher unbound fraction of ceftriaxone owing to
lower plasma protein concentrations. Neurological ADRs were, al-
though the most common, too rare to perform a relevant statistic-
al subgroup analysis. Also, the rate of ADRs might have been
underestimated by the physicians involved, a phenomenon
reported even in clinical trials.34 We tried to counterbalance this
risk with an independent expert committee that systematically
reviewed all included cases to optimize the detection of ADRs and
the drug causality analysis. As expected, this method allowed the
identification of a higher number of ceftriaxone-related ADRs than
those detected solely by the investigators.
The limited toxicity of high-dose ceftriaxone evidenced in this
study confirms a satisfying tolerability profile and supports the use
of a high-dose regimen (4 g/day) in CNS infections as recom-
mended by the French guidelines. In patients with advanced age
or renal insufficiency, prescription should be done with caution and
therapeutic drug monitoring may be useful.
Acknowledgements
Preliminary results of this study were presented at the Twenty-seventh
European Congress of Clinical Microbiology and Infectious Diseases,
Vienna, Austria, 2017 (Abstract EP0689).
We want to thank all members of the High-Dose Ceftriaxone CNS
Infections Study group.
Members of the High-Dose Ceftriaxone CNS Infections
Study Group
Steering committee: Nathalie Asseray, Eric Dailly, Dominique Navas and
Véronique Sébille. Scientific board: Pierre Abgueguen, Nathalie Asseray
(Principal Investigator), Louis Bernard, David Boutoille, Cédric

6 of 8
Tolerability of high-dose ceftriaxone in CNS infections JAC
Table 3. Factors associated with the occurrence of ceftriaxone-related ADRs (univariate analysis)

Variables Unadjusted OR 95% CI P value

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Age (!1 year) 1.06 1.02–1.10 0.004
Male gender 5.05 1.12–22.74 0.035
BMI 25 kg/m2 2.10 0.73–6.05 0.169
Pre-existing neurological condition 0.94 0.32–2.80 0.911
Baseline MDRD CLCR (!1 mL/min) 0.98 0.97–1.00 0.010
Mental status alteration at hospital admission 2.19 0.69–6.97 0.186
ICU admission 0.90 0.33–2.46 0.834
Corticosteroid therapy 2.20 0.73–6.64 0.161
Dosage 8 g/day 2.54 0.90–7.18 0.078
Total ceftriaxone plasma trough concentration (!1 mg/L) 1.02 1.01–1.02 ,0.001
Free ceftriaxone plasma trough concentration (!1 mg/L) 1.09 1.04–1.14 ,0.001

Significant P values (P , 0.05) are shown in bold.

Bretonnière, Jocelyne Caillon, Anne Chiffoleau, Eric Dailly, Martin Dary,

Denis Garot, Thomas Guimard, Jérôme Hoff, Laurene Leclair-Visonneau,
Monique Marguerite, Dominique Navas, François Raffi (chair), Véronique
Sébille, Pierre Tattevin and Yves-Marie Vandamme. Expert committee:
David Boutoille, Anne Chiffoleau, Martin Dary and Dominique Navas.
Investigators group: Pierre Abgueguen, Nicolas Crochette and Yves-Marie
Vandamme (Angers); Kostas Bakoumas, Elsa Bieber, Gwenaël Colin,
Maud Fiancette, Thomas Guimard, Aurélie Joret, Matthieu Henry-
Lagarrigue, Jean-Claude Lacherade, Jean Baptiste Lascarrou, Christine
Lebert, Laurent Martin-Lefevre, Jean Reignier, Eve Trebouet, Isabelle
Vinatier, Bertrand Weys and Aihem Yehia (La Roche sur Yon); Charlotte
Biron, Cédric Bretonnière, Magali Brière, Laurent Brisard, Jocelyne Caillon,
Eric Dailly, Marie Dalichampt, Guillaume Deslandes, Anne-Catherine Di
Prizio, Guillemette Favet, Mathieu Grégoire, Line Happi Djeukou, Laurene
Leclair-Visonneau, Maeva Lefebvre, Armelle Magot, Monique Marguerite,
Arnaud Peyre, Samuel Pineau, Jérémie Orain, Sylvie Raoul and Marion
Rigot (Nantes); Cédric Arvieux, Adèle Lacroix, Enora Ouamara-Digue,
Solène Patrat-Delon, Caroline Piau-Couapel, Maja Ratajczak, Mathieu
Revest, Paul Sauleau and Pierre Tattevin (Rennes); Céline Chevalier,
Patricia Courouble, Jérôme Hoff and Alix Phelizot (Saint Nazaire); and
Frédéric Bastides, Laeticia Bodet-Contentin, Rodolphe Buzele, Pierre-
François Dequin, Stephan Ehrmann, Karine Fevre, Denis Garot, Guillaume
Gras, Antoine Guillon, Youenn Jouan, Annick Legras, Emmanuelle
Mercier, Maja Ogielska and Emmanuelle Rouve (Tours).
Funding
This work was supported by a grant from the French Ministry of Health
[Programme Hospitalier de Recherche Clinique Interrégional (PHRCI;
Interregional French Clinical Hospital Research Programme) grant 2012–
API12N037].
Transparency declarations
None to declare.
Author contributions
Data collection: D. G., T. G., L. B., P. T., Y. M. V., J. H., A. C., M. D., L. L.-V., M.
G., D. B., E. D. and N. A. Statistical analysis: V. S., M. P., P. L. T, N. A., D. N.
and A. C. Drafting of article: P. L. T., N. A., D. N., M. P., V. S. and A. C.
Reviewing of article: D. B., M. G. and E. D.
Supplementary data
Figure S1 is available as Supplementary data at JAC Online.
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