Effect of a Declined Plasma Concentration of Valproic Acid Induced by Meropenem on the Antiepileptic Efficacy of Valproic Acid

Design

Retrospective chart review

N= 61

Objective

To indicate whether a declined plasma concentration of valproic acid (VPA) induced by co-administration of meropenem (MEPM) could affect the antiepileptic efficacy of VPA

Study Groups

Exposure group (n= 50)

Control group (n= 11)

Inclusion Criteria

Adult patients with epilepsy or status epilepticus (SE)

Exclusion Criteria

VPA was not concomitantly used with MEPM or in the form of co‐administration for <24 h; VPA used for seizure prophylaxis

Methods

Patients from China were screened and assigned to the exposure group, in which VPA and MEPM were co-administered during hospitalization, or the control group, in which VPA and other broad-spectrum antibiotics (e.g., ceftazidime, cefepime, piperacillin‐tazobactam, and cefoperazone‐sulbactam) were co-administered during hospitalization. 

Duration

June 2010 to January 2019

Outcome Measures

Change in seizure frequency from baseline to the start and end of co‐administration; change in seizure duration from baseline to the start and end of co‐administration; change in concomitant use of antiepileptic drugs (AEDs) from baseline to the start and end of co‐administration

Baseline Characteristics

Control group (n= 11)

Exposure group (n= 50)

Age, years

Female

Type of epilepsy

Epilepsy

SE

9 (81.8%)

2 (18.2%)

42 (84.0%)

8 (16.0%)

Dose of VPA, g/day

Concomitant AEDs

Ccr level was higher in the exposure group (p= 0.024), and both groups possessed sufficient renal function. Albumin level was lower in the exposure group vs control group (p = 0.034), suggesting that inflammatory status was more serious in the exposure group.

The median duration of VPA administration before co‐administration was 8 (range 1-51) days. The median duration of co‐administration was 7.5 (range 1-52) days.

Results

Endpoint

Control group (n= 11)

Exposure group (n= 50)

p-value

Seizure frequency

ΔDuring‐before

ΔAfter‐before

-0.002 ± 0.080

-0.026 ± 0.099

-0.004 ± 0.017

-0.004 ± 0.020

0.328

0.505

Seizure duration

ΔDuring‐before

ΔAfter‐before

0.228 ± 0.950

-0.125 ± 1.155

-0.186 ± 1.615

-0.397 ± 1.192

0.172

0.983

Abbreviations: NS, not significant

The dosages and plasma concentrations of VPA in the exposure and control groups are depicted via figure. The plasma concentration of VPA significantly decreased during co‐administration vs before co-administration in the exposure group (24.6 ± 4.3 mcg/mL vs 88.8 ± 13.6 mcg/mL; p< 0.0001), with partial recovery after co-administration termination (39.8 ± 13.2 mcg/mL, p= NS). Dosage and plasma concentration of VPA remained stable in the control group (p= NS).

There were no significant differences in the concomitant administration of AEDs between the two groups during and after the administration of MEPM (p= 0.507 and 0.065, respectively).

There were no significant differences in seizure frequency between the periods of before‐during and before‐after (p= 0.074 and 0.153, respectively).

There were no significant differences in the concomitant use of AEDs between the periods of before‐during and before‐after (p= 1.000 and 0.267, respectively).

Adverse Events

Common Adverse Events: No significant differences in ALT, AST, or estimated Ccr levels during any timeframe

Serious Adverse Events: 2 patients (1 acute progressive brainstem infarction, 1 mediastinal emphysema)

Percentage that Discontinued due to Adverse Events: 5 patients (2 hyperammonemia; 2 ≥3 times upper limit of normal [ULN] for serum ALT level; 1 decreased WBCs)

Study Author Conclusions

In this study, the reduced plasma concentration of VPA induced by the co-administration of MEPM did not affect the antiepileptic efficacy of VPA. This conclusion should be interpreted with caution, and more research is warranted.

InpharmD Researcher Critique

This study's limitations include those inherent to a retrospective and observational study design, as well as the small sample size and collection of data from a single center. The use of data from a Chinese hospital may not accurately reflect patient demographics from a domestic population. Free VPA serum concentrations were not available for the study.

A prospective study of drug-drug interaction between antiepileptic drugs and meropenem in patients in a tertiary hospital in China from January 2020 to March 2023

Design

Prospective study

N= 91

Objective

To determine the minimum interaction between different antiepileptic drugs (AEDs) and meropenem (MEPM) for clinical treatment

Study Groups

VPA (n= 47)

CBZ (n= 16)

LEV (n= 28)

Inclusion Criteria

Aged 18-80 years; weight >40 kg; documented history of seizures; currently taking oral valproic acid (VPA), carbamazepine (CBZ), or levetiracetam (LEV) monotherapy at regular intervals; current severe infection; and stable serum AED concentrations upon admission

Exclusion Criteria

Hemodynamic instability; did not require anti-infective therapy with MEPM during the hospitalization according to treatment guidelines; discontinued AEDs during hospitalization

Methods

Patients from China were subject to therapeutic drug monitoring (TDM) after treatment with VPA, CBZ, or LEV for at least five half-lives and attained a steady-state serum concentration. Subsequent serum trough concentration periods were scheduled at temporal intervals, as well as collection of liver and kidney functions and other clinical response data. Average intravenous (IV) fluid intake was calculated 48 h before and after MEPM treatment to limit potential confounding effects of fluid volume changes.

Duration

January 2020 to March 2023

Outcome Measures

Interactions between AEDs and MEPM

Baseline Characteristics

VPA (n= 47)

CBZ (n= 16)

Age, years

Female

Weight, kg

Average IV fluid intake, L

48 h before MEPM

48 h after MEPM

3.07 ± 1.01

3.10 ± 1.19

2.57 ± 0.84

2.75 ± 0.93

3.07 ± 1.04

3.10 ± 1.12

The doses of AEDs varied among patients and were not standardized. Severe pulmonary infection was the prevailing type of infection observed in all groups, and hypertension was the predominant underlying disease in all groups.

Results

Endpoint

VPA (n= 47)

CBZ (n= 16)

LEV (n= 28)

p-value

Death

Trend of serum VPA trough concentrations before and after MEPM usage is depicted via figure. Compared with point 1 (69.08±8.57 mcg/mL), the serum trough concentrations of VPA decreased significantly (p< 0.05) at points 2 (36.25 ± 8.22 mcg/mL, 24 ± 12 h after VPA + MEPM usage) and 3 (34.99 ± 11.17 mcg/mL, 96 ± 12 h after VPA + MEPM usage), but there was no significant difference between points 2 and 3.

Overall, serum VPA trough concentrations decreased significantly after MEPM usage, and decreased by >50% in 19/47 (40.43%) patients. Age may be an independent risk factors for interactions betwen VPA and MEPM based on binary logistic regression analysis.

Regardless of MEPM daily dose amounts, VPA trough concentrations decreased significantly (p< 0.05) when administered with MEPM, but no significant differences were found between the different daily doses at any time point.

Based on analysis, the liver injury rate significantly increased, but the kidney injury rate decreased after VPA administration with MEPM. The liver and kidney injury rates were not affected by the combination use of CBZ + MEPM or LEV + MEPM.

Adverse Events

Common Adverse Events: Liver injury in 8 (17.02%) VPA patients, kidney injury in 9 (19.15%) VPA patients at 48 h after MEPM administration

Serious Adverse Events: 6 deaths (2 VPA, 2 CBZ, 1 LEV)

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

The interaction between VPA and MEPM decreased serum VPA concentrations, increased liver injury rates, and decreased kidney injury rates. In addition, the co-administration of MEPM and CBZ reduced serum CBZ concentrations. Clinicians should be aware of this potential interaction and closely monitor the relevant biochemical indices and number of seizures.

InpharmD Researcher Critique

All patients enrolled in the study had severe infections, which may explain the protective effect of combination use with MEPM observed; extrapolation of these findings to patients with less severe infections is uncertain. A small sample size and variability in both AED and MEPM doses further limits applicability.

Clinical impact of carbapenems in critically ill patients with valproic acid therapy: A propensity-matched analysis

Design

Retrospective observational cohort study

N= 1,227

Objective

To compare the prognosis of critically ill patients treated with valproic acid (VPA) and concomitant carbapenems (CBPs) or other broad-spectrum antibiotics

Study Groups

Study population (N= 1,227)

Population after propensity-score matching (n= 426)

CBP group (n= 213)

Non-CBP group (n= 213)

Inclusion Criteria

Exclusion Criteria

Stayed in the intensive care unit (ICU) for < 48 hours, those who received VPA therapy for <48 h, and those who developed status epilepticus before concomitant administration

Methods

Data were retrieved from patients admitted to the ICU and received VPA for epileptic seizures. Patients were further stratified by antibiotics: either CBPs or other broad-spectrum antibiotics (non-CBPs). Carbapenems included in this study were imipenem/cilastatin, meropenem, ertapenem, and doripenem.

Duration

Outcome Measures

Primary: Risk of lower VPA serum concentration and risk of seizures and SE during concomitant administration.

Secondary: In-hospital mortality, length of stay, cost

Baseline Characteristics

Study population (N= 1,,227)

Age, years

Female

Etiology of epileptic seizures

Post-stroke

Post-traumatic

CNS infection

Brain tumor

Other

54.0%

26.2%

13.7%

9.8%

16.4%

Antiepileptic drug used

Monotherapy

Dual therapy

Polytherapy

58.1%

26.6%

15.3%

SOFA score

Charlson comorbidity index

Hospital-acquired infection

Length of hospital stay after concomitant use of valproic acid and antibiotics, days

In-hospital mortality

Results

Endpoint

CBP group (n= 213)

Adjusted odds ratio (95% confidence interval [CI])

p-value

VPA serum concentration, mg/L (interquartile range [IQR])

15.8 (7.5 to 24.9)

--

< 0.0001

Epileptic seizures during concomitant administration

109 (51.2%)

2.19 (1.48 to 3.24)

< 0.0001

Status epilepticus during concomitant administration

29 (13.6%)

0.0014

In-hospital mortality rate

Length of hospital stay after concomitant administration, days

Expenditure of healthcare

Adverse Events

Study Author Conclusions

Our results provide the strongest observational evidence to date of the effect of concomitant administration with VAP and CBPs in critically ill ICU patients. Our results highlight that the CBPs should be avoided prescribing to patients with epilepsy undergoing VPA therapy in ICU. If patients with VAP need CBP therapy, we should monitor seizures closely and manage seizures carefully. Changing AED will be better management than increasing the VPA dosage. Further studies are warranted to investigate the reason for the poor outcomes and whether avoiding the co-administration of VPA and CBP can improve the outcomes of epileptic patients.

InpharmD Researcher Critique

Effect of concomitant administration of meropenem and valproic acid in an elderly Chinese patient

Design

Case presentation

An 85-year-old Chinese male inpatient, bedridden for approximately 8 years, had a history of cerebral infarction and hemorrhage over 10 years ago. He was taking several medications, including valproic acid 800 mg daily (300 mg at 7 AM, 300 mg at 1 PM, and 200 mg at 7 PM), topiramate 50 mg every night, rivastigmine hydrogen tartrate 3 mg BID, vitamin E  100 mg once daily, and finasteride 5 mg every night. His serum valproic acid levels typically ranged from 39.2 to 62.6 mcg/mL but occasionally fell below the therapeutic range of 50-120 mcg/mL. The patient had not experienced seizures in nearly 12 months.

On February 2, 2008, he was diagnosed with pneumonia and initially received intravenous (IV) cefmetazole (non-FDA approved agent). His valproic acid concentration was 48 mcg/mL before treatment. On day 10, due to the identification of Klebsiella pneumoniae (ESBL+) and Pseudomonas aeruginosa, he was switched to IV meropenem 0.5 g q8h. His valproic acid level dropped to 13.63 mcg/mL on day 11, with subsequent decreases to below therapeutic levels on days 13 (9.12 mcg/mL), 20 (10.90 mcg/mL), and 22 (10.37 mcg/mL). Throughout this treatment period, no seizures occurred.

Meropenem was discontinued on day 23, and his valproic acid levels gradually returned to normal, with readings of 14.60, 16.89, 31.76, and 41.95 mcg/mL on days 26, 27, 33, and 40, respectively. In May 2008, the patient developed pneumonia again and received IV meropenem 1 g q12h. Four days prior to this treatment, his valproic acid concentration was 39.54 mcg/mL. After starting meropenem, his valproic acid level decreased to 10.39 mcg/mL, leading to the onset of seizures on day 10. Consequently, meropenem was replaced with IV cefoperazone-sulbactam (non-FDA approved agent). 

Valproic acid was increased to 1600 mg/d, but levels fell to 9.16 mcg/mL on day 11, which resulted in the patient experiencing status epilepticus on day 12. To manage the persistent seizures, the valproic acid dosage was further escalated to 2000 mg/d, and temporary administration of phenobarbital and diazepam was initiated. Seizures were successfully controlled by day 15 and ceased completely by day 18. Valproic acid concentrations were subsequently maintained at therapeutic levels. The Naranjo adverse drug reaction probability scale indicated a score of 7, suggesting that the seizures observed were probably related to the concomitant administration of meropenem and valproic acid.

Study Author Conclusions

Various factors make the effect of concomitant administration of meropenem and valproic acid unpredictable, even in the same patient. Caution should be used when administering meropenem and valproic acid concomitantly, especially in elderly patients with central nervous system disorders, even if the patient has had a successful prior experience with these 2 drugs. If concomitant administration is essential, very close serum concentration monitoring and clinical observation are necessary.

Epileptic seizures caused by low valproic acid levels from an interaction with meropenem

Design

Case presentation

A 50-year-old female who had an intravenous (IV) ventricle ependymoma required surgery and implantation of a ventricular-peritoneal cerebrospinal fluid (CSF) derivation. Since the surgery, the patient developed epileptic seizures. Due to dermatological reactions to phenytoin and carbamazepine, treatment with valproic acid was started at 1500 mg/daily, which controlled her seizures for several years and maintained therapeutic concentrations.

The patient was eventually hospitalized due to derivation valve dehiscence. On day 39 of her hospitalization, the patient became hyperthermic and received a diagnosis of pneumonia, which worsened due to aspiration caused by problems swallowing. Meropenem was initiated on day 40 at a dose of 500 mg twice daily intravenously. On day 45, numerous myoclonic episodes occurred involving the patient's arms and face. Blood samples that day revealed a valproic acid level of 20.7 mcg/mL, which was followed by levels of 7.6 and 6.4 mcg/mL on days 47 and 50, respectively, despite the valproic acid level being gradually increased up to a maximum dose of 2,750 mg daily. 

On day 50, meropenem was discontinued, and the last episode of seizures was reported that day. Valproic acid was continued at high doses, and blood samples showed an increase to 20, 31, 76, and 83 mcg/mL on days 53, 54, 57, and 59, respectively. The valproic acid dose was eventually lowered to 1,750 mg daily.

Study Author Conclusions

If concomitant administration of valproic acid and meropenem (or other carbapenems) is essential, very close monitoring and dose adjustment of valproic acid is necessary to avoid the development of seizures.

Acute seizures due to a probable interaction between valproic acid and meropenem

Design

Case presentation

A 21-year-old woman, with no significant past medical or surgical history and no known drug allergies, presented to the emergency department with a new-onset generalized tonic–clonic seizure. Upon admission, the patient experienced three episodes of generalized tonic–clonic seizures, which resolved following the administration of 10 mg of intravenous (IV) diazepam. She was then started on intravenous phenytoin at a dosage of 100 mg TID. The diagnosis of status epilepticus was made, and the patient was subsequently admitted to the intensive care unit (ICU). 

The serum concentrations of phenytoin were maintained within therapeutic levels (10–20 mcg/mL). On day 2, the patient experienced generalized tonic–clonic seizures, which ceased after intravenous administration of 1 mg clonazepam. Treatment with valproic acid was initiated at a continuous intravenous infusion of 1000 mg over 24 hours. The patient gradually became obtunded and required intubation for airway protection. Due to ongoing seizures, a barbiturate coma was induced using an initial dose of 180 mg (3 mg/kg) of thiopental, followed by a continuous infusion of 2 mg/kg/h. By day 3, thiopental and phenytoin were gradually tapered, while the valproic acid infusion was increased to 1920 mg over 24 hours, with no seizure activity detected on the electroencephalogram.

The serum valproic acid concentration was 52.5 mcg/mL and remained therapeutic on days 8, 10, and 12. On day 13, fever recurred, leading to the discontinuation of amoxicillin/clavulanic acid and the initiation of meropenem (1 g TID). Two days later, while afebrile, the patient experienced myoclonic episodes; the serum valproic acid level was 42 mcg/mL, prompting an increase to 2880 mg over 24 hours. Despite this increase, a generalized tonic–clonic seizure occurred on day 17, with valproic acid dropping to 7 mcg/mL. The following day, the dose was raised to 3600 mg, but serum levels remained below 10 MCg/mL. On day 19, due to blood culture results and a suspected interaction between meropenem and valproic acid, meropenem was discontinued, and the patient was started on ceftazidime (1 g TID) and ciprofloxacin (400 mg BID). Valproic acid levels increased to therapeutic concentrations, and seizures did not recur.

By day 24, the patient was afebrile and, after 48 hours without myoclonic episodes, was discharged from the ICU with valproic acid concentrations in the therapeutic range. Three days later, the valproic acid concentration was 52.4 mcg/mL, with a dose/concentration ratio of 30.5 to 37.8 prior to meropenem treatment, rising to 450 afterward. When the carbapenem was discontinued, the ratio returned to values similar to those obtained before meropenem therapy was started. On day 30, the patient was asymptomatic, and she was discharged from the hospital and placed on a regimen of valproic acid 500 mg orally every 8 hours. She was followed up in the outpatient clinic and, 6 months later, had not experienced any further seizures.  

Study Author Conclusions

Seizure Worsening Caused by Decreased Serum Valproate During Meropenem Therapy

Design

Case presentation

A 9.5-year-old female with infantile neuroaxonal dystrophy and epilepsy was bedridden with profound hypotonia, areflexia, tetraplegia, dementia, and optic atrophy. Electroencephalogram revealed diffuse fast activity during the waking and sleeping states. Frequent multifocal spike and spike-wave discharges were also present, and epileptiform abnormalities were activated by sleep. The patient was previously initiated on valproate due to epileptic tonic events at the age of 7.5 years. Seizures ceased for several months, but while rarer, reappeared (one a week or less).

The child suffered from severe pneumonia, worsened by aspiration owing to swallowing problems. Multiple antimicrobial agents had little effect. Thus, intravenous meropenem 600 mg three times daily was initiated. She was taking valproate 200 mg three times daily at the time, with valproate serum concentrations before meropenem determined to be 46.5 to 63.3 mg/L. However, on the fifth day of meropenem therapy, the child presented with multiple tonic seizures a day, with serum valproate concentrations dropping to subtherapeutic levels (below 10 to 16.9 mg/L). The valproate dose was increased to 750 mg/day, and meropenem was discontinued on resolution of pneumonia. Three days later, serum valproate concentrations doubled (28 to 44 mg/L), and 14 days later, they increased to 74.3 to 86.9 mg/L. The seizures stopped, and the child continued the current valproate dose.

Subsequently, 1 month later, the child became hyperthermic, and a radiographic investigation found severe pneumonia. She was reinitiated on meropenem 600 mg three times daily intravenously. Serum valproate concentrations again dropped to subtherapeutic levels (below 10 to 19 mg/L). Meropenem was discontinued, and valproate concentrations quickly increased to 35 to 65 m/L and 65 to 82 mg/L 7 and 20 days later, respectively. Seizure frequency again declined to less than once a week.

Study Author Conclusions

Meropenem (like panipenem-betamipron) should be administered with caution in patients treated with valproate owing to the risk of inducing severe intractable seizures possibly caused by the rapid lowering of serum valproate concentration to subtherapeutic levels. If carbapenem therapy is deemed essential, serum valproate concentrations must be strictly monitored and, if necessary, the dose should be changed immediately.

Evaluating Clinical Sequelae of the Carbapenem-Valproate Interaction: A Retrospective Analysis

Design

Retrospective analysis

N= 78 (258 episodes)

Objective

To investigate the clinical and therapeutic implications of the carbapenem-valproate drug-drug interaction

Study Groups

Patients treated with valproate and carbapenem (N= 78)

Inclusion Criteria

Hospitalized adult patients (age ≥ 18 years), concomitantly administered any carbapenem antimicrobial and valproate product within 24 hours of each other

Exclusion Criteria

Patients without prolonged exposures to valproate prior to hospitalization, those without valproate levels drawn both before and after carbapenem administration within the same hospitalization

Methods

Patient data were compiled via retrospective chart review of patients treated across two institutions in Massachusetts. 

Duration

Treated between January 2017 to June 2022

Outcome Measures

Baseline Characteristics

All patients (N= 78)

Age, years (IQR)

Male

Weight, kg (IQR)

VPA indication

Seizure disorder

Mood-related disorder

41 (52.6%)

37 (47.4%)

Carbapenem

Meropenem

Ertapenem

Imipenem-cilastatin

Imipenem-cilastatin-relebactam

Meropenem-vaborbactam

N= 258 encounters

48.8%

25.6%

21.3%

2.3%

1.9%

Median duration of CBP use, days (IQR)

IQR, interquartile range

Results

Endpoint

All patients (N= 78)

Incidence of disturbance

Seizure

Behavioral

62 (46.3%)

63 (50.8%)

Seizure patients

VPA level < 50 mcg/mL

Median time to event, days (IQR)

44 (71.0%)

2.6 (1.6 to 5.4)

Mood disorder patients

VPA dose increase

Median time to event, days (IQR)

40 (32.3%)

5.2 (2.6 to 7.6)

Adverse Events

Study Author Conclusions

This study demonstrates significant clinical implications of the carbapenem-valproate interaction. Clinicians should be aware of this interaction and consider alternative antimicrobial and/or antiepileptic agents whenever possible. Adding or increasing doses of antiepileptic agents and/or consultation with a neurologist prior to concomitant use should be considered when this combination cannot be avoided.

InpharmD Researcher Critique

The study provides valuable insights into the clinical implications of the carbapenem-valproate interaction with a robust sample size. However, the retrospective design may introduce biases and data incompleteness. The reliance on keywords and consult services to identify behavioral events limits the ability to establish a causal relationship. Additionally, the variability in valproate serum concentration obtainment and interpretation was not tracked, which could affect the results