Effect of carbapenem and VPA coadministration on seizure outcomes: a retrospective single-center study

Effect of carbapenem and VPA coadministration on seizure outcomes: a retrospective single-center study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effect of carbapenem and VPA coadministration on seizure outcomes: a retrospective single-center study yu fu, quan wang, wenqi shi, xia luo, xingling liu, ye li, lejia xu, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9145557/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The concomitant use of carbapenem antibiotics and valproate is generally avoided because carbapenems markedly reduce serum valproate concentrations, raising concern about increased seizure risk. However, robust clinical evidence linking this pharmacokinetic interaction to worsened seizure control remains scarce. Methods This single‑center, retrospective, self‑controlled study included 189 patients with epilepsy or status epilepticus who received valproate together with meropenem and/or imipenem. Serum valproate concentrations, seizure incidence, and seizure frequency were compared across the pre‑concomitant, concomitant, and post‑concomitant periods. Results During concomitant therapy, median serum valproate concentration declined by 74.7% (from 48.04 to 12.15 µg/mL). Despite this reduction, no significant increase in seizure rate or frequency was observed. Seizure rates were 28.0% pre‑concomitantly, 20.6% during therapy ( P = 0.5602), and 8.5% post‑therapy ( P = 0.0086). Seizure frequency remained 0 (0–0.5), 0 (0–0), and 0 (0–0) per person‑week, respectively. No significant differences in valproate concentrations were found between patients with and without seizures. Conclusions These findings challenge current precautionary recommendations and support a more nuanced, evidence‑based approach to managing this drug combination in clinical practice. Valproate Carbapenems Seizures Drug interactions Retrospective study Figures Figure 1 Introduction Epilepsy is a prevalent chronic neurological disorder that affects an estimated 65 million individuals worldwide, and has an annual incidence of 50–100 per 100,000 population. The incidence is notably higher among infants under one year of age and adults over 85 years 1 . Sodium valproate (VPA) occupies an irreplaceable role in epilepsy management due to its broad-spectrum antiseizure activity, unique multi-target mechanism of action, preferred status in specific epilepsy syndromes, suitability for monotherapy, and well-established pharmacokinetic and safety profile 2 , 3 . Bacterial infections of the central nervous system represent one of the most frequent and preventable risk factors for acute symptomatic seizures and acquired epilepsy 4 , 5 . Infections can also trigger status epilepticus, a high-mortality condition defined by continuous or recurrent seizures lasting more than five minutes 4 . Carbapenem antibiotics have become cornerstone therapeutic agents for severe infections owing to their broad antimicrobial spectrum and efficacy against multidrug-resistant organisms 6 . Given their pronounced efficacy against multidrug-resistant and Gram-negative bacteria, meropenem and imipenem dominate clinical use and are among the most frequently administered carbapenems in critically ill patients 7 . In clinical practice, managing patients with concurrent infection and epilepsy or those at high seizure risk often necessitates the concomitant use of carbapenems and VPA. However, the safety of this combination, particularly its impact on seizure control, remains a subject of long-standing controversy. The prevailing view posits that carbapenems significantly reduce serum VPA concentrations, primarily by enhancing the clearance of VPA glucuronide conjugates and inhibiting its enterohepatic recirculation, thereby potentially compromising therapeutic efficacy 8 , 9 . Several case reports and small observational studies have documented worsened seizure control or even status epilepticus following co-administration 8 . An alternative perspective notes that therapeutic antiseizure activity is primarily mediated by free (unbound) valproic acid. Some preclinical studies found that concomitant use did not decrease free VPA concentrations, suggesting a potentially neutral effect on seizure risk 10 , 11 . Despite this, international guidelines generally recommend avoiding the combination or, if unavoidable, implementing close therapeutic drug monitoring of VPA with corresponding antiseizure regimen adjustments. This recommendation poses a significant clinical dilemma: critically ill patients often have a clear indication for carbapenems, while alternative antibiotics may offer limited efficacy or greater toxicity. Furthermore, as time-dependent antimicrobials, insufficient carbapenem exposure increases the risk of infection relapse or treatment failure 12 . Conversely, VPA is crucial for seizure control in many patients, and inappropriate substitution or discontinuation carries substantial risk. More importantly, current evidence suggesting an increased seizure risk from this drug interaction largely stems from case reports and small-scale studies, highlighting a significant gap in large-scale, systematic clinical evidence. Therefore, a large-scale, systematic study to evaluate the true seizure risk associated with concomitant carbapenem and VPA use is urgently needed to address this clinical dilemma and evidence gap. ​Materials and methods Study design This single-center, retrospective, self-controlled study was conducted through a review of electronic medical records. It aimed to evaluate the effects of concomitant VPA and carbapenem antibiotic (meropenem or imipenem) therapy on serum VPA concentrations and antiseizure efficacy. Study population Data source Inpatients treated at The Third Affiliated Hospital of Sun Yat-sen University between June 2013 and June 2023 were eligible. Meropenem and imipenem were administered intravenously; VPA was administered either intravenously or orally. Inclusion criteria Patients were included if they met the following criteria: (1) a confirmed diagnosis of epilepsy or status epilepticus, and (2) concomitant administration of VPA with meropenem and/or imipenem. Exclusion criteria Exclusion criteria were: (1) non-concurrent use of VPA and carbapenems or a concomitant duration of less than 24 hours; (2) prophylactic use of VPA; or (3) missing essential clinical or laboratory data. Methods Data collection Data were systematically extracted using a standardized case report form. Clinical information included epilepsy/status epilepticus diagnosis, seizure etiology, indication for carbapenem use, duration and dosage of VPA and carbapenem therapy, seizure activity, VPA discontinuation (and reason if applicable), and number/type of other antiseizure medications. Laboratory data consisted of liver function tests: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin, and albumin. The infection markers: white blood cell (WBC) count, neutrophil percentage, C-reactive protein (CRP), and procalcitonin (PCT), measured before and during concomitant therapy. Data processing To assess the influence of concomitant therapy, each patient’s hospital stay was divided into three intervals: pre-concomitant, concomitant, and post-concomitant (up to 14 days after carbapenem discontinuation). For patients discharged earlier, data were recorded until the discharge date. For each interval, the following were recorded: serum VPA concentration, seizure occurrence (yes/no and frequency), and seizure duration. Statistical analysis Analyses were performed using GraphPad Prism 8. Categorical variables are summarized as number (percentage). Continuous variables are presented as mean ± standard deviation if normally distributed, or as median (interquartile range) otherwise. Based on data distribution and design, group comparisons were made using independent or paired t-tests, one-way or repeated-measures ANOVA, or corresponding non-parametric tests (Mann–Whitney U, Kruskal–Wallis, Wilcoxon signed-rank, or Friedman tests). A two-sided P-value < 0.05 defined statistical significance. Results Patient selection and baseline characteristics We retrospectively analyzed 309 cases from The Third Affiliated Hospital of Sun Yat-sen University (June 2013 to June 2023) involving concomitant use of VPA with meropenem and/or imipenem. Following the application of inclusion and exclusion criteria, 120 cases were excluded: 86 for non-concurrent use of VPA and carbapenems, 29 for a concomitant duration <24 hours, 4 for prophylactic VPA use, and 1 due to missing data. Consequently, 189 patients were included in the final analysis (Figure 1). Among the 189 included patients, 174 (92.1%) had a diagnosis of epilepsy and 15 (7.9%) had status epilepticus. The distribution of underlying etiologies was as follows: cerebrovascular disease (n = 87, 46.0%), metabolic/toxic/septic encephalopathy (n = 25, 13.2%), encephalitis or meningoencephalitis (n = 24, 12.7%), pre-existing epilepsy (n = 20, 10.6%), traumatic brain injury (n = 14, 7.4%), brain tumor (n = 10, 5.3%), and post-cardiopulmonary-cerebral resuscitation (n = 9, 4.8%). Detailed baseline characteristics are presented in Table 1. Table 1. Baseline characteristics and diagnoses of included patients (n = 189). Characteristic n (%) Epilepsy diagnosis Epilepsy 174 (92.1%) Status epilepticus 15 (7.9%) Etiology Cerebrovascular Disease 87 (46.0%) Metabolic/Toxic/Septic Encephalopathy 25 (13.2%) Encephalitis/Meningoencephalitis 24 (12.7%) Pre-existing epilepsy 20 (10.6%) Traumatic brain injury 14 (7.4%) Brain tumor 10 (5.3%) Post-cardiopulmonary-cerebral resuscitation 9 (4.8%) Values are presented as n (%). The duration and indications for concomitant antibiotic therapy are summarized in Table 2. Meropenem was administered to 151 patients with a median concomitant duration of 8 days (IQR 4-12). Indications included pulmonary infection (n = 120), central nervous system (CNS) infection (n = 23), and other infections (n = 8; e.g., urinary tract infection [UTI], skin infection, sepsis). Imipenem was given to 31 patients for a median of 8 days (IQR 4-14), primarily for pulmonary infection (n = 30), with one case for other infection (postoperative). Seven patients received both imipenem and meropenem concurrently for a median of 21 days (IQR 10-42), all for pulmonary infection. Table 2. Utilization of meropenem and imipenem. Values are presented as median [IQR]. Item Meropenem (n = 151) Imipenem (n = 31) Imipenem + Meropenem (n = 7) Median concomitant duration, days 8 (4-12) 8 (4-14) 21 (10-42) Indication, n (%) Pulmonary infection 120 (79.5%) 30 (96.8%) 7 (100.0%) CNS Infection 23 (15.2%) 0 0 Other Infection 8 (5.3%) 1 (3.2%) 0 Among the 189 patients, 161 (85.2%) received concomitant antiseizure medications (ASMs) in addition to VPA, whereas 28 (14.8%) remained on VPA monotherapy. The median number of concomitant ASMs was 2 (interquartile range [IQR] 1–3). Levetiracetam was the most frequently co-administered agent (n = 113), followed by lamotrigine (n = 47), phenobarbital (n = 42), clonazepam (n = 30), magnesium sulfate (n = 29), topiramate (n = 26), oxcarbazepine (n = 24), and carbamazepine (n = 12) (Table 3). Table 3. Concomitant use of other antiseizure medications. Values are presented as median [IQR]. Category n (%) / Detail Patients on other ASMs 161 (85.2%) Patients on VPA monotherapy 28 (14.8%) Number of concomitant ASMs, median (IQR) 2（1-3） Specific ASMs used, n Levetiracetam 113 Lamotrigine 47 Phenobarbital 42 Clonazepam 30 Magnesium sulfate 29 Topiramate 26 Oxcarbazepine 24 Carbamazepine 12 Impact of concomitant VPA and carbapenem use on laboratory parameters Serially measured biochemical parameters were analyzed using median values from the pre-concomitant and concomitant periods (Table 4). Assessed serum indices included markers of inflammation—WBC count, neutrophil percentage, CRP, and PCT—and markers of liver function—AST, ALT, ALP, total bilirubin, and albumin. No significant differences were found in WBC count, neutrophil percentage, CRP, or PCT between the two periods. This likely reflects that most patients were not in an active infectious state prior to concomitant therapy and that infections were adequately controlled during treatment. Regarding liver function, ALT levels were significantly higher and albumin levels were significantly lower during concomitant therapy compared to the pre-concomitant period, though both remained within normal clinical limits. Other liver function parameters (AST, ALP, total bilirubin) did not change significantly. Furthermore, comparisons of inflammation and liver function markers between patients with and without seizures during the concomitant period showed no significant differences (Table 5), indicating no clear association between seizure occurrence and these laboratory parameters after initiating combination therapy. Table 4. Inflammatory and liver function markers before and during concomitant VPA and carbapenem therapy. Parameter Pre-concomitant Period Concomitant Period P-value WBC (×10⁹/L), n = 78 9.210（6.910-12.70） 8.830（6.538-12.68） 0.8169 Neutrophil %, n = 76 0.7445（0.6643-0.8316） 0.7595（0.6549-0.8276） 0.9293 CRP (mg/L), n = 96 17.49（6.803-52.23） 30.38（5.750-70.94） 0.6124 PCT (ng/mL), n = 54 0.2025（0.09638-0.5443） 0.3015（0.1083-1.333） 0.8226 AST (U/L), n = 114 24.00（18.00-37.50） 26.00（19.00-39.50） 0.1968 ALT (U/L), n = 116 10.79（5.013-24.75） 17.00（7.959-27.38） 0.0002 ALP (U/L), n = 39 76.00（56.00-109.0） 78.00（56.20-99.00） 0.7326 Total bilirubin (µmol/L), n = 71 7.400（4.910-10.99） 7.260（4.700-10.62） 0.2737 Albumin (g/L), n = 111 36.50（33.85-40.20） 34.70（30.15-38.50） 0.0159 Values are presented as median [IQR]. Abbreviations: WBC, white blood cell; CRP, C-reactive protein; PCT, procalcitonin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase. Table 5. Inflammatory and liver function markers in patients with and without seizures during concomitant therapy. Parameter Pre-concomitant Period Concomitant Period P-value WBC (×10⁹/L), n = 78 9.110（6.655-13.24） 10.12（6.774-12.43） 0.8920 Neutrophil %, n = 76 0.7490（0.6570-0.8220） 0.7733（0.6563-0.8255） 0.5198 CRP (mg/L), n = 96 29.70（8.500-70.93） 23.75（2.255-56.38） 0.1786 PCT (ng/mL), n = 54 0.2540（0.1178-1.353） 0.2025（0.093-0.5084） 0.2397 AST (U/L), n = 114 25.00（19.00-38.00） 29.00（18.00-50.00） 0.2874 ALT (U/L), n = 116 16.00（8.000-31.00） 18.00（7.040-27.50） 0.9503 ALP (U/L), n = 39 72.50（55.00-98.25） 78.00（61.25-117.0） 0.4284 Total bilirubin (µmol/L), n = 71 7.500（4.720-10.95） 7.325（5.530-16.88） 0.4435 Albumin (g/L), n = 111 34.58（29.74-38.38） 37.05（32.70-38.70） 0.0587 Values are presented as median [IQR]. Abbreviations: WBC, white blood cell; CRP, C-reactive protein; PCT, procalcitonin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase. Impact of concomitant VPA and carbapenem use on serum concentrations and seizure control The median daily VPA dose was 1.0 g (IQR 0.6–1). Concomitant use of meropenem and/or imipenem was associated with a substantial reduction in serum VPA levels, while no clinically significant worsening in seizure control was observed. Prior to concomitant therapy, the median serum VPA concentration was 48.04 µg/mL (IQR 29.63–73.11; n = 50 measurements) in the overall cohort of 189 patients. Concentrations were 51.64 µg/mL (28.36–73.98; n=33) in the 136 seizure-free patients and 45.30 µg/mL (31.55–71.55; n = 17) in the 53 patients with seizures. During the concomitant period, the median concentration decreased to 12.15 µg/mL (6.283–30.05; n = 58) overall, with levels of 11.49 µg/mL (6.47–29.28; n = 39) in 150 seizure-free patients and 15.09 µg/mL (3.21–32.91; n = 19) in 39 patients with seizures. Within 14 days after discontinuing concomitant therapy, the median concentration was 28.99 µg/mL (11.00–39.31; n = 16) overall, 28.99 µg/mL (14.32–38.34; n = 10) in 173 seizure-free patients, and 32.02 µg/mL (7.995–57.25; n = 6) in 16 patients with seizures. These data demonstrate that concomitant carbapenem use reduced the median serum VPA concentration from 48.04 µg/mL to 12.15 µg/mL, corresponding to a decline of approximately 74.7%. Although concentrations partially recovered to 28.99 µg/mL within 14 days after discontinuation—a 138.6% increase from the concomitant period—they remained about 39.6% below pre-concomitant levels and did not return to baseline (see Tables 6 and 7). This indicates that the carbapenem-induced reduction in serum VPA is not readily reversible in the short term. No significant differences in VPA concentrations were observed between patients with and without seizures across the pre-concomitant, concomitant, and post-concomitant periods. Table 6. Serum VPA concentrations across study periods. Values are presented as median [IQR]. Observation Period Serum VPA Concentration (µg/mL) Change from Pre-concomitant Level Pre-concomitant (n = 189) 48.04 (29.63–73.11) [n = 50] — During concomitant use (n = 189) 12.15 (6.283–30.05) [n = 58] –74.7% Within 14 days post-concomitant (n = 189) 28.99 (11.00–39.31) [n = 16] –39.6% Table 7. Serum VPA concentrations in patients with and without seizures during concomitant therapy. Values are presented as median [IQR]. Observation Period Serum VPA Concentration (µg/mL) No seizures during concomitant therapy (n=150) 11.49 (6.47–29.28) [n=39] Seizures during concomitant therapy (n=39) 15.09 (3.21–32.91) [n=19] Analysis of seizure outcomes revealed seizure rates of 28.0% in the pre‑concomitant period, 20.6% during concomitant therapy, and 8.5% within 14 days after discontinuation (Table 8). No statistically significant difference was observed between the pre‑concomitant and concomitant periods ( P = 0.5602), whereas the difference between the pre‑concomitant period and the 14‑day post‑concomitant interval was statistically significant ( P = 0.0086). Seizure frequency was 0 (0–0.5) seizures per person per week in the pre‑concomitant period, 0 (0–0) during concomitant therapy, and 0 (0–0) within 14 days after discontinuation (Table 8). No statistically significant difference was found between the pre‑concomitant and concomitant periods ( P > 0.9999), while a statistically significant difference existed between the pre‑concomitant period and the 14‑day post‑concomitant interval ( P = 0.0128). These results suggest that neither the seizure rate nor the seizure frequency was clearly associated with concomitant carbapenem use. Table 8. Effect of concomitant use of VPA with carbapenems on seizure control. Values are presented as median [IQR]. Observation period Seizure incidence (%) Seizure frequency (per person/week) Pre‑concomitant (n = 189) 28.0 0 (0–0.5) During concomitant therapy (n = 189) 20.6 ( P = 0.5602) 0 (0–0) ( P > 0.9999) Within 14 days after discontinuation (n = 189) 8.5 ( P = 0.0086) 0 (0–0) ( P = 0.0128) Discussion Epilepsy is a chronic neurological disorder characterized by recurrent seizures, whose associated cognitive decline and psychosocial comorbidities often substantially impair quality of life and impose a considerable burden on patients, families, and society 1 . Pharmacological therapy remains the cornerstone of management, aiming to achieve symptom control and reduce seizure frequency 8 . VPA is one of the most widely used and efficacious antiseizure medications, with a well-established role spanning over five decades in the treatment of generalized, focal, and specific epilepsy syndromes 8 . Infection is a major preventable cause of epilepsy globally. Antibiotic use in patients with epilepsy requires careful consideration of potential interactions with antiseizure drugs and of antibiotic-related effects on seizure threshold 13 . Notably, several antibiotic classes—such as carbapenems, penicillins, cephalosporins, fluoroquinolones, and antimalarials—exhibit proconvulsant properties and may precipitate seizures even in individuals without epilepsy 14 , 15 . Among carbapenems, imipenem has long been a first-line option for severe mixed and multidrug-resistant infections due to its broad β-lactamase stability 16 . Meropenem offers enhanced activity against non-fermenting Gram-negative bacilli (e.g., Pseudomonas aeruginosa, Acinetobacter baumannii) and a relatively lower risk of central nervous system toxicity, rendering it preferable for conditions such as meningitis, hospital-acquired pneumonia, and mixed aerobic/anaerobic infections 17 . Concomitant use of carbapenems with VPA has consistently been associated with a marked decrease in total plasma VPA concentrations, commonly attributed to pharmacokinetic interactions 8 . However, VPA is highly protein-bound (~ 90–95%), and its pharmacological activity is mediated primarily by the free (unbound) fraction. The observed reduction in total concentration may partly reflect methodological limitations in conventional assays. Preclinical studies have shown that although total VPA clearance increases during carbapenem co-administration, the unbound fraction remains stable, suggesting that free VPA concentrations—and thus antiseizure activity—may be preserved 10 . Other evidence indicates that the decrease in total concentration results from inhibition of enterohepatic recirculation, without necessarily reducing free drug levels 18 . These observations raise the possibility that the reported decline in total VPA concentration could represent a methodological artifact, while stable free VPA concentrations may explain maintained seizure control in many patients receiving the combination. Despite numerous case reports and small studies highlighting reduced VPA concentrations during carbapenem therapy, robust evidence linking this interaction to an increased risk of seizures has been lacking. Large-scale, real-world analyses systematically evaluating clinical seizure outcomes have been notably absent. In this retrospective study of 189 patients receiving VPA with meropenem or imipenem, we confirmed a substantial decrease in total serum VPA concentrations but found no corresponding increase in the seizure rate or seizure frequency. This finding challenges the conventional caution against concomitant use and supports a more nuanced, evidence-based approach to clinical decision-making. Prospective, multicenter studies incorporating therapeutic drug monitoring of both total and free VPA, along with detailed seizure diaries, are warranted to refine risk stratification and guide management. In conclusion, our large real-world analysis indicates that concomitant carbapenem and VPA therapy, while significantly lowering total VPA concentrations, does not increase the risk of seizures. Despite its contributions, this study has several limitations. First, as a single-center retrospective analysis, it is subject to selection bias and heterogeneity in patient management, which may affect the generalizability of our findings. Second, the majority of patients received concomitant antiseizure medications in addition to VPA, potentially confounding the assessment of VPA-specific seizure control during carbapenem therapy. Third, while total serum VPA concentrations were routinely monitored, free VPA concentrations—which more accurately reflect pharmacological activity—were not measured, limiting our ability to fully elucidate the pharmacokinetic interaction. Finally, the follow-up period was confined to 14 days after carbapenem discontinuation; longer-term outcomes regarding seizure recurrence, VPA concentration recovery, and safety with repeated exposures remain unknown and warrant further investigation in prospective studies. Conclusions Concomitant use of meropenem or imipenem with VPA significantly lowers total serum VPA concentrations but does not increase seizure rate or frequency. These findings challenge current precautionary recommendations and support a more evidence-based approach to clinical practice. Abbreviations VPA, Valproate; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; ALP, Alkaline phosphatase; WBC, White blood cell; CRP, C-reactive protein; PCT, Procalcitonin; ASM, Antiseizure medication; CNS, Central nervous system; IQR, Interquartile range; UTI, Urinary tract infection . Declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University (Approval No. ZSSYEC II2024-019-01, approved on 17 January 2024). This study was conducted in accordance with the ethical principles of the Declaration of Helsinki. The requirement for informed consent was waived by the ethics committee in accordance with relevant Chinese regulations and guidelines, including the Measures for Ethical Review of Life Sciences and Medical Research Involving Humans (2023). Consent for publication Not applicable. Availability of data and materials The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request but are not publicly accessible due to data privacy restrictions. Competing interests The authors declare that they have no competing interests. Funding This study was supported partly by a grant from the China Medical Foundation (2025CMFC1) and the Zhong Nanshan Medical Foundation of Guangdong Province [ZNSXS-20250133]. The funder had no role in the study design, data collection, analysis, interpretation, or manuscript writing. Authors' contributions FY, XL, LY and MH conducted the research design. FY and WQ participated in the writing of the paper. FY, WQ and LY analyzed and explained the data; LX, LX and WQ collected and helped with analyzing the data of the study. All authors read and approved the final manuscript. Acknowledgements The authors thank all the patients participated in the study. Authors' information 1 Department of Pharmacy, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Tianhe District, Guangzhou, People’s Republic of China. 2 Big Data and Artificial Intelligence Center, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Tianhe District, Guangzhou, People’s Republic of China. Clinical trial number Not applicable. References Majeed CN, Rudnick SR, Bonkovsky HL. Review of Antiseizure Medications for Adults With Epilepsy. JAMA . 2022;328(7):680. doi:10.1001/jama.2022.10594. Sodium valproate. Lancet . 1988;2(8622):1229-1231. Pinder RM, Brogden RN, Speight TM, Avery GS. Sodium valproate: a review of its pharmacological properties and therapeutic efficacy in epilepsy. Drugs . 1977;13(2):81-123. doi:10.2165/00003495-197713020-00001. Lowenstein DH. Treatment options for status epilepticus. Curr Opin Pharmacol . 2005;5(3):334-339. doi:10.1016/j.coph.2005.04.003. Vezzani A, Fujinami RS, White HS, et al. Infections, inflammation and epilepsy. Acta Neuropathol . 2016;131(2):211-234. doi:10.1007/s00401-015-1481-5. Zhanel GG, Wiebe R, Dilay L, et al. Comparative review of the carbapenems. Drugs . 2007;67(7):1027-1052. doi:10.2165/00003495-200767070-00006. You X, Dai Q, Hu J, et al. Therapeutic drug monitoring of imipenem/cilastatin and meropenem in critically ill adult patients. J Glob Antimicrob Resist . 2024;36:252-259. doi:10.1016/j.jgar.2024.01.004. Chai PY, Chang CT, Chen YH, Chen HY, Tam KW. Effect of drug interactions between carbapenems and valproate on serum valproate concentration: a systematic review and meta-analysis. Expert Opin Drug Saf . 2021;20(2):215-223. doi:10.1080/14740338.2021.1865307. Mori H, Takahashi K, Mizutani T. Interaction between valproic acid and carbapenem antibiotics. Drug Metab Rev . 2007;39(4):647-657. doi:10.1080/03602530701690341. Yokogawa K, Iwashita S, Kubota A, et al. Effect of meropenem on disposition kinetics of valproate and its metabolites in rabbits. Pharm Res . 2001;18(9):1320-1326. doi:10.1023/a:1013046229699. Yamamura N, Imura K, Naganuma H, Nishimura K. Panipenem, a carbapenem antibiotic, enhances the glucuronidation of intravenously administered valproic acid in rats. Drug Metab Dispos . 1999;27(6):724-730. Suchánková H, Rychlíčková J, Urbánek K. Farmakokinetika karbapenemů [Pharmacokinetics of carbapenems]. Klin Mikrobiol Infekc Lek . 2012;18(3):68-74. Sander JW, Perucca E. Epilepsy and comorbidity: infections and antimicrobials usage in relation to epilepsy management. Acta Neurol Scand Suppl . 2003;180:16-22. doi:10.1034/j.1600-0404.108.s180.3.x. Sutter R, Rüegg S, Tschudin-Sutter S. Seizures as adverse events of antibiotic drugs: A systematic review. Neurology . 2015;85(15):1332-1341. doi:10.1212/WNL.0000000000002023. Wanleenuwat P, Suntharampillai N, Iwanowski P. Antibiotic-induced epileptic seizures: mechanisms of action and clinical considerations. Seizure . 2020;81:167-174. doi:10.1016/j.seizure.2020.08.012. Buckley MM, Brogden RN, Barradell LB, Goa KL. Imipenem/cilastatin. A reappraisal of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy. Drugs . 1992;44(3):408-444. doi:10.2165/00003495-199244030-00008. Steffens NA, Zimmermann ES, Nichelle SM, Brucker N. Meropenem use and therapeutic drug monitoring in clinical practice: a literature review. J Clin Pharm Ther . 2021;46(3):610-621. doi:10.1111/jcpt.13369. Kojima S, Nadai M, Kitaichi K, Wang L, Nabeshima T, Hasegawa T. Possible mechanism by which the carbapenem antibiotic panipenem decreases the concentration of valproic acid in plasma in rats. Antimicrob Agents Chemother . 1998;42(12):3136-3140. doi:10.1128/AAC.42.12.3136. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9145557","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":615495392,"identity":"c562cec6-5123-4cf3-bae3-07cabc2797be","order_by":0,"name":"yu fu","email":"","orcid":"","institution":"Third Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"yu","middleName":"","lastName":"fu","suffix":""},{"id":615495394,"identity":"e21fe2cd-bea2-442f-9b60-a69ec35d7285","order_by":1,"name":"quan wang","email":"","orcid":"","institution":"Third Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"quan","middleName":"","lastName":"wang","suffix":""},{"id":615495397,"identity":"24c4619e-6014-4430-b018-ae5f0b175135","order_by":2,"name":"wenqi shi","email":"","orcid":"","institution":"Third Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"wenqi","middleName":"","lastName":"shi","suffix":""},{"id":615495398,"identity":"22b01ce3-bd17-42b6-be5d-a0557f1efc46","order_by":3,"name":"xia luo","email":"","orcid":"","institution":"Third Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"xia","middleName":"","lastName":"luo","suffix":""},{"id":615495400,"identity":"996061f0-6797-4f66-8bb1-ebd4152418e8","order_by":4,"name":"xingling liu","email":"","orcid":"","institution":"Third Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"xingling","middleName":"","lastName":"liu","suffix":""},{"id":615495402,"identity":"31706e4e-1dd3-487d-96e8-a76066477112","order_by":5,"name":"ye li","email":"","orcid":"","institution":"Third Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"ye","middleName":"","lastName":"li","suffix":""},{"id":615495404,"identity":"bb403c25-a7b9-4d6f-9dbb-cdd5f3cd8aff","order_by":6,"name":"lejia xu","email":"","orcid":"","institution":"Third Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"lejia","middleName":"","lastName":"xu","suffix":""},{"id":615495406,"identity":"91298284-6e77-4e76-9e4d-0a4dea527d2b","order_by":7,"name":"haiyan mai","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIiWNgGAWjYFACxjYGhgoGBjZ2uEgCMVrOALUwE6+FgQ2si4FoLbrth9se887bJs/HzMD8mefPYQZ+9hwDhp87cGsxO5PYbsy77bZhGzMDmzRv22EGyZ43Boy9Z/BoOZDYJg3UwgjSwszbcJjB4EaOATPYqbi0nH8I1DLntn0bzGH2BLXcANnScDsRqIVBmocNaIsEQS0P2yTnHLud3AZUJjm3LZ1H4syzgoO9eB2W/kziTc1t2/ntzYc/vPljLcffnrzxwU88WkCAiQdMMTaAGGD2AfwagGp/oDNGwSgYBaNgFCADAKvkTNP95grGAAAAAElFTkSuQmCC","orcid":"","institution":"Third Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":true,"prefix":"","firstName":"haiyan","middleName":"","lastName":"mai","suffix":""}],"badges":[],"createdAt":"2026-03-17 08:01:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9145557/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9145557/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105923577,"identity":"8ddae948-a597-444e-b271-97f7f58881bd","added_by":"auto","created_at":"2026-04-01 12:59:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":82534,"visible":true,"origin":"","legend":"\u003cp\u003ePatient screening process\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-9145557/v1/2a1905e0a8faa04f9c920b96.png"},{"id":106200251,"identity":"8da7d831-94b4-48c9-8f3a-7bd161a89fe9","added_by":"auto","created_at":"2026-04-06 02:39:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1207698,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9145557/v1/974422a3-635a-4891-80e3-98cf05573cd6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effect of carbapenem and VPA coadministration on seizure outcomes: a retrospective single-center study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEpilepsy is a prevalent chronic neurological disorder that affects an estimated 65\u0026nbsp;million individuals worldwide, and has an annual incidence of 50\u0026ndash;100 per 100,000 population. The incidence is notably higher among infants under one year of age and adults over 85 years\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Sodium valproate (VPA) occupies an irreplaceable role in epilepsy management due to its broad-spectrum antiseizure activity, unique multi-target mechanism of action, preferred status in specific epilepsy syndromes, suitability for monotherapy, and well-established pharmacokinetic and safety profile \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBacterial infections of the central nervous system represent one of the most frequent and preventable risk factors for acute symptomatic seizures and acquired epilepsy\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Infections can also trigger status epilepticus, a high-mortality condition defined by continuous or recurrent seizures lasting more than five minutes\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Carbapenem antibiotics have become cornerstone therapeutic agents for severe infections owing to their broad antimicrobial spectrum and efficacy against multidrug-resistant organisms\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Given their pronounced efficacy against multidrug-resistant and Gram-negative bacteria, meropenem and imipenem dominate clinical use and are among the most frequently administered carbapenems in critically ill patients\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn clinical practice, managing patients with concurrent infection and epilepsy or those at high seizure risk often necessitates the concomitant use of carbapenems and VPA. However, the safety of this combination, particularly its impact on seizure control, remains a subject of long-standing controversy. The prevailing view posits that carbapenems significantly reduce serum VPA concentrations, primarily by enhancing the clearance of VPA glucuronide conjugates and inhibiting its enterohepatic recirculation, thereby potentially compromising therapeutic efficacy\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Several case reports and small observational studies have documented worsened seizure control or even status epilepticus following co-administration\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. An alternative perspective notes that therapeutic antiseizure activity is primarily mediated by free (unbound) valproic acid. Some preclinical studies found that concomitant use did not decrease free VPA concentrations, suggesting a potentially neutral effect on seizure risk\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e Despite this, international guidelines generally recommend avoiding the combination or, if unavoidable, implementing close therapeutic drug monitoring of VPA with corresponding antiseizure regimen adjustments. This recommendation poses a significant clinical dilemma: critically ill patients often have a clear indication for carbapenems, while alternative antibiotics may offer limited efficacy or greater toxicity. Furthermore, as time-dependent antimicrobials, insufficient carbapenem exposure increases the risk of infection relapse or treatment failure\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Conversely, VPA is crucial for seizure control in many patients, and inappropriate substitution or discontinuation carries substantial risk. More importantly, current evidence suggesting an increased seizure risk from this drug interaction largely stems from case reports and small-scale studies, highlighting a significant gap in large-scale, systematic clinical evidence. Therefore, a large-scale, systematic study to evaluate the true seizure risk associated with concomitant carbapenem and VPA use is urgently needed to address this clinical dilemma and evidence gap.\u003c/p\u003e"},{"header":"​Materials and methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis single-center, retrospective, self-controlled study was conducted through a review of electronic medical records. It aimed to evaluate the effects of concomitant VPA and carbapenem antibiotic (meropenem or imipenem) therapy on serum VPA concentrations and antiseizure efficacy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData source\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInpatients treated at The Third Affiliated Hospital of Sun Yat-sen University between June 2013 and June 2023 were eligible. Meropenem and imipenem were administered intravenously; VPA was administered either intravenously or orally.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients were included if they met the following criteria: (1) a confirmed diagnosis of epilepsy or status epilepticus, and (2) concomitant administration of VPA with meropenem and/or imipenem.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eExclusion criteria were: (1) non-concurrent use of VPA and carbapenems or a concomitant duration of less than 24 hours; (2) prophylactic use of VPA; or (3) missing essential clinical or laboratory data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData were systematically extracted using a standardized case report form. Clinical information included epilepsy/status epilepticus diagnosis, seizure etiology, indication for carbapenem use, duration and dosage of VPA and carbapenem therapy, seizure activity, VPA discontinuation (and reason if applicable), and number/type of other antiseizure medications. Laboratory data consisted of liver function tests: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin, and albumin. The infection markers: white blood cell (WBC) count, neutrophil percentage, C-reactive protein (CRP), and procalcitonin (PCT), measured before and during concomitant therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData processing\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo assess the influence of concomitant therapy, each patient\u0026rsquo;s hospital stay was divided into three intervals: pre-concomitant, concomitant, and post-concomitant (up to 14 days after carbapenem discontinuation). For patients discharged earlier, data were recorded until the discharge date. For each interval, the following were recorded: serum VPA concentration, seizure occurrence (yes/no and frequency), and seizure duration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnalyses were performed using GraphPad Prism 8. Categorical variables are summarized as number (percentage). Continuous variables are presented as mean \u0026plusmn; standard deviation if normally distributed, or as median (interquartile range) otherwise. Based on data distribution and design, group comparisons were made using independent or paired t-tests, one-way or repeated-measures ANOVA, or corresponding non-parametric tests (Mann\u0026ndash;Whitney U, Kruskal\u0026ndash;Wallis, Wilcoxon signed-rank, or Friedman tests). A two-sided P-value \u0026lt; 0.05 defined statistical significance.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient selection and baseline characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe retrospectively analyzed 309 cases from The Third Affiliated Hospital of Sun Yat-sen University (June 2013 to June 2023) involving concomitant use of VPA with meropenem and/or imipenem. Following the application of inclusion and exclusion criteria, 120 cases were excluded: 86 for non-concurrent use of VPA and carbapenems, 29 for a concomitant duration \u0026lt;24 hours, 4 for prophylactic VPA use, and 1 due to missing data. Consequently, 189 patients were included in the final analysis (Figure 1).\u003c/p\u003e\n\u003cp\u003eAmong the 189 included patients, 174 (92.1%) had a diagnosis of epilepsy and 15 (7.9%) had status epilepticus. The distribution of underlying etiologies was as follows: cerebrovascular disease (n = 87, 46.0%), metabolic/toxic/septic encephalopathy (n = 25, 13.2%), encephalitis or meningoencephalitis (n = 24, 12.7%), pre-existing epilepsy (n = 20, 10.6%), traumatic brain injury (n = 14, 7.4%), brain tumor (n = 10, 5.3%), and post-cardiopulmonary-cerebral resuscitation (n = 9, 4.8%). Detailed baseline characteristics are presented in Table 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eBaseline characteristics and diagnoses of included patients (n = 189).\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable style=\"width: 4.3e+2pt;border: none;\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eEpilepsy diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eEpilepsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e174 (92.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eStatus epilepticus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15 (7.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eEtiology\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCerebrovascular Disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e87 (46.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMetabolic/Toxic/Septic Encephalopathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e25 (13.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eEncephalitis/Meningoencephalitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24 (12.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePre-existing epilepsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20 (10.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTraumatic brain injury\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14 (7.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBrain tumor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10 (5.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePost-cardiopulmonary-cerebral resuscitation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9 (4.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eValues are presented as n (%).\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe duration and indications for concomitant antibiotic therapy are summarized in Table 2. Meropenem was administered to 151 patients with a median concomitant duration of 8 days (IQR 4-12). Indications included pulmonary infection (n = 120), central nervous system (CNS) infection (n = 23), and other infections (n = 8; e.g., urinary tract infection [UTI], skin infection, sepsis). Imipenem was given to 31 patients for a median of 8 days (IQR 4-14), primarily for pulmonary infection (n = 30), with one case for other infection (postoperative). Seven patients received both imipenem and meropenem concurrently for a median of 21 days (IQR 10-42), all for pulmonary infection.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eUtilization of meropenem and imipenem. Values are presented as median [IQR].\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable style=\"width: 4.3e+2pt;border: none;\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eItem\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMeropenem\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 151)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eImipenem\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 31)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eImipenem + Meropenem\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMedian concomitant duration, days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8 (4-12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8 (4-14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e21 (10-42)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eIndication, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePulmonary infection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e120 (79.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30 (96.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7 (100.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCNS Infection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23 (15.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eOther Infection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8 (5.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 (3.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAmong the 189 patients, 161 (85.2%) received concomitant antiseizure medications (ASMs) in addition to VPA, whereas 28 (14.8%) remained on VPA monotherapy. The median number of concomitant ASMs was 2 (interquartile range [IQR] 1\u0026ndash;3). Levetiracetam was the most frequently co-administered agent (n = 113), followed by lamotrigine (n = 47), phenobarbital (n = 42), clonazepam (n = 30), magnesium sulfate (n = 29), topiramate (n = 26), oxcarbazepine (n = 24), and carbamazepine (n = 12) (Table 3). \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u0026nbsp;\u003c/strong\u003eConcomitant use of other antiseizure medications.\u003cstrong\u003eValues are presented as median [IQR].\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable style=\"width: 4.3e+2pt;border: none;\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eCategory\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003en (%) / Detail\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePatients on other ASMs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e161 (85.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePatients on VPA monotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28 (14.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNumber of concomitant ASMs, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2（1-3）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSpecific ASMs used, n\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eLevetiracetam\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e113\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eLamotrigine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePhenobarbital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eClonazepam\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMagnesium sulfate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTopiramate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eOxcarbazepine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCarbamazepine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eImpact of concomitant VPA and carbapenem use on laboratory parameters\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSerially measured biochemical parameters were analyzed using median values from the pre-concomitant and concomitant periods (Table 4). Assessed serum indices included markers of inflammation\u0026mdash;WBC count, neutrophil percentage, CRP, and PCT\u0026mdash;and markers of liver function\u0026mdash;AST, ALT, ALP, total bilirubin, and albumin. No significant differences were found in WBC count, neutrophil percentage, CRP, or PCT between the two periods. This likely reflects that most patients were not in an active infectious state prior to concomitant therapy and that infections were adequately controlled during treatment. Regarding liver function, ALT levels were significantly higher and albumin levels were significantly lower during concomitant therapy compared to the pre-concomitant period, though both remained within normal clinical limits. Other liver function parameters (AST, ALP, total bilirubin) did not change significantly. Furthermore, comparisons of inflammation and liver function markers between patients with and without seizures during the concomitant period showed no significant differences (Table 5), indicating no clear association between seizure occurrence and these laboratory parameters after initiating combination therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4.\u0026nbsp;\u003c/strong\u003eInflammatory and liver function markers before and during concomitant VPA and carbapenem therapy.\u0026nbsp;\u003c/p\u003e\n\u003cdiv align=\"ceter\"\u003e\n \u003ctable style=\"width: 4.3e+2pt;border: none;\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eParameter\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePre-concomitant Period\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eConcomitant Period\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eWBC (\u0026times;10⁹/L), n = 78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9.210（6.910-12.70）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8.830（6.538-12.68）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.8169\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNeutrophil %, n = 76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.7445（0.6643-0.8316）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.7595（0.6549-0.8276）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.9293\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCRP (mg/L), n = 96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e17.49（6.803-52.23）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30.38（5.750-70.94）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.6124\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePCT (ng/mL), n = 54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.2025（0.09638-0.5443）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.3015（0.1083-1.333）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.8226\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAST (U/L), n = 114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24.00（18.00-37.50）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e26.00（19.00-39.50）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.1968\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eALT (U/L), n = 116\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10.79（5.013-24.75）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e17.00（7.959-27.38）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.0002\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eALP (U/L), n = 39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e76.00（56.00-109.0）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e78.00（56.20-99.00）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.7326\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTotal bilirubin (\u0026micro;mol/L), n = 71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.400（4.910-10.99）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.260（4.700-10.62）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.2737\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAlbumin (g/L), n = 111\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e36.50（33.85-40.20）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34.70（30.15-38.50）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.0159\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eValues are presented as median [IQR].\u003c/strong\u003e Abbreviations: WBC, white blood cell; CRP, C-reactive protein; PCT, procalcitonin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5.\u0026nbsp;\u003c/strong\u003eInflammatory and liver function markers in patients with and without seizures during concomitant therapy. \u0026nbsp;\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable style=\"width: 4.3e+2pt;border: none;\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eParameter\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePre-concomitant Period\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eConcomitant Period\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eWBC (\u0026times;10⁹/L), n = 78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9.110（6.655-13.24）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10.12（6.774-12.43）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.8920\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNeutrophil %, n = 76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.7490（0.6570-0.8220）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.7733（0.6563-0.8255）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.5198\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCRP (mg/L), n = 96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29.70（8.500-70.93）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23.75（2.255-56.38）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.1786\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePCT (ng/mL), n = 54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.2540（0.1178-1.353）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.2025（0.093-0.5084）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.2397\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAST (U/L), n = 114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e25.00（19.00-38.00）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29.00（18.00-50.00）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.2874\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eALT (U/L), n = 116\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16.00（8.000-31.00）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e18.00（7.040-27.50）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.9503\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eALP (U/L), n = 39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e72.50（55.00-98.25）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e78.00（61.25-117.0）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.4284\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTotal bilirubin (\u0026micro;mol/L), n = 71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.500（4.720-10.95）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.325（5.530-16.88）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.4435\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAlbumin (g/L), n = 111\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34.58（29.74-38.38）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e37.05（32.70-38.70）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.0587\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eValues are presented as median [IQR].\u003c/strong\u003e Abbreviations: WBC, white blood cell; CRP, C-reactive protein; PCT, procalcitonin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImpact of concomitant VPA and carbapenem use on serum concentrations and seizure control\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median daily VPA dose was 1.0 g (IQR 0.6\u0026ndash;1). Concomitant use of meropenem and/or imipenem was associated with a substantial reduction in serum VPA levels, while no clinically significant worsening in seizure control was observed.\u003c/p\u003e\n\u003cp\u003ePrior to concomitant therapy, the median serum VPA concentration was 48.04 \u0026micro;g/mL (IQR 29.63\u0026ndash;73.11; n = 50 measurements) in the overall cohort of 189 patients. Concentrations were 51.64 \u0026micro;g/mL (28.36\u0026ndash;73.98; n=33) in the 136 seizure-free patients and 45.30 \u0026micro;g/mL (31.55\u0026ndash;71.55; n = 17) in the 53 patients with seizures. During the concomitant period, the median concentration decreased to 12.15 \u0026micro;g/mL (6.283\u0026ndash;30.05; n = 58) overall, with levels of 11.49 \u0026micro;g/mL (6.47\u0026ndash;29.28; n = 39) in 150 seizure-free patients and 15.09 \u0026micro;g/mL (3.21\u0026ndash;32.91; n = 19) in 39 patients with seizures. Within 14 days after discontinuing concomitant therapy, the median concentration was 28.99 \u0026micro;g/mL (11.00\u0026ndash;39.31; n = 16) overall, 28.99 \u0026micro;g/mL (14.32\u0026ndash;38.34; n = 10) in 173 seizure-free patients, and 32.02 \u0026micro;g/mL (7.995\u0026ndash;57.25; n = 6) in 16 patients with seizures.\u003c/p\u003e\n\u003cp\u003eThese data demonstrate that concomitant carbapenem use reduced the median serum VPA concentration from 48.04 \u0026micro;g/mL to 12.15 \u0026micro;g/mL, corresponding to a decline of approximately 74.7%. Although concentrations partially recovered to 28.99 \u0026micro;g/mL within 14 days after discontinuation\u0026mdash;a 138.6% increase from the concomitant period\u0026mdash;they remained about 39.6% below pre-concomitant levels and did not return to baseline (see Tables 6 and 7). This indicates that the carbapenem-induced reduction in serum VPA is not readily reversible in the short term. No significant differences in VPA concentrations were observed between patients with and without seizures across the pre-concomitant, concomitant, and post-concomitant periods.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 6.\u0026nbsp;\u003c/strong\u003eSerum VPA concentrations across study periods. \u003cstrong\u003eValues are presented as median [IQR].\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable style=\"width: 4.3e+2pt;border: none;\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eObservation Period\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSerum VPA Concentration (\u0026micro;g/mL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eChange from Pre-concomitant Level\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePre-concomitant (n = 189)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e48.04 (29.63\u0026ndash;73.11) [n = 50]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDuring concomitant use (n = 189)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12.15 (6.283\u0026ndash;30.05) [n = 58]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026ndash;74.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eWithin 14 days post-concomitant (n = 189)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28.99 (11.00\u0026ndash;39.31) [n = 16]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026ndash;39.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eTable 7.\u0026nbsp;\u003c/strong\u003eSerum VPA concentrations in patients with and without seizures during concomitant therapy. \u003cstrong\u003eValues are presented as median [IQR].\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable style=\"width: 4.3e+2pt;border: none;\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eObservation Period\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSerum VPA Concentration (\u0026micro;g/mL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNo seizures during concomitant therapy (n=150)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11.49 (6.47\u0026ndash;29.28) [n=39]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSeizures during concomitant therapy (n=39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15.09 (3.21\u0026ndash;32.91) [n=19]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAnalysis of seizure outcomes revealed seizure rates of 28.0% in the pre‑concomitant period, 20.6% during concomitant therapy, and 8.5% within 14 days after discontinuation (Table 8). No statistically significant difference was observed between the pre‑concomitant and concomitant periods (\u003cem\u003eP\u003c/em\u003e = 0.5602), whereas the difference between the pre‑concomitant period and the 14‑day post‑concomitant interval was statistically significant (\u003cem\u003eP\u003c/em\u003e = 0.0086). Seizure frequency was 0 (0\u0026ndash;0.5) seizures per person per week in the pre‑concomitant period, 0 (0\u0026ndash;0) during concomitant therapy, and 0 (0\u0026ndash;0) within 14 days after discontinuation (Table 8). No statistically significant difference was found between the pre‑concomitant and concomitant periods (\u003cem\u003eP\u003c/em\u003e \u0026gt; 0.9999), while a statistically significant difference existed between the pre‑concomitant period and the 14‑day post‑concomitant interval (\u003cem\u003eP\u003c/em\u003e = 0.0128). These results suggest that neither the seizure rate nor the seizure frequency was clearly associated with concomitant carbapenem use.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 8.\u0026nbsp;\u003c/strong\u003eEffect of concomitant use of VPA with carbapenems on seizure control. \u003cstrong\u003eValues are presented as median [IQR].\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cdiv align=\"cener\"\u003e\n \u003ctable style=\"width: 4.3e+2pt;border: none;\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eObservation period\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSeizure incidence (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSeizure frequency (per person/week)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePre‑concomitant (n = 189)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0 (0\u0026ndash;0.5) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDuring concomitant therapy (n = 189)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20.6 (\u003cem\u003eP\u003c/em\u003e = 0.5602)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0 (0\u0026ndash;0) (\u003cem\u003eP\u003c/em\u003e \u0026gt; 0.9999)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eWithin 14 days after discontinuation (n = 189)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8.5 (\u003cem\u003eP\u003c/em\u003e = 0.0086)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0 (0\u0026ndash;0) (\u003cem\u003eP\u003c/em\u003e = 0.0128)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eEpilepsy is a chronic neurological disorder characterized by recurrent seizures, whose associated cognitive decline and psychosocial comorbidities often substantially impair quality of life and impose a considerable burden on patients, families, and society\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Pharmacological therapy remains the cornerstone of management, aiming to achieve symptom control and reduce seizure frequency\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. VPA is one of the most widely used and efficacious antiseizure medications, with a well-established role spanning over five decades in the treatment of generalized, focal, and specific epilepsy syndromes\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eInfection is a major preventable cause of epilepsy globally. Antibiotic use in patients with epilepsy requires careful consideration of potential interactions with antiseizure drugs and of antibiotic-related effects on seizure threshold\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Notably, several antibiotic classes\u0026mdash;such as carbapenems, penicillins, cephalosporins, fluoroquinolones, and antimalarials\u0026mdash;exhibit proconvulsant properties and may precipitate seizures even in individuals without epilepsy\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Among carbapenems, imipenem has long been a first-line option for severe mixed and multidrug-resistant infections due to its broad β-lactamase stability\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Meropenem offers enhanced activity against non-fermenting Gram-negative bacilli (e.g., Pseudomonas aeruginosa, Acinetobacter baumannii) and a relatively lower risk of central nervous system toxicity, rendering it preferable for conditions such as meningitis, hospital-acquired pneumonia, and mixed aerobic/anaerobic infections\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Concomitant use of carbapenems with VPA has consistently been associated with a marked decrease in total plasma VPA concentrations, commonly attributed to pharmacokinetic interactions\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. However, VPA is highly protein-bound (~\u0026thinsp;90\u0026ndash;95%), and its pharmacological activity is mediated primarily by the free (unbound) fraction. The observed reduction in total concentration may partly reflect methodological limitations in conventional assays. Preclinical studies have shown that although total VPA clearance increases during carbapenem co-administration, the unbound fraction remains stable, suggesting that free VPA concentrations\u0026mdash;and thus antiseizure activity\u0026mdash;may be preserved\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Other evidence indicates that the decrease in total concentration results from inhibition of enterohepatic recirculation, without necessarily reducing free drug levels\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. These observations raise the possibility that the reported decline in total VPA concentration could represent a methodological artifact, while stable free VPA concentrations may explain maintained seizure control in many patients receiving the combination.\u003c/p\u003e \u003cp\u003eDespite numerous case reports and small studies highlighting reduced VPA concentrations during carbapenem therapy, robust evidence linking this interaction to an increased risk of seizures has been lacking. Large-scale, real-world analyses systematically evaluating clinical seizure outcomes have been notably absent. In this retrospective study of 189 patients receiving VPA with meropenem or imipenem, we confirmed a substantial decrease in total serum VPA concentrations but found no corresponding increase in the seizure rate or seizure frequency. This finding challenges the conventional caution against concomitant use and supports a more nuanced, evidence-based approach to clinical decision-making. Prospective, multicenter studies incorporating therapeutic drug monitoring of both total and free VPA, along with detailed seizure diaries, are warranted to refine risk stratification and guide management. In conclusion, our large real-world analysis indicates that concomitant carbapenem and VPA therapy, while significantly lowering total VPA concentrations, does not increase the risk of seizures.\u003c/p\u003e \u003cp\u003eDespite its contributions, this study has several limitations. First, as a single-center retrospective analysis, it is subject to selection bias and heterogeneity in patient management, which may affect the generalizability of our findings. Second, the majority of patients received concomitant antiseizure medications in addition to VPA, potentially confounding the assessment of VPA-specific seizure control during carbapenem therapy. Third, while total serum VPA concentrations were routinely monitored, free VPA concentrations\u0026mdash;which more accurately reflect pharmacological activity\u0026mdash;were not measured, limiting our ability to fully elucidate the pharmacokinetic interaction. Finally, the follow-up period was confined to 14 days after carbapenem discontinuation; longer-term outcomes regarding seizure recurrence, VPA concentration recovery, and safety with repeated exposures remain unknown and warrant further investigation in prospective studies.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eConcomitant use of meropenem or imipenem with VPA significantly lowers total serum VPA concentrations but does not increase seizure rate or frequency. These findings challenge current precautionary recommendations and support a more evidence-based approach to clinical practice.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eVPA, Valproate; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; ALP, Alkaline phosphatase; WBC, White blood cell; CRP, C-reactive protein; PCT, Procalcitonin; ASM, Antiseizure medication; CNS, Central nervous system; IQR, Interquartile range; UTI, Urinary tract infection .\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University (Approval No. ZSSYEC II2024-019-01, approved on 17 January 2024). This study was conducted in accordance with the ethical principles of the Declaration of Helsinki. The requirement for informed consent was waived by the ethics committee in accordance with relevant Chinese regulations and guidelines, including the Measures for Ethical Review of Life Sciences and Medical Research Involving Humans (2023).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request but are not publicly accessible due to data privacy restrictions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported partly by a grant from the China Medical Foundation (2025CMFC1) and the Zhong Nanshan Medical Foundation of Guangdong Province [ZNSXS-20250133].\u003c/p\u003e\n\u003cp\u003eThe funder had no role in the study design, data collection, analysis, interpretation, or manuscript writing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFY, XL, LY and MH conducted the research design. FY and WQ participated in the writing of the paper. FY, WQ and LY analyzed and explained the data; LX, LX and WQ collected and helped with analyzing the data of the study. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank all the patients participated in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eDepartment of Pharmacy, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Tianhe District, Guangzhou, People\u0026rsquo;s Republic of China. \u003csup\u003e2\u003c/sup\u003eBig Data and Artificial Intelligence Center, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Tianhe District, Guangzhou, People\u0026rsquo;s Republic of China.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMajeed CN, Rudnick SR, Bonkovsky HL. Review of Antiseizure Medications for Adults With Epilepsy. \u003cem\u003eJAMA\u003c/em\u003e. 2022;328(7):680. doi:10.1001/jama.2022.10594.\u003c/li\u003e\n\u003cli\u003eSodium valproate. \u003cem\u003eLancet\u003c/em\u003e. 1988;2(8622):1229-1231.\u003c/li\u003e\n\u003cli\u003ePinder RM, Brogden RN, Speight TM, Avery GS. Sodium valproate: a review of its pharmacological properties and therapeutic efficacy in epilepsy. \u003cem\u003eDrugs\u003c/em\u003e. 1977;13(2):81-123. doi:10.2165/00003495-197713020-00001.\u003c/li\u003e\n\u003cli\u003eLowenstein DH. Treatment options for status epilepticus. \u003cem\u003eCurr Opin Pharmacol\u003c/em\u003e. 2005;5(3):334-339. doi:10.1016/j.coph.2005.04.003.\u003c/li\u003e\n\u003cli\u003eVezzani A, Fujinami RS, White HS, et al. Infections, inflammation and epilepsy. \u003cem\u003eActa Neuropathol\u003c/em\u003e. 2016;131(2):211-234. doi:10.1007/s00401-015-1481-5.\u003c/li\u003e\n\u003cli\u003eZhanel GG, Wiebe R, Dilay L, et al. Comparative review of the carbapenems. \u003cem\u003eDrugs\u003c/em\u003e. 2007;67(7):1027-1052. doi:10.2165/00003495-200767070-00006.\u003c/li\u003e\n\u003cli\u003eYou X, Dai Q, Hu J, et al. Therapeutic drug monitoring of imipenem/cilastatin and meropenem in critically ill adult patients. \u003cem\u003eJ Glob Antimicrob Resist\u003c/em\u003e. 2024;36:252-259. doi:10.1016/j.jgar.2024.01.004.\u003c/li\u003e\n\u003cli\u003eChai PY, Chang CT, Chen YH, Chen HY, Tam KW. Effect of drug interactions between carbapenems and valproate on serum valproate concentration: a systematic review and meta-analysis. \u003cem\u003eExpert Opin Drug Saf\u003c/em\u003e. 2021;20(2):215-223. doi:10.1080/14740338.2021.1865307.\u003c/li\u003e\n\u003cli\u003eMori H, Takahashi K, Mizutani T. Interaction between valproic acid and carbapenem antibiotics. \u003cem\u003eDrug Metab Rev\u003c/em\u003e. 2007;39(4):647-657. doi:10.1080/03602530701690341.\u003c/li\u003e\n\u003cli\u003eYokogawa K, Iwashita S, Kubota A, et al. Effect of meropenem on disposition kinetics of valproate and its metabolites in rabbits. \u003cem\u003ePharm Res\u003c/em\u003e. 2001;18(9):1320-1326. doi:10.1023/a:1013046229699.\u003c/li\u003e\n\u003cli\u003eYamamura N, Imura K, Naganuma H, Nishimura K. Panipenem, a carbapenem antibiotic, enhances the glucuronidation of intravenously administered valproic acid in rats. \u003cem\u003eDrug Metab Dispos\u003c/em\u003e. 1999;27(6):724-730.\u003c/li\u003e\n\u003cli\u003eSuch\u0026aacute;nkov\u0026aacute; H, Rychl\u0026iacute;čkov\u0026aacute; J, Urb\u0026aacute;nek K. Farmakokinetika karbapenemů [Pharmacokinetics of carbapenems].\u003cem\u003e Klin Mikrobiol Infekc Lek\u003c/em\u003e. 2012;18(3):68-74.\u003c/li\u003e\n\u003cli\u003eSander JW, Perucca E. Epilepsy and comorbidity: infections and antimicrobials usage in relation to epilepsy management. \u003cem\u003eActa Neurol Scand Suppl\u003c/em\u003e. 2003;180:16-22. doi:10.1034/j.1600-0404.108.s180.3.x.\u003c/li\u003e\n\u003cli\u003eSutter R, R\u0026uuml;egg S, Tschudin-Sutter S. Seizures as adverse events of antibiotic drugs: A systematic review. \u003cem\u003eNeurology\u003c/em\u003e. 2015;85(15):1332-1341. doi:10.1212/WNL.0000000000002023.\u003c/li\u003e\n\u003cli\u003eWanleenuwat P, Suntharampillai N, Iwanowski P. Antibiotic-induced epileptic seizures: mechanisms of action and clinical considerations. \u003cem\u003eSeizure\u003c/em\u003e. 2020;81:167-174. doi:10.1016/j.seizure.2020.08.012.\u003c/li\u003e\n\u003cli\u003eBuckley MM, Brogden RN, Barradell LB, Goa KL. Imipenem/cilastatin. A reappraisal of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy. \u003cem\u003eDrugs\u003c/em\u003e. 1992;44(3):408-444. doi:10.2165/00003495-199244030-00008.\u003c/li\u003e\n\u003cli\u003eSteffens NA, Zimmermann ES, Nichelle SM, Brucker N. Meropenem use and therapeutic drug monitoring in clinical practice: a literature review. \u003cem\u003eJ Clin Pharm Ther\u003c/em\u003e. 2021;46(3):610-621. doi:10.1111/jcpt.13369.\u003c/li\u003e\n\u003cli\u003eKojima S, Nadai M, Kitaichi K, Wang L, Nabeshima T, Hasegawa T. Possible mechanism by which the carbapenem antibiotic panipenem decreases the concentration of valproic acid in plasma in rats. \u003cem\u003eAntimicrob Agents Chemother\u003c/em\u003e. 1998;42(12):3136-3140. doi:10.1128/AAC.42.12.3136.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Valproate, Carbapenems, Seizures, Drug interactions, Retrospective study","lastPublishedDoi":"10.21203/rs.3.rs-9145557/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9145557/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe concomitant use of carbapenem antibiotics and valproate is generally avoided because carbapenems markedly reduce serum valproate concentrations, raising concern about increased seizure risk. However, robust clinical evidence linking this pharmacokinetic interaction to worsened seizure control remains scarce.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis single‑center, retrospective, self‑controlled study included 189 patients with epilepsy or status epilepticus who received valproate together with meropenem and/or imipenem. Serum valproate concentrations, seizure incidence, and seizure frequency were compared across the pre‑concomitant, concomitant, and post‑concomitant periods.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eDuring concomitant therapy, median serum valproate concentration declined by 74.7% (from 48.04 to 12.15 \u0026micro;g/mL). Despite this reduction, no significant increase in seizure rate or frequency was observed. Seizure rates were 28.0% pre‑concomitantly, 20.6% during therapy (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.5602), and 8.5% post‑therapy (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0086). Seizure frequency remained 0 (0\u0026ndash;0.5), 0 (0\u0026ndash;0), and 0 (0\u0026ndash;0) per person‑week, respectively. No significant differences in valproate concentrations were found between patients with and without seizures.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThese findings challenge current precautionary recommendations and support a more nuanced, evidence‑based approach to managing this drug combination in clinical practice.\u003c/p\u003e","manuscriptTitle":"Effect of carbapenem and VPA coadministration on seizure outcomes: a retrospective single-center study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-01 12:59:31","doi":"10.21203/rs.3.rs-9145557/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"150f382c-feb3-4db0-b182-d88d0396967e","owner":[],"postedDate":"April 1st, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-06T02:38:16+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-01 12:59:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9145557","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9145557","identity":"rs-9145557","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}