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|NI FEATURE: THE QUEST - COMMENTARY
|Year : 2018 | Volume
| Issue : 6 | Page : 1732-1740
Neurotoxicity of the antibiotics: A comprehensive study
Naghmeh Javanshir Rezaei1, Amir Mohammad Bazzazi2, Seyed Ahmad Naseri Alavi3
1 Department of Microbiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
2 Department of Neurosurgery, Aalinasab Hospital, Tabriz, Iran
3 Department of Neurosurgery, Tabriz University of Medical Sciences, Tabriz, Iran
|Date of Web Publication||28-Nov-2018|
Dr. Seyed Ahmad Naseri Alavi
Department of Neurosurgery, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz
Source of Support: None, Conflict of Interest: None
Antibiotics are among the most widely used medications in clinical settings. Seizures, encephalopathy, optic neuropathy, peripheral neuropathy, and exacerbation of myasthenia gravis are important examples of neurotoxic adverse events associated with the use of antibiotics. This article aims to review the most common and important neurotoxic adverse effects associated with various antibiotics routinely used in a clinical setting.
Keywords: Antibiotics, neurotoxicity, review
Key Message: The key neurotoxic side effects associated with various antibiotics commonly being used in clinical practice are reviewed in this article.
|How to cite this article:|
Rezaei NJ, Bazzazi AM, Naseri Alavi SA. Neurotoxicity of the antibiotics: A comprehensive study. Neurol India 2018;66:1732-40
Antibiotics are among the most widely used medications in the clinical settings. Despite their undeniable benefits and necessity, antibiotics may have some adverse effects; among them, the neurotoxic ones are very important because they may lead to a significant morbidity and even mortality. Seizures, encephalopathy, optic neuropathy, peripheral neuropathy, and exacerbation of myasthenia gravis (MG) are important examples of neurotoxic adverse events in association with antibiotic usage. They are more common in the elderly patients with renal insufficiency, and in patients with preexisting problems in the central nervous system (CNS). Many of these neurotoxic events are reversible if identified early, therefore, health-care providers and physicians need to be aware of their clinical presentations., Beta-lactams and quinolones are the antibiotics most commonly associated with neurotoxic side effects. It should, however, be noted that many other antibiotics such as aminoglycosides, tetracyclines, clindamycin, erythromycin, polymyxins, ethambutol, isoniazid, and chloramphenicol may also cause serious neurotoxicity. This article aims to review the most common and important neurotoxic adverse events associated with various antibiotics routinely used in the clinical setting.
| » Literature Search|| |
We identified all the studies by a literature search of electronic databases, including the EMBASE, MEDLINE, and Google scholar for studies published between 1960 and August 2016. The search terms were: “Antibiotics Neurotoxicity” OR “Antibiotics and Neurotoxicity” AND “Seizures” “Encephalopathy.” All review articles, case reports, letter to editors, and other relevant data were enrolled in the study after the agreement and review by two of the authors was obtained. Finally, 181 publications were enrolled in the study.
| » Discussion|| |
The penicillins, including benzylpenicillin, penicillin G, piperacillin, ticarcillin, ampicillin, amoxicillin, and oxacillin, are among the well-known neurotoxic antibiotics., They may cause a wide variety of neurotoxic complications, such as psychological problems, confusion, disorientation, myoclonus, seizure, encephalopathy, and nonconvulsive status epilepticus.,,,, The epileptogenic properties of penicillin were first reported by Johnson and Walker in 1945. The risk of neurotoxicity after intrathecal and intravenous administration of penicillin has been documented in humans. The risk factors that may be associated with penicillin-induced neurotoxicity are previous central nervous system (CNS) diseases, renal insufficiency,, low-birth weight in newborns, and an increased permeability of the blood–brain barrier (BBB). The major cause of penicillin-induced neurotoxicity is suggested to be an inhibitory effect on gamma-aminobutyric acid (GABA) transmission.,,,, This effect is thought to be due to the structural resemblance of their beta-lactam ring with GABA, because an enzymatic cleavage of this ring resulted in the loss of epileptogenic activity., In addition, the thiazolidine ring and side-chain length may also contribute to the epileptogenic potential of penicillin.,,, A study on rats has suggested that penicillins are capable of reducing the number of benzodiazepine receptors and thus reducing inhibition and altering neuronal excitability [Table 1].
|Table 1: The effects of different class of antibiotics on neurotoxicity and the mechanism of action|
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All the four generations of cephalosporins may cause neurotoxicity. The most high-risk agents in this group are cefazolin, cefoselis, ceftazidime, cefoperazone, and cefepime. Cephalexin, cefotaxime, and ceftriaxone have also been associated with some neurotoxic effects, but their probability of causing side effects is lower than that in the former group.,, The reported clinical presentations of cephalosporin-induced neurotoxicity are lethargy, tardive seizures, encephalopathy, myoclonus, chorea-athetosis, asterixis, seizures, nonconvulsive status epilepticus, and coma. They may be associated with various electroencephalogram manifestations.,,,,,,, The risk factors of neurotoxicity with cephalosporins are the advanced age, renal impairment, preexisting CNS disease, and an excess amount of medication in the blood stream. Like penicillins, the principle mechanisms of cephalosporin-induced neurotoxicity are the diminished release of GABA from nerve terminals, the elevated levels of excitatory amino acids and the cytokine release. Other suggested causes are an induction of endotoxins and glutaminergic mechanisms. The treatment includes withdrawal of the offending medication, hemodialysis in patients with renal failure, and the use of anticonvulsants (benzodiazepines, in particular) in subjects with status epilepticus [Table 1].
Carbapenems including imipenem, meropenem, panipenem, ertapenem, doripenem, and ceftaroline are components of another group of beta-lactam antibiotics with known neurotoxic side effects such as headache, seizures, and encephalopathy.,,,,,, Renal insufficiency, infections of the CNS (such as meningitis), a history of seizure, old age, and a low body weight are presumed to be the risk factors responsible for the carbapenem-induced neurotoxicity., The main mechanism is believed to be an inhibition of GABA-A receptors, and possibly binding to gluatamate. N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazolepropionate receptor complex interactions have also been suggested as possible mechanisms responsible for causing epilepsy.,,,, Due to their structural differences, the risk of neurotoxicity differs between various subclasses of carbapenems. For example, it has been shown that due to differences in the C-2 side chain, meropenem is less neurotoxic than imipenem,,, [Table 1].
Some of the most widely used antibiotics in every day clinical practice are aminoglycosides, including gentamicin, streptomycin, amikacin, tobramycin, neomycin, and kanamycin. The most common neurotoxic side effect related to aminoglycosides is ototoxicity, but other related problems such as peripheral neuropathy, encephalopathy, and neuromuscular and autonomic transmission blockade have also been reported.,,,, The neuromuscular blocking effects of aminoglycosides are particularly important in patients with myasthenia gravis (MG) or Lambert Eaton myasthenic syndrome, because their use in such patients may exacerbate neuromuscular weakness and cause morbidity and even mortality. Ototoxicity is believed to be caused by an excitotoxic activation of NMDA receptors within the cochlea, which could lead to oxidative stress and cell death. In the CNS, this oxidative damage may cause gliosis. On the other hand, a presynaptical inhibition of quantal release of acetylcholine in the neuromuscular junction and a postjunctional binding of aminoglycosides to the acetylcholine receptor complex with resultant calcium depletion may underlie neuromuscular blockades. A blockade of neuronal calcium channels has also been suggested in this regard. The neurotoxic complications of aminoglycosides are dose-dependent and more frequent in patients with increased CNS permeability.
With a wide range of antimicrobial activity, quinolones are widely used as antibacterial agents. In addition, ciprofloxacin, norfloxacin, ofloxacin, gemifloxacin, levofloxacin, and gatifloxacin are also known for their neurotoxic side effects.,,, The side effects are headache, seizures, confusion, insomnia, encephalopathy, myoclonus, orofacial dyskinesias, delirium, toxic psychosis, a Tourette-like syndrome, and extrapyramidal manifestations such as gait disturbance, dysarthria, and choreiform movements.,,,,,,,,,,,,
These CNS effects have been shown to be dose-dependent. It has been suggested that these neurotoxic effects come from the inhibition of GABA-A receptors as well as activation of excitatory NMDA receptors by quinolones.,,,,,, Other receptors that may play a part in the CNS excitatory effects of quinolones are adenosine and amino acid receptors, while the effects of dopamine and opioid receptors have also been proposed. An increased oxidative stress has also been suggested as a possible mechanism in this regard. Some studies have suggested a relationship between the chemical structure of quinolones and their neurotoxic side effects. For example, quinolones with 7-piperazine (e.g., ciprofloxacin, norfloxacin) and 7-pyrrolidine (e.g., tosufloxacin, clinafloxacin) have been found to be highly associated with epilepsy, while others containing 7-piperazinyl or 7-pyrollidinyl (e.g. levofloxacin) are less neurotoxic. Nonetheless, gemifloxacin, levofloxacin, and moxifloxacin lack the specific structure–toxicity relationships but still cause seizures.,, An overall trend in the occurrence of quinolone-related CNS adverse effects has been reported as follows: norfloxacin > ciprofloxacin > ofloxacin > levofloxacin. Extra doses of medications and CNS diseases with a compromised BBB may predispose patients to the neurotoxic effects of quinolones, [Table 1].
Macrolides/azalides including erythromycin, clarithromycin, azithromycin, and dirithromycin are very popular in treating upper respiratory infections, but at the same time they may cause neurotoxicity such as ototoxicity via damage to the cochlea, as well as CNS depression (confusion, obtundation) or excitation (agitation, insomnia, delirium, psychosis), and exacerbation of MG., Some of these adverse effects may cause permanent lesions; thus, an early detection of the onset of adverse effects is important. Psychiatric illnesses and renal insufficiency have been proposed as risk factors for the clarithromycin-induced neurotoxicity. These side effects have been shown to be dose-dependent. In addition, some drugs have been found to cause interaction with macrolides, including tetracyclic antidepressants, calcium channel blockers, cyclosporine, cisapride, antiepileptics, antiretroviral drugs, and digoxin. Although the exact mechanism(s) underlying neurotoxicity caused by macrolides is unknown, a direct neurotoxic effect, an increased level of serum cortisol, prostaglandins, and other hormones associated with mania, or an increased blood level of another drug via the effect on the P450 isoenzymes of the CYP3A family (includes all the known members of the 3A subfamily of the cytochrome P450 superfamily of genes) have been suggested [Table 1].,,,,,,,,,,,,,,,,,,,,
Trimethoprim/sulfamethoxazole is rarely associated with tremor, psychosis (delirium, agitation, hallucination), and encephalopathy. These neurotoxic effects are transient and resolve immediately after drug discontinuation. The predisposing factors have been shown to be old age and an immunocompromised status. The exact mechanism of neurotoxicity associated with trimethoprim/sulfamethoxazole is not known, but it should be noted that this antibiotic easily penetrates the CNS.,,, Neurotoxicity related to trimethoprim/sulfamethoxazole in children is less frequent than in adults, possibly because of the lower dose used for therapy, and the lack of significant concurrent diseases and drug interactions in children [Table 1].
Oxazolidinones and particularly linezolid may cause neurotoxicity in rare conditions. Encephalopathy, peripheral neuropathy, optic neuropathy, and Bell's palsy are among these neurotoxic side effects.,,,,, Mitochondrial toxicity has been suggested as a possible cause of linezolid-induced optic neuropathy. Linezolid has some dopaminergic properties that may cause the serotonin syndrome if a monoamine oxidase inhibitor is co-administered. Using linezolid in combination with an anticholinergic substance such as an antihistamine may increase the risk of encephalopathy [Table 1].
Metronidazole is a widely used antibiotic, that is used in a spectrum of disorders ranging from local skin lesions to potentially hazardous systemic infections. The neurotoxicity associated with metronidazole may manifest clinically as headache, dizziness, confusion, cerebellar toxicity (ataxia and dysarthria) [with transient cerebellar lesions seen on brain magnetic resonance images], encephalopathy, optic neuropathy, and peripheral neuropathy.,,,, Such adverse effects usually develop with the long-term use of the medication and resolve unremarkably after drug discontinuation. The exact underlying mechanism is unknown, but some researchers have proposed an axonal swelling secondary to metronidazole-induced vasogenic edema [Table 1].
Polymyxins including polymyxin B and colistin (polymyxin E) at one time were excluded from the antibiotic lists routinely used for clinical purposes because of their neurotoxic effects. With the emergence of multidrug-resistant gram-negative bacilli, however, these drugs have become available for clinical use again. Their common neurologic side effects are paresthesias and ataxia, and less commonly, encephalopathy, diplopia, ptosis and nystagmus, vertigo, confusion, hallucinations, ataxia, seizures, and partial deafness. The proposed mechanisms are neuromuscular blockade, a prolonged depolarization phase secondary to calcium depletion, and a direct interaction with neurons due to their high lipid content. Co-administration with narcotics, sedatives, anesthetic drugs, corticosteroids, and/or muscle relaxants, especially in patients with MG and renal insufficiency, may increase the risk of neurotoxicity by polymyxins [Table 1].
Medications used for treating tuberculosis including isoniazid, ethambutol and cycloserine (aminoglycosides and fluoroquinolones have been discussed elsewhere) may cause both central and peripheral nervous system side effects. Isoniazid could lead to peripheral neuropathy, psychosis, and seizures. Optic neuropathy is a known neurotoxic manifestation of ethambutol; and cycloserine could cause psychosis and seizures. Optic neuropathy is believed to be secondary to ethambutol-induced mitochondrial dysfunction. Pathological examinations have demonstrated demyelinating lesions in the optic nerve and chiasm of patients with ethambutol-induced optic neuropathy [Table 1].
Tetracyclines may cause cranial nerve toxicity and neuromuscular blockage. There is also a report suggesting the occurrence of benign intracranial hypertension after tetracycline use [Table 1].
As a widely used antibiotic,, clindamycin has been rarely associated with neurotoxicity. There is only one case report in the literature that described abnormal body movements (abdomen, shoulders, and jaw) in a children after taking clindamycin, which resolved uneventfully after drug withdrawal. In a recent animal study on hamsters, Afaf El-Ansary showed that clindamycin caused a significant decrease in dopamine in the brain (cortex and medulla) and GABA in the cerebral cortex. They argued that the overuse of clindamycin may cause an increase in pathogenic bacteria in the gut, of which Clostridium infections could be playing a role in the pathophysiology of autism.
Vancomycin has been shown to cause local neurotoxic consequences when it is administered intraventricularly. The findings were cerebrospinal fluid (CSF) pleocytosis and eosinophilia, which are believed to be mediated by vancomycin-induced inflammatory process within the CSF, and could be prevented by dose adjustment.
Nitrofurantoin may cause neurotoxicity in children, which manifests as sensorimotor polyneuropathy (dysesthesias and paresthesias) and intracranial hypertension.,,, These side effects go away with drug discontinuation.
The use of dapsone has been associated with pure motor neuropathy and sensory impairment in some reports.,
Chloramphenicol can result in optic neuritis.,
Bismuth can cause a myoclonic encephalopathy in rare cases.
The neurotoxic effects classified by the antibiotic types are shown in [Table 2].,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
| » Conclusion|| |
Neurotoxicity is one of the main side effects of antibiotics. The presentations of these neurotoxic manifestations may differ based upon different ages. These manifesations can present as psychological problems, confusion, disorientation, myoclonus, seizure, encephalopathy, nonconvulsive status epilepticus, seizures, optic neuropathy, encephalopathy, peripheral neuropathy, and as exacerbations of the manifestations of MG. The precise knowledge of the side effect of drugs can help us in preventing further complications.
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[Table 1], [Table 2]
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