Epilepsia, 49(Suppl.
6):47–49, 2008
doi: 10.1111/j.1528-1167.2008.01756.x
SUPPLEMENT - CENTRAL NERVOUS SYSTEM INFECTIONS
Perspectives on interactions between antiepileptic
drugs (AEDs) and antimicrobial agents
Joy Desai
Department of Neurology, Jaslok Hospital, Mumbai, India
SUMMARY
In the treatment of seizures and epilepsy associ-
ated with central nervous system (CNS) infections,
drug–drug interactions may significantly and unex-
pectedly impact outcome not only of epilepsy but
also of the infectious disorders in both emergent
and chronic care situations. A case is described
in whom, the administration of the antimicrobial
agent, meropenem presumably reduced serum val-
proate concentrations resulting in impaired seizure
Interactions between antiepileptic drugs (AEDs) and an-
timicrobial agents are of critical concern in the manage-
ment of both central nervous system (CNS) infectious dis-
orders and of seizures and epilepsy in the setting of CNS
infections. Knowledge of these interactions is essential for
the management of patients with multisystem diseases. The
following case report illustrates this point typically.
C ASE R EPORT
A morbidly obese female, aged 71 years was admit-
ted into hospital for an emergency coronary artery by-
pass graft surgery due to unstable angina. She had a back-
ground medical history of obstructive sleep apnea, being
treated with nocturnal positive airway pressure therapy and
right hemicorporeal seizures due to a left parietal lobe
arteriovenous malformation that had earlier failed to re-
spond to embolization. She was referred to the neurologist
for perioperative seizure management. An electrocardio-
gram at admission revealed first-degree heart block. There-
fore, intravenous sodium valproate was chosen to manage
her symptomatic epilepsy during the perioperative period.
The immediate postoperative course was uneventful and
Address correspondence to Joy Desai, Department of Neurology,
Jaslok Memorial Hospital, Mumbai, India. E-mail: desaijoy@gmail.com
Wiley Periodicals, Inc.

C 2008 International League Against Epilepsy
47
control. Other situations are reviewed in which
interactions between antiepileptic drugs (AEDs)
and antimicrobial agents may be of clinical sig-
nificance. These include: (1) seizure management
in individuals with neurocysticercosis, (2) manage-
ment of seizures in patients with lobar tuberculo-
mas, (3) management of seizures due to cerebral
abscess, and (4) management of seizures in HIV-
seropositive individuals.
KEY WORDS: Antiepileptic drugs, Antimicrobial
agents, Drug interactions.
her seizures were well-controlled. However, 5 days later,
she developed sternal pain and local examination revealed
wound infection with dehiscence of the edges. Swab cul-
tures from the wound grew Pseudomonas aeruginosa re-
sistant to many antibiotics. She was administered intra-
venous meropenem (3 g/day). The very next day, she ex-
perienced frequent right upper limb focal motor and apha-
sic seizures that did not respond to intravenous supplemen-
tation of sodium valproate. At this point of time, serum
levels of sodium valproate were found to be markedly
subtherapeutic despite intravenous augmentation. She was
then switched over to levetiracetam and her seizures
abated.
D ISCUSSION
De Turck et al. (1998), first reported an interaction be-
tween meropenem and valproic acid in two adults. They
found that plasma levels of valproic acid were decreased by
concomitant administration of meropenem and amikacin.
Because this effect was not observed when amikacin was
administered alone, they suggested that this effect was
mediated by meropenem. Yokogawa et al. (2001), stud-
ied the effects of meropenem on valproic acid metabolism
in rabbits. They noted that plasma levels of valproic
acid were lowered by the simultaneous administration of
meropenem. Nacarkucuk et al. (2004), reported similar
findings in three children suggesting that the interaction
48
J. Desai
between meropenem and valproic acid merits clinical vig-
ilance, especially in a setting of critical illness.
In clinical practice, several additional clinical situa-
tions warrant vigilance for AED–antimicrobial interac-
tions. These are discussed below.
Seizure management in neurocysticercosis
Phenytoin and carbamazepine increase the first-pass
metabolism of praziquantel, plasma concentrations of
which are reduced by 74–90% (Bittencourt et al., 1992).
This interaction may potentially contribute to therapeutic
failure of praziquantel. It may be surmised that a sim-
ilar interaction could occur with the administration of
phenobarbital which is also a potent inducer of drug me-
tabolizing enzymes. Phenobarbital, phenytoin, and carba-
mazepine also increase the metabolism of albendazole (the
other more commonly used agent for neurocysticercosis)
by 50–65% due to stimulation of CYP3A4 (Lanchote et al.,
2002).
Drug interactions in the management
of cerebral tuberculomas
Isoniazid inhibits the metabolism of various AEDs in-
cluding phenytoin, carbamazepine, valproic acid, and etho-
suximide, producing high serum levels of these drugs and
resulting in potential clinical toxicity (Miller et al., 1979;
Valsalan & Cooper, 1982; van Wieringen & Vrijlandt,
1983; Jonville et al., 1991). Conversely, the enzyme-
inducing antitubercular agent, rifampicin reduces plasma
concentrations of phenytoin, carbamazepine, valproic acid,
ethosuximide, and lamotrigine, thus making some of
these AEDs relatively ineffective in the clinical context
of this combination. When combined with isoniazid, ri-
fampicin counteracts the former’s inhibitory effect on the
metabolism of phenytoin (Kay et al., 1985).
Drug interactions in the management
in cerebral abscess
Chloramphenicol may cause AED toxicity by increas-
ing the plasma concentrations of phenytoin and pheno-
barbital (Krasinski et al., 1982). Phenobarbital increases
the metabolism of chloramphenicol thus reducing its ef-
fectiveness and phenytoin seems to have the opposite ef-
fect (Krasinski et al., 1982). Interactions between valproate
and meropenem have already been discussed (De Turck
et al., 1998; Yokogawa et al., 2001; Nacarkucuk et al.,
2004). Some macrolide antibiotics like erythromycin are
potent inhibitors of CYP3A4 and have the potential to in-
crease plasma levels of carbamazepine resulting in clini-
cal toxicity (Babany et al., 1988; Pauwels, 2002). Rarely,
erythromycin can produce increase in serum levels of val-
proate resulting in clinical toxicity (Redington et al., 1992).
The author has come across one such case with severe CNS
toxicity induced by an interaction between erythromycin
and valproate. Oxcarbazepine, tiagabine, felbamate, top-
iramate, and levetiracetam appear not to be affected by
Epilepsia, 49(Suppl. 6):47–49, 2008
doi: 10.1111/j.1528-1167.2008.01756.x
the concomitant administration of erythromycin (Keranen
et al., 1992; Thomsen et al., 1998).
Drug interactions in HIV-positive individuals
on antiretroviral treatment
Seizures may occur in 11–15% of HIV-seropositive indi-
viduals (Wong et al., 1990). Many antiretroviral agents in-
cluding nevirapine, efavirenz, delavirdine, indinavir, riton-
avir, and saquinavir are metabolized by hepatic CYP3A4.
Therefore, enzyme-inducing AEDs such as phenytoin, car-
bamazepine, and phenobarbital could potentially lead to
insufficient plasma levels of the antiretroviral agents, the
dose of which may have to be increased (Romanelli et al.,
2000). The plasma concentration of indinavir was found
reduced by 16 times after the addition of carbamazepine
(Hugen et al., 2000). In contrast, sodium valproate may
inhibit the metabolism of antiretroviral drugs as docu-
mented with zidovudine (Lertora et al., 1994). Nevirapine
and efavirenz are inducers of hepatic CYP3A4, whereas
indinavir, ritonavir, and delavirdine are inhibitors of hep-
atic CYP3A4 (Joly & Yeni, 1999). Ritonavir can cause 2-
to 3-fold increase in serum carbamazepine levels causing
clinical signs of toxicity (Garcia et al., 2000). Therefore,
it seems prudent to try and combine antiretroviral therapy
with AEDs with the least likelihood of producing drug in-
teractions, for example, topiramate or levetericetam. It is
imperative to perform clinical trials in these settings to ob-
tain objective evidence in favor of this hypothesis.
Conflict of interest: We confirm that we have read the Journal’s posi-
tion on issues involved in ethical publication and affirm that this report is
consistent with those guidelines. The author has declared no conflicts of
interest.
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Epilepsia, 49(Suppl. 6):47–49, 2008
doi: 10.1111/j.1528-1167.2008.01756.x