Panipenem with betamipron dramatically reduces valproate serum levels.

Ertapenem, imipenem and

(a) Ertapenem
A report describes a patient taking valproate semisodium 2 g daily who had recurring tonic-clonic seizures after
starting ertapenem. His serum valproic acid levels had decreased from 130 micrograms/mL (measured about 3
months earlier) to 70 micrograms/mL on day 7 of treatment with ertapenem 1 g daily when the seizures occurred. He
was given intravenous valproic acid 750 mg and the dose of valproate semisodium was increased to 2.75 g daily.
Four days later he presented with recurrent seizures and serum valproic acid levels of 10.7 micrograms/mL. He was
given intravenous valproic acid 1 g followed by oral valproate semisodium 100 mg. Ertapenem was discontinued and
the next day his serum valproic acid was 55 micrograms/mL. An increase in his valproate semisodium dose followed
by a gradual decrease allowed therapeutic levels to be achieved and he had no further seizures. 1
In another case report, total valproate levels in a patient taking valproic acid solution 1.1 g daily in divided doses
(separated from enteral nutrition she was receiving) fell from 72 micrograms/mL to 36.4 micrograms/mL
about 4 days after she was also given ertapenem 1 g daily. The valproic acid dose was increased to 1.6 g daily, but 2
days later valproate levels had further decreased to 18.4 micrograms/mL. The dose of valproic acid was further
increased to 2 g daily and levels 4 days later had decreased to about 1 microgram/mL. Ertapenem was discontinued
and intravenous valproic acid was given as a loading dose of 800 mg then 400 mg every 6 hours. Once valproate
levels returned to the therapeutic range she was given valproic acid solution 1.4 g daily. 2

b) Imipenem
A report describes a reduction in valproate levels from 80 micrograms/mL to 24 micrograms/mL then 33
micrograms/mL in a patient with epilepsy 4 and 11 days after imipenem was given to treat a Pseudomonas
aeruginosa infection.3 In another report, a patient taking valproate 800 mg daily had a 57% reduction in plasma
valproate levels during treatment with imipenem 500 mg twice daily for 5 days. A second patient taking valproate
600 mg daily had a reduction in plasma valproate levels of 49% when given imipenem 500 mg twice daily for 7 days. 4
Decreased valproate levels and recurrence of tonic-clonic convulsions occurred in another patient during concurrent
treatment with imipenem

c) meropenem

A report describes 2 patients whose valproate levels fell when meropenem and amikacin were given. The first patient
had been maintained on intravenous valproate 1.2 to 1.6 g daily with valproate levels of between 50 and
100 micrograms/mL. Two days after the addition of the antibacterials the levels had halved, and after 3 days of
subtherapeutic levels, phenytoin was substituted for valproate. The other patient experienced a drop in valproate
levels from 44 micrograms/mL to 5 micrograms/mL within 24 hours of being given meropenem, despite being given
greater doses of valproic acid.6 Other reports3,7-14 describe reductions in valproate levels in several
other patients when they were also given meropenem: 4 of them developed seizures.3,11-13 A retrospective study of an
18-month period identified 39 patients who had been treated with valproate and meropenem. Plasma valproate levels
fell in all patients by an average of 66% (range 34 to 92%) within 24 hours of concurrent use. Clinical assessment of
the interaction in 20 of the patients found worsening seizures or epileptic activity on EEG or both in 11 patients (55%).

(d) Panipenem
A report describes 3 cases of Japanese children taking antiepileptic drugs who had marked reductions in valproate
serum levels while receiving panipenem with betamipron for serious chest infections. 15 An increased seizure
frequency occurred in 2 of the patients. In one case the serum valproate levels fell from 30.1 micrograms/mL to 1.53
micrograms/mL within 4 days of starting panipenem, and rose again when it was stopped. All 3 patients were also
taking carbamazepine but its serum levels were unchanged by the antibacterial. In a further 3 cases, 60 to 100%
reductions in valproate levels were reported, which occurred within 2 days of starting concurrent treatment: increased
seizure frequency occurred in 2 cases

Mechanism
Unknown, but the speed of the interaction is said to be inconsistent with enzyme induction, and accelerated renal
excretion has been suggested.6 Altered protein binding has been shown in animal and in vitro studies.17 Enhanced
glucuronidation of valproate, by up-regulation of the catalyzing cofactor, is reported to increase hepatic intrinsic
clearance and renal excretion of valproate.18 Decreased hydrolysis of glucuronidated valproate due to inhibition of the
hydrolytic enzyme by carbapenems may also be involved. 18,19 It has been suggested that decreased plasma
valproate levels may partly be due to an increase in the distribution of valproate into erythrocytes. 4
Importance and management
Although there are few reports of an interaction between valproate and imipenem or ertapenem, there are now
several reports of the interaction between valproate and meropenem or panipenem. Seizures or increased seizure
frequency as well as significant decreases in valproate levels have been reported. It would therefore seem prudent to
monitor the valproate levels in any patient also given a carbapenem, being alert for the need to increase the valproate
dose, or to use another antibacterial, or an alternative to valproate. Carbamazepine 15 and phenytoin6 did not interact
in the above reports.