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 Table of Contents  
Year : 2020  |  Volume : 2  |  Issue : 2  |  Page : 28-35

Neurotoxicity Associated with Cefepime: An Update to Neurocritical Care: A Narrative Review

1 Department of Neurosurgery, University of Cartagena, Cartagena de Indias, Colombia
2 Department of Biochemistry, Medical College and Hospital, 88 College Street, Kolkata, India
3 Department of Community Medicine, MGM Medical College and LSK Hospital, Kishanganj, Bihar, India
4 Department of Neurosurgery, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
5 Department of Neurosurgery, Holy Family Red Crescent, Medical College, Dhaka, Bangladesh

Date of Submission06-Oct-2020
Date of Acceptance24-Nov-2020
Date of Web Publication31-Dec-2020

Correspondence Address:
Dr. Amit Agrawal
Department of Neurosurgery, All India Institute of Medical Sciences, Saket Nagar, Bhopal - 462 020, Madhya Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jtccm.jtccm_21_20

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Neurotoxicity has been an adverse effect described for almost all B-lactams; since its launch in 1994, there are numerous reports of patients treated with cefepime, covering a wide spectrum of clinical manifestations ranging from delirium to a nonconvulsive status epilepticus (NCSE), being the most of them reported in patients with decreased renal function, but also in patients with preserved renal function. We attempted to illustrate the clinical spectrum of cefepime neurotoxicity in relation to neurocritical care. We identified 13 publications describing neurotoxicity following cefepime administration from PubMed using search terms were cefepime, neurotoxicity, seizures, delirium, encephalopathy, NCSE, myoclonus, confusion, aphasia, agitation, coma, disability, and death. Two reviewers independently assessed identified articles for eligibility and used for this review writing. Most reports occur in elderly patients, although cases have been described in children and newborns. In general, patients recover soon after stopping beta-lactams or after reducing the dose or replacing them with another antibiotic; however, there is a likelihood of recurrence of symptoms after reintroducing Cefepime again at a dose low.

Keywords: Adverse events, blood–brain barrier, cefepime, intensive care units, neurotoxicity, seizures, status epilepticus

How to cite this article:
Moscote-Salazar LR, Ghosh A, Pal R, Raj S, Rahman MM, Agrawal A. Neurotoxicity Associated with Cefepime: An Update to Neurocritical Care: A Narrative Review. J Transl Crit Care Med 2020;2:28-35

How to cite this URL:
Moscote-Salazar LR, Ghosh A, Pal R, Raj S, Rahman MM, Agrawal A. Neurotoxicity Associated with Cefepime: An Update to Neurocritical Care: A Narrative Review. J Transl Crit Care Med [serial online] 2020 [cited 2023 Mar 29];2:28-35. Available from: http://www.tccmjournal.com/text.asp?2020/2/2/28/305790

  Introduction Top

Adverse drug reactions (ADRs) differ from adverse drug events (ADEs), as ADEs are inclusive of events beyond ADRs by including tissue/organ/system injury related to a variety of health care-related errors. ADEs are preventable issues by systems approaches of mitigation, plan, and implementation of clinical practice guidelines on the medication errors, ADRs, allergic reactions, and overdoses. The diagnosis of ADEs associated with cephalosporins needs high levels of cognitive and affective interventions.[1] Various ADRs have been reported with administration of the cephalosporins and other commonly used antimicrobials; among the most common adverse effects, gastrointestinal reactions are described; allergic reactions are rare and are mediated by immunoglobulin E (IgE).[2] Neurological alterations may present in a smaller percentage; these are more frequent in patients who present a decrease in their renal function.[3] The most frequent clinical manifestations are seizures or nonconvulsive status epilepticus (NCSE), followed in frequency by myoclonus,[3] psychosis, personality changes, among others, may also be present,[4],[5] which can become evident a few days after the start of antibiotic therapy. The empirical use in pyrexia of unknown origin, with empiric broad-spectrum antibiotics including cefepime and other cephalosporins pending blood cultures and antibiogram, may prevent life-threatening sepsis. Yet, treating physicians have to be competent with a high index of suspicions for downstream pathologies and management of different issues lies mainly in the suspension of treatment and replacement by alternative therapies leading to improvement in the clinical picture.[6],[7] In the above context, this research group attempted to outline the clinical spectrum of cefepime neurotoxicity in the neurocritical care context.

  Materials and Methods Top

Database search was attempted by this research group from the available literature on the neurotoxicity risk correlates related to cefepime administration from various online databases. This methodical literature search identified publications describing neurotoxicity from cefepime administration for randomized controlled trials (RCTs), non-RCTs, and prospective and retrospective cohort studies were performed on the following databases using pertinent search engines on health-care publications to find the relevant articles published from PubMed Central. Thereafter, all these published literature from downstream secondary exploration related to our search items were added to the pool of potentially eligible studies. Wherever data were missing in the publications, the authors were contacted and some doubts were clarified by consensus. Criteria for online searches following keywords (MeSH Terms) were used for the search: were cefepime, neurotoxicity, seizures, delirium, encephalopathy, NCSE, myoclonus, confusion, aphasia, agitation, coma, disability, and death. All the studies were further subjected to screening for eligibility by two reviewers independently to include in this study. From all these publications ultimately, this research group could finally concentrate on the 13 studies decided for our study criteria, namely hospitalized adults with cefepime administration, symptoms of neurotoxicity, and any study design across the globe. [Table 1] Primary outcome variables were cefepime neurotoxicity with or without comorbidities.
Table 1: Summary of characteristics of Cefepime-induced neurotoxicity in selected studies

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  Overview Top

Cefepime is empirically being increasingly used in high doses for managing febrile illnesses with neutropenia, in the midst of increased mortality risks from neurotoxicity noted by meta-analysis, especially in presence of levels of renal dysfunction.[4],[7],[8] Cefepime is a fourth-generation cephalosporin and its elimination is predominantly through the kidneys, obtaining from 80% to 85% of the nonmetabolized drug. It has a half-life of 2 h in adults with preserved renal function; in patients with renal insufficiency, its half-life can increase significantly.[4],[7] Up to 70% of a dose can be eliminated by performing hemodialysis in approximately 3 h.[4]

  Cefepime Toxicity in the Nervous System Top

Neurotoxicity as an adverse effect of β-lactams has been related to the β-lactam ring, since its degradation does not allow the appearance of seizures.[5] It has been shown that there is the participation of various neurotransmitters, finding a decrease in inhibition mediated by γ-aminobutyric acid (GABA), and an increase in the excitatory capacity of N-methyl-D-aspartate, which leads to excitotoxicity.[3],[5],[9] The receptor most involved is the GABA class A receptor (GABAAR), under normal conditions, its activation by endogenous GABA leads to the entry of chloride ions into the intracellular space, which generates an inhibitory postsynaptic potential (IPSP) increasing thus the threshold for the generation of the action potential.[3],[4],[5] Greater neurotoxicity has been found in patients with kidney disease, with a prevalence of up to 92% of cases.[3] Other factors that have been associated with neurotoxicity are life extremes (older adults or newborns), central nervous system (CNS) diseases, and concomitant use of nephrotoxic and anticonvulsant medications.[5],[10] In the Belgian retrospective study, the latency period, i.e. the time space between the start of treatment and reported neurological deterioration was 4.75 ± 2.55 days (range: 1–10 days).[11] The Korean review appraised that cefepime administration causes neurotoxicity by crossing blood-brain barrier even with normal renal function and appropriate dosage schedules with associated clinically toxic encephalopathy and definite EEG abnormalities.[12]

  Adverse Reactions of Cefepime Top

ADRs differ from ADEs, as ADEs are inclusive of events beyond ADRs by including tissue/organ/system injury related to a variety of health care-related errors. ADEs are preventable issues by system approaches of mitigation, plan and implementation of clinical practice guidelines on the medication errors, ADRs, allergic reactions, and overdoses. The beta-lactam ring of the cephalosporins causes immediate and delayed ADRs mediated by specific IgE and non-IgE-mediated immunological mechanisms.[1] Antibiotics containing β-lactams have been incriminated with the majority of drug-related adverse events. In general, these are mild under proper dosing and judicious selection.[5] Cefepime has been identified as one of the most high-risk cephalosporins, that has reportedly causing neurotoxicity.[13] The most frequently reported adverse effects after parenteral administration of cefepime include nausea, vomiting, diarrhea, phlebitis, rash, headache, and occasionally neurological abnormalities manifested with encephalopathy, myoclonus, and seizures.[2] IgE-mediated anaphylaxis induced by cefepime is rare.[2] Currently, there have been very few cases described in the medical literature, however, the pathophysiological mechanisms that participate in this type of phenomena have already been previously described[14]. Three patterns can be identified in immediate-type hypersensitivity reactions toward cephalosporins:[15] (1) the presence of preexisting IgE against the beta-lactam portion of the molecule, so cross-reactivity may occur with other drugs that are part of the group of beta-lactams; (2) cross-reactivity between the different cephalosporins by recognition of the structure of the beta-lactam ring or by recognition of the structure of its side chain; and (3) presence of preexisting IgE against the specific cephalosporin that generates said reaction, either by a fragment of it or its complete structure. In the management of allergic events secondary to the use of cephalosporins, it is essential to evaluate and identify the responsible drug, as well as the determinants of said event.[2],[15] In the Belgium retrospective study, on 8 hospital-based renal insufficiency cases admitted from June 1999 to October 2006, all developed reduced conscience, confusion, agitation, global aphasia, myoclonus, chorea-athetosis, convulsions, and coma. It should be noted that the predominant route of elimination of cefepime is through glomerular filtration. Its renal clearance is very similar to creatinine clearance, so the dose to be used in a specific patient depends largely on the renal function of the same. Most cases of cefepime toxicity occur due to overdose in patients with renal failure, so the measurement of nitrogen compounds can be a key point during the clinical management of these patients.[11]

  Cefepime Toxicity in the Nervous System Top

Neurotoxicity as an adverse effect of β-lactams has been related to the β-lactam ring since its degradation does not allow the appearance of seizures.[5] In the French study, measurement of cefepime concentrations in cerebrospinal fluid (CSF) study of two patients cases confirmed brain accumulation of the drug.[9] It has been shown that there is the participation of various neurotransmitters, finding a decrease in inhibition mediated by GABA, and an increase in the excitatory capacity of N-methyl-D-aspartate, which leads to excitotoxicity.[3],[5],[9] The receptor most involved is the GABAAR, under normal conditions, its activation by endogenous GABA leads to the entry of chloride ions into the intracellular space, which generates an IPSP increasing thus the threshold for the generation of the action potential.[3],[4],[5] Greater neurotoxicity has been found in patients with kidney disease, with a prevalence of up to 92% of cases.[3] Other factors that have been associated with neurotoxicity are life extremes (older adults or newborns), CNS diseases, and concomitant use of nephrotoxic and anticonvulsant medications.[5],[10] Boston case series was the first to report asynchronous myoclonus and expressive aphasia with normal kidney function after administration of cefepime. Differential diagnosis of altered mental status showed progressive expressive aphasia, asynchronous myoclonic limb activity within 4–5 days of cefepime initiation; resolved within 3 days of discontinuation.[16] A research group from New York reported a correlation between cefepime clearance (CL) and creatinine clearance (CLCR) in normal and abnormal renal function in 36 patient case series while exploring cefepime neurotoxicity.[17]

The Swiss study investigated cefepime trough concentrations (high-performance liquid chromatography) with cases on higher daily dosages adjusted to glomerular filtration rate to find the association of consistent neurological symptoms and/or signs (by NCI criteria). Median cefepime concentration posttherapy and neurotoxicity (altered mental status, hallucinations, or myoclonia) were attributed for 20% of patients; cefepime discontinuation leads to complete neurological recovery in five cases and improvement in one.[8]

  Clinical Manifestations of Neurotoxicity Top

Cefepime neurotoxicity is infrequently reported an ADR in pharmacovigilance.[10] Beta-lactamase-induced encephalopathy can manifest with different signs and symptoms, mainly seizures and NCSE,[18] followed in frequency by myoclonus.[3] Other symptoms that may be present are altered state of consciousness such as confusion, psychosis, personality changes, panic attacks or agitation, aphasia,  Parkinsonism More Details, and coma.[4],[5] Symptoms can become evident from a few seconds to 20 days after the administration of the antibiotic, having a progressive recovery after stopping the drug, reducing the dose, or replacing it.[5] These clinical findings can occur in patients with elevated serum cefepime levels and abnormal electroencephalographic findings. Taking into account that the latency of neurotoxicity can vary between 1 and 16 days starting from the start of therapy.[4] The systematic review from United States noted that in all the cefepime-induced neurotoxicity cases generally altered mental status was present with reduced consciousness (47%), myoclonus (42%), confusion (42%); 98 (73%).[19]

  Risk Correlates Top

Elderly age was observed in almost all the studies as the most important risk factor. In the systematic review of researchers from the United States, cefepime-induced neurotoxicity on 135 cases reported from 37 studies had median age 69 years and comorbidities renal dysfunction (80%) and on intensive care (81%).[19] A French study on cefepime neurotoxicity with the acute or chronic kidney diseases (CKD) had four cases of supplementary dialysis sessions done to decrease the cefepime levels.[9] The research group noted old age, fever, and neutropenia as risk factors for cefepime ADRs; additional risk correlates are the history of stroke and seizures[10]. Brazilian researchers noted cefepime neurotoxicity while treating pneumonia in elderly Caucasian diabetic men.[18] In Boston case series, three patients presented to the hospital with confusion after cefepime use to treat urinary tract infection and health care-associated pneumonia.[16] In the Spanish case report on a 78-year-old male, admitted with mixed slow evolution ulcers, after 10 days of cefepime, both renal and neurological functions deteriorated (delirium, excitability, and restlessness). Renal ultrasound showed a smaller kidney with EEG changes.[20]

  Dosing Dilemma Top

The systematic review of the United States noted that as per Food and Drug Administration-approved dosing guidance, 48% were overdosed; 26% had neurotoxicity with appropriate dose; median cefepime serum and CSF concentrations were 45 mg/L and 13 mg/L, respectively.[19] A French research group observed that cefepime overdosage in blood level assay and neurological status got better in all of the study participants after drug withdrawal; reduction in cefepime concentration was noted in five cases parallel with neurological improvement; even in one case drug was continued after adjusting the dosage,[9] while other research group reported NCSE in a patient receiving renally adjusted dosages of cefepime.[10] In the elderly, considering the age-related reduced renal function, the treating health-care providers should adjust the dose of cefepime when CLCR <50 ml\min.[21] In a Swiss study, multivariate logistic regression confirmed high cefepime concentrations as an independent predictor of neurotoxicity (50% probability threshold at >22 mg/l).[8]

  Monitoring Patients Intoxicated with Cefepime Top

Neurotoxicity related to the use of cefepime is estimated to affect approximately 3% of patients treated with it, although the true incidence of this phenomenon may be underestimated.[3],[9],[16] In patients in whom cefepime is considered as an antibiotic treatment, renal function assessment should be considered for dose adjustment.[17] A French research group opined that with the clinical suspicion ADR with cefepime, a blood sample can be obtained to measure the plasma levels of the drug. In case of overdose, the suspension of the drug restores the neurological status of patients. Normally, the ratio between the plasma concentration of cefepime and the concentration in the CSF is around 10%. In some cases, where the permeability of the blood–brain barrier is increased, this relationship can increase up to 45%, which makes the appearance of an adverse neurological event more likely.[9] An elderly woman with renal-adjusted dosing reported compromised mental status and orofacial myokymia on the 4th day of drug administration.[10] In a review of Korean studies, toxic encephalopathy was reported 2–6 days after administration and disappeared 3 days after discontinuation of cefepime. Cefepime-induced neurotoxicity was reversible with early detection and discontinuation-definitive treatment; anticonvulsant therapy necessary with convulsive seizure or definite NCSE.[12] The systematic review at the University of Washington on Cefepime Neurotoxicity with 5 additional cases totaled 198 cases (mean age 67 years; 87% renal dysfunction). Appa et al in single-center review estimated incidence toxicity as 1in 480 of cefepime use with diminished consciousness levels (80%), disorientation/agitation (47%), myoclonus (40%); non-convulsive status epilepticus was reported more (31%) than convulsive seizures (11%).[22]

  Noninvasive Investigations for Neurotoxicity Top

The systematic review of the United States reported EEG changes: NCSE (25%), myoclonic status epilepticus (7%), triphasic waves (40%), and focal sharp waves (39%).[19] In the Belgium retrospective study, EEG changes were diffuse slow-wave activity (delta) and triphasic sharp-wave activity – these findings confirmed possible neurotoxicity with cefepime in patients with renal failure. In none of the deceased, a causal relationship of neurotoxicity and mortality was found.[11] In a 70-year-old admitted woman with febrile neutropenia, EEG confirmed NCSE.[10] Two days after mental status alteration with cefepime neurotoxicity in elderly diabetic adults in the study reported from Brazil, the EEG showed diffuse slow-wave activity (delta) and triphasic sharp-wave activity. After discontinuation of cefepime, the patient improved after 4 days and the new EEG revealed only diffuse delta.[18] In Boston case series, computed tomography and magnetic resonance imaging of the brain were within normal limits though electroencephalogram showed diffuse slowing activity with triphasic waves consistent with encephalopathy.[16] In the Spanish case report, EEG showed constant bilateral slow, acute, and triphasic waves. Head CT in the elderly case showed the sole finding of corticosubcortical atrophy. Urgent hemodialysis started. After three dialysis, patients improved and a new EEG showed improvement. However, creatinine levels were higher even after 2 months.[20] In the review of Korean studies, EEG abnormalities were a triphasic wave, currently renamed as generalized periodic discharge with triphasic morphology more than of NCSE.[12]

  Treatment Top

Neurotoxicities are notable effects in renal compromised patients on high dosage cefepime; reported up to 3% of treated cases, though with possible underestimate.[9] In general, the symptoms are resolved after the suspension of cefepime administration and the change to alternative antimicrobials and should be done with permanent electroencephalographic monitoring, until the patient's mental state returns to normal.[6] EEG findings support anticonvulsant treatment in patients with overt seizures or NCSE. Recommended first-line medications include lorazepam and/or phenytoin. In the presence of refractory seizures, valproic acid, phenobarbital, propofol, midazolam, or pentobarbital can be administered.[7] Because cephalosporins are dialyzable, hemodialysis is considered an option for patients with neurotoxicity, mainly in patients with decreased kidney function, resulting in a decrease in drug concentrations in body fluids (serum, CSF) with a definitive improvement in the clinical picture.[6],[7] Therefore, because the neurotoxicity induced by cephalosporins is reversible, long-term anticonvulsant therapy is not necessary, which is why it is considered to have a good prognosis.[6] In acute neurocritical care settings, earliest neurotoxicities with cefepime were changed or modified mental status; suggested replacement of therapy was broad-spectrum antibiotics with Gram-negative coverage, viz. piperacillin-tazobactam or ceftazidime.[7] The systematic review of the United States reported symptomatic improvement (89%), survival to hospital discharge (87%); median delay from starting the drug to symptom onset 4 days; median resolution 2 days after intervention-included cefepime discontinuation, antiepileptic administration, or hemodialysis.[19]

  Outcome Top

In the Belgium retrospective study, all died 17 ± 14.7 days (range: 1–42 days) after becoming symptomatic; 3 died shortly after neurological deterioration; 5 developed neurological “tableau” with global aphasia; and 3 had clinical improvement after drug discontinuation. This research group suggested graded challenge tests to any cephalosporin before administration; in cases of test being positive, antimicrobials with dissimilar side chain should be tried.[14] After neurological deterioration or aphasia with cefepime, the treating physician should immediately stop the drug on the intuition of potential drug hazards.[11] Critical assay of blood concentration is a valuable tool for diagnosis and prognosis of cefepime neurotoxicity along with supplementation of levels of CSF drug concentrations.[9] Status epilepticus was reported as fully reversible; prompt diagnosis and immediate discontinuation of cefepime will prevent downstream morbidity, disability, and mortality.[10] Brazilian researchers noted that in elderly diabetic adults on cefepime neurotoxicity 30 days after discontinuation, the patient had full recovery in mental status.[18] The Swiss study concluded that high cefepime plasma concentrations were associated with neurotoxicity in febrile neutropenia with mild renal dysfunction. This demand precise dosing per 100 ml/min glomerular filtration rate: a moral/ethical dilemma for this life-threatening condition.[8] In the Spanish case report, the research group felt that close monitoring of renal function in patients with cefepime, early suspicion of neurological insult, and urgent hemodialysis may have a favorable prognosis in cefepime-induced encephalopathy.[20] In the review on Korean studies, the researcher felt that emergency hemodialysis was life-saving with frequent neurologic and renal monitoring, especially elderly patients with impaired renal function or a history of previous CNS injury.[12] In the cefepime neurotoxicity case series (n=100) from Mayo Clinic of United States among intensive care unit patients (mean age 65.8 years ± 12.7 years), common features were impaired consciousness, myoclonus, disorientation and non-convulsive status epilepticus. Cefepime dose adjusted for renal clearance in 64 (75.3%) without cefepime neurotoxicity and 4 patients (28.6%) with neurotoxicity; CKD, 30 (35.3%) without neurotoxicity and 10 (66.7%) with neurotoxicity; critically ill CKD patients were particularly susceptible with myoclonus and impaired consciousness as predominant clinical manifestations; more often with nonadjusted cefepime dose for renal function, still occur despite modifications.[23] The systematic review at the University of Washington concluded that older ages with renal dysfunction are risk factors of cefepime neurotoxicity and new-onset encephalopathy, especially if concurrent myoclonus is present.[22]

  Conclusion Top

There is a widespread concern regarding the neurotoxicity of cefepime reported from the developed countries, but the economic and humanitarian effects of this neurotoxicity are greater in the developing world, where the information is pouring in from emergency departments. Current systems approach of collation, triangulation and dissemination of information require supplementation and reinforcement of data which is possible by improving, refining, and re-defining conceptual and contextual signals of both the favorable and unfavorable events. By the reflection and metacognition of the neurotoxicity of cefepime, the real-time reporting of the pharmacovigilance will be able to metamorphose beyond the traditional approaches. Neurotoxicity induced by cefepime should be an adverse effect considered in those patients who present some degree of neurological deterioration not justified by some other organic alteration, especially if they present some compromise of their renal function. It should be taken into account that up to 25% of these cases can occur in patients who were receiving adequate doses of the drug. The drug may be stopped or dose adjusted after empirical review of temporal association of symptoms suggestive of cefepime neurotoxicity by clinical acumen.

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  References Top

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