Category: Professional Posters
A decrease in seizure threshold is a well-known side effect of the carbapenem B-lactams. In addition, a clinically significant reduction in valproic acid plasma levels has been reported when combined with a carbapenem. Postulated mechanisms for this interaction include: increased metabolism of valproic acid to the glucuronide conjugate, increased renal elimination of the glucuronide conjugate, decreased intestinal absorption of valproic acid secondary to inhibition of intestinal transporters, increased distribution of valproic acid into erythrocytes, and decreased enterohepatic recirculation of valproic acid.
Pertinent literature review shows that the interaction is a class effect of the carbapenems and can occur starting 24 hours after the initiation of the carbapenem. The magnitude of this interaction ranges from about a 50% to an 80% reduction in valproic acid plasma concentrations. The half-life of valproic acid is reduced from 15 to 4 hours with concurrent carbapenem administration. Increasing the dose of valproic acid during the combined use period of both agents does not result in increasing valproic acid level back to its therapeutic range. Following the discontinuation of the carbapenem, the effect on valproic acid has been noted to continue for 7 to 14 days.
We present three patient cases receiving valproic acid for epilepsy who were started on meropenem which resulted in sub-therapeutic valproic acid plasma levels. The indication for meropenem on the three patients was hospital acquired pneumonia and the antibiotic doses were appropriate based on renal function. An anti-pseudomonal carbapenem is the preferred empirical option for hospital acquired pneumonia at our institution because of the high incidence of extended spectrum beta-lactamase producing organisms (around 30% of our Escherichia coli and Klebsiella pneumonia strains). The three patients were stable on valproic acid and had the following therapeutic plasma levels upon admission: 72, 71, and 62 mcg/ml (target level: 50-100 mcg/ml). After the initiation of meropenem, valproic acid concentrations measured 3, 5, and 10 days later on the three patients were: 20, 17, and 12 mcg/ml respectively (75-80% reduction from admission plasma concentrations). Two of the patients developed seizures after the initiation of meropenem. The duration of therapy of meropenem for the three patients ranged between 7-10 days as the culture results were negative and the patients were clinically improving. Valproic acid dose was increased and another anticonvulsant (phenytoin or levetiracetam) was added and continued after stopping antimicrobial therapy. The management of the patients eventually led to the resolution of seizures and stabilization of the patients’ conditions.
The combination of valproic acid and carbapenems should be avoided when possible. Close monitoring of valproic acid plasma levels and patient’s clinical status is required when there is no alternative antimicrobial. In most cases, adding another antiepileptic drug is warranted if a carbapenem is to be combined with valproic acid.