Cefepime Neurotoxicity in Patients With Normal Renal Function: An Overlooked Cause of Encephalopathy in the Intensive Care Unit

Abstract

Cefepime is a fourth-generation cephalosporin with extended antimicrobial coverage. Concerns have been raised about the side effects of cefepime including myoclonus, encephalopathy, and seizures, especially when renal impairment is present. There have been reports of cases of adverse neurological consequences despite appropriate renal adjustment. Here, we present a case of a 69-year-old patient initially diagnosed with pneumonia and treated with cefepime. The patient later developed altered mental status, leading to differential diagnoses including stroke, drug overdose, or non-convulsive seizures. Following a comprehensive workup, it was determined that she had cefepime-induced encephalopathy, despite having normal kidney function, which resolved completely after discontinuing the medication. In addition, we include similar cases retrieved from PubMed up to the present date, to the best of our knowledge.

Introduction

Encephalopathy is acute onset central nervous system dysfunction without underlying cerebral disease. Identifying the etiology of encephalopathy in the hospital setting can be difficult due to a wide range of potential causes, especially without risk factors. ¹ Cefepime-induced encephalopathy (CIE) is an underappreciated cause, with an incidence of up to 15% in intensive care unit (ICU) patients. ² Numerous reports have documented the potential for cefepime to affect neurological status, yet awareness of this association remains limited. Diagnosing cefepime-induced neurotoxicity (CIN) can be particularly challenging, especially in critically ill patients with a myriad of symptoms. ²

This case describes a patient with normal renal function who developed CIE. This challenges the assumption that CIE exclusively affects those with renal impairment. There are infrequent reports of CIE in patients with normal renal function (Table 1).

Table 1.

Previous Reports of Cefepime-Induced Neurotoxicity in Patients With Normal Renal Function.

Year	Age/gender	Time to symptoms onset (days)	Dose of cefepime	Symptoms	Use of antiseizure medications	Outcome
2017 3	57/F	10	2 g q8h	AMS, non-convulsive status epilepticus, GCS 7	Yes	Full recovery after 4 days
2001 4	65/M	12	2 g q24h	Non-convulsive status epilepticus	None documented	Unclear neurologic outcome
2001 4	75/M	15	2 g q24h	AMS, generalized myoclonus	None documented	Unclear neurologic outcome
2001 4	71/M	3	2 g q12h	AMS, asterixis, seizure-like activity on EEG	None documented	Full recovery within 2 days of cefepime withdrawal
2011 5	70/F	4	Unspecified	AMS, myokymia, non-convulsive status epilepticus	Yes	Improvement of neurologic status within 24 hours of cefepime cessation, return to baseline after 3 days
2022 6	16/F	3	1630 mg q8h	AMS, twitches, horizontal nystagmus, non-convulsive status epilepticus	Yes	Disappearance of seizure-like activity on EEG and return to baseline neurologic function within 2 days of cefepime withdrawal
2023 7	95/F	3	2 g q8h	AMS, global aphasia, seizure-like activity on EEG	Yes	Minimal neurologic improvement following cefepime withdrawal, transition to hospice care, death within 3 weeks of admission
2021 8	86/F	4	Unspecified	Negative myoclonus without AMS	None documented	Initial improvement of neurologic status within 24 hours of cefepime withdrawal, full resolution of symptoms within 4 days

AMS: altered mental status, GCS: Glasgow Coma Scale, EEG: electroencephalogram, q: every, h: hour.

Case Presentation

A 69-year-old female presented with a 1-week history of fever and worsening cough. Her past medical history was significant for atrial fibrillation managed with apixaban and chronic pain syndrome treated with oxycodone. She was initially diagnosed with pneumonia and treated with azithromycin and cefdinir. Owing to worsening condition, including tachypnea at 40 cycles/minute and desaturation to 80% on room air necessitating non-invasive ventilation, she was admitted to the intensive care unit for treatment. Chest imaging confirmed pneumonia without complications. Initial treatment with ceftriaxone was switched to cefepime upon detecting Pseudomonas aeruginosa in sputum culture. However, 4 days later, she developed neurological deficits including confusion, aphasia, and anisocoria, prompting concern for a potential stroke. Neuroimaging including computed tomography (CT) head and magnetic resonance imaging (MRI) brain ruled out acute pathology. Another potential consideration was opioid toxicity from oxycodone used for musculoskeletal chest pain. However, intravenous administration of naloxone did not result in any improvement.

Laboratory investigations of a comprehensive metabolic panel, ammonia, thyroid-stimulating hormone (TSH), and arterial blood gases revealed no metabolic abnormality. The glomerular filtration rate (GFR) at this time was 70 mL/min/1.73 m². White blood cell (WBC) trended down from 24 × 10⁹/L at the time of admission to 10 × 10⁹/L. Owing to concerns of non-convulsive seizures, an electroencephalogram (EEG) was performed and showed triphasic waves highly suspicious with medication toxicity, likely cefepime. At that time, she completed a 7-day course of cefepime which was discontinued. Cessation of cefepime led to gradual improvement, with the patient regaining consciousness and experiencing significant recovery within 3 days, and subsequently, she was discharged home.

Discussion

Cefepime, a fourth-generation cephalosporin with extended-spectrum activity, is used for managing mild and severe infections and febrile neutropenia. Its metabolism primarily occurs in the liver, but its elimination mainly occurs through renal pathways. In individuals with a GFR of less than 10 mL/min, the half-life of cefepime is approximately 5 times longer compared to those with normal renal function. ¹

Cefepime’s potential for neurologic complications, particularly seizures, has received recent attention. In June 2012, the US Food and Drug Administration reminded clinicians to adjust cefepime doses in renal-impaired patients due to the risk of seizures, including non-convulsive status epilepticus (NCSE). The report emphasized seizure activity, a concerning adverse event. Between its approval in 1996 and February 2012, 59 cases of NCSE were reported following the use of cefepime. These cases included ongoing seizures, which contributed to at least 1 patient’s death. In some cases, discussions about withdrawing life-sustaining measures had occurred due to the severity of their condition. Among these 59 patients, 58 had some degree of renal impairment.^3,9

The mechanism of CIN is associated with the antagonism of the effect of γ-aminobutyric acid (GABA) by binding to it. Cefepime’s ability to cross the blood-brain barrier allows it to interfere with the inhibitory neurotransmission mechanism in the brain, resulting in a range of symptoms, as mentioned previously. The renal elimination of cefepime renders patients with renal dysfunction susceptible to higher plasma concentrations of the drug, thus serving as a predisposing factor for neurotoxicity. The exact mechanism is yet to be completely understood.^2,10

Risk factors for CIN are numerous, as shown in Table 2, with renal impairment being the most associated. Renal impairment reduces the clearance of cefepime, leading to drug accumulation in the body and increasing susceptibility to neurotoxicity.^2,11 Even with renal dose adjustments, cefepime demonstrates notable adverse effects. In 2013, Fugate et al. assessed 100 intensive care unit patients for neurotoxicity, identifying 15 likely cases of CIE and 7 definite cases. Remarkably, 4 of these patients had their cefepime doses adjusted for renal function yet still encountered CIN. ⁹ However, it is important to note that CIN can occur in patients with normal renal function ¹² , as in our case.

Table 2.

Features of CIN.

Risk factors	Clinical presentation	EEG patterns	Management
- Renal impairment - Advanced age - Critical illness - Overdose - Altered blood-brain barrier	Altered mental status Myoclonus Aphasia Agitation Seizures	Tri-phasic waves Generalized slowing Multifocal sharp waves non-convulsive seizures Myoclonus	Cefepime discontinuation Cefepime-free interval with dose reduction Hemodialysis Benzodiazepine

CIN: cefepime-induced neurotoxicity, EEG: electroencephalogram.

In our data analysis, there were 8 cases in which patients did not have any documented renal injury, consistent with previous literature reviews indicating that CIN can occur even in the absence of kidney injury. This aligns with our case, wherein our patient had normal renal function, emphasizing that renal impairment is not requirement to develop CIN. This observation highlights the need for clinicians to maintain a high index of suspicion for CIN in patients receiving cefepime therapy, irrespective of their renal status, and to promptly recognize and manage neurotoxic symptoms.

Diagnosis of CIN may be suggested by the onset of neurological symptoms within a range of 2 to 15 days after the initiation of cefepime therapy, with a median time of 4 days a few days after initiation of cefepime therapy, EEG abnormalities, exclusion of other toxic or metabolic causes of encephalopathy, resolution of symptoms and EEG abnormalities following discontinuation of the drug, and abnormally elevated drug levels. Table 2 refers to the features of CIN.^2,13,14 Common symptoms observed in our analysis include altered mental status, abnormal motor movements, myokymia, aphasia, and seizure-like activity.

Age and clinical presentation of CIN can vary significantly. In a systematic review conducted by Ajibola et al., it was observed that patients aged 65 and older accounted for more than 50% of the cases, suggesting a strong association between neurotoxicity caused by cefepime and older age; however, CIN can even affect pediatrics.^15,16 In a retrospective study by Appa et al., which included 198 patients, it was noted that a decreased level of consciousness was the most prevalent clinical feature, affecting 80% of the patients. This was followed by disorientation, which was observed in 47% of cases, and myoclonus which was observed in 40%. Seizures, including both convulsive and non-convulsive types, were also common, with incidences of 11% and 31%, respectively. ¹⁷ In our review of the available case reports, the age at presentation ranged between 57 and 95 years with only 1 reported case at the age of 16, with most cases clustered around 70 years old. Cefepime-induced neurotoxicity affected both genders, with a slight predominance for females. Patients developed symptoms within a range of 3 to 15 days after initiation of cefepime, with most cases occurring around the fourth day post-initiation.

Cefepime-induced neurotoxicity has been observed in patients with normal renal function, as shown in Table 2, emphasizing the importance of vigilance regardless of renal function. In this study, a patient with normal renal function developed neurotoxicity attributed to cefepime use. Differential diagnoses included infectious, metabolic, and neurological causes of encephalopathy. lectroencephalography revealed diffuse slowing with triphasic waves, consistent with previous studies. ¹⁸ Despite a thorough workup, no alternative etiology was identified, and full neurological recovery occurred within 72 hours of discontinuing cefepime. These results highlight the importance of considering alternative antibiotics in cases of acute confusion associated with cefepime use when other causes have been ruled out.

In addition, a retrospective cohort study conducted for 4 years compared the effect of neurotoxicity caused by cefepime between low-dose and high-dose cefepime. Interestingly, the study found no difference in incidence between high-dose and low-dose cefepime in patients with renal dysfunction. ¹⁹ On the contrary, Boshung et al. discovered a notable difference in their retrospective study involving nearly 600 patients. Their findings have shown a statistically significant association between higher plasma cefepime trough levels and the risk of neurotoxicity. ²⁰ In our analysis, patients received cefepime dosages ranging from 2 to 6 g per day, administered at frequencies varying from every 8 to every 48 hours. Interestingly, some patients developed CIN at lower dosages, which aligns with previous findings, suggesting no significant difference in incidence across dosage levels, as previously reported. ¹⁹

Cefepime-induced neurotoxicity typically resolves within 2 days of discontinuation, as reported by Payne et al. In their review of 135 cases, symptoms improved following interventions such as discontinuation of the drug or administration of antiepileptic medications in cases involving seizures. However, it is important to note that symptoms may not always be resolved, as evidenced by 11 patient cases, 4 of which received antiepileptics yet did not experience symptom resolution. ² As noted earlier in our analysis, most of the patients experienced resolution of symptoms within 1 to 4 days of drug cessation and/or administering seizure medications. It is worth highlighting that all patients showed overall symptom improvement. However, it is crucial to acknowledge that 1 case experienced death, which may be related to other causes. Notably, despite our patient having normal renal function, she experienced CIN and recovered within 72 hours, consistent with the recovery patterns observed in most cases.

This review is limited by the availability of case series and single-case reports, restricting us to descriptive reporting. In addition, the observational nature of reports on interventions for cefepime neurotoxicity precludes definitive statements on the effectiveness of specific strategies, except for noting that symptoms did not resolve spontaneously. In addition, differentiating CIN from other conditions in critically ill patients is challenging due to concurrent diagnoses. Septic patients often exhibit EEG abnormalities and encephalopathy, which may be exacerbated by sepsis-related effects on the blood-brain barrier, potentially increasing the risk of cefepime neurotoxicity. ²

Conclusion

Patients exhibiting unexplained altered mental status are frequently seen in clinical settings in patients on cefepime. Although CIN primarily arises from excessive doses in patients with renal dysfunction, some cases are reported in patients with normal renal function. Because cefepime neurotoxicity is a reversible (and preventable) cause of severe neurologic symptoms, it is important for clinicians to be aware of this possibility and for the use of alternative antibiotics to be considered in patients with risk factors. Further research into CIN can enhance our understanding of at-risk patients and improve management strategies.