| Article Access Statistics|
| Viewed||2012 |
| Printed||41 |
| Emailed||0 |
| PDF Downloaded||39 |
| Comments ||[Add] |
Click on image for details.
|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|
Click here to view
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.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Bhattacharyya S, Darby R, Berkowitz AL. Antibiotic-induced neurotoxicity. Curr Infect Dis Rep 2014;16:448.
Ashwin Kamath; Fluoroquinolone induced neurotoxicity: A review. J Adv Pharm Edu Res 2013;3:72-5.
Thomas RJ. Neurotoxicity of antibacterial therapy. South Med J 1994;87:869-74.
Grill MF, Maganti RK. Neurotoxic effects associated with antibiotic use: Management considerations. Br J Clin Pharmacol 2011;72:381-93.
Chow KM, Hui AC, Szeto CC. Neurotoxicity induced by beta-lactam antibiotics: From bench to bedside. Eur J Clin Microbiol Infect Dis 2005;24:649-53.
Saito T, Nakamura M, Watari M, Isse K. Tardive seizure and antibiotics: Case reports and review of the literature. JECT 2008;24:275-6.
Kolb R, Gogolak G, Huck S, Jaschek I, Stumpf C. Neurotoxicity and CSF level of three penicillins. Arch Int Pharmacodyn Ther 1976;222:149-56.
Smith H, Lerner PI, Weinstein L. Neurotoxicity and “massive” intravenous therapy with penicillin. A study of possible predisposing factors. Arch Intern Med 1967;120:47-53.
Chow KM, Szeto CC, Hui AC, Wong TY, Li PK. Retrospective review of neurotoxicity induced by cefepime and ceftazidime. Pharmacotherapy 2003;23:369-73.
Penicillin, ceftazidime, and the epilepsies. Lancet 1992;340:400-1.
Walker AE, Johnson HC, Kollros JJ. Penicillin convulsions; The convulsive effects of penicillin applied to the cerebral cortex of monkey and man. Surg Gynecol Obstet 1945;81:692-701.
Dumoff-Stanley E, Dowling HF, Sweet LK. The absorption into and distribution of penicillin in the cerebrospinal fluid. J Clin Invest 1946;25:87-93.
Lin CS, Cheng CJ, Chou CH, Lin SH. Piperacillin/tazobactam-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Am J Med Sci 2007;333:181-4.
Huang WT, Hsu YJ, Chu PL, Lin SH. Neurotoxicity associated with standard doses of piperacillin in an elderly patient with renal failure. Infection 2009;37:374-6.
Shaffer CL, Davey AM, Ransom JL, Brown YL, Gal P. Ampicillin-induced neurotoxicity in very-low-birth-weight neonates. Ann Pharmacother 1998;32:482-4.
Schliamser SE, Cars O, Norrby SR. Neurotoxicity of beta-lactam antibiotics: Predisposing factors and pathogenesis. J Antimicrob Chemother 1991;27:405-25.
DeLorey TM, Olsen RW. Gamma-aminobutyric acid A receptor structure and function. J Biol Chem 1992;267:16747-50.
Sugimoto M, Fukami S, Kayakiri H, Yamazaki S, Matsuoka N, Uchida I, et al
. The beta-lactam antibiotics, penicillin-G and cefoselis have different mechanisms and sites of action at GABA(A) receptors. Br J Pharmacol 2002;135:427-32.
Lindquist CE, Dalziel JE, Cromer BA, Birnir B. Penicillin blocks human alpha 1 beta 1 and alpha 1 beta 1 gamma 2S GABAA channels that open spontaneously. Eur J Pharmacol 2004;496:23-32.
Sugimoto M, Uchida I, Mashimo T, Yamazaki S, Hatano K, Ikeda F, et al
. Evidence for the involvement of GABA(A) receptor blockade in convulsions induced by cephalosporins. Neuropharmacology 2003;45:304-14.
Grondahl TO, Langmoen IA. Epileptogenic effect of antibiotic drugs. J Neurosurg 1993;78:938-43.
Gutnick MJ, Prince DA. Penicillinase and the convulsant action of penicillin. Neurology 1971;21:759-64.
Esplin B, Theoret Y, Seward E, Capek R. Epileptogenic action of penicillin derivatives: Structure-activity relationship. Neuropharmacology 1985;24:571-5.
De Sarro A, De Sarro GB, Ascioti C, Nistico G. Epileptogenic activity of some beta-lactam derivatives: Structure-activity relationship. Neuropharmacology 1989;28:359-65.
Hantson P, Leonard F, Maloteaux JM, Mahieu P. How epileptogenic are the recent antibiotics? Acta Clin Belg 1999;54:80-7.
Shiraishi H, Ito M, Go T, Mikawa H. High doses of penicillin decreases [3H]flunitrazepam binding sites in rat neuron primary culture. Brain Dev 1993;15:356-61.
Chatellier D, Jourdain M, Mangalaboyi J, Ader F, Chopin C, Derambure P, et al
. Cefepime-induced neurotoxicity: An underestimated complication of antibiotherapy in patients with acute renal failure. Intensive Care Med 2002;28:214-7.
Grill MF, Maganti R. Cephalosporin-induced neurotoxicity: Clinical manifestations, potential pathogenic mechanisms, and the role of electroencephalographic monitoring. Ann Pharmacother 2008;42:1843-50.
Sonck J, Laureys G, Verbeelen D. The neurotoxicity and safety of treatment with cefepime in patients with renal failure. Nephrol Dail Transplant 2008;23:966-70.
Barbey F, Bugnon D, Wauters JP. Severe neurotoxicity of cefepime in uremic patients. Annals Intern Med 2001;135:1011.
Bragatti JA, Rossato R, Ziomkowski S, Kliemann FA. Cefepime-induced encephalopathy: Clinical and electroencephalographic features in seven patients. Arq Neuropsiquiatr 2005;63:87-92.
De Silva DA, Pan AB, Lim SH. Cefepime-induced encephalopathy with triphasic waves in three Asian patients. Ann Acad Med Singapore 2007;36:450-1.
Capparelli FJ, Diaz MF, Hlavnika A, Wainsztein NA, Leiguarda R, Del Castillo ME. Cefepime- and cefixime-induced encephalopathy in a patient with normal renal function. Neurology 2005;65:1840.
Roncon-Albuquerque R Jr, Pires I, Martins R, Real R, Sousa G, von Hafe P. Ceftriaxone-induced acute reversible encephalopathy in a patient treated for a urinary tract infection. Neth J Med 2009;67:72-5.
Lamoth F, Erard V, Asner S, Buclin T, Calandra T, Marchetti O. High imipenem blood concentrations associated with toxic encephalopathy in a patient with mild renal dysfunction. International J Antimicrob Agents 2009;34:386-8.
Seto AH, Song JC, Guest SS. Ertapenem-associated seizures in a peritoneal dialysis patient. Ann Pharmacother 2005;39:352-6.
Wong VK, Wright HT Jr, Ross LA, Mason WH, Inderlied CB, Kim KS. Imipenem/cilastatin treatment of bacterial meningitis in children. Pediatr Infect Dis J 1991;10:122-5.
Bazan JA, Martin SI, Kaye KM. Newer beta-lactam antibiotics: Doripenem, ceftobiprole, ceftaroline, and cefepime. Med Clin North Am 2011;95:743-60.
Bazan JA, Martin SI, Kaye KM. Newer beta-lactam antibiotics: Doripenem, ceftobiprole, ceftaroline, and cefepime. Infect Dis Clin North Am 2009;23:983-96.
Norrby SR. Neurotoxicity of carbapenem antibacterials. Drug Saf 1996;15:87-90.
Calandra G, Lydick E, Carrigan J, Weiss L, Guess H. Factors predisposing to seizures in seriously ill infected patients receiving antibiotics: Experience with imipenem/cilastatin. Am J Med 1988;84:911-8.
Koppel BS, Hauser WA, Politis C, van Duin D, Daras M. Seizures in the critically ill: The role of imipenem. Epilepsia 2001;42:1590-3.
Snavely SR, Hodges GR. The neurotoxicity of antibacterial agents. Ann Intern Med 1984;101:92-104.
Sunagawa M, Matsumura H, Sumita Y, Nouda H. Structural features resulting in convulsive activity of carbapenem compounds: Effect of C-2 side chain. J Antibiot 1995;48:408-16.
Harrison MP, Moss SR, Featherstone A, Fowkes AG, Sanders AM, Case DE. The disposition and metabolism of meropenem in laboratory animals and man. J Antimicrob Chemother 1989;24:265-77.
Suzuki H, Sawada Y, Sugiyama Y, Iga T, Hanano M, Spector R. Transport of imipenem, a novel carbapenem antibiotic, in the rat central nervous system. J Pharmacol Exp Ther 1989;250:979-84.
de Sarro A, Imperatore C, Mastroeni P, de Sarro G. Comparative convulsant potencies of two carbapenem derivatives in C57 and DBA/2 mice. J Pharm Pharmacol 1995;47:292-6.
Schliamser SE, Broholm KA, Liljedahl AL, Norrby SR. Comparative neurotoxicity of benzylpenicillin, imipenem/cilastatin and FCE 22101, a new injectible penem. J Antimicrob Chemother 1988;22:687-95.
Norrby SR, Gildon KM. Safety profile of meropenem: A review of nearly 5,000 patients treated with meropenem. Scandi J Infect Dis 1999;31:3-10.
Norrby SR. Neurotoxicity of carbapenem antibiotics: Consequences for their use in bacterial meningitis. J Antimicrob Chemother 2000;45:5-7.
Bischoff A, Meier C, Roth F. Gentamicin neurotoxicity (polyneuropathy-encephalopathy). Schweiz Med Wochenschr 1977;107:3-8.
Watanabe I, Hodges GR, Dworzack DL, Kepes JJ, Duensing GF. Neurotoxicity of intrathecal gentamicin: A case report and experimental study. Ann Neurol 1978;4:564-72.
Hashimoto Y, Shima T, Matsukawa S, Satou M. A possible hazard of prolonged neuromuscular blockade by amikacin. Anesthesiology 1978;49:219-20.
Boliston TA, Ashman R. Tobramycin and neuromuscular blockade. Anaesthesia 1978;33:552.
Paradelis AG, Triantaphyllidis C, Giala MM. Neuromuscular blocking activity of aminoglycoside antibiotics. Methods Find Exp Clin Pharmacol 1980;2:45-51.
Segal JA, Harris BD, Kustova Y, Basile A, Skolnick P. Aminoglycoside neurotoxicity involves NMDA receptor activation. Brain Res 1999;815:270-7.
Darlington CL, Smith PF. Vestibulotoxicity following aminoglycoside antibiotics and its prevention. Curr Opin Investig Drugs 2003;4:841-6.
Fiekers JF. Effects of the aminoglycoside antibiotics, streptomycin and neomycin, on neuromuscular transmission. II. Postsynaptic considerations. J Pharmacol Exp Ther 1983;225:496-502.
Knaus HG, Striessnig J, Koza A, Glossmann H. Neurotoxic aminoglycoside antibiotics are potent inhibitors of [125I]-Omega-Conotoxin GVIA binding to guinea-pig cerebral cortex membranes. Naunyn Schmiedebergs Arch Pharmacol 1987;336:583-6.
Andriole VT. The quinolones: Past, present, and future. Clin Infect Dis 2005;41:S113-9.
Naber KG, Adam D. Classification of fluoroquinolones. Int J Antimicrob Agents 1998;10:255-7.
Neuman M. Clinical pharmacokinetics of the newer antibacterial 4-quinolones. Clin Pharmacokinet 1988;14:96-121.
Owens RC Jr, Ambrose PG. Antimicrobial safety: Focus on fluoroquinolones. Clin Infect Dis 2005;41:S144-57.
Unseld E, Ziegler G, Gemeinhardt A, Janssen U, Klotz U. Possible interaction of fluoroquinolones with the benzodiazepine- GABAA-receptor complex. Br J Clin Pharmacol 1990;30:63-70.
Fernandez-Torre JL. Levofloxacin-induced delirium: Diagnostic considerations. Clin Neurol Neurosurg 2006;108:614.
Hakko E, Mete B, Ozaras R, Tabak F, Ozturk R, Mert A. Levofloxacin-induced delirium. Clin Neurol Neurosurg 2005;107:158-9.
Kushner JM, Peckman HJ, Snyder CR. Seizures associated with fluoroquinolones. The Ann Pharmacother 2001;35:1194-8.
De Bleecker JL, Vervaet VL, De Sarro A. Reversible orofacial dyskinesia after ofloxacin treatment. Mov Disord 2004;19:731-2.
MacLeod W. Case report: Severe neurologic reaction to ciprofloxacin. Can Fam Physician 2001;47:553-5.
Ball P, Mandell L, Patou G, Dankner W, Tillotson G. A new respiratory fluoroquinolone, oral gemifloxacin: A safety profile in context. Int J Antimicrob Agents 2004;23:421-9.
Stahlmann R. Clinical toxicological aspects of fluoroquinolones. Toxicol Lett 2002;127:269-77.
Stahlmann R, Lode H. Safety considerations of fluoroquinolones in the elderly: An update. Drugs Aging 2010;27:193-209.
Pastor P, Moitinho E, Elizalde I, Cirera I, Tolosa E. Reversible oral-facial dyskinesia in a patient receiving ciprofloxacin hydrochloride. J Neurol 1996;243:616-7.
Schwartz MT, Calvert JF. Potential neurologic toxicity related to ciprofloxacin. DICP 1990;24:138-40.
Wang SH, Xie YC, Jiang B, Zhang JY, Qu Y, Zhao Y, et al
. Fluoroquinolone associated myasthenia gravis exacerbation: Clinical analysis of 9 cases. Zhonghua Yi Xue Za Zhi 2013;93:1283-6.
Bowie WR, Willetts V, Jewesson PJ. Adverse reactions in a dose-ranging study with a new long-acting fluoroquinolone, fleroxacin. Antimicrob Agents Chemother 1989;33:1778-82.
Akahane K, Tsutomi Y, Kimura Y, Kitano Y. Levofloxacin, an optical isomer of ofloxacin, has attenuated epileptogenic activity in mice and inhibitory potency in GABA receptor binding. Chemotherapy 1994;40:412-7.
Akahane K, Sekiguchi M, Une T, Osada Y. Structure-epileptogenicity relationship of quinolones with special reference to their interaction with gamma-aminobutyric acid receptor sites. Antimicrob Agents Chemother 1989;33:1704-8.
Takayama S, Hirohashi M, Kato M, Shimada H. Toxicity of quinolone antimicrobial agents. J Toxicol Environ Health 1995;45:1-45.
Schmuck G, Schurmann A, Schluter G. Determination of the excitatory potencies of fluoroquinolones in the central nervous system by an in vitro
model. Antimicrob Agents Chemother 1998;42:1831-6.
Domagala JM. Structure-activity and structure-side-effect relationships for the quinolone antibacterials. J Antimicrob Chemother 1994;33:685-706.
Ilgin S, Can OD, Atli O, Ucel UI, Sener E, Guven I. Ciprofloxacin-induced neurotoxicity: Evaluation of possible underlying mechanisms. Toxicol Mech Methods 2015;25:374-81.
Thomas RJ, Reagan DR. Association of a Tourette-like syndrome with ofloxacin. Ann Pharmacother 1996;30:138-41.
Zhang LR, Wang YM, Chen BY, Cheng NN. Neurotoxicity and toxicokinetics of norfloxacin in conscious rats. Acta Pharmacol Sin 2003;24:605-9.
Bandettini di Poggio M, Anfosso S, Audenino D, Primavera A. Clarithromycin-induced neurotoxicity in adults. J Clin Neurosci 2011;18:313-8.
Babaeinejad S, Khodaeiani E, Fouladi RF. Comparison of therapeutic effects of oral doxycycline and azithromycin in patients with moderate acne vulgaris: What is the role of age? J Dermatolog Treat 2011;22:206-10.
Cadisch R, Streit E, Hartmann K. Exacerbation of pseudoparalytic myasthenia gravis following azithromycin (Zithromax). Schweiz Med Wochenschr 1996;126:308-10.
Principi N, Esposito S. Comparative tolerability of erythromycin and newer macrolide antibacterials in paediatric patients. Drug Saf 1999;20:25-41.
Trivedi S, Hyman J, Lichstein E. Clarithromycin and digoxin toxicity. Ann Intern Med 1998;128:604.
Geiderman JM. Central nervous system disturbances following clarithromycin ingestion. Clin Infect Dis 1999;29:464-5.
Pollak PT, Sketris IS, MacKenzie SL, Hewlett TJ. Delirium probably induced by clarithromycin in a patient receiving fluoxetine. Ann Pharmacother 1995;29:486-8.
Prime K, French P. Neuropsychiatric reaction induced by clarithromycin in a patient on highly active antiretroviral therapy (HAART). Sex Transm Infect 2001;77:297-8.
Neff NE, Kuo G. Acute manic psychosis induced by triple therapy for H. pylori
. The J Am Board Fam Pract 2002;15:66-8.
Steinman MA, Steinman TI. Clarithromycin-associated visual hallucinations in a patient with chronic renal failure on continuous ambulatory peritoneal dialysis. Am J Kidney Dis 1996;27:143-6.
Ozsoylar G, Sayin A, Bolay H. Clarithromycin monotherapy-induced delirium. J Antimicrob Chemother 2007;59:331.
Mermelstein HT. Clarithromycin-induced delirium in a general hospital. Psychosomatics 1998;39:540-2.
Cone LA, Sneider RA, Nazemi R, Dietrich EJ. Mania due to clarithromycin therapy in a patient who was not infected with human immunodeficiency virus. Clin Infect Dis 1996;22:595-6.
Jimenez P, Navarro-Ruiz A, Sendra P, Martinez-Ramirez M, Garcia-Motos C, Montesinos-Ros A. Hallucinations with therapeutic doses of clarithromycin. Int J Clin Pharmacol Ther 2002;40:20-2.
Brooks JO 3rd
, Hoblyn JC. Secondary mania in older adults. Am J Psychiatry 2005;162:2033-8.
Nightingale SD, Koster FT, Mertz GJ, Loss SD. Clarithromycin-induced mania in two patients with AIDS. Clin Infect Dis 1995;20:1563-4.
Finkenbine RD, Frye MD. Case of psychosis due to prednisone-clarithromycin interaction. Gen Hosp Psychiatry 1998;20:325-6.
Abouesh A, Hobbs WR. Clarithromycin-induced mania. Am J Psychiatry 1998;155:1626.
Kouvelou E, Pourzitaki C, Aroni F, Papazisis G, Kouvelas D. Acute psychosis induced by clarithromycin in a healthy adult? J Clin Psychopharmacol 2008;28:579-80.
Pijlman AH, Kuck EM, van Puijenbroek EP, Hoekstra JB. Acute delirium, probably precipitated by clarithromycin. Ned Tijdschr Geneeskd 2001;145:225-8.
Fernandez Arenas O, Gutierrez Garcia M, Hidalgo Correas FJ, Garcia Diaz B. Hallucinations by administration of a standard regimen of clarithromycin. Farm Hosp 2007;31:321-3.
Gomez-Gil E, Garcia F, Pintor L, Martinez JA, Mensa J, de Pablo J. Clarithromycin-induced acute psychoses in peptic ulcer disease. Eur J Clin Microbiol Infect Dis 1999;18:70-1.
Tse KC, Li FK, Tang S, Lam MF, Chan TM, Lai KN. Delusion of worm infestation associated with clarithromycin in a patient on peritoneal dialysis. Perit Dial Int 2001;21:415-6.
Gomez Gil E, Gabilondo Cuellar A, Pablo Rabasso JJ. Three new cases of severe affective disorders induced by clarithromycin. Med Clin 2002;119:119.
Ortiz-Dominguez A, Berlanga C, Gutierrez-Mora D. A case of clarithromycin-induced manic episode (antibiomania). Int J Neuropsychopharmacol 2004;7:99-100.
Saidinejad M, Ewald MB, Shannon MW. Transient psychosis in an immune-competent patient after oral trimethoprim-sulfamethoxazole administration. Pediatrics 2005;115:e739-41.
Cooper GS, Blades EW, Remler BF, Salata RA, Bennert KW, Jacobs GH. Central nervous system Whipple's disease: Relapse during therapy with trimethoprim-sulfamethoxazole and remission with cefixime. Gastroenterology 1994;106:782-6.
Patey O, Lacheheb A, Dellion S, Zanditenas D, Jungfer-Bouvier F, Lafaix C. A rare case of cotrimoxazole-induced eosinophilic aseptic meningitis in an HIV-infected patient. Scand J Infect Dis 1998;30:530-1.
Patterson RG, Couchenour RL. Trimethoprim-sulfamethoxazole- induced tremor in an immunocompetent patients. Pharmacotherapy 1999;19:1456-8.
Karpman E, Kurzrock EA. Adverse reactions of nitrofurantoin, trimethoprim and sulfamethoxazole in children. J Urol 2004;172:448-53.
Fletcher J, Aykroyd LE, Feucht EC, Curtis JM. Early onset probable linezolid-induced encephalopathy. J Neurology 2010;257:433-5.
Thai XC, Bruno-Murtha LA. Bell's palsy associated with linezolid therapy: Case report and review of neuropathic adverse events. Pharmacotherapy 2006;26:1183-9.
Ferry T, Ponceau B, Simon M, Issartel B, Petiot P, Boibieux A, et al
. Possibly linezolid-induced peripheral and central neurotoxicity: Report of four cases. Infection 2005;33:151-4.
Narita M, Tsuji BT, Yu VL. Linezolid-associated peripheral and optic neuropathy, lactic acidosis, and serotonin syndrome. Pharmacotherapy 2007;27:1189-97.
Sotgiu G, Centis R, D'Ambrosio L, Alffenaar JW, Anger HA, Caminero JA, et al
. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: Systematic review and meta-analysis. Eur Respir J 2012;40:1430-42.
Saijo T, Hayashi K, Yamada H, Wakakura M. Linezolid-induced optic neuropathy. Am J Ophthalmol 2005;139:1114-6.
Javaheri M, Khurana RN, O'Hearn TM, Lai MM, Sadun AA. Linezolid-induced optic neuropathy: A mitochondrial disorder? Br J Ophthalmol 2007;91:111-5.
Khodaeiani E, Fouladi RF, Yousefi N, Amirnia M, Babaeinejad S, Shokri J. Efficacy of 2% metronidazole gel in moderate acne vulgaris. Indian J Dermatol 2012;57:279-81.
] [Full text]
Tan CH, Chen YF, Chen CC, Chao CC, Liou HH, Hsieh ST. Painful neuropathy due to skin denervation after metronidazole-induced neurotoxicity. J Neurol Neurosurg Psychiatry 2011;82:462-5.
Sarma GR, Kamath V. Acute painful peripheral neuropathy due to metronidazole. Neurol India 2005;53:372-3.
] [Full text]
McGrath NM, Kent-Smith B, Sharp DM. Reversible optic neuropathy due to metronidazole. Clin Exp Ophthalmol 2007;35:585-6.
Hobson-Webb LD, Roach ES, Donofrio PD. Metronidazole: Newly recognized cause of autonomic neuropathy. J Child Neurol 2006;21:429-31.
Carroll MW, Jeon D, Mountz JM, Lee JD, Jeong YJ, Zia N, et al
. Efficacy and safety of metronidazole for pulmonary multidrug-resistant tuberculosis. Antimicrob Agents Chemother 2013;57:3903-9.
Patel K, Green-Hopkins I, Lu S, Tunkel AR. Cerebellar ataxia following prolonged use of metronidazole: Case report and literature review. Int J Infect Dis 2008;12:e111-4.
Ahmed A, Loes DJ, Bressler EL. Reversible magnetic resonance imaging findings in metronidazole-induced encephalopathy. Neurology 1995;45:588-9.
Landman D, Georgescu C, Martin DA, Quale J. Polymyxins revisited. Clin Microbiol Rev 2008;21:449-65.
Wolinsky E, Hines JD. Neurotoxic and nephrotoxic effects of colistin patients with renal disease. N Engl J Med 1962;266:759-62.
Duncan DA. Colistin toxicity. Neuromuscular and renal manifestations. Two cases treated by hemodialysis. Minn Med 1973;56:31-5.
Kubikowski P, Szreniawski Z. The Mechanism of the neuromuscular blockade by antibiotics. Arch Int Pharmacodyn Ther 1963;146:549-60.
Weinstein L, Doan TL, Smith MA. Neurotoxicity in patients treated with intravenous polymyxin B: Two case reports. Am J Health Syst Pharm 2009;66:345-7.
Kass JS, Shandera WX. Nervous system effects of antituberculosis therapy. CNS Drugs 2010;24:655-67.
Lessell S. Histopathology of experimental ethambutol intoxication. Invest Ophthalmol Vis Sci 1976;15:765-9.
Kesler A, Goldhammer Y, Hadayer A, Pianka P. The outcome of pseudotumor cerebri induced by tetracycline therapy. Acta Neurol Scand 2004;110:408-11.
Baharivand N, Mahdavifard A, Fouladi RF. Intravitreal clindamycin plus dexamethasone versus classic oral therapy in toxoplasmic retinochoroiditis: A prospective randomized clinical trial. Int Ophthalmol 2013;33:39-46.
Khodaeiani E, Fouladi RF, Amirnia M, Saeidi M, Karimi ER. Topical 4% nicotinamide vs. 1% clindamycin in moderate inflammatory acne vulgaris. Int J Dermatol 2013;52:999-1004.
Malone RP, Harvey JA. Abnormal movements with the addition of clindamycin to risperidone in a girl with autism. J Child Adolesc Psychopharmacol 2008;18:221-2.
El-Ansary A, Shaker G, Siddiqi NJ, Al-Ayadhi LY. Possible ameliorative effects of antioxidants on propionic acid/clindamycin- induced neurotoxicity in Syrian hamsters. Gut Pathog 2013;5:32.
El-Ansary A, Shaker GH, El-Gezeery AR, Al-Ayadhi L. The neurotoxic effect of clindamycin-induced gut bacterial imbalance and orally administered propionic acid on DNA damage assessed by the comet assay: Protective potency of carnosine and carnitine. Gut Pathog 2013;5:9.
Nava-Ocampo AA, Mojica-Madera JA, Villanueva-Garcia D, Caltenco-Serrano R. Antimicrobial therapy and local toxicity of intraventricular administration of vancomycin in a neonate with ventriculitis. Ther Drug Monit 2006;28:474-6.
Bafeltowska JJ, Buszman E, Mandat KM, Hawranek JK. Therapeutic vancomycin monitoring in children with hydrocephalus during treatment of shunt infections. Surg Neurol 2004;62:142-50.
Toole JF, Parrish ML. Nitrofurantoin polyneuropathy. Neurology 1973;23:554-9.
Coraggio MJ, Gross TP, Roscelli JD. Nitrofurantoin toxicity in children. Pediatr Infect Dis J 1989;8:163-6.
D'Arcy PF. Nitrofurantoin. Drug Intell Clin Pharm 1985;19:540-7.
Sharma DB, James A. Letter: Benign intracranial hypertension associated with nitrofurantoin therapy. Br Med J 1974;4:771.
Saqueton AC, Lorincz AL, Vick NA, Hamer RD. Dapsone and peripheral motor neuropathy. Arch Dermatol 1969;100:214-7.
Venegas-Francke P, Fruns-Quintana M, Oporto-Caroca M. Bilateral optic neuritis caused by chloramphenicol. Rev Neurol 2000;31:699-700.
Ramilo O, Kinane BT, McCracken GH Jr. Chloramphenicol neurotoxicity. Pediatr Infect Dis J 1988;7:358-9.
Moellering RC Jr, Eliopoulos GM, Sentochnik DE. The carbapenems: New broad spectrum beta-lactam antibiotics. J Antimicrob Chemother 1989;24:1-7.
Cannon JP, Lee TA, Clark NM, Setlak P, Grim SA. The risk of seizures among the carbapenems: A meta-analysis. J Antimicrob Chemother 2014;69:2043-55.
Lerner PI, Smith H, Weinstein L. Penicillin neurotoxicity. Ann N Y Acad Sci 1967;145:310-8.
Frytak S, Moertel CH, Childs DS. Neurologic toxicity associated with high-dose metronidazole therapy. Ann Intern Med 1978;88:361-2.
Maw G, Aitken P. Isoniazid overdose: A case series, literature review and survey of antidote availability. Clin Drug Invest 2003;23:479-85.
Lode H. Potential interactions of the extended-spectrum fluoroquinolones with the CNS. Drug Saf 1999;21:123-35.
Linden P. Safety profile of meropenem: An updated review of over 6,000 patients treated with meropenem. Drug Saf 2007;30:657-68.
Arcieri GM, Becker N, Esposito B, Griffith E, Heyd A, Neumann C, et al
. Safety of intravenous ciprofloxacin. A review. Am J Med 1989;87:92S-7S.
Yagawa K. Latest industry information on the safety profile of levofloxacin in Japan. Chemotherapy 2001;47:38-43.
Samarakoon N, Harrisberg B, Ell J. Ciprofloxacin-induced toxic optic neuropathy. Clin Exp Ophthalmol 2007;35:102-4.
Das S, Mondal S. Oral levofloxacin-induced optic neuritis progressing in loss of vision. Ther Drug Monit 2012;34:124-5.
Godel V, Nemet P, Lazar M. Chloramphenicol optic neuropathy. Arch Ophthalmol 1980;98:1417-21.
Sharma P, Sharma R. Toxic optic neuropathy. Indian J Ophthalmol 2011;59:137-41.
] [Full text]
Weimer LH, Sachdev N. Update on medication-induced peripheral neuropathy. Curr Neurol Neurosci Rep 2009;9:69-75.
Manji H. Drug-induced neuropathies. Hand Clin Neurol 2013;115:729-42.
Pratt RW, Weimer LH. Medication and toxin-induced peripheral neuropathy. Semin Neurol 2005;25:204-16.
Hokkanen E. Antibiotics in myasthenia gravis. Br Med J 1964;1:1111-2.
Hokkanen E. The aggravating effect of some antibiotics on the neuromuscular blockade in myasthenia gravis. Acta Neurol Scand 1964;40:346-52.
Jones SC, Sorbello A, Boucher RM. Fluoroquinolone-associated myasthenia gravis exacerbation: Evaluation of postmarketing reports from the US FDA adverse event reporting system and a literature review. Drug Saf 2011;34:839-47.
Pradhan S, Pardasani V, Ramteke K. Azithromycin-induced myasthenic crisis: Reversibility with calcium gluconate. Neurol India 2009;57:352-3.
] [Full text]
Pijpers E, van Rijswijk RE, Takx-Kohlen B, Schrey G. A clarithromycin-induced myasthenic syndrome. Clin Infect Dis 1996;22:175-6.
Absher JR, Bale JF Jr. Aggravation of myasthenia gravis by erythromycin. J Pediatr 1991;119:155-6.
May EF, Calvert PC. Aggravation of myasthenia gravis by erythromycin. Ann Neurol 1990;28:577-9.
Wittbrodt ET. Drugs and myasthenia gravis. An update. Arch Intern Med 1997;157:399-408.
Argov Z, Mastaglia FL. Drug therapy: Disorders of neuromuscular transmission caused by drugs. N Engl J Med 1979;301:409-13.
Dobrev D, Ravens U. Therapeutically relevant concentrations of neomycin selectively inhibit P-type Ca2+ channels in rat striatum. Eur J Pharmacol 2003;461:105-11.
Harnett MT, Chen W, Smith SM. Calcium-sensing receptor: A high-affinity presynaptic target for aminoglycoside-induced weakness. Neuropharmacology 2009;57:502-5.
Sieb JP, Milone M, Engel AG. Effects of the quinoline derivatives quinine, quinidine, and chloroquine on neuromuscular transmission. Brain Res 1996;712:179-89.
Sieb JP. Fluoroquinolone antibiotics block neuromuscular transmission. Neurology 1998;50:804-7.
Bertrand D, Bertrand S, Neveu E, Fernandes P. Molecular characterization of off-target activities of telithromycin: A potential role for nicotinic acetylcholine receptors. Antimicrob Agents Chemother 2010;54:5399-402.
[Table 1], [Table 2]