Cefepime Neurotoxicity: Underrecognized Risk or Overblown Concern?

Cefepime Neurotoxicity Underrecognized Risk or Overblown Concern

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Introduction

Cefepime stands as one of the most important antimicrobial agents in modern medicine’s arsenal against serious bacterial infections. Introduced in the 1990s, this fourth-generation cephalosporin quickly gained acceptance for its broad spectrum of activity against both gram-positive and gram-negative bacteria, including many resistant strains. Its ability to penetrate bacterial cell walls effectively while maintaining stability against various beta-lactamases made it particularly valuable in treating hospital-acquired infections, sepsis, and other life-threatening conditions.

Despite its proven efficacy and generally favorable safety profile, cefepime has attracted attention for an unexpected adverse effect: neurotoxicity. Reports of neurological complications associated with cefepime use began appearing in medical literature shortly after its introduction, describing patients who developed confusion, seizures, encephalopathy, and other neurological symptoms while receiving the medication. These reports raised important questions about the true risk-benefit ratio of cefepime therapy and whether neurological complications were being adequately recognized and managed in clinical practice.

The debate surrounding cefepime neurotoxicity has evolved over the past two decades, with healthcare professionals, researchers, and regulatory authorities attempting to determine the actual incidence, severity, and clinical impact of these neurological adverse events. Some experts argue that cefepime neurotoxicity represents an underrecognized risk that requires greater awareness and more careful monitoring. Others contend that concerns may be overblown, potentially leading to unnecessary avoidance of an otherwise valuable antibiotic.

This discussion carries particular importance in an era of increasing antimicrobial resistance, where effective antibiotics like cefepime play crucial roles in treating serious infections. Healthcare providers must make informed decisions about antibiotic selection, balancing the proven benefits of cefepime therapy against potential neurological risks. Understanding the true nature and scope of cefepime neurotoxicity becomes essential for optimal patient care and antibiotic stewardship.

The purpose of this paper is to examine current evidence surrounding cefepime neurotoxicity, analyzing available data on incidence rates, risk factors, clinical presentations, and outcomes. Through careful evaluation of recent research findings, case reports, and clinical experience, we aim to provide healthcare professionals with a balanced perspective on this important safety issue.

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Background and Pharmacology

Cefepime belongs to the fourth-generation cephalosporin class of beta-lactam antibiotics, designed to overcome some limitations of earlier cephalosporin generations. Its molecular structure incorporates a positively charged pyridinium group at the C-3 position, which facilitates rapid penetration through bacterial cell walls and provides enhanced stability against many beta-lactamases. This structural modification allows cefepime to maintain activity against bacteria that have developed resistance to earlier cephalosporins.

The drug exhibits broad-spectrum antimicrobial activity against both gram-positive and gram-negative organisms. Against gram-positive bacteria, cefepime demonstrates good activity against methicillin-sensitive Staphylococcus aureus and Streptococcus species, though it lacks activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. Its gram-negative coverage includes Enterobacteriaceae, Pseudomonas aeruginosa, and many extended-spectrum beta-lactamase (ESBL)-producing organisms, making it particularly valuable for treating serious hospital-acquired infections.

Cefepime’s pharmacokinetic properties contribute to its clinical utility but may also influence its neurotoxic potential. The drug distributes well into various tissues, including cerebrospinal fluid, achieving concentrations that may be therapeutically beneficial for treating central nervous system infections but could potentially contribute to neurological adverse effects. Elimination occurs primarily through renal excretion, with approximately 85% of the administered dose recovered unchanged in urine within 24 hours.

The renal elimination pathway becomes particularly relevant when considering neurotoxicity risk. Patients with impaired kidney function may experience reduced clearance of cefepime, leading to drug accumulation and potentially higher concentrations in the central nervous system. This relationship between renal function and neurotoxicity risk has been consistently observed in clinical studies and case reports.

Beta-lactam antibiotics, including cefepime, can cross the blood-brain barrier to varying degrees. While this penetration may be beneficial for treating central nervous system infections, it also creates the potential for neurological adverse effects. The exact mechanism of cefepime neurotoxicity remains incompletely understood, but several theories have been proposed based on available evidence.

One proposed mechanism involves interference with gamma-aminobutyric acid (GABA) neurotransmission. GABA serves as the primary inhibitory neurotransmitter in the central nervous system, and disruption of GABAergic signaling can lead to neuronal hyperexcitability, seizures, and other neurological symptoms. Some research suggests that cefepime may antagonize GABA receptors or interfere with GABA synthesis or release, though the exact mechanism remains under investigation.

Another potential mechanism involves direct neuronal toxicity or metabolic interference. High concentrations of cefepime in brain tissue might disrupt normal cellular processes, leading to neuronal dysfunction and clinical symptoms. The reversible nature of most cefepime neurotoxicity cases supports the idea that the effects are functional rather than structural, suggesting interference with normal neuronal activity rather than permanent tissue damage.

 

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Clinical Manifestations and Presentation

Cefepime neurotoxicity presents with a diverse range of neurological symptoms that can vary from mild cognitive changes to severe encephalopathy and life-threatening seizures. The clinical presentation often develops within the first few days of treatment, though onset can occur at any time during therapy. Recognition of these symptoms requires a high index of suspicion, as the manifestations may be subtle initially and can be attributed to other causes in critically ill patients.

The most commonly reported neurological symptoms include altered mental status, confusion, and disorientation. Patients may exhibit difficulty with attention and concentration, appearing drowsy or stuporous. Family members and healthcare providers often notice personality changes, agitation, or inappropriate behavior that differs from the patient’s baseline mental state. These cognitive symptoms can range from mild confusion to severe encephalopathy with marked impairment of consciousness.

Seizure activity represents one of the more serious manifestations of cefepime neurotoxicity. Seizures can present as focal or generalized convulsions and may progress to status epilepticus in severe cases. Some patients experience non-convulsive seizures that may be difficult to recognize without electroencephalographic monitoring. The seizure threshold appears to be particularly low in patients with predisposing factors such as renal impairment or underlying neurological conditions.

Motor symptoms have been frequently reported, including tremor, myoclonus, and asterixis. Patients may develop involuntary muscle contractions or jerking movements that can be distressing for both patients and families. These movement disorders typically affect the extremities but can involve facial muscles and other body regions. The severity can range from mild tremor to pronounced myoclonic jerks that interfere with normal activities.

Psychotic symptoms, including hallucinations and delusions, have been documented in some cases of cefepime neurotoxicity. Patients may report visual or auditory hallucinations that can be frightening and contribute to agitation and behavioral changes. Paranoid thoughts and delusional thinking may develop, making patient management challenging and potentially leading to misdiagnosis of primary psychiatric conditions.

Sleep disturbances commonly accompany cefepime neurotoxicity, with patients experiencing altered sleep-wake cycles, insomnia, or excessive daytime sleepiness. These sleep disruptions can exacerbate other neurological symptoms and contribute to overall cognitive impairment. The disruption of normal circadian rhythms may be particularly problematic in hospitalized patients who are already at risk for delirium and sleep disorders.

Headache is another frequently reported symptom, ranging from mild discomfort to severe pain that may resemble migraine or tension-type headaches. The headache may be accompanied by photophobia, nausea, and other associated symptoms that can further complicate the clinical picture.

The temporal relationship between cefepime initiation and symptom onset varies among patients. Some individuals develop symptoms within hours of receiving their first dose, while others may not manifest neurological effects until several days into treatment. The onset pattern may be related to individual patient factors, including renal function, age, and underlying health conditions.

Symptom severity can fluctuate throughout the day, with some patients experiencing worsening of neurological symptoms at certain times. This fluctuation can make assessment challenging and may lead to delayed recognition of drug-related causes. Healthcare providers must maintain awareness that seemingly minor neurological changes in patients receiving cefepime could represent early signs of neurotoxicity.

 

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Risk Factors and Patient Populations

Several patient-related and treatment-related factors have been identified as increasing the risk of developing cefepime neurotoxicity. Understanding these risk factors is essential for healthcare providers to make informed decisions about antibiotic selection and to implement appropriate monitoring strategies for patients at higher risk.

Renal impairment stands as the most consistently identified risk factor for cefepime neurotoxicity. Patients with acute kidney injury or chronic kidney disease demonstrate reduced clearance of cefepime, leading to drug accumulation and higher tissue concentrations. The relationship between renal function and neurotoxicity risk appears to be dose-dependent, with higher degrees of renal impairment associated with greater risk. Even mild reductions in kidney function may increase susceptibility to neurological adverse effects, particularly in elderly patients or those with other risk factors.

Advanced age represents another important risk factor, with elderly patients showing increased susceptibility to cefepime neurotoxicity. Age-related changes in renal function, blood-brain barrier integrity, and neuronal vulnerability may contribute to this increased risk. Elderly patients also tend to have multiple comorbidities and may be receiving other medications that could interact with cefepime or lower the seizure threshold.

Dosing regimens and total daily doses influence neurotoxicity risk. Patients receiving higher doses or more frequent dosing intervals appear to be at greater risk for developing neurological complications. This relationship highlights the importance of appropriate dose adjustment based on renal function and patient characteristics. Standard dosing protocols that do not account for individual patient factors may result in relative overdosing and increased neurotoxicity risk.

Pre-existing neurological conditions may predispose patients to cefepime neurotoxicity. Individuals with a history of seizure disorders, brain tumors, traumatic brain injury, or stroke may have lower thresholds for developing neurological symptoms. The presence of structural brain lesions or disrupted blood-brain barrier function could facilitate cefepime penetration into the central nervous system and increase the likelihood of adverse effects.

Critically ill patients in intensive care settings appear to be at higher risk for cefepime neurotoxicity. The combination of multiple organ dysfunction, altered drug metabolism, and concurrent medications may create conditions that favor the development of neurological complications. Sepsis and systemic inflammation may also alter drug distribution and increase central nervous system permeability.

Patients with electrolyte imbalances, particularly hyponatremia, may be more susceptible to cefepime neurotoxicity. Electrolyte disturbances can affect neuronal excitability and may lower the threshold for seizures and other neurological symptoms. The correction of electrolyte abnormalities may help reduce neurotoxicity risk, though this relationship requires further study.

Duration of treatment appears to influence neurotoxicity risk, with longer courses of cefepime therapy associated with higher rates of neurological complications. However, symptoms can develop early in treatment, indicating that duration alone is not the primary determinant. The cumulative dose and steady-state drug concentrations may be more important factors than treatment duration.

Concurrent use of other medications that affect the central nervous system may increase the risk of cefepime neurotoxicity. Drugs that lower the seizure threshold, impair cognitive function, or interfere with neurotransmitter systems could have additive effects with cefepime. Healthcare providers should carefully review medication lists and consider potential interactions when prescribing cefepime to high-risk patients.

Genetic factors may also play a role in determining individual susceptibility to cefepime neurotoxicity, though this area requires additional research. Variations in drug metabolism enzymes, transporter proteins, or neurotransmitter receptor sensitivity could contribute to interindividual differences in neurotoxicity risk.

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Current Evidence and Research Findings

The body of evidence regarding cefepime neurotoxicity has grown substantially over the past two decades, providing healthcare professionals with increasingly detailed information about this adverse effect. Current research encompasses case reports, case series, observational studies, and systematic reviews that collectively paint a clearer picture of the incidence, risk factors, and clinical impact of cefepime-associated neurological complications.

Large-scale observational studies have attempted to quantify the true incidence of cefepime neurotoxicity in clinical practice. These studies typically report incidence rates ranging from 1% to 15% of patients receiving cefepime, with variation depending on patient population, risk factors, and criteria used to define neurotoxicity. Higher rates are consistently observed in patients with renal impairment, elderly populations, and critically ill patients in intensive care settings.

A systematic review and meta-analysis published in recent years examined data from multiple studies to provide more precise estimates of neurotoxicity incidence. The analysis found that overall rates of neurological adverse events were relatively low in patients with normal renal function but increased substantially in those with kidney dysfunction. The study emphasized the importance of appropriate dose adjustment and monitoring in high-risk populations.

Comparative studies have examined neurotoxicity rates between cefepime and other broad-spectrum antibiotics, such as piperacillin-tazobactam and carbapenems. These comparisons have yielded mixed results, with some studies suggesting higher neurotoxicity rates with cefepime while others found similar or lower rates compared to alternative agents. The variability in findings may reflect differences in patient populations, dosing protocols, and outcome definitions used across studies.

Recent research has focused on identifying specific risk factors and developing predictive models for cefepime neurotoxicity. These studies have confirmed the primary importance of renal function in determining risk while identifying additional factors such as age, concurrent medications, and underlying medical conditions. Some researchers have proposed scoring systems or algorithms to help clinicians identify patients at highest risk for neurological complications.

Pharmacokinetic studies have provided insights into the relationship between cefepime plasma concentrations and neurotoxicity risk. Research suggests that higher plasma levels, particularly in patients with impaired renal clearance, correlate with increased likelihood of neurological symptoms. These findings support the importance of therapeutic drug monitoring in high-risk patients, though routine monitoring is not yet standard practice.

Studies examining the reversibility and long-term outcomes of cefepime neurotoxicity have generally found reassuring results. Most cases resolve completely within days to weeks after discontinuing cefepime or reducing the dose, with few reports of permanent neurological sequelae. However, some patients may experience prolonged recovery, particularly those with severe symptoms or underlying neurological conditions.

Electroencephalographic (EEG) studies in patients with cefepime neurotoxicity have revealed characteristic patterns of abnormal brain activity. Common findings include generalized slowing, epileptiform discharges, and triphasic waves similar to those seen in metabolic encephalopathy. These EEG changes typically resolve as clinical symptoms improve, supporting the functional nature of cefepime-induced neurological effects.

Imaging studies using computed tomography (CT) and magnetic resonance imaging (MRI) in patients with cefepime neurotoxicity typically show normal results, indicating that the neurological effects are not associated with structural brain damage. This finding is consistent with the generally reversible nature of the condition and supports theories about functional interference with neurotransmitter systems rather than direct tissue toxicity.

Animal studies have attempted to elucidate the mechanisms of cefepime neurotoxicity and identify potential protective strategies. These preclinical investigations have provided support for theories involving GABA receptor antagonism and have explored the effects of dose reduction and co-administration of protective agents. While animal data cannot be directly extrapolated to humans, these studies provide valuable insights into potential mechanisms and therapeutic approaches.

Research into genetic factors influencing cefepime neurotoxicity susceptibility remains in early stages, but preliminary findings suggest that individual variations in drug metabolism and receptor sensitivity may contribute to differential risk. Future studies in pharmacogenomics may help identify patients at particularly high or low risk for neurological complications.

Quality improvement studies from healthcare institutions have examined the impact of educational interventions and protocol changes on recognition and management of cefepime neurotoxicity. These studies suggest that increased awareness among healthcare providers can lead to earlier recognition, more appropriate dosing, and better patient outcomes.

 

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Diagnostic Approaches and Assessment

Diagnosing cefepime neurotoxicity presents unique challenges, as the neurological symptoms are nonspecific and can be attributed to various other causes in hospitalized patients. A systematic approach to assessment, combining clinical evaluation with appropriate diagnostic testing, is essential for accurate identification and timely management of this adverse effect.

The diagnostic process begins with maintaining a high index of suspicion in patients receiving cefepime who develop new or worsening neurological symptoms. Healthcare providers must consider cefepime neurotoxicity in the differential diagnosis whenever patients exhibit altered mental status, seizures, or other neurological changes during antibiotic therapy. The temporal relationship between cefepime initiation and symptom onset provides important diagnostic clues, though symptoms can develop at any time during treatment.

Clinical assessment should include a thorough neurological examination to characterize the nature and extent of symptoms. Mental status evaluation should assess orientation, attention, memory, and cognitive function, comparing findings to the patient’s baseline when possible. Motor examination may reveal tremor, myoclonus, asterixis, or other movement disorders characteristic of cefepime neurotoxicity. The presence of focal neurological deficits might suggest alternative diagnoses requiring further investigation.

Laboratory evaluation plays a crucial role in both diagnosis and management of suspected cefepime neurotoxicity. Renal function assessment through serum creatinine and estimated glomerular filtration rate helps determine whether dose adjustment is necessary and provides insight into the likelihood of drug accumulation. Electrolyte panels, particularly sodium levels, can identify contributing factors that may lower the seizure threshold or exacerbate neurological symptoms.

Therapeutic drug monitoring, when available, can provide valuable information about cefepime plasma concentrations and help guide dosing decisions. However, routine monitoring is not widely available, and therapeutic ranges for preventing neurotoxicity have not been definitively established. Research suggests that higher plasma concentrations increase neurotoxicity risk, but individual patient factors also influence susceptibility.

Electroencephalography (EEG) can be particularly useful in evaluating patients with suspected cefepime neurotoxicity, especially those with altered mental status or possible seizure activity. EEG findings in cefepime neurotoxicity often show characteristic patterns of abnormal brain activity, including generalized slowing, triphasic waves, and epileptiform discharges. These changes typically resolve as clinical symptoms improve following cefepime discontinuation or dose reduction.

Neuroimaging studies using CT or MRI are typically normal in patients with cefepime neurotoxicity, but these tests may be necessary to exclude other causes of neurological symptoms. Structural brain lesions, hemorrhage, or evidence of central nervous system infection would suggest alternative diagnoses requiring specific treatment. The absence of structural abnormalities on imaging supports the diagnosis of drug-induced neurotoxicity.

Lumbar puncture and cerebrospinal fluid analysis are generally not necessary for diagnosing cefepime neurotoxicity unless there is clinical suspicion for central nervous system infection or other inflammatory conditions. When performed, cerebrospinal fluid findings are typically normal or show only mild nonspecific changes.

The diagnostic approach must also consider alternative causes of neurological symptoms that are common in hospitalized patients. Metabolic encephalopathy due to organ dysfunction, electrolyte imbalances, or other medications can produce similar symptoms. Sepsis-associated encephalopathy, withdrawal syndromes, and primary neurological conditions must be excluded through appropriate evaluation.

A therapeutic trial involving cefepime discontinuation or dose reduction can provide valuable diagnostic information. Improvement in neurological symptoms following these interventions supports the diagnosis of cefepime neurotoxicity, though the time course of improvement may vary among patients. Some individuals experience rapid resolution of symptoms within hours, while others may require days to weeks for complete recovery.

Documentation of the diagnostic workup and clinical reasoning is essential for patient care and contributes to the medical literature on cefepime neurotoxicity. Detailed case reports help healthcare professionals recognize similar cases and improve diagnostic accuracy. Reporting suspected cases to pharmacovigilance systems also contributes to ongoing safety monitoring efforts.

 

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Management Strategies and Treatment

The management of cefepime neurotoxicity centers on prompt recognition, discontinuation or dose modification of the offending agent, and supportive care tailored to the patient’s specific symptoms and clinical condition. Early intervention typically leads to better outcomes and faster resolution of neurological symptoms.

The most important initial management step involves discontinuing cefepime or reducing the dose based on the severity of symptoms and the underlying infection being treated. For patients with mild neurological symptoms and less serious infections, complete discontinuation may be appropriate with substitution of alternative antimicrobial therapy. In cases where cefepime is considered essential for treating life-threatening infections, dose reduction with close monitoring may be considered.

Dose adjustment should be based on the patient’s renal function, with more aggressive reduction in patients with kidney impairment. Published guidelines provide recommendations for dose modification based on creatinine clearance, but individual patient factors may require further adjustment. Some experts recommend reducing the dose by 50% or more in patients with significant renal dysfunction who develop neurological symptoms.

Alternative antibiotic selection requires consideration of the specific pathogens being treated and local resistance patterns. Piperacillin-tazobactam, carbapenems, or other broad-spectrum agents may provide similar antimicrobial coverage while avoiding continued neurotoxicity risk. The choice of alternative therapy should be guided by culture results when available and institutional antibiogram data.

Supportive care measures focus on managing specific neurological symptoms and preventing complications. Patients with altered mental status require close monitoring and safety precautions to prevent falls and injury. Frequent neurological assessments help track symptom progression and response to treatment interventions.

Seizure management follows standard protocols for treating drug-induced seizures. Benzodiazepines such as lorazepam or diazepam serve as first-line therapy for active seizures, with antiepileptic drugs reserved for refractory cases. The generally self-limited nature of cefepime-induced seizures means that long-term anticonvulsant therapy is usually not necessary, though short-term treatment may be appropriate in some cases.

Agitation and behavioral symptoms may require careful management with sedative medications, though these should be used judiciously to avoid masking neurological changes or contributing to delirium. Non-pharmacological approaches, including environmental modifications and family involvement, can be helpful in managing confused or agitated patients.

Electrolyte correction, particularly normalization of sodium levels, may help reduce neurological symptoms and lower seizure risk. Other metabolic abnormalities should also be addressed as part of the overall management approach. Maintaining adequate hydration while monitoring renal function is important for optimizing drug clearance.

In patients with severe renal impairment, hemodialysis or continuous renal replacement therapy can enhance cefepime elimination and potentially accelerate symptom resolution. However, the decision to initiate dialysis specifically for cefepime removal must be weighed against the risks and benefits of the procedure, considering that most cases resolve with supportive care alone.

Monitoring during recovery involves regular neurological assessments to track symptom improvement and ensure complete resolution. The timeline for recovery varies among patients, with some experiencing rapid improvement within 24-48 hours while others may require several days to weeks for full recovery. Factors that may influence recovery time include the severity of initial symptoms, patient age, renal function, and presence of comorbidities.

Patient and family education about the condition helps reduce anxiety and ensures appropriate follow-up care. Explaining that cefepime neurotoxicity is typically reversible and does not usually cause permanent damage can be reassuring. Patients should be advised to report any worsening or new neurological symptoms promptly.

Documentation in the medical record should include details about the suspected adverse drug reaction, management interventions, and patient response. This information is valuable for future healthcare encounters and helps ensure that cefepime avoidance is noted in allergy lists or medication alerts. Reporting to pharmacovigilance systems contributes to ongoing safety monitoring efforts.

Long-term follow-up is generally not necessary for patients who recover completely from cefepime neurotoxicity. However, patients with prolonged symptoms or underlying neurological conditions may benefit from neurology consultation and continued monitoring. Most patients can safely receive other beta-lactam antibiotics in the future, as cross-reactivity for neurotoxicity appears to be uncommon.

 

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Prevention and Risk Mitigation

Preventing cefepime neurotoxicity requires a proactive approach that combines careful patient selection, appropriate dosing, and vigilant monitoring. Healthcare providers can implement several strategies to minimize the risk of neurological complications while preserving the antimicrobial benefits of cefepime therapy.

Patient risk assessment forms the foundation of prevention efforts. Before prescribing cefepime, clinicians should evaluate individual risk factors, with particular attention to renal function, age, and neurological history. Patients with significant kidney impairment, elderly individuals, and those with previous neurological conditions require especially careful consideration. The risk-benefit analysis should weigh the likelihood of neurotoxicity against the clinical need for cefepime’s specific antimicrobial spectrum.

Dose optimization based on renal function represents one of the most effective prevention strategies. Standard dosing recommendations provide guidance for dose adjustment based on creatinine clearance, but individual patient factors may require further modification. Conservative dosing approaches in high-risk patients can reduce neurotoxicity risk while maintaining therapeutic efficacy. Some experts recommend reducing the standard dose by 25-50% in elderly patients or those with multiple risk factors.

Alternative antibiotic selection should be considered when the risk of neurotoxicity appears elevated. Piperacillin-tazobactam, carbapenems, or other broad-spectrum agents may provide similar antimicrobial coverage with potentially lower neurological risk. The choice among alternatives should consider local resistance patterns, patient allergies, and specific pathogen susceptibilities when known.

Monitoring protocols for patients receiving cefepime can facilitate early detection of neurological symptoms before they become severe. Regular neurological assessments, particularly in high-risk patients, help identify subtle changes that might represent early neurotoxicity. Healthcare providers should be trained to recognize the diverse presentations of cefepime neurotoxicity and maintain a high index of suspicion.

Education initiatives for healthcare providers play a crucial role in prevention efforts. Medical and nursing staff should be aware of cefepime neurotoxicity risk factors, clinical presentations, and management strategies. Educational programs can improve recognition rates and reduce the time to diagnosis and treatment. Regular updates and case discussions help maintain awareness and share clinical experience.

Clinical decision support systems integrated into electronic health records can provide real-time alerts and dosing recommendations. These systems can flag high-risk patients, suggest dose adjustments based on renal function, and remind clinicians to monitor for neurological symptoms. Technology-assisted interventions have shown promise in improving prescribing practices and reducing adverse drug events.

Antimicrobial stewardship programs should incorporate cefepime neurotoxicity considerations into their guidelines and recommendations. Stewardship teams can help ensure appropriate patient selection, optimal dosing, and timely alternative therapy when needed. Regular review of cefepime prescribing patterns can identify opportunities for improvement and risk reduction.

Institutional protocols and guidelines can standardize approaches to cefepime prescribing and monitoring. These protocols should address risk assessment, dose adjustment procedures, monitoring requirements, and management of suspected neurotoxicity. Clear guidelines help ensure consistent practices across different healthcare providers and clinical areas.

Quality improvement initiatives can focus on reducing cefepime neurotoxicity rates through systematic interventions. These efforts might include prescriber education, protocol development, enhanced monitoring procedures, and feedback on prescribing patterns. Tracking neurotoxicity rates and outcomes provides data for ongoing improvement efforts.

Research into predictive biomarkers or genetic factors could eventually enable more precise risk prediction and personalized dosing strategies. While this area remains investigational, future developments may allow for better identification of patients at highest risk for neurological complications.

Patient communication about neurotoxicity risk may be appropriate in some cases, particularly for patients with multiple risk factors or those receiving outpatient therapy. Educating patients and families about potential symptoms can facilitate early recognition and prompt medical attention when needed.

 

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Comparison with Other Antibiotics

Understanding cefepime neurotoxicity requires placing it in the context of neurological adverse effects associated with other antimicrobial agents. This comparison helps healthcare providers make informed decisions about antibiotic selection and understand the relative risks of different therapeutic options.

Other beta-lactam antibiotics, including penicillins and earlier-generation cephalosporins, can also cause neurological adverse effects, though the patterns and incidence may differ from cefepime. High-dose penicillin G, particularly when administered intravenously, has been associated with seizures and encephalopathy, especially in patients with renal impairment or central nervous system pathology. The mechanism appears similar to cefepime, involving interference with GABA neurotransmission.

Piperacillin-tazobactam, a frequently used alternative to cefepime, has also been reported to cause neurological complications, including seizures and altered mental status. Comparative studies examining neurotoxicity rates between cefepime and piperacillin-tazobactam have yielded mixed results, with some suggesting higher rates with cefepime while others found similar or lower incidence. The variation may reflect differences in patient populations, dosing regimens, and diagnostic criteria used across studies.

Carbapenem antibiotics, including meropenem, imipenem, and doripenem, represent another important comparison group. These agents are known to lower seizure threshold and can cause neurological adverse effects, particularly in patients with central nervous system disorders or renal impairment. Imipenem has been associated with the highest seizure risk among carbapenems, leading many clinicians to prefer meropenem or doripenem when treating patients with neurological risk factors.

Fluoroquinolone antibiotics present a different pattern of neurological toxicity, with reports of central nervous system stimulation, confusion, and seizures. The mechanism differs from beta-lactam neurotoxicity, involving interference with GABA receptors through a different pathway. Fluoroquinolones may also cause peripheral neuropathy and other neurological effects not typically seen with cefepime.

Aminoglycoside antibiotics primarily cause ototoxicity and nephrotoxicity rather than central nervous system effects, making them distinct from cefepime in terms of neurological risk. However, their renal toxicity can indirectly increase the risk of neurotoxicity from other agents by impairing drug clearance.

When comparing antimicrobial spectra, cefepime offers advantages in certain clinical situations that must be weighed against neurotoxicity risk. Its activity against Pseudomonas aeruginosa and many ESBL-producing organisms makes it particularly valuable for treating hospital-acquired infections. Alternative agents may not provide equivalent coverage, potentially compromising treatment effectiveness.

The reversibility of neurological effects appears similar across different beta-lactam antibiotics, with most cases resolving after drug discontinuation or dose reduction. However, the time course of recovery may vary, and some agents may be associated with more prolonged symptoms than others.

Dosing frequency and administration routes may influence the comparative risk of neurotoxicity. Cefepime is typically administered every 8-12 hours, while some alternatives require more frequent dosing or continuous infusion. The pharmacokinetic differences among agents may affect peak concentrations and duration of exposure, potentially influencing neurological risk.

Cost considerations also enter into antibiotic selection decisions, as newer or brand-name alternatives to cefepime may be more expensive. Healthcare systems must balance clinical effectiveness, safety profiles, and economic factors when developing prescribing guidelines and formulary decisions.

Resistance patterns in local healthcare environments significantly influence antibiotic selection choices. In settings with high rates of ESBL-producing organisms or carbapenem-resistant bacteria, cefepime may remain an important therapeutic option despite neurotoxicity concerns. The availability of effective alternatives varies based on local resistance epidemiology.

 

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Regulatory Perspectives and Guidelines

Regulatory agencies worldwide have addressed cefepime neurotoxicity through various mechanisms, including label updates, safety communications, and prescribing guidance. The Food and Drug Administration (FDA) and European Medicines Agency (EMA) have both acknowledged neurological risks associated with cefepime and provided recommendations for healthcare providers.

The FDA initially approved cefepime in 1996, and the prescribing information has been updated multiple times to include neurological adverse effects. Current labeling includes warnings about central nervous system adverse reactions, particularly in patients with renal impairment. The label emphasizes the importance of dose adjustment based on kidney function and monitoring for neurological symptoms.

In 2007, the FDA conducted a comprehensive review of cefepime safety following concerns about increased mortality rates in clinical trials. While this review focused primarily on mortality rather than neurotoxicity, it led to enhanced scrutiny of cefepime’s safety profile and reinforced the importance of appropriate prescribing practices.

European regulatory authorities have also addressed cefepime neurotoxicity in their prescribing guidance. The European Summary of Product Characteristics includes detailed information about neurological adverse effects and provides specific recommendations for dose adjustment in patients with renal impairment. The guidance emphasizes the need for careful monitoring and prompt recognition of neurological symptoms.

Professional medical societies and organizations have incorporated cefepime neurotoxicity considerations into their clinical practice guidelines. The Infectious Diseases Society of America (IDSA) and other specialty organizations acknowledge neurological risks in their antimicrobial prescribing recommendations, particularly for high-risk patient populations.

Pharmacovigilance systems continue to monitor cefepime safety through spontaneous adverse event reporting and periodic safety reviews. Healthcare providers are encouraged to report suspected cases of cefepime neurotoxicity to help maintain accurate safety databases and identify potential new risk factors or patient populations.

International drug regulatory harmonization efforts have worked to ensure consistent safety information and prescribing guidance across different countries and regions. This coordination helps provide healthcare providers with reliable, evidence-based information about cefepime neurotoxicity regardless of their geographic location.

The World Health Organization (WHO) includes cefepime on its Essential Medicines List, recognizing its importance in treating serious bacterial infections. However, the WHO also acknowledges safety considerations and emphasizes the need for appropriate prescribing practices and monitoring.

Regulatory agencies continue to evaluate new evidence about cefepime neurotoxicity as it becomes available. Emerging research findings may lead to further label updates or additional safety communications to ensure healthcare providers have current information for clinical decision-making.

The regulatory approach to cefepime neurotoxicity reflects a balance between acknowledging legitimate safety concerns while preserving access to an important antimicrobial agent. Rather than restricting use, agencies have focused on education, appropriate prescribing guidance, and enhanced monitoring recommendations.

Future regulatory actions may incorporate advances in personalized medicine, such as pharmacogenomic testing or biomarker-based risk prediction, as these technologies become more established. The goal remains ensuring optimal patient outcomes through informed prescribing decisions and appropriate risk management strategies.

 

 

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Future Directions and Research Needs

The field of cefepime neurotoxicity research continues to evolve, with several important areas requiring further investigation to improve patient care and clinical decision-making. Future research efforts should focus on better understanding mechanisms, improving risk prediction, and developing optimal management strategies.

Mechanistic studies remain a priority for understanding how cefepime causes neurological adverse effects. While theories about GABA receptor interference and direct neuronal toxicity have been proposed, the exact mechanisms require further elucidation. Advanced laboratory techniques, including molecular pharmacology and neurobiology approaches, may provide insights into cellular and molecular targets.

Pharmacokinetic and pharmacodynamic research should focus on defining therapeutic ranges that optimize antimicrobial efficacy while minimizing neurotoxicity risk. Current dosing recommendations are based primarily on antimicrobial effectiveness, with safety considerations applied secondarily. Integrated approaches that simultaneously consider efficacy and toxicity endpoints could lead to improved dosing strategies.

Predictive modeling and risk stratification tools represent important areas for development. Current risk factors are generally qualitative, but quantitative models that incorporate multiple patient variables could provide more precise risk estimates. Machine learning and artificial intelligence approaches may help identify complex patterns and interactions that influence neurotoxicity susceptibility.

Biomarker research could identify laboratory tests or other objective measures that predict neurotoxicity risk or detect early neurological effects before clinical symptoms become apparent. Blood-based biomarkers, cerebrospinal fluid analysis, or neurophysiological testing might provide earlier warning of developing neurotoxicity.

Genetic studies examining pharmacogenomic factors influencing cefepime neurotoxicity susceptibility could enable personalized prescribing approaches. Variations in drug metabolism enzymes, transporter proteins, or neurotransmitter receptors might explain individual differences in neurotoxicity risk. Large-scale genomic studies would be needed to identify relevant genetic variants.

Comparative effectiveness research should continue examining neurotoxicity rates among different antimicrobial agents in various patient populations and clinical settings. Head-to-head comparisons using standardized outcome measures would provide clearer guidance for antibiotic selection decisions. Real-world evidence studies using electronic health record data could provide large-scale safety comparisons.

Long-term outcome studies should examine whether cefepime neurotoxicity has any lasting effects on cognitive function or neurological health. While most cases appear to resolve completely, systematic follow-up studies have not been conducted to rule out subtle long-term consequences. Neuropsychological testing and imaging studies could provide more detailed outcome assessments.

Prevention strategy research should evaluate the effectiveness of different approaches to reducing neurotoxicity rates. Clinical trials testing alternative dosing regimens, monitoring protocols, or risk mitigation strategies could provide evidence for optimal prevention approaches. Quality improvement studies can also contribute valuable information about effective prevention interventions.

Therapeutic drug monitoring research should establish target concentrations and monitoring strategies for patients at high risk for neurotoxicity. Current therapeutic drug monitoring for cefepime is not routine, but defined target ranges and monitoring protocols could improve safety in high-risk patients.

Technology development, including clinical decision support systems and mobile health applications, could enhance recognition and management of cefepime neurotoxicity. These tools might provide real-time risk assessment, dosing recommendations, and monitoring reminders to healthcare providers.

Pediatric research represents an important gap, as most neurotoxicity data comes from adult populations. Children may have different susceptibility patterns and require age-specific dosing and monitoring recommendations. Dedicated pediatric studies would help optimize cefepime use in younger patients.

Global health perspectives should examine cefepime neurotoxicity in diverse populations and healthcare settings worldwide. Most current evidence comes from developed countries with advanced healthcare systems, but the risk-benefit balance may differ in resource-limited settings with different disease patterns and healthcare capabilities.

 

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Applications and Use Cases

Cefepime remains an important antimicrobial agent in various clinical scenarios, and understanding its neurotoxicity risk helps healthcare providers make informed decisions about its appropriate use. Different clinical applications present varying risk-benefit considerations that influence prescribing decisions.

Hospital-acquired pneumonia represents one of the primary indications for cefepime therapy, particularly in critically ill patients or those with risk factors for resistant organisms. The drug’s activity against Pseudomonas aeruginosa and other hospital pathogens makes it valuable in this setting. However, many patients with hospital-acquired pneumonia have risk factors for neurotoxicity, including advanced age, renal impairment, and critical illness. Careful dose adjustment and monitoring are essential in these cases.

Intra-abdominal infections often require broad-spectrum antimicrobial coverage, and cefepime may be selected for its gram-negative activity. Combination therapy with metronidazole or other anaerobic coverage is typically necessary. Patients with complicated intra-abdominal infections may have acute kidney injury or other risk factors that increase neurotoxicity susceptibility.

Urinary tract infections, particularly complicated cases or those involving resistant organisms, may warrant cefepime therapy. The drug achieves high urinary concentrations and maintains activity against many ESBL-producing Enterobacteriaceae. However, patients with urinary tract infections often have underlying kidney disease, requiring careful attention to dosing and monitoring.

Febrile neutropenia in cancer patients represents another important application for cefepime. These immunocompromised patients require prompt, effective antimicrobial therapy for potentially life-threatening infections. The benefits of cefepime may outweigh neurotoxicity risks in this population, though monitoring remains important, particularly in patients receiving concurrent chemotherapy that may affect renal function.

Skin and soft tissue infections caused by gram-negative bacteria may require cefepime therapy when other agents are ineffective or contraindicated. These infections are often less immediately life-threatening than pneumonia or sepsis, potentially allowing for more conservative antibiotic selection if neurotoxicity risk is elevated.

Sepsis and septic shock patients often receive cefepime as part of empirical broad-spectrum therapy. The critical nature of these infections may justify accepting higher neurotoxicity risk, but close monitoring is essential as these patients frequently have multiple organ dysfunction that could predispose to neurological complications.

Central nervous system infections present a unique situation where cefepime’s ability to penetrate the blood-brain barrier may be beneficial for treating bacterial meningitis or brain abscesses. However, the same property that enables therapeutic CNS penetration may also increase neurotoxicity risk. Careful consideration of alternative agents and close monitoring are particularly important in this setting.

Outpatient parenteral antimicrobial therapy (OPAT) programs sometimes use cefepime for patients who require extended courses of intravenous antibiotics. The neurotoxicity risk may be of particular concern in this setting, as patients are not under continuous hospital observation. Careful patient selection, family education, and regular monitoring are essential for safe outpatient use.

Pediatric applications of cefepime require special consideration of age-specific factors that may influence neurotoxicity risk. Children may have different pharmacokinetic properties and neurological susceptibility compared to adults. Limited pediatric safety data makes careful risk-benefit assessment particularly important in younger patients.

Elderly patients represent a population where cefepime neurotoxicity concerns are heightened due to age-related risk factors. However, this population also has high rates of serious bacterial infections that may require effective antimicrobial therapy. Careful dose adjustment and enhanced monitoring can help balance efficacy and safety considerations.

Patients with chronic kidney disease present ongoing challenges for cefepime prescribing, as reduced renal clearance increases neurotoxicity risk while chronic infections may require effective antimicrobial therapy. These patients often require marked dose reduction and careful monitoring throughout treatment.

 

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Challenges and Limitations

Several challenges and limitations affect our understanding and management of cefepime neurotoxicity, influencing both clinical practice and research efforts. Recognizing these limitations is essential for appropriate interpretation of available evidence and identification of areas requiring further investigation.

Underdiagnosis and underreporting represent major challenges in determining the true incidence and clinical impact of cefepime neurotoxicity. Neurological symptoms in hospitalized patients are common and often attributed to other causes such as sepsis, metabolic disturbances, or underlying medical conditions. Healthcare providers may not consider drug-induced causes, particularly for mild or nonspecific symptoms that could represent early neurotoxicity.

The lack of standardized diagnostic criteria for cefepime neurotoxicity complicates both clinical recognition and research efforts. Different studies and clinical reports use varying definitions of neurotoxicity, making it difficult to compare incidence rates and risk factors across different populations. The absence of specific biomarkers or diagnostic tests further complicates accurate diagnosis.

Attribution of neurological symptoms to cefepime can be challenging in critically ill patients who often have multiple potential causes for altered mental status or seizures. Sepsis, organ dysfunction, electrolyte abnormalities, and other medications can all produce similar neurological effects, making definitive attribution difficult without clear temporal relationships and response to drug discontinuation.

The reversible nature of most cefepime neurotoxicity cases, while generally reassuring, can also contribute to underrecognition. Mild symptoms that resolve spontaneously may not be reported or investigated thoroughly, leading to missed opportunities for learning and prevention. Healthcare providers may not recognize the relationship between cefepime and neurological symptoms if improvement occurs without specific intervention.

Limited availability of therapeutic drug monitoring for cefepime restricts the ability to correlate plasma concentrations with neurotoxicity risk in clinical practice. While research studies have suggested relationships between drug levels and neurological effects, routine monitoring is not widely available, limiting personalized dosing approaches.

Research limitations include the predominance of case reports and observational studies rather than controlled clinical trials. Randomized controlled trials specifically examining neurotoxicity are ethically challenging and practically difficult to conduct. Most evidence comes from retrospective analyses and case series that may be subject to selection bias and incomplete data collection.

The heterogeneity of patient populations and clinical settings makes it difficult to develop universally applicable risk prediction models or prevention strategies. Factors that influence neurotoxicity risk may vary significantly between different healthcare environments, patient demographics, and clinical indications for cefepime use.

Regulatory and legal considerations may influence reporting and recognition of cefepime neurotoxicity. Healthcare providers may be reluctant to document suspected adverse drug reactions due to concerns about liability or quality metrics. This hesitancy can contribute to underreporting and limit opportunities for learning from clinical experience.

Educational gaps among healthcare providers represent another important limitation. Many clinicians may not be aware of cefepime neurotoxicity risk factors, clinical presentations, or management strategies. Medical and nursing education programs may not adequately address drug-induced neurological complications, leading to knowledge deficits in clinical practice.

Economic pressures and formulary considerations may influence antibiotic selection decisions in ways that don’t optimally balance efficacy and safety. Cost considerations or institutional preferences may lead to continued use of cefepime in high-risk patients when safer alternatives might be available.

Cultural and linguistic barriers can affect recognition of neurological symptoms in diverse patient populations. Subtle changes in mental status or cognitive function may be particularly difficult to assess in patients with limited English proficiency or different cultural expressions of distress.

The complexity of modern healthcare, with multiple specialists and care transitions, can fragment responsibility for monitoring and recognizing adverse drug reactions. Patients may be cared for by different teams during their hospitalization, potentially leading to discontinuity in assessment and management of drug-related complications.

Technology limitations in electronic health records and clinical decision support systems may not adequately flag high-risk patients or provide appropriate dosing recommendations. Many systems lack sophisticated clinical decision support for complex dosing adjustments or risk assessment algorithms.

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Conclusion   

Key Takeaways

The evidence regarding cefepime neurotoxicity presents a complex picture that requires healthcare providers to balance proven antimicrobial benefits against potential neurological risks. Several key points emerge from the current literature and clinical experience that can guide clinical decision-making and patient care.

Cefepime neurotoxicity is a real clinical entity that can cause serious neurological complications, including seizures, encephalopathy, and altered mental status. However, the overall incidence remains relatively low in appropriately selected patients, and most cases are reversible with prompt recognition and management. The condition should be considered an important but manageable risk rather than a contraindication to cefepime use.

Risk factors for neurotoxicity are well-established, with renal impairment being the most important predictor. Advanced age, high doses, and underlying neurological conditions also increase risk. Healthcare providers can use these risk factors to identify patients who require more careful monitoring or consideration of alternative antimicrobial agents.

Appropriate dosing based on renal function represents the most effective prevention strategy. Current dosing recommendations provide guidance for dose adjustment, but individual patient factors may require further modification. Conservative dosing approaches in high-risk patients can reduce neurotoxicity risk while maintaining therapeutic efficacy.

Early recognition and prompt management lead to better outcomes and faster symptom resolution. Healthcare providers should maintain awareness of cefepime neurotoxicity presentations and consider this diagnosis in patients who develop neurological symptoms during treatment. Most cases resolve completely within days to weeks after drug discontinuation or dose reduction.

The risk-benefit analysis for cefepime use must consider the specific clinical situation, patient risk factors, and availability of alternative agents. In life-threatening infections where cefepime provides optimal antimicrobial coverage, the benefits may justify accepting higher neurotoxicity risk with enhanced monitoring. For less serious infections in high-risk patients, alternative agents should be strongly considered.

Education and awareness among healthcare providers remain crucial for optimal management of cefepime neurotoxicity risk. Regular educational programs, clinical guidelines, and decision support tools can help ensure appropriate prescribing practices and early recognition of neurological complications.

Future research should focus on improving risk prediction, understanding mechanisms, and developing optimal prevention and management strategies. Advances in personalized medicine may eventually enable more precise risk assessment and tailored dosing approaches.

The regulatory and clinical communities have appropriately balanced acknowledging legitimate safety concerns while preserving access to an important antimicrobial agent. Current approaches emphasize education, appropriate prescribing guidance, and enhanced monitoring rather than restrictive use limitations.

 

Frequently Asked Questions:   

FAQ Section

Q: How common is cefepime neurotoxicity?

A: The incidence of cefepime neurotoxicity varies depending on the patient population and risk factors, typically ranging from 1-15% of patients receiving the drug. Rates are higher in patients with renal impairment, elderly individuals, and critically ill patients. Most patients receiving appropriate doses with normal kidney function do not experience neurological complications.

Q: What are the early warning signs of cefepime neurotoxicity?

A: Early signs may include mild confusion, difficulty concentrating, changes in personality or behavior, and mild tremor. More severe symptoms can include altered mental status, seizures, hallucinations, and pronounced movement disorders. Healthcare providers and patients should be alert to any new neurological symptoms that develop during cefepime treatment.

Q: Is cefepime neurotoxicity permanent?

A: No, cefepime neurotoxicity is typically reversible. Most patients experience complete resolution of symptoms within days to weeks after discontinuing cefepime or reducing the dose. Permanent neurological damage is extremely rare, though recovery time may be longer in some patients, particularly those with severe symptoms or underlying health conditions.

Q: Who is at highest risk for developing cefepime neurotoxicity?

A: Patients at highest risk include those with kidney disease or acute kidney injury, elderly individuals, patients receiving high doses or prolonged treatment, those with underlying neurological conditions, and critically ill patients. The presence of multiple risk factors increases the likelihood of developing neurological complications.

Q: Can patients safely receive other antibiotics if they develop cefepime neurotoxicity?

A: Yes, most patients can safely receive other antibiotics, including other beta-lactam agents. Cross-reactivity for neurotoxicity between different antibiotics appears to be uncommon. However, healthcare providers should document the adverse reaction and consider it when selecting future antimicrobial therapy.

Q: Should cefepime be avoided in elderly patients?

A: Cefepime is not contraindicated in elderly patients, but it should be used more cautiously with appropriate dose adjustment and enhanced monitoring. Age alone is not a reason to avoid cefepime if it is the most appropriate antibiotic for treating a particular infection. The risk-benefit analysis should consider the severity of infection and availability of alternatives.

Q: How should cefepime doses be adjusted in patients with kidney disease?

A: Dose adjustment should be based on the patient’s estimated glomerular filtration rate or creatinine clearance, following published guidelines. Patients with moderate to severe kidney impairment typically require dose reductions of 50% or more. Some high-risk patients may benefit from even more conservative dosing approaches.

Q: What should patients and families know about cefepime neurotoxicity?

A: Patients and families should be aware that neurological side effects can occur but are usually reversible. They should report any new confusion, behavioral changes, tremor, or other neurological symptoms promptly to healthcare providers. Understanding that the condition is typically temporary can help reduce anxiety if symptoms develop.

Q: Are there any tests that can predict who will develop cefepime neurotoxicity?

A: Currently, there are no specific tests that can definitively predict who will develop neurotoxicity. Risk assessment is based on clinical factors such as kidney function, age, and medical history. Research into biomarkers and genetic factors may eventually provide better predictive tools.

Q: When should cefepime be discontinued if neurotoxicity is suspected?

A: The decision to discontinue cefepime depends on the severity of symptoms and the importance of continued treatment for the underlying infection. Mild symptoms in patients with less serious infections may warrant immediate discontinuation, while patients with life-threatening infections might continue treatment with dose reduction and close monitoring. This decision requires careful medical judgment and individual assessment.

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References:  

1. Appa, A. A., Jain, R., Rakita, R. M., Hakimian, S., & Sandoval, M. (2017). Characterizing cefepime neurotoxicity: A systematic review. Open Forum Infectious Diseases, 4(4), ofx170.
2. Boschung-Pasquier, L., Atkinson, A., Kastner, L. K., Banholzer, S., Haschke, M., Buetti, N., … & Furrer, D. I. (2020). Cefepime neurotoxicity: Thresholds and risk factors. A retrospective cohort study. Clinical Microbiology and Infection, 26(3), 333-339.
3. Dakdouki, G. K., & Al-Awar, G. N. (2004). Cefepime-induced encephalopathy. International Journal of Infectious Diseases, 8(1), 59-61.
4. Fugate, J. E., Kalimullah, E. A., Hocker, S. E., Clark, S. L., Wijdicks, E. F., & Rabinstein, A. A. (2013). Cefepime neurotoxicity in the intensive care unit: A cause of severe, underappreciated encephalopathy. Critical Care, 17(6), R264.
5. Grill, M. F., & Maganti, R. K. (2011). Neurotoxic effects associated with antibiotic use: Management considerations. British Journal of Clinical Pharmacology, 72(3), 381-393.
6. Huber, M., Raglio, A., Gasperini, S., Zecca, M., & Merlini, G. (2007). Cefepime-induced hyperexcitability and non-convulsive status epilepticus. Journal of Clinical Pharmacy and Therapeutics, 32(1), 87-91.
7. Jallon, P., Fankhauser, L., Du Pasquier, R., Coeytaux, A., Picard, F., Hefft, S., & Assal, F. (2000). Severe but reversible encephalopathy associated with cefepime. Neurophysiologie Clinique, 30(6), 383-386.
8. Kim, B. H., Choi, E. J., Jun, E. J., Kim, Y. K., Hwang, J. H., Kim, J. Y., … & Kim, H. J. (2019). Risk factors associated with cefepime-induced neurotoxicity. Journal of Antimicrobial Chemotherapy, 74(8), 2427-2435.
9. Lamoth, F., Buclin, T., Pascual, A., Vora, S., Bolay, S., Decosterd, L. A., … & Marchetti, O. (2010). High cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients with mild impairment of renal function. Antimicrobial Agents and Chemotherapy, 54(10), 4360-4367.
10. Lachaine, J., Beauchemin, C., & Landry, P. A. (2010). An economic evaluation of cefepime and ceftazidime in the treatment of severe nosocomial pneumonia and complicated intra-abdominal infections in Canada. Canadian Journal of Infectious Diseases and Medical Microbiology, 21(1), 33-40.
11. Maganti, R., Jolin, D., Rishi, D., & Biswas, A. (2005). Nonconvulsive status epilepticus due to cefepime in a patient with normal renal function. Epilepsy & Behavior, 6(2), 312-314.
12. Payne, L. E., Gagnon, D. J., Riker, R. R., Seder, D. B., Glisic, E. K., Morris, J. G., & Fraser, G. L. (2017). Cefepime-induced neurotoxicity: A systematic review. Critical Care, 21(1), 276.
13. Tam, V. H., McKinnon, P. S., Akins, R. L., Rybak, M. J., & Drusano, G. L. (2003). Pharmacokinetics and pharmacodynamics of cefepime in patients with various degrees of renal function. Antimicrobial Agents and Chemotherapy, 47(6), 1853-1861.
14. Thorpe, K. E., Joski, P., & Johnston, K. J. (2018). Antibiotic-resistant infection treatment costs have doubled since 2002, now exceeding $2 billion annually. Health Affairs, 37(4), 662-669.
15. Yahav, D., Paul, M., Fraser, A., Sarid, N., & Leibovici, L. (2007). Efficacy and safety of cefepime: A systematic review and meta-analysis. The Lancet Infectious Diseases, 7(5), 338-348.

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