Experience from clinical trials as well as several case reports corroborates the presence of a valproate-carbapenem drug interaction with concomitant administration, resulting in a significantly decreased serum concentration of valproate derivatives. Subsequently, this subtherapeutic serum concentration has resulted in instances of breakthrough seizures in some patients. This reduction in serum valproic acid concentration occurs rapidly, within 24 hours of concomitant administration. While some data indicates serum valproic acid levels generally return to normal shortly following discontinuation of carbapenem, other data suggests normalization of levels may take more time. Across the various publications, a consistent and rapid decrease in serum valproic acid concentrations was observed within 24 hours of starting carbapenem therapy, often resulting in subtherapeutic levels and seizure exacerbation. For instance, a retrospective cohort of 28 pediatric patients reported subtherapeutic valproic acid levels in 88% of cases post-carbapenem initiation, with 54.5% experiencing breakthrough seizures. Similarly, an observational series of 54 adults treated with both valproic acid and carbapenems found that 48% experienced seizure recurrence, with valproic acid concentrations dropping up to 99% depending on the specific agent used—meropenem and ertapenem yielded sharper declines than imipenem. Furthermore, a 36-patient pharmacokinetic analysis measuring serial valproic acid levels revealed an average 82% reduction in serum concentration within 24 hours of meropenem initiation, with levels remaining suppressed up to 7 days post-discontinuation. Numerous case reports corroborated these findings, noting up to 90% reductions in valproic acid levels and corresponding electroclinical deterioration. Collectively, these findings underscore the preference to avoid coadministration of valproic acid and carbapenems when possible and support therapeutic alternatives or proactive antiepileptic adjustment when concurrent therapy is unavoidable. If concomitant use is still indicated, therapeutic drug monitoring is recommended to assess valproate serum concentrations. [1]
The mechanism responsible for the interaction between valproic acid and carbapenems is largely unknown, but it is thought that carbapenems act by inhibiting the activity of the acylpeptide hydrolase enzyme that converts valproic acid-glucuronide to valproic acid. This leads to increased elimination, a shorter half-life, and subtherapeutic plasma concentrations of valproic acid. Data suggests the half-life of valproic acid is reduced from 15 to 4 hours with concurrent carbapenem administration. Following discontinuation of the carbapenem, the effect on valproic acid has been noted to continue for 7 to 14 days. This prolonged duration of the interaction despite the short half-life of carbapenems is due to irreversible inhibition of acylpeptide hydrolase by the carbapenem, resulting in a half-life for recovery of deconjugation estimated to be approximately 2 days. [2]
The ultimate impact of carbapenems on valproic acid levels vary across the related literature. Some reports note a 10 to 15% decrease in valproic acid concentrations from baseline for adult patients. In pediatric patients, carbapenem has been reported to result in an approximate 60% decrease in valproate levels. [3, 4]
Pooled data investigating the effects of this drug-drug interaction has been presented in recent meta-analyses. A 2021 meta-analysis included 12 observational studies (N= 633 patients) to evaluate the pharmacokinetic interaction between valproate and carbapenem antibiotics. The pooled analysis revealed a significant reduction in mean serum valproate concentrations during concurrent administration of carbapenems and valproate, with an overall mean difference of -43.98 mg/L (95% CI -48.18 to -39.78), regardless of the specific carbapenem used. Notably, serum valproate concentrations reductions were observed within 1 to 3 days of carbapenem initiation and persisted throughout the course of treatment. Following carbapenem discontinuation, serum valproate concentrations began to recover, returning to pre-carbapenem baseline levels within 1 to 2 weeks (mean difference -10.39 mg/L; 95% CI -21.04 to 0.26). Approximately 26.3% of patients experienced increased seizure frequency during combination treatment, highlighting the clinical significance of the interaction. No correlation was identified between valproate or carbapenem dosage and mitigation of the concentration decline, suggesting that dose adjustments are ineffective. These findings highlight the clinical importance of promptly discontinuing carbapenems or substituting valproate when co-administration is unavoidable. [5]
Similarly, a 2018 systematic review and meta-analysis also evaluated pharmacokinetic DDIs between antiepileptic drugs and antibiotics, incorporating data from 86 eligible publications, including 31 clinical studies and 55 case reports. Carbapenem co-administration with valproic acid resulted in a pronounced reduction in valproic acid trough plasma concentrations by a mean of 42.9 µg/mL (p<0.001) based on 262 patients across nine studies, with substantial inter-study heterogeneity (I²= 93%). Average valproic acid concentrations were lowered from therapeutic (62 µg/mL) to subtherapeutic levels (19 µg/mL). This reduction, frequently associated with breakthrough seizures and electroencephalogram abnormalities, emphasizes the necessity of vigilant therapeutic drug monitoring and individualized pharmacotherapy when antiepileptic drugs are co-administered with antimicrobials. [6]