Valproic acid-carbapenem interaction: report of six cases and a review of the literature

Abstract

Aim: To evaluate the drug interactions between valproic acid (VPA) and carbapenem antibiotics.

Methods: The effects of concurrent use of VPA and carbapenem antibiotics were evaluated in a retrospective observational study of hospitalized adults. Patients receiving both VPA and a carbapenem with at least two plasma VPA concentrations serially measured prior to, during, and/or after this combined treatment were included.

Results: Six critically ill VPA-treated patients were identified who concurrently received meropenem (n=4), imipenem (n=1), or ertapenem (n=1). As compared with values obtained while not receiving treatment with the carbapenem, mean plasma VPA trough concentrations decreased by 58% (from 51.7 [95% confidence interval {CI} 28.0-75.4] to 21.8 [95% CI 11.1-32.5] mg/L; p = 0.025). Estimated mean VPA clearance increased by 191% (from 0.0158 [95% CI 0.0041-0.0275] to 0.0302 [95% CI 0.0169-0.0591] L/h/kg; p = 0.007). All VPA concentrations measured during concurrent VPA-carbapenem treatment were below the lower boundary of the usual therapeutic range. Five patients (83%) experienced generalized seizures during concurrent VPA-carbapenem treatment, including two with no prior history of seizures or epilepsy.

Conclusions: All recipients showed evidence of a complex pharmacokinetic and pharmacodynamic drug interaction between VPA and a carbapenem. Concurrent use of these medications should be avoided.