Highlights
- •Epileptic seizures may be an adverse effect of antibiotic therapy.
- •Gamma-aminobutyric acid receptor antagonism is a commonly described mechanism.
- •N-methyl-D-Aspartate receptor agonism may generate seizures.
- •Patients with risk factors are more susceptible to antibiotic-induced seizures.
- •There are potential interactions between antibiotics and antiseizure drugs.
Abstract
In recent years, there has been growing interest in the development of epileptic seizures as an adverse effect of antibiotic therapy. The most commonly accepted mechanisms underlying the development of antibiotic-induced seizures include direct- and indirect gamma-aminobutyric acid (GABA) antagonism, inhibition of GABA synthesis, and glutaminergic N-methyl-D-Aspartate (NMDA) receptor agonistic activity. Inhibitory pathway inhibition leads to increased neuronal excitability and lowered seizure threshold. Blockage of myoneural presynaptic acetylcholine release, mitochondrial dysfunction, interference of neural protein synthesis, and oxidative stress caused by the generation of neurotoxic radicals also contributes to the development of neurotoxicity. Patients with pre-existing risk factors such as renal or hepatic insufficiency, central nervous system pathology, neurological diseases, history of epilepsy or seizures, critical illness, and increased age are more susceptible to seizure development as a consequence of antibiotic therapy. Administration of antibiotics, together with antiseizure drugs, may also lead to enhanced seizure risk due to drug interactions, which predisposes to alterations in drug metabolism and therapeutic efficacy.
Keywords
1. Introduction
There exists a considerable body of literature on the increased risk of developing epileptic seizures as an adverse effect of antibiotic therapy. β-lactams and fluoroquinolones are most frequently associated with central nervous system toxicity and neurological side effects [
[1]
]. Although infrequent, other classes of antibiotics have also been reported to induce neurotoxicity or trigger epileptic seizures. Gamma-aminobutyric acid (GABA) receptor antagonism is a common mechanism shared by penicillins, cephalosporins, imipenem, and fluoroquinolones [[2]
,[3]
]. Alternatively, isoniazid has been shown to inhibit GABA synthesis [[4]
]. Antibiotic-induced seizures are usually self-limiting, however repetitive and prolonged seizures may require pharmacological management [- Meldrum B.S.
GABAergic mechanisms in the pathogenesis and treatment of epilepsy.
Br J Clin Pharmacol. 1989; 27 (3S-11S)https://doi.org/10.1111/j.1365-2125.1989.tb03454.x
[5]
].- Appa A.A.
- Jain R.
- Rakita R.M.
- Hakimian S.
- Pottinger P.S.
Characterizing Cefepime Neurotoxicity: A Systematic Review.
Open Forum Infect Dis. 2017; 4https://doi.org/10.1093/ofid/ofx170
Previous literature have reported drug-drug interactions between antiseizure drugs (ASD) and antibiotics. Due to alterations in drug metabolism, efficacy, and pharmacokinetic properties, antibiotics should be administered with caution in patients currently on treatment with antiseizure drugs to ensure that therapeutic doses are reached and to prevent toxicity [
[6]
]. A number of antiseizure drugs, especially those of older generations may induce or inhibit the metabolism of the antibiotics. Induction of ASD metabolism predisposes to ineffective control of seizures, whereas inhibition of drug metabolism may result in toxic levels of ASDs [[7]
,[8]
].In this review, the epileptogenic properties of different classes of antibiotics will be explored, focusing on the various mechanisms underlying seizure development, clinical details, predisposing risk factors, ASD-antibiotic interactions, and management of patients with antibiotic-induced convulsions. Clinicians should consider antibiotics as a possible trigger of new-onset seizure development, especially in patients with risk factors and comorbidities. We aim to provide a greater insight of antibiotic-induced seizures, as prompt drug discontinuation may significantly influence patient outcome.
2. Antibiotics and their epileptogenic properties
GABA, an inhibitory neurotransmitter in the brain, blocks neuronal communication by binding to GABAA receptor (GABAAR) complexes which are ligand-gated pentameric chloride channels present on the postsynaptic membrane. Antibiotic-induced epileptic seizures are believed to be initiated by disturbances in GABAergic transmission. Binding of GABA to its receptor leads to influx of chloride ions, membrane hyperpolarization, and reduced firing of neurons. Direct GABA antagonists may produce neuronal excitability and convulsions by binding to the GABAAR, blocking the GABA-binding sites. Indirect antagonists bind to other sites within the GABAAR complex to prevent GABA binding by allosteric inhibition or diminishing chloride influx [
[4]
]. Isoniazid alters GABAergic transmission by inhibiting the synthesis of GABA, primarily by competitive inhibition of pyridoxine kinase. Inhibition of pyridoxine kinase results in decreased production of pyridoxal phosphate, a cofactor required for the synthesis of GABA from glutamate by glutamate decarboxylase (GAD), an enzyme that catalyzes the decarboxylation of glutamate to GABA. Moreover, isoniazid also inhibits GABA synthesis by direct binding to GAD [- Meldrum B.S.
GABAergic mechanisms in the pathogenesis and treatment of epilepsy.
Br J Clin Pharmacol. 1989; 27 (3S-11S)https://doi.org/10.1111/j.1365-2125.1989.tb03454.x
[3]
,[4]
]. [Table 1] provides a summary of the mechanisms underlying antibiotic-induced seizures.- Meldrum B.S.
GABAergic mechanisms in the pathogenesis and treatment of epilepsy.
Br J Clin Pharmacol. 1989; 27 (3S-11S)https://doi.org/10.1111/j.1365-2125.1989.tb03454.x
Table 1Mechanisms of action underlying the development of epileptogenic seizures associated with different classes of antibiotics.
| Mechanism of action | Antibiotics |
|---|---|
| Direct antagonists | |
| Direct binding to GABAA receptor complex | Penicillin, cephalosporin, imipenem, fluoroquinolones |
| Indirect antagonists | |
| Inhibition of GABA synthesis PK competitive inhibition Direct binding to GAD | Isoniazid |
| Indirect binding to sites within GABAA receptor complex Allosteric inhibition of GABA binding Prevention of chloride influx | Penicillin, aztreonam |
| Benzodiazepine receptor binding | Penicillin |
PK, pyridoxine kinase; GAD, glutamate decarboxylase; GABA, gamma-aminobutyric acid
2.1 β-lactams
The seizure inducing potential of the β-lactam drugs have been described in the first clinical trial of penicillin G. Studies have shown that the convulsive properties are due to binding of the β-lactam ring to GABA, resulting in a reduction of inhibitory neurotransmitter concentration and excitation of cortical afferents, producing epileptiform bursts [
9
, 10
, 11
]. GABA receptors are categorized into GABAA (GABAAR) and GABAB receptors (GABABR). Studies have found that GABAAR is the main type of receptor responsible for the pro-convulsive effects of β-lactams, featuring both non-competitive inhibition and voltage-dependent changes [[12]
]. The β-lactam ring structure is an important determinant of the epileptogenic properties. Evidence suggests that substitutions occurring at the 7-aminocephalosporanic or 6-aminopenicillanic acid (6-APA) positions may lead to alterations in epileptogenic activity [[13]
]. The thiazolidine ring and side chain length also plays a role in determining the pro-convulsive effects of β-lactam drugs [[1]
].2.1.1 Penicillins
Penicillins are one of the oldest groups of antibiotics still widely used in clinical practice. They are bactericidal and highly efficacious against susceptible organisms. Penicillin G, piperacillin, ticarcillin, ampicillin, amoxicillin, and oxacillin have been associated with neurological and psychological side effects such as confusion, disorientation, myoclonus, seizures, non-convulsive status epilepticus (NCSE), and encephalopathy [
[1]
]. The neurotoxic effects of penicillin were first described after intraventricular administration of penicillin G, with subsequent development of myoclonic twitching [[14]
]. Penicillins share a common basic structure, 6-aminopenicillanic acid, which consists of a thiazolidine ring and a of β-lactam ring carrying an amino group at the C-6 position [[15]
]. Loss of epileptogenic activity was observed after enzymatic cleavage of the β-lactam ring, suggesting its significant role in inducing convulsions [[16]
]. Interference of inhibitory synaptic transmission by inhibition of GABA binding to the GABAAR is a widely accepted mechanism explaining the pathogenesis of β-lactam- induced central nervous system excitation. Transmembrane GABAAR complexes are ligand-gated chloride channels consisting of multiple subunits, and chloride influx is modulated by ligand binding to different binding sites. Diminished GABA-mediated inhibition of chloride influx may occur through various mechanisms, including direct blockage by binding to chloride ionophores, binding to the GABA binding site, reduced chloride conduction by allosteric inhibition, or binding to the benzodiazepine binding site [- Gutnick MJ, Prince DA
Penicillinase and the convulsant action of penicillin. Neurology. 1971; 21: 759-764https://doi.org/10.1212/wnl.21.7.759
9
, 10
, 11
].Risk factors for the development of penicillin-induced seizures include previous CNS diseases, renal insufficiency, low birthweight in the newborn, and increased permeability of the blood-brain barrier (BBB) [
[17]
]. Penicillin G has the highest epileptogenic potential, regardless of its concentration within the cerebrospinal fluid (CSF) [[18]
]. After amoxicillin administration, short bursts of multifocal clonic jerks and β-frequency spikes and polyspikes were observed on electroencephalogram (EEG), which provided evidence supporting its seizure inducing properties [[19]
]. Substitution of the benzylic hydrogen, present within the structure of penicillin G, with a sulfonic group or an amino group resulted in marked reduction of its proconvulsant property [[13]
]. Toxic doses of penicillin given intravenously induced myoclonic jerks in experimental models. The seizure activity was reversed by penicillinase [[20]
].Administration of piperacillin/tazobactam, a combination of β-lactam and β-lactamase inhibitor is also associated with neurotoxicity. Lin et al. [
[17]
] reported a 57 year-old patient without any previous history of neurological diseases on continuous ambulatory peritoneal dialysis (CAPD) for end-stage renal disease who was treated with piperacillin/tazobactam for bronchiectasis with secondary infection. The patient developed new-onset generalized tonic-clonic seizures, slurred speech, mental confusion, behavioral changes, and tremors. The patient was successfully treated with high flux hemodialysis, which resulted in the resolution of piperacillin-induced encephalopathy. Penicillin G also binds to the GABAAR at the same site as picrotoxin, a CNS stimulant. Sugimoto et al. [[2]
] discovered that a tyrosine to phenylalanine mutation at position 256 on the β-2 subunit of the GABAAR receptor completely abolished the inhibitory effects of picrotoxin, a non-competitive antagonist of GABA, without impairing the channel function. Administration of the mutated β- subunit together with the wildtype ɑ- and γ- subunits significantly reduced the ability of penicillin G to inhibit GABA-induced currents, however, the effects were not completely eliminated [[2]
]. This mutagenesis study provides evidence to support that penicillin G binds to the same site as picrotoxin, or to a different site within close proximity to the picrotoxin binding site, deep within the GABAAR channel pore.2.1.2 Cephalosporins
The structural difference between penicillins and cephalosporins is that cephalosporins contain a β-lactam ring fused to a 6-member thiazolidine ring. Compounds containing heterocyclic rings at positions 7 and 3 of 7-aminocephalosporanic acid were found to produce signs of seizure activity. Such compounds, cephaloridine, ceftezole, cefotiam, and cefazolin had equivalent or even higher potency of generating epileptic activity than penicillins. Compared with substitutions at position 7, compounds with heterocyclic substitutions at position 3 were also more likely to provoke epileptiform activity. In the absence of heterocyclic rings on 7-aminocephalosporanic acid in compounds such as cephalexin, seizure activity was not observed [
[21]
]. This denotes that substitution of compounds with heterocyclic rings at positions 3 and 7 may be responsible for the epileptogenic activity of cephalosporins. Cephalosporins are competitive antagonists of the GABAA receptor. Besides GABA inhibition, another mechanism involves glutamatergic N-methyl-D-Aspartate (NMDA) receptor agonism [[12]
]. Among the cephalosporins, cefazolin and cefepime are most strongly associated with seizure-triggering properties.Cefepime is a fourth-generation cephalosporin and is most commonly prescribed empirically for nosocomial infections. It is an essential component of the parenteral therapy of neutropenic fever and healthcare infections such as pneumonia, urinary tract infections, skin, and soft tissue infections. Treatment with cefepime exhibited higher rates of mortality in comparison to other β-lactams due to associations with increased risk of developing periodic epileptiform discharges [
[22]
]. Since cefepime is renally excreted, decreased clearance can result in drug accumulation within the blood and cerebrospinal fluid, with subsequent blood-brain barrier penetration [[5]
,- Appa A.A.
- Jain R.
- Rakita R.M.
- Hakimian S.
- Pottinger P.S.
Characterizing Cefepime Neurotoxicity: A Systematic Review.
Open Forum Infect Dis. 2017; 4https://doi.org/10.1093/ofid/ofx170
[23]
]. Cefepime acts as a competitive antagonist, which prevents the binding of GABA to the GABAA receptor, leading to over-excitation of the electrical activity and development of seizures. This is often observed in patients with decreased drug clearance as a result of reduced glomerular filtration, however, it may also occur despite normal renal function [[24]
]. In patients with renal impairment, up to 45% of the serum concentration of cefepime may cross the blood-brain barrier due to decreased protein binding. Clinical improvement occurs with cessation of the drug and seizure control [[25]
].- Payne L.E.
- Gagnon D.J.
- Riker R.R.
- Seder D.B.
- Glisic E.K.
- Morris J.G.
- et al.
Cefepime-induced neurotoxicity: a systematic review.
Crit Care. 2017; 21https://doi.org/10.1186/s13054-017-1856-1
Development of non-convulsive status epilepticus may occur following treatment with cefepime, despite normal renal profiles [
[26]
]. Clinicians are therefore recommended to perform EEG studies if patients present with neurological complications such as altered level of consciousness or mental status changes during the course of treatment with cephalosporins [[24]
,[26]
]. EEG changes include polyspike discharges, rhythmic slow waves or irregular spikes or sharps which may initially be confined to one region, and subsequently spread to involve both hemispheres [[27]
]. Neurotoxicity may also develop with cefepime use, even after dose adjustments for renal dysfunction. This illustrates the importance of acknowledging the presence of risk factors such as previous stroke, history of epilepsy, and other neurological disorders as potential contributors to seizure development [[28]
]. In patients with renal failure, decreased clearance of cefepime results in toxic levels of the drug or its metabolite N-Methylpyrrolidine. Cephalosporins are poorly lipophilic, however when the BBB integrity is disrupted, such as in patients with uremia or meningitis, higher drug volumes are able to cross [[26]
].A neurosurgical patient was reported to develop generalized convulsions following preoperative single-dose rapid intravenous administration of ceftazidime. Previous reports on ceftazidime neurotoxicity were observed in patients with diminished renal function or in those who received multiple doses [
[29]
]. Contributing factors to the development of neurological side effects include reduced renal clearance, high CNS penetration, excessively high dose, and increased unbound form of the drug due to hypoalbuminemia [[25]
]. Besides hypoalbuminemia, this patient’s renal function, blood glucose, and electrolyte levels were all normal. No seizure recurrence was observed after ceftazidime withdrawal. Although the patient did not have renal insufficiency, presence of an intracranial tumor may alter the blood-brain barrier integrity. Thus, the presence of intracranial pathology itself should strongly be considered as a major cause of increased CSF concentrations of the drug, and lowered seizure threshold. Therefore, antibiotic therapy should be administered with extra caution in patients with pre-existing central nervous system disease. Drugs should be infused slowly, with constant monitoring of any mental status changes or seizure development during therapy [- Payne L.E.
- Gagnon D.J.
- Riker R.R.
- Seder D.B.
- Glisic E.K.
- Morris J.G.
- et al.
Cefepime-induced neurotoxicity: a systematic review.
Crit Care. 2017; 21https://doi.org/10.1186/s13054-017-1856-1
[27]
].2.1.3 Carbapenems and monobactams
Carbapenems are commonly used to treat multidrug resistant infections, with the majority being hospital-acquired and are usually administered as a last resort. Due to their stability against beta-lactamase hydrolysis and broad spectrum of antimicrobial activity, carbapenems have the highest treatment efficacy in comparison to other β-lactams. Carbapenems are effective against extended spectrum beta-lactamase (ESBL) producing bacteria, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), and various other gram-negative organisms [
[30]
]. Imipenem/cilastatin, meropenem, ertapenem, doripenem, and biapenem are examples of carbapenems that harbors epileptogenic properties. Less is known about newer carbapenems due to the avoidance of study conduction on patients with a history of seizures [[31]
].Carbapenems are β-lactam antibiotics associated with proconvulsive and epileptogenic properties. Imipenem is typically administered with cilastatin, a dehydropeptidase inhibitor which inhibits renal antibiotic breakdown. Among all carbapenems, imipenem is associated with the highest frequency of seizure development [
[32]
]. Cilastatin has no effect on lowering seizure threshold. The risk of seizure development with imipenem was found to be as high as 3-33%, as opposed to doripenem and ertapenem which brings a risk of less than 1% [[33]
]. Ertapenem administration is associated with a 0.18% risk of seizures [[34]
]. Continuous epileptiform discharges were identified in 0.19% of patients receiving meropenem [[22]
]. Generalized seizures most commonly occurs in carbapenem induced seizures, however, patients may also present with partial seizures (simple or complex) or generalized tonic-clonic seizures [[34]
]. Besides inhibition of the inhibitory properties of GABAA, interactions with AMPA/NMDA receptor complexes are also responsible for the pro-convulsive effects [[35]
]. Enhanced affinity of imipenem towards GABAA receptor in comparison to other carbapenems, such as meropenem, may be explanatory for the highly elevated epileptogenic properties [[36]
]. Moreover, evidence also claims that the C-2 side chain basicity strength, amino acid steric hindrance and distance from carboxyl group are all determinants of the degree of convulsive activity. Due to structural differences between carbapenems, meropenem was found to have less proconvulsive effects than imipenem and panipenem [[37]
]. Differences in beta-lactam structures may also influence convulsive liability [[13]
]. However, some studies have found no significant differences in the epileptogenic properties of imipenem and meropenem [[32]
]. Although usually available in intravenous form, there are also orally administered carbapenems such as tebipenem pivoxil (TBPM-PI). In experimental models, TBPM-PI was associated with lower risk of inducing convulsions than intravenous imipenem/cilastatin [[38]
]. Doripenem, meropenem, and biapenem harbors low proconvulsive liability [[39]
,[40]
].There are numerous factors which may increase the risk of developing seizures after carbapenem administration. The most important risk factors to address before administering carbapenems are renal insufficiency, history of injury to the central nervous system (CNS) and CNS disease including pre-existing epilepsy, cerebrovascular disease such as prior stroke, trauma, and presence of CNS neoplasms [
[12]
,[41]
,[42]
]. Other risk factors which may lower the seizure threshold include elderly patients, liver disease, concomitant treatment with drugs carrying neurotoxic risk, current infection, and sepsis. Pseudomonas infection has also been associated with increased seizure risk with imipenem/cilastatin [[43]
]. Renal insufficiency leads to impairment of carbapenem elimination, therefore it is essential that patients receive dose adjustments corrected for current renal function since excessive doses may also lead to seizure induction [[42]
]. Administering excessively high doses of carbapenems in patients with CNS disease, such as those with prior seizure episodes are linked to a higher probability of seizure development [[44]
].Many studies have reported the occurrence of seizures in association with the use of different carbapenems, mostly in patients with pre-existing risk factors. Recent evidence reported the development of status epilepticus and delirium after 3 doses of ertapenem in an elderly patient suffering from chronic kidney disease and silent ischemic cerebrovascular disease. Seizures occurred following episodes of diminished creatinine clearance and delirium [
[45]
]. Due to limited evidence supporting the proconvulsive properties of ertapenem and low incidence of ertapenem induced seizures, it was suggested that renal failure might have contributed. Discontinuation of ertapenem led to cessation of seizures and recovery from delirium. Longer drug half-life in chronic renal disease, decreased protein binding due to decreased albumin levels, and accumulation of toxic metabolites as a result of uremia may all promote the neurotoxic effects of ertapenem [- Lin H.
- Chew Sth.
Status Epilepticus and Delirium Associated with Ertapenem in a Very Elderly Patient with Chronic Kidney Disease and Silent Ischaemic Cerebrovascular Disease.
Drug Saf Case Rep. 2015; 2https://doi.org/10.1007/s40800-015-0021-5
[46]
]. A patient with end-stage renal disease, without any history of CNS damage undergoing peritoneal dialysis treated with ertapenem also developed generalized tonic-clonic seizures 5 days after treatment initiation, which was discovered to be induced by ertapenem. Another study described the development of new-onset seizures after receiving ertapenem with dose corrected for the patient’s chronic kidney disease, however severe renal dysfunction and CNS disease were not present in this case, illustrating the possibility of ertapenem-induced epileptic seizures in the absence of any prior CNS disease [[47]
]. Ertapenem induced seizures are rare and most patients who develop seizures either have pre-existing chronic renal disease or CNS injury, suggesting that carbapenems, including those associated with low proconvulsive properties such as ertapenem, should be used with caution in patients at risk [[48]
]. Furthermore, prior history of cerebrovascular events may be a relative contraindication for ertapenem treatment due to effects on lowering seizure threshold [[49]
]. Job et al. [[41]
] reported increased seizure activity with imipenem treatment in patients with cerebrovascular injury or head trauma without any renal disease.In neurosurgical patients, studies reported no increased risk of seizures with imipenem and meropenem treatment. Prior episodes of seizures and disturbances in creatinine clearance were also discovered not to increase seizure risk with proper corrected dose [
[50]
]. Despite many studies suggesting the proconvulsant properties of imipenem enhanced by renal failure, Koppel et al. [[35]
] claimed that with appropriate dosages, below 2 g/day and corrected for the patient’s body mass and renal dysfunction, imipenem is safe and does not further elevate the risk of developing seizures. Furthermore, in contrast to other studies, metabolic derangements, stroke, and renal failure were found to have no influence on seizure incidence.Although rarely associated with adverse effects of neurotoxicity, treatment with monobactams may produce seizures, however there is still very limited supporting evidence [
[51]
]. Due to structural differences, aztreonam is much less likely to induce seizures than imipenem [[13]
]. In experimental models, intracerebroventricular or intraperitoneal administration of aztreonam and carumonam induced seizures through many possible mechanisms such as binding to GABA receptors and slowed clearance from the CNS, maintaining a high concentration for an extended period of time [[52]
].2.2 Fluoroquinolones
Fluoroquinolones are commonly used to treat urinary tract, gastrointestinal, skin and soft tissue infections. Studies have reported CNS side effects of quinolones, such as headaches, confusion, tremors, psychosis, and seizures. Elderly patients are at higher risk of developing convulsions following fluoroquinolone therapy. From the literature, patients with quinolone-induced seizures were reported to have underlying risk factors, such as a history of epilepsy or seizures, cerebral trauma, presence of CNS disease, history of renal or hepatic failure, excessive doses, electrolyte abnormalities, and drug interactions [
[53]
,[54]
]. Underlying thyrotoxicosis should also be included as a potential risk factor for seizures in patients treated with ciprofloxacin [[54]
]. A commonly accepted mechanism is the activation of epileptic activity following GABA receptor stimulation in the brain [[55]
]. The chemical structure of quinolones play a role in determining the drug’s epileptogenic activity. Norfloxacin and ciprofloxacin contain GABA-like structures at their 7 positions, which are able to antagonize GABA receptors and further increase the risk of developing seizures in susceptible patients [[56]
]. Akahane et al. [[57]
] used baclofen, a GABAB receptor agonist to inhibit levofloxacin and ciprofloxacin-induced seizures in experimental models, which showed more promising results than with GABAAR agonism, supporting that fluoroquinolones interact mainly with the GABAB, rather than the GABAA receptor. Moreover, fluoroquinolones also activate the N-methyl-D aspartate (NMDA) receptor, leading to decreased seizure threshold [[58]
,[59]
]. Kynurenic acid (KYNA) is an endogenous ligand of the glutamate receptor. The similarity between the structures of fluoroquinolones and KYNA suggests that quinolones may also interact with ligand-gated glutamate receptors. Administration of AP-5 or AP-7, which are selective antagonists of the glutamate binding site of the NMDA receptor, was found to inhibit the pro-convulsive action of the quinolones [[57]
].Other incidences of quinolone-induced convulsions were reported in patients concomitantly taking non-steroidal anti-inflammatory drugs (NSAIDs), patients with electrolyte imbalances, and those with impaired renal function [
[60]
]. Drugs such as methylxanthine derivatives or NSAIDs are able to potentiate the proconvulsive activity of fluoroquinolones due to interactions with the GABAAR. Moreover, interactions between quinolones and dopamine and opiate receptors have also been investigated [- Medford A.R.L.
Fluoroquinolones and theophylline can also lower the seizure threshold.
BMJ. 2012; 345https://doi.org/10.1136/bmj.e5304
[61]
]. Moxifloxacin was recognized as the cause of generalized tonic-clonic seizure in a 23 year-old patient with liver and renal insufficiency who previously underwent brain surgery for intracerebral hemorrhage. No further seizure episodes were noted after the treatment was replaced by cefuroxime [[62]
].2.3 Macrolides
Erythromycin, clarithromycin, and azithromycin are macrolide antibiotics commonly prescribed to patients with upper respiratory infections [
[63]
]. Caution should be exercised when co-administering macrolides with antiseizure drugs due to potential drug interactions. CYP3A4 inhibition by clarithromycin and erythromycin may influence the level of antiseizure drugs metabolized by the same enzyme, such as carbamazepine. Patients should be closely monitored and receive dose adjustments in order to decrease the risk of drug toxicity, which may lead to the development of seizures or status epilepticus. Clarithromycin increases neuronal activity by stimulating CA3 pyramidal neurons through a reduction in the GABAergic signaling [[64]
]. Development clarithromycin-induced delirium due to NCSE improved significantly after clarithromycin therapy was discontinued [[65]
]. Azithromycin, however, does not inhibit CYP3A4 and was found not to harbor seizure inducing effects [[9]
]. Nevertheless, the mechanisms behind macrolide induced neurotoxicity still remains unclear and warrants further research. Although there is limited evidence in the literature with regards to the epileptogenic properties of macrolides, clinicians should still be aware of the potential neurotoxic side effects of clarithromycin, and are encouraged to perform EEG in those who develop neurotoxic side effects to differentiate seizures from other neurological or psychiatric diagnosis.2.4 Metronidazole
Metronidazole is an antibiotic within the nitroimidazole group with blood-brain barrier penetrability. It is commonly used for the treatment of protozoal infections, anaerobic, and microaerophilic bacterial infections [
[66]
]. Although rare, metronidazole has been associated with seizure induction when high doses are given for a long period of time. High cumulative doses, rather than serum level, determines the proconvulsive properties [[67]
]. However, convulsions may also occur with short-term therapy in doses appropriate for the infection, as described in an elderly patient with chronic renal failure due to accumulation of metronidazole and its metabolites [[68]
]. Some evidence claimed that neurotoxicity does not correlate with the dose or duration of treatment [[69]
]. Cantador et al. [[70]
] reported a case of non-convulsive status epilepticus after receiving metronidazole, with magnetic resonance imaging (MRI) suggestive of metronidazole encephalopathy in a patient who was successfully treated for NCSE in the past. Exact mechanisms behind why patients treated with metronidazole are predisposed to seizure development requires further research. However, it is proposed that neurotransmitter modulation through inhibition of GABA receptors, direct drug binding to neural RNA interfering with protein synthesis, generation of neurotoxic radicals as a result of reactions with catecholamine neurotransmitters, and mitochondrial dysfunction may all play a role in enhancing the risk of seizures [[12]
]. Neurotoxic effects of metronidazole is also illustrated by the presence of CNS lesions on neuroimaging such as cytotoxic and vasogenic edema observed at different locations within the brain. Recently, the presence of asymmetric white matter changes was determined to be involved in metronidazole-induced encephalopathy [[71]
]. Other MRI changes characteristic of metronidazole-induced neurotoxicity includes symmetrical cerebellar dentate nuclei and pontine T2 hyperintensities and cytotoxic edema visualized in the corpus callosum [- Hwang E.
- Chang S.-K.
- Lee S.-A.
- Choi J.-A.
A Case of Metronidazole-Induced Encephalopathy: Atypical Involvement of the Brain on MRI.
Investigative Magnetic Resonance Imaging. 2018; 22: 200-203https://doi.org/10.13104/imri.2018.22.3.200
[72]
,- Ueno T.
- Ito M.
- Arai A.
- Suzuki C.
- Tomiyama M.
Convulsive seizures caused by metronidazole-induced encephalopathy.
Postgraduate Medical Journal. 2019; 95 (217–217)https://doi.org/10.1136/postgradmedj-2018-136353
[73]
].- Mulcahy H.
- Chaddha S.K.B.
MRI of Metronidazole-Induced Encephalopathy.
Radiol Case Rep. 2015; (3)https://doi.org/10.2484/rcr.v3i4.239
Seizures as a consequence of metronidazole therapy are reversible and usually resolves with drug cessation. However, in a minority of cases, permanent damage may occur which predisposes to a poor prognosis [
[74]
]. Although neurotoxicity rarely occurs, metronidazole should be used with caution in patients with pre-existing risk factors such as renal insufficiency and prior CNS injury, even in the absence of seizure history [[75]
]. Patients with new-onset epileptic seizures or multifocal myoclonus after receiving metronidazole, without any previous history of epilepsy and no abnormalities identified in electrophysiological activity, neuroimaging, or metabolic activity should be highly suspicious for metronidazole-induced encephalopathy [[76]
]. Prompt cessation of therapy increases the likelihood of full recovery [[77]
].- Roy U.
- Panwar A.
- Pandit A.
- Das S.K.
- Joshi B.
Clinical and Neuroradiological Spectrum of Metronidazole Induced Encephalopathy: Our Experience and the Review of Literature.
J Clin Diagn Res. 2016; 10 (OE01–09)https://doi.org/10.7860/JCDR/2016/19032.8054
2.5 Polymyxins
Polymyxin B and colistin are bactericidal antibiotics used to treat gram-negative bacterial infections. Colistin was once discontinued due to nephrotoxicity and neurotoxicity, however increasing multidrug resistant gram-negative infections have led to the resurgence of colistin use [
[78]
]. Administration of intravenous colistin methanesulfonate resulted in focal seizures. Although several studies have found correlation between high doses of colistin and seizure development, low doses of colistin was also found to provoke seizures, especially in critically ill patients with concomitant renal failure undergoing hemodialysis. Moreover, decreased drug clearance due to renal dysfunction and the poor dialyzability of polymyxin B may lead to increased susceptibility to convulsions [- Vaara M.
Polymyxins and Their Potential Next Generation as Therapeutic Antibiotics.
Front Microbiol. 2019; 10https://doi.org/10.3389/fmicb.2019.01689
[79]
,[80]
]. Sulfated forms such as polymyxin B are associated with higher toxicity than colistin and other unsulfated polymyxins at low doses, however toxicities are indifferent at higher doses [[81]
]. Since studies have described colistin as a potential trigger of focal and generalized tonic-clonic seizures, careful use of colistin is recommended, especially in critically ill patients with renal failure. Onset of convulsions, even with low doses of colistin, should always raise suspicion of polymyxin-induced seizures after ruling out other causes [- Grill M.F.
- Maganti R.K.
Neurotoxic effects associated with antibiotic use: management considerations.
British Journal of Clinical Pharmacology. 2011; 72: 381-393https://doi.org/10.1111/j.1365-2125.2011.03991.x
[80]
].Mechanisms behind polymyxin-induced seizures are still inconclusive, however direct drug binding to the brain tissues and neuronal interactions due to their high lipid properties have been suggested to play a role in neuronal damage [
[81]
]. Competitive and non-competitive myoneural presynaptic blockade of acetylcholine release, oxidative stress and mitochondrial dysfunction are other mechanisms believed to mediate neurotoxicity [- Grill M.F.
- Maganti R.K.
Neurotoxic effects associated with antibiotic use: management considerations.
British Journal of Clinical Pharmacology. 2011; 72: 381-393https://doi.org/10.1111/j.1365-2125.2011.03991.x
[80]
,[82]
,- Nigam A.
- Kumari A.
- Jain R.
- Batra S.
Colistin neurotoxicity: revisited.
BMJ Case Rep. 2015; 2015https://doi.org/10.1136/bcr-2015-210787
[83]
]. Risk factors include concomitant use of sedatives, narcotics, corticosteroids, and muscle relaxants. Hypoxic patients or those receiving drugs for anesthesia are also at enhanced risk of developing neurotoxicity with polymyxin administration. However, it remains unclear why females are more predisposed to neurotoxicity [[84]
]. The state of systemic inflammation may alter blood-brain barrier permeability, thus resulting in enhanced drug entry and greater concentration within the central nervous system [[85]
].2.6 Isoniazid
The antitubercular drug, isoniazid (INH), has been one of the most common drugs associated with recurrent seizures at toxic levels [
[86]
,[87]
]. The underlying mechanism involves interference with GABA synthesis through inhibition of pyridoxal-5 phosphate, a cofactor required for the enzymatic activity of glutamic acid decarboxylase. This leads to decreased levels of GABA and enhanced seizure susceptibility. Moreover, since the decarboxylation reaction involved in GABA synthesis is pyridoxine dependent, INH induced pyridoxine depletion also leads to reduction of GABA concentrations [[88]
,[89]
]. Although seizures have been described in INH toxicity, therapeutic doses may also induce convulsive seizures [[90]
]. Tajender and Saluja [[91]
] reported a patient who developed status epilepticus after receiving INH at therapeutic doses. The seizures responded poorly to antiseizure drugs but resolved with pyridoxine administration. Thus, administration of INH, even at therapeutic doses should always raise suspicion of pyridoxine deficiency as a cause of seizures. The importance of pyridoxine supplementation should also be addressed [[87]
].3. Drug interactions between antiseizure drugs and antibiotics
When co-administered, changes in the pharmacokinetics and efficacy of drugs occur as a result of drug-drug interactions between antiseizure drugs and antibiotics [
[6]
,[92]
]. Some older generation antiseizure drugs may induce or inhibit the metabolism of antibiotics, thus leading to ineffective control of seizures or heightened antiseizure drug toxicity. Likewise, antiseizure drugs may also influence antibiotic metabolism. Rifamycin was discovered to enhance ASD metabolism, predisposing to increased risk of seizures. Carbapenems such as meropenem decreases the concentration of valproic acid, which may result in ineffective control of epilepsy [Major Antimicrobial-Anticonvulsant Interactions. Epilepsy Foundation n.d. https://www.epilepsy.com/learn/professionals/resource-library/tables/major-antimicrobial-anticonvulsant-interactions (accessed May 6, 2020).
[7]
,[8]
]. One suggested mechanism is the ability of carbapenems, which harbors an open β-lactam ring within their structures, to inhibit a glucuronide hydrolase enzyme present in the cytosol of human liver, acylpeptide hydrolase, leading to decreased serum levels of valproic acid [[93]
]. On the contrary, meropenem was proven not to influence serum levels of levetiracetam [[94]
]. Amoxicillin-clavulanic acid administration with valproic acid did not reveal any significant pharmacokinetic changes [[95]
]. Inhibition of ASD metabolism by antibiotics such as clinafloxacin, ciprofloxacin, macrolides, isoniazid, metronidazole, trimethoprim-sulfamethoxazole, and chloramphenicol may result in toxic serum concentrations of ASDs. Although newer generation ASDs have fewer drug-drug interactions and effects on drug metabolism, usage of older ASDs is still the mainstay of treatment. Primidone, carbamazepine, phenytoin, and phenobarbital are examples of enzyme-inducing ASDs known to decrease serum levels of antimicrobials through altering the activities of cytochrome P450 enzymes. Valproic acid and oxcarbazepine are inhibitors of drug metabolism [96
, 97
, 98
]. [Table 2] summarizes the drug-drug interactions previously identified between ASDs and various antibiotics.Table 2Potential interactions between antiseizure drugs and antibiotics.
| Antibiotic | Antiseizure drug | Interaction remarks |
|---|---|---|
| Amoxicillin-clavulanic acid | Valproic acid | No significant alterations in pharmacokinetics of valproic acid. |
| Macrolides | Carbamazepine, phenytoin, pregabalin, tiagabine, felbamate | - Macrolides inhibit CYP3A4. - Increased level of antiseizure drugs, increased toxicity. |
| Clinafloxacin, ciprofloxacin | Phenytoin | Reduced phenytoin metabolism, increased toxicity. |
| Doxycycline | Carbamazepine | - Carbamazepine induces metabolism of doxycycline - Monitor antibiotic level. - Doxycycline may lower carbamazepine level. - Increased risk of seizures. |
| Isoniazid | Carbamazepine, valproic acid, ethosuximide, phenytoin | - Increased serum level of antiseizure drugs. |
| Rifampicin | Lamotrigine, carbamazepine, valproic acid, ethosuximide, phenytoin | - Reduced level of antiseizure drugs. - Administration with isoniazid counteracts inhibition of antiseizure drug metabolism. |
| Carbapenems | Valproic acid | Increased seizure risk, decreased antiseizure drugs concentration. |
| Metronidazole | Phenobarbital, phenytoin, Carbamazepine | - Phenytoin, phenobarbital- decreased level of metronidazole. - Concentration of carbamazepine increases with metronidazole use. |
| Trimethoprim-sulfamethoxazole and sulfonamides | Phenytoin | Increased toxicity of phenytoin |
| Chloramphenicol | Phenobarbital, phenytoin | Increased concentration of phenobarbital and phenytoin |
It is important to address the drug interactions which may occur with co-administration of ASDs and antibiotics, ensuring the achievement of therapeutic concentrations and preventing the development of toxicity. Drug-drug interactions are usually clinically significant during the first 5 days of therapy. Therefore, when administering antibiotics to patients under epilepsy control with ASDs, careful dosing, therapeutic drug monitoring, electroencephalogram studies, and patient monitoring for any adverse effects are recommended [
[6]
].4. Management of antibiotic-induced epileptic seizures
Airway stabilization, proper oxygenation and ventilation, management of blood pressure and heart rate, measurement of serum glucose concentration, and control of hyperthermia are essential in the primary management of seizures [
[99]
,[100]
]. Early recognition of drug-induced epileptic activity is important, as cessation of current antibiotic therapy is critical in preventing seizure recurrence. Drug-induced seizures are typically self-limiting, however, repetitive or prolonged seizures may lead to irreversible neurological injury, requiring medical management [[100]
]. Fever, CNS infections such as meningitis and encephalitis, and systemic infections may all contribute to the induction of acute symptomatic seizures and status epilepticus [[101]
,[102]
]. Persistent release of proinflammatory cytokines may result in blood-brain barrier damage, neuronal hyperexcitability, excitotoxicity, and lowered seizure threshold [[101]
]. Therefore, it is important to consider fever, electrolyte imbalances, metabolic disturbances, and infections as contributors to seizure induction, since the removal of these factors can result in the resolution of seizures [[103]
]. The presence of such factors in patients who are receiving antibiotic therapy may also complicate the decision of whether or not the antibiotic regimen is responsible for seizure generation.Benzodiazepines enhance the activity of GABAA by increasing the rate of the chloride channel opening, resulting in neuronal hyperpolarization and thus, are effective in controlling drug-induced seizures caused by GABA antagonism. Intravenous lorazepam, a medium-acting benzodiazepine is recommended as the first-line treatment [
[5]
]. Although specific studies have not been conducted, data indicates that carbapenem-associated seizures are best managed with benzodiazepines, followed by other agents that enhance GABA transmission [- Appa A.A.
- Jain R.
- Rakita R.M.
- Hakimian S.
- Pottinger P.S.
Characterizing Cefepime Neurotoxicity: A Systematic Review.
Open Forum Infect Dis. 2017; 4https://doi.org/10.1093/ofid/ofx170
[44]
]. Second-line drugs which were found effective in managing drug-induced status epilepticus includes phenobarbital and propofol. Barbiturates work by binding to the GABAA complex, prolonging the duration of chloride channel opening. In patients irresponsive to benzodiazepine therapy, phenobarbital may be administered [[100]
]. Although similar in efficacy, phenobarbital requires longer infusion time than lorazepam. Propofol enhances GABA binding to its receptor and may also increase the opening of the chloride channel at higher concentrations. In contrast to benzodiazepines and barbiturates which only mediates GABAA activity, propofol may also induce seizure activity through NMDA receptor antagonism and is usually reserved for patients with refractory status epilepticus [[100]
,[104]
].5. Conclusions
Numerous research has shed light on the mechanisms behind the seizure-inducing properties associated with different classes of antibiotics. Antagonism of GABAA receptors play a significant role in mediating the proconvulsive properties of β-lactams through competitive and non-competitive interactions. Agonistic effects on NMDA receptors have also been associated with cephalosporins, fluoroquinolones, and carbapenems. Although interactions of monobactams with GABA receptors were postulated, more research is warranted regarding their epileptogenic properties. Seizures in patients treated with macrolides are extremely rare, with only a limited number of reported cases of tonic-clonic and generalized seizures as a side effect of erythromycin and clarithromycin therapy. With evidence supporting that the majority of seizures are triggered by altered GABAergic transmission, drugs which influence GABA activity such as benzodiazepines are recommended as first-line treatment.
It is important to be aware that drug interactions may occur with co-administration of ASDs and antibiotics due to altered pharmacokinetic activity and treatment efficacy. Some antibiotics may alter levels of ASDs through induction and inhibition of metabolism, resulting in ineffective seizure control or toxic serum levels of ASDs. More research is certainly required on the different mechanisms mediating the neurotoxic and epileptogenic properties of antibiotics, which would be promising in future development of therapeutic strategies. Dose adjustments should be exercised when administering antibiotics in patients with pre-existing epilepsy, history of CNS damage, renal failure, critically ill patients, sepsis and in the presence of other risk factors which may predispose patients to a greater risk of seizure development. Most importantly, prompt diagnosis of antibiotic-induced seizures is critical since early discontinuation has shown promising effects in preventing seizure recurrence. Due to the possibility of developing non-convulsive status epilepticus, clinicians are encouraged to perform EEG studies to rule out seizure activity if patients develop neurological symptoms after receiving antibiotic therapy.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
Pitchaya Wanleenuwat: Conceptualization, Project administration, Supervision, Visualization, Writing - review & editing. Nanthushan Suntharampillai: Conceptualization, Project administration, Supervision, Visualization, Writing - review & editing. Piotr Iwanowski: Project administration, Supervision, Visualization, Writing - review & editing.
Declaration of Competing Interest
None.
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Publication history
Published online: August 14, 2020
Accepted:
August 12,
2020
Received in revised form:
August 10,
2020
Received:
May 18,
2020
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Copyright
© 2020 British Epilepsy Association. Published by Elsevier Ltd.
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