Journal of Critical Care 62 (2021) 151–156

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Journal of Critical Care

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Interactions between carbapenems and valproic acid among the patients

in the intensive care units
I-Ling Chen a,b,c, Chen-Hsiang Lee c,d,e,⁎, Shu-Chen Hsiao a, Fu-Yuan Shih f
a
Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
b
School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
c
Infection Control Team, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
d
Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
e
Chang Gung University College of Medicine, Kaohsiung, Taiwan
f
Department of Neurosurgery, Chang Gung University College of Medicine and Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan

a r t i c l e i n f o a b s t r a c t

Purpose: To evaluate risk factors for epileptic seizures or status epilepticus (SE) in patients concomitantly receiv-
ing valproic acid (VPA) and carbapenems.
Materials and methods: Adult patients in the intensive care units (ICUs) who concomitantly received VPA and car-
Keywords: bapenems from 2007 to 2017 were included. The impacts of different carbapenems on serum concentration of
Epileptic seizure VPA were compared.
Status epilepticus Results: Among 162 patients included, 104 (64.2%) and 45 (27.8%) developed epileptic seizures and SE, respec-
Valproic acid tively. The risk factors for epileptic seizures were age (per year increase, adjusted odds ratio [aOR], 1.03), initial
Carbapenem antiepileptic regimen (monotherapy and polytherapy, aOR, 0.43 and 0.18, respectively), and VPA serum
Drug-drug interaction concentration after concomitant carbapenem administration (per 1 μg/mL increase, aOR, 0.96). VPA serum
concentration after concomitant carbapenem administration was an independent risk factor for SE (per μg/mL
increase, aOR, 0.98). Concomitant imipenem/cilastatin administration did not significantly decrease VPA serum
concentration compared to that by meropenem or ertapenem. The length of stay and number of days on venti-
lation after concomitant carbapenem administration in the ICUs were significantly more in those with epileptic
seizures or SE.
Conclusions: Carbapenems decreased VPA serum concentration and increased the risk of epileptic seizures and
SE, which led to increased length of ICU stay.
© 2020 Elsevier Inc. All rights reserved.

1. Introduction concentration in the range of 50 to 100 μg/mL [4]. A rapid decrease in

Carbapenems are broad-spectrum antibiotics used for the treatment
of serious infections caused by multidrug-resistant bacteria in the inten-
sive care units (ICUs) [1,2]. Valproic acid (VPA) was approved by the
Food and Drug Administration in 1978 and has become one of the
most commonly prescribed drugs for the treatment or prophylaxis of
epilepsy [3]. To reduce the risk of adverse effects during antiepileptic
treatment, VPA serum concentrations are monitored to ensure a
Abbreviations: AEDs, antiepileptic drugs; aOR, adjusted odds ratio; CCI, Charlson
Comorbidity Index; CNS, central nervous system; ICU, intensive care unit; LOS, length of
stay; SE, status epilepticus; SOFA, sequential organ failure assessment; VPA, valproic
acid; VPAGas, VPA-glucuronide deconjugation enzyme.
⁎ Corresponding authors at: Division of Infectious Diseases, Department of Internal
Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta-Pei Road, Niao Sung
District, Kaohsiung 83301, Taiwan.
E-mail addresses: iling10@cgmh.org.tw (I.-L. Chen), lee900@cgmh.org.tw (C.-H. Lee),
e71@cgmh.org.tw (S.-C. Hsiao), 8902055@cgmh.org.tw (F.-Y. Shih).
VPA serum concentration in patients concomitantly receiving carbapen-
ems with subsequent breakthrough epileptic seizures have been
reported in several cases [5]. The mechanisms for the interaction be-
tween VPA and carbapenems may include 1) decrease in VPA intestinal
absorption and enterohepatic circulation; 2) increase in the synthesis
and inhibition of VPA-glucuronide hydrolysis; 3) inhibition of VPA ef-
flux from erythrocytes; and 4) increase in the urinary excretion of
VPA-glucuronide. However, the precise underlying mechanism remains
to be identified [6], and the concomitant use of carbapenems and VPA is
not recommended [7].
Many case reports and series have shown that concomitant use of
meropenem can significantly and rapidly reduce VPA serum concentra-
tion [7-10]. However, few studies have investigated VPA serum concen-
tration in patients concomitantly treated with VPA and ertapenem or
imipenem/cilastatin. Furthermore, the extent of drug–drug interactions
between carbapenems and VPA should be evaluated individually.
Therefore, we conducted a retrospective study to evaluate the risk

https://doi.org/10.1016/j.jcrc.2020.12.005
0883-9441/© 2020 Elsevier Inc. All rights reserved.
I.-L. Chen, C.-H. Lee, S.-C. Hsiao et al. Journal of Critical Care 62 (2021) 151–156

factors for epileptic seizures or status epilepticus (SE) and the outcomes
of ICU patients concomitantly treated with VPA and ertapenem,
imipenem/cilastatin, or meropenem.
2. Materials and methods
2.1. Patients and setting
This retrospective study included adult patients (age ≥ 18 years)
admitted to the ICUs of Kaohsiung Chang Gung Memorial Hospital
between January 1, 2007, and December 31, 2017 who concomitantly
received VPA and a carbapenem (imipenem/cilastatin, ertapenem, or
meropenem). We excluded patients who: 1) were admitted to the
ICUs for less than 48 h; 2) had epileptic seizures due to adverse drug re-
actions; 3) received concomitant therapy for less than 24 h; 4) had out-
of-hospital cardiac arrest; 5) were diagnosed with a bacterial infection
in central nervous system (CNS); 6) had a seizure before concomitant
therapy; 7) were transferred to other hospitals; 8) were lacking com-
plete data; and 9) were prescribed of VPA, but not for the treatment of
epilepsy (Fig. 1). The study was approved (approval no. 20180716B0)
by the Institutional Review Board of Chang Gung Medical Foundation.
2.2. Data collection and definitions
The variables of interest were retrieved from the patients' medical
records and the Chang Gung Research Database (CGRDS), and reviewed
for the information on demographics, pharmacy dispensing records,
and clinical measures including diagnoses, laboratory results, and
healthcare use. The collected variables included demographics, comor-
bidities, Charlson Comorbidity Index (CCI), antiepileptic drug (AED)
therapy, type of carbapenem used, dosage of VPA, serum concentration
of VPA, sequential organ failure assessment (SOFA) score, invasive me-
chanical ventilation, outcome at ICU discharge, ICU length of stay (LOS)
after concomitant treatment with VPA and carbapenems, medical care
cost in the ICU, hospital LOS, and seizure frequency before and during
concomitant treatment with VPA and carbapenems. The dosage of
VPA was calculated by daily VPA dose (milligram per kilogram).
Serum concentrations of VPA were measured at least 3 days after the
VPA initiation and before inception of the concomitant use of carbapen-
ems, and 2–7 days after the inception of concomitant use of carbapen-
ems. We recorded the point near the inception of the concomitant
therapy, if VPA serum concentration had been measured several times
during hospitalization. Patients without seizures were compared to
those with epileptic seizures or SE to determine the risk factors for the
development of epileptic seizures or SE. SE was defined as seizures last-
ing for more than 5 min or recurrent epileptic activity over a period of
more than 5 min without regaining the pre-existing level of conscious-
ness [11]. Hospital-acquired infections were diagnosed by the infection
control team according to the criteria of the Centers for Disease Control
and Prevention during daily active surveillance [2]. The change in VPA
concentration (Δ [VPA]) was calculated as follows: Δ [VPA] = (VPA
serum concentration before concomitant therapy - VPA serum concen-
tration during concomitant therapy)/VPA serum concentration before
concomitant therapy × 100%.
2.3. Statistical analysis
Dichotomous variables were analyzed with the χ2 or Fisher's exact
test, and continuous variables were analyzed with the Mann–Whitney
U test or Student's t-test. For multivariate analysis, variables with a
p-value of <0.2 were used as dependent variables. Clinical outcomes
of the patients without epileptic seizures, those who developed epilep-
tic seizures, and those whose seizures evolved into SE were compared
using one-way analysis of variance. A logistic regression model was
used for multivariate analysis. The effects of different carbapenems
(ertapenem, imipenem/cilastatin, and meropenem) on VPA serum con-
centration before and during concomitant therapy were compared
using a two-tailed paired t-test. To address the issue of missing data in

Adult patients (age ≥18 years) admitted to ICUs between January 2007
and December 2017 who received valproic acid and carbapenems
concomitantly (N=265)

Exclusion (N=103): Imipenem/cilastatin (N=46)

1. CNS infection
2. ICU stay <48 h
3. Adverse drug reaction-induced seizures
4. Out-of-hospital cardiac arrest Meropenem (N=68)
5. Seizures before concomitant therapy
6. Concomitant therapy <24 h
7. Transfer to other hospitals
8. Lack of complete data
9. Indication of valproic acid not for Ertapenem (N=48)
epilpesy

Seizures (N=104) No seizures (N=58)

Status epilepticus (N=45) No status epilepticus (N= 117)

CNS: central nervous system; ICU: intensive care unit

Fig. 1. Flow chart of the study. CNS: central nervous system; ICU: intensive care unit

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I.-L. Chen, C.-H. Lee, S.-C. Hsiao et al. Journal of Critical Care 62 (2021) 151–156

the model, we used multivariate imputation by chained equation, using
regression including all of the variables in the main models [12]. All
analyses were performed using SAS version 9.4 software (SAS Institute,
Cary NC, USA).
3. Results
3.1. Baseline characteristics
[CI], 1.01–1.06; p = 0.01), the number of AED regimens (for mono-
therapy, aOR, 0.43; 95% CI, 0.19–0.99; p = 0.05 and for polytherapy,
aOR, 0.18; 95% CI, 0.07–0.51; p < 0.01), and VPA serum concentra-
tion during concomitant therapy (per μg/mL increase, aOR, 0.96;
95% CI: 0.95–0.98; p < 0.01) were independent risk factors for
epileptic seizures. Only VPA serum concentration during concomi-
tant therapy (per μg/mL increase, aOR, 0.98; 95% CI, 0.96–1.00;
p = 0.05) was an independent risk factor for SE (Table 2).

During the 10-year study period, we identified 265 critically ill pa-
tients undergoing treatment with VPA and who concomitantly received
carbapenems for the treatment of bacterial infections. Among these pa-
tients, 103 were excluded for the following reasons: admission to the
ICU for less than 48 h (N = 11), indication of VPA not for epilepsy
(N = 7), concomitant therapy for less than 24 h (N = 16), lack of com-
plete data (N = 17), worsening of seizures before the concomitant ther-
apy (N = 15), adverse drug reactions (N = 9), out-of-hospital cardiac
arrest before admission to an ICU (N = 6), CNS infection (N = 10),
and transfer to other hospitals (N = 12). Finally, a total of 162 ICU pa-
tients who were concomitantly treated with VPA and carbapenems
were included in the analysis. Among these 162 patients, 104 (64.2%)
had epileptic seizures and 45 (27.8%) progressed to SE. With regard to
the concomitant administration of carbapenems, 46 (28.4%) patients re-
ceived imipenem/cilastatin, 68 (42.0%) received meropenem, and 48
(29.6%) received ertapenem.
3.2. Analysis of risk factors
The factors associated with epileptic seizures and SE develop-
ment after concomitant therapy in the univariate analysis are
shown in Table 1. In the multivariate analysis, age (per year in-
crease, adjusted odds ratio [aOR], 1.03; 95% confidence interval
3.3. Impact of different carbapenems on VPA serum concentration
VPA serum concentration was sub-therapeutic (50 μg/mL) in 92.0%
of the patients when carbapenems were administered. VPA serum con-
centrations were decreased by 11.9%, 65.2%, and 69.1% during concom-
itant treatment with imipenem/cilastatin, meropenem, and ertapenem,
respectively. Among these carbapenems, only imipenem/cilastatin did
not significantly decrease VPA serum concentration when administered
concomitantly (Fig. 2).
3.4. Clinical outcomes of the patients with epileptic seizures or SE
The LOS (days) in the ICU after concomitant therapy was signifi-
cantly longer in the patients with epileptic seizures (23.0 ± 20.7) and
SE (33.6 ± 24.6) than in those without epileptic seizures (16.6 ± 14.4,
p < 0.01). The duration (days) of ventilator use was also longer in the
patients with epileptic seizures (9.4 ± 11.6) and SE (17.9 ± 18.7)
than in those without epileptic seizures (7.9 ± 11.3, p = 0.02). The
medical care expenditure after concomitant therapy during hospital
stay was not significantly different between the patients with epileptic
seizures or SE and those without epileptic seizures (Table 3).

Table 1
Demographic and clinical characteristics.

Variables Epileptic seizures after p value Status epilepticus after p value

concomitant therapy concomitant therapy

Yes (N = 104) No (N = 58) Yes (N = 45) No (N = 117)

Age, mean (SD), years 72.0 ± 14.7 65.1 ± 14.1 0.02 69.6 ± 12.7 67.8 ± 15.3 0.64
Sex
Male (%) 63 (60.6) 38 (65.5) 0.53 31 (68.1) 70 (59.8) 0.29
SOFA score, median (IQR) 8 (6–11) 7 (6–10) 0.80 8 (6–10) 7 (6–10) 0.74
CCI, median (IQR) 4 (2.5–5.5) 4.5 (3.0–6.0) 0.41 6 (4.0–8.0) 4 (3.0–6.0) 0.74
Comorbidities (%)
Cerebrovascular disease 64 (61.5) 38 (65.5) 0.62 26 (57.8) 76 (65.0) 0.40
Acute myocardial infarction 5 (4.8) 4 (6.9) 0.72 3 (6.7) 6 (5.1) 0.71
Congestive heart failure 21 (20.2) 13 (22.4) 0.74 8 (17.8) 26 (22.2) 0.53
Chronic obstructive pulmonary disease 42 (40.4) 18 (31.0) 0.24 18 (40.0) 42 (35.9) 0.63
Liver disease# 25 (24.0) 17 (29.3) 0.46 10 (22.2) 32 (27.4) 0.50
Chronic renal disease## 32 (30.8) 12 (20.7) 0.17 14 (31.1) 30 (25.6) 0.48
Diabetes mellitus 41 (39.4) 30 (51.7) 0.13 18 (40.0) 53 (45.3) 0.54
Malignant tumors 27 (26.0) 17 (29.3) 0.65 13 (28.9) 31 (26.5) 0.76
Hospital-acquired infection 16 (15.4) 14 (24.1) 0.17 7 (4.1) 23(19.7) 0.55
Type of carbapenems (%)
Ertapenem 34 (32.7) 14 (24.2) <0.01 18 (40.0) 30 (25.6) 0.05
Imipenem/cilastatin 20 (19.2) 26 (44.8) 7 (15.6) 39 (33.3)
Meropenem 50 (48.1) 18 (31.0) 20 (44.4) 48 (41.0)
Number of AEDs (%)
Monotherapy 40 (38.5) 29 (50.0) <0.01 18 (40.0) 51 (43.6) 0.14
Duotherapy 52 (50.0) 14 (24.1) 23 (51.1) 43 (36.8)
Polytherapy (≥3 AEDs) 12 (11.5) 15 (25.9) 4 (8.9) 23 (19.7)
Admission with status epilepticus (%) 15 (14.4) 12 (20.7) 0.31 6 (13.3) 21 (18.0) 0.48
VPA dose before concomitantly therapy (mg/kg/day) 25.5 ± 9.5 26.3 ± 9.8 0.82 26.7 ± 10.4 25.9 ± 9.4 0.65
VPA concentration before concomitant therapy, mg/L⁎ (SD) 59.3 ± 17.9 63.2 ± 17.7 0.16 61.9 ± 21.8 60.3 ± 16.2 0.82
VPA concentration during concomitant therapy, mg/L** (SD) 24.9 ± 16.8 37.0 ± 22.7 <0.01 24.1 ± 17.2 31.2 ± 20.6 0.04

# Liver disease was defined as a history of chronic viral hepatitis, liver cirrhosis, and liver tumor; ## Chronic renal disease was defined as an insufficient renal function with a glomerular
filtration rate of 50mL/min/1.73m2 or less; *10 missing in meropenem, 9 missing in ertapenem, and 9 missing in imipenem/cilastatin groups; **5 missing in meropenem, 8 missing in
ertapenem, and 18 missing in imipenem/cilastatin groups.
AED: antiepileptic drug; CCI: Charlson Comorbidity Index; IQR: interquartile range; SD: standard deviation; SOFA: sequential organ failure assessment; VPA: valproic acid.

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Table 2
Independent risk factors for epileptic seizures or status epilepticus after concomitant therapy.
Risk factor
Age (years)
VPA level during concomitant therapy with carbapenem
Initial AEDs therapy (duotherapy as reference)
Monotherapy
Polytherapy (≥ 3 AEDs)
AED: antiepileptic drug; VPA: valproic acid.
4. Discussion
Analysis of the AED regimen and risk of epileptic seizures after con-
comitant therapy with VPA and carbapenems revealed that VPA mono-
therapy and polytherapy with two other AEDs significantly decreased
the frequency of epileptic seizures (Table 2). Compared to the patients
who received monotherapy or polytherapy with AEDs after the
concomitant administration of VPA and carbapenems, those who re-
ceived dual AED therapy had a higher frequency of epileptic seizures if
the VPA serum concentration was within the sub-therapeutic range. A
possible reason for this finding is that VPA is an inhibitor rather than
an inducer of drug-metabolizing enzymes and is highly bound to
plasma proteins. In addition, it may be displaced from protein binding
sites when medications other than VPA work inefficiently, which
could then reduce the desired AED therapeutic level resulting in diffi-
culty in seizure control [13].
The VPA serum concentration during concomitant therapy with car-
bapenems was markedly associated with a risk of epileptic seizures and
SE in this study (Table 2). This observation suggests that the drug-drug
interactions changed the pharmacokinetics and pharmacodynamics,
resulting in substantially decreased VPA serum concentration, which
in turn aggravated epileptic seizures or led to the development of SE.
The concomitant administration of carbapenems has been reported to
decrease VPA serum concentration to 50–80% of the original concentra-
tion due to an increase in VPA clearance by 191% and a reduction in the
half-life of VPA from 15 h to 4 h [14]. This interaction has been reported
to occur after the administration of a single dose of carbapenems,
Fig. 2. Interactions between valproic acid and carbapenems. The effect of different carbapenems on valproic acid (VPA) concentration before and during concomitant therapy. Values
represent mean ± standard deviation of the mean. p level: VPA levels versus baseline VPA levels as assessed using a paired sample t-test. VPA: valproic acid.
Journal of Critical Care 62 (2021) 151–156
Epileptic Seizure Status epilepticus
Adjusted odds ratio Adjusted odds ratio
(95% confidence interval) p value (95% confidence interval) p value
1.03 (1.01–1.06) 0.01
0.96 (0.95–0.98) <0.01 0.98 (0.96–1.0) 0.05
0.43 (0.19–0.99) 0.05
0.18 (0.07–0.51) <0.01
resulting in sub-therapeutic VPA trough serum concentration within
24–72 h [5], and this could be responsible for the occurrence of epileptic
seizures or the development of SE. Tobin et al. reported varying degrees
of interactions between various carbapenems and VPA, suggesting a
class effect, when VPA was co-administered both orally and intrave-
nously [15]. We also observed varying effects of different carbapenems
on VPA serum concentration when administered concomitantly.
Imipenem/cilastatin had the least effect on serum VPA concentrations
among all the carbapenems used. One proposed mechanism of this
drug-drug interaction is a reduction in the deconjugation of VPA-
glucuronide through the inhibition of deconjugation enzymes.
Masuo et al. found that a putative VPA-glucuronide deconjugation
enzyme (VPAGase), other than β-glucuronidase, was responsible for
the deconjugation of VPA-glucuronide [16]. In addition, they found
that VPAGase inhibition occurred immediately after carbapenem ad-
ministration, so that the effect continued for at least 12 h, and that
VPAGase activity gradually returned to approximately 80% of the
original activity 96 h after carbapenem discontinuation [16]. More-
over, the capacity for VPAGase inhibition was different among vari-
ous carbapenems, which supports our findings that imipenem/
cilastatin was a weaker inhibitor than ertapenem or meropenem.
However, this finding is not consistent with several previous studies,
which reported that imipenem/cilastatin administration reduced VPA
serum levels by 52% [17,18]. In the present study, the patients did
not receive other carbapenems before imipenem/cilastatin was con-
comitantly administered with VPA, which excluded the probability
of the inhibitory effect on VPAGase and thus a reduction in VPA
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Table 3
Comparison of clinical outcomes with epileptic seizures or status epilepticus after concomitant therapy.

Variables No epileptic seizures Epileptic seizures Status epilepticus p

after concomitant after concomitant after concomitant value
therapy (N = 58) therapy (N = 59) therapy (N = 45)

Medical care cost (US dollars), mean ± SD 22,539 ± 15,232 27,131 ± 22,062 26,604 ± 19,956 0.66
Ventilator-days after carbapenem therapy, 7.9 ± 11.3 9.4 ± 11.6 17.9 ± 18.7 0.02
mean ± SD
Post concomitant therapy ICU stay, mean ± SD 16.6 ± 14.4 23.0 ± 20.7 33.6 ± 24.6 <0.01
Post concomitant therapy hospital stay, mean ± SD 43.7 ± 28.3 53.4 ± 40.2 53.5 ± 33.9 0.35

SD: standard deviation; ICU: intensive care unit.

serum concentration due to other carbapenems. The mechanism un-
derlying the drug-drug interactions between imipenem/cilastatin and
VPA when used concomitantly remains unknown, and further studies
are needed to clarify this issue.
The type of carbapenem used did not significantly influence the de-
velopment of epileptic seizures in this study. We observed that not all
patients concomitantly treated with imipenem/cilastatin and VPA
showed a decrease in VPA serum concentration, and that the VPA
serum concentration in some patients was sub-therapeutic before the
concomitant use of carbapenems. Furthermore, imipenem/cilastatin
has been reported to have the highest rate of epileptogenicity (0.9 to
3%) among the carbapenems used [19-21]. Moreover, Winston et al. re-
ported that when imipenem/cilastatin was used in patients with
existing CNS disorders and low seizure thresholds, the highest reported
rate of seizure was 10.3% [22]. The main findings of the present study
are that VPA serum concentration, age of the patients, and AED regimen
rather than the use of carbapenems were related to epileptic seizures or
the development of SE in ICU patients concomitantly treated with VPA
and carbapenems. Therefore, other antimicrobial agents should be con-
sidered as alternatives to carbapenems wherever possible, and if a con-
current carbapenem is necessary, using an additional AED is
recommended.
This study had several limitations. First, it was retrospective and may
involve selection bias related to different carbapenems and AEDs. Sec-
ond, some patients did not receive therapeutic drug monitoring for
VPA serum concentration and the free VPA serum concentration data
were not available in the current study. VPA is extensively bound to
plasma proteins, and only the free fraction is pharmacologically active.
Further studies are needed to explore the influence of carbapenems
on free VPA serum concentration. More number of patients with
available drug serum concentration data is needed to verify the correla-
tion between VPA serum concentration and SE development in future
studies. Third, records from CGRDS did not provide information on so-
cioeconomic factors, lifestyle factors (smoking and alcohol consump-
tion), sleep deprivation, exertion, and emotional stress in the ICU.
However, these factors may contribute to confounding effects when an-
alyzing associations between VPA used concomitantly with carbapen-
ems and epileptic seizures or SE.
5. Conclusions
Carbapenem-VPA interactions reduced VPA serum concentration
and increased the risk of epileptic seizures and SE in this study.
Among the carbapenems used, imipenem/cilastatin was observed to
least affect the VPA serum concentration. Therapeutic drug monitoring
of VPA serum concentration is warranted, especially when initiating or
discontinuing carbapenems.
Funding
This study was supported by grants from Chang Gung Memorial
Hospital, Taiwan (CMRPP8J0391, CMRPG8G0451). The funders had no
role in study design, data collection and analysis, preparation of the
manuscript, or decision to publish.
Authors' contribution
I-L C conceived the content, retrieved the data, wrote the manuscript
and approved the final version. C\\H L retrieved the data, revised the
manuscript critically and approved the final version. S\\C H retrieved
the data, and approved the final version. F\\Y S helped in data extrac-
tion, and approved the final version.
Declaration of Competing Interest
None.
Acknowledgements
We would like to thank the Biostatistics Center, Kaohsiung Chang
Gung Memorial Hospital for the statistics work. We would also like to
thank Dr. Chien-Ching Hung at the Department of Internal Medicine,
National Taiwan University Hospital, for his critical review of this
manuscript.
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