Cefepime-induced encephalopathy in an older patient with polypharmacy and renal insufficiency: a case report

Abstract

The world population is rapidly aging. Societal aging poses many challenges for individuals, families, nations, and the global healthcare system. Therefore, geriatric care is a crucial issue that demands our attention. In this case report, we describe a woman in her early 70s with multiple comorbidities, polypharmacy, and renal insufficiency who developed cefepime-induced encephalopathy with moderate to severe cerebral dysfunction during treatment of a urinary tract infection. The patient’s consciousness level gradually improved, and no further seizures were observed following the discontinuation of cefepime for several days. This case report underscores the fact that polypharmacy and medication safety are significant concerns that are often overlooked when caring for older patients. The report also highlights the increased susceptibility of older individuals to antibiotic-associated adverse reactions during the management of infectious diseases. Therefore, optimization of antibiotic therapy for older patients is a critical issue that requires thorough investigation and consideration in geriatric care.

Introduction

The world population is aging at a rapid rate. In 2019, the number of people aged ≥60 years was 1.0 billion. This number will likely increase to 1.4 billion by 2030 and 2.1 billion by 2050. ¹ An aging society poses many challenges for individuals, families, nations, and the global healthcare system. Polypharmacy and medication safety are important concerns that are often overlooked when caring for older patients. The prevalence of polypharmacy is approximately 45% in adults aged >65 years. ² Older individuals are at increased risk for drug–drug and drug–disease interactions because of age-related alterations in pharmacokinetics and pharmacodynamics, such as decreased drug metabolism in the presence of renal insufficiency. Furthermore, compared with young individuals, older individuals are more likely to experience adverse drug reactions. These factors can result in poor health, disability, hospitalization, and, in severe cases, even mortality.^3–5 Moreover, caring for older individuals is complex because their underlying medical conditions often present with atypical symptoms, making it challenging to discern the etiologies. Adverse drug reactions may contribute to the aforementioned complexities. Consequently, avoiding inappropriate prescriptions and promptly identifying drug–drug reactions are crucial in geriatric care.

Infectious diseases introduce significant challenges to acute care for older individuals. ⁶ With the widespread use of antibiotics and the emergence of new antibiotics, an increase in multi-drug-resistant bacterial strains has been observed, especially in hospitalized patients. Antibiotic-associated adverse drug reactions are more common in the older population. Therefore, optimizing antibiotic use in older individuals is an issue that demands our attention.^7–9 This case report describes a geriatric patient with multiple comorbidities, polypharmacy, and renal insufficiency who developed cefepime-induced encephalopathy during treatment of a urinary tract infection.

Case report

A woman in her early 70s with a medical history of hypertension, type 2 diabetes mellitus, atrial fibrillation, coronary artery disease, congestive heart failure, cerebrovascular infarction, chronic kidney disease, and a prior left femoral fracture was undergoing polypharmacy with regular follow-up at an outpatient clinic. The patient resided in a nursing home and was bedridden with clear consciousness 2 years after a left hip fracture, and she required neither a nasogastric tube nor Foley catheter. During the previous 6 months, she had been readmitted four times, primarily because of infectious conditions (acute pyelonephritis, pneumonia, and COVID-19); however, one admission was associated with acute myocardial infarction.

One morning, the patient was brought to the emergency department with altered consciousness and unresponsiveness. No signs of fever, hypotension, desaturation, cough, dyspnea, stool abnormalities, or vomiting were observed. Additionally, no indication of pitting edema was present in either leg. The caregiver reported poor food intake for nearly 1 month because of a broken denture. Initial brain computed tomography revealed no remarkable findings. However, laboratory investigations revealed hyponatremia, hypokalemia, acute kidney injury, bacteriuria, and pyuria.

The tentative diagnosis was urinary tract infection, and the patient was admitted to the hospital. Empirical antibiotic therapy with ceftriaxone was initiated and subsequently refined according to the urine culture results. However, the patient’s clinical symptoms continued to fluctuate until she was transitioned to cefepime on the basis of the urine culture results, which revealed the presence of multi-drug–resistant Pseudomonas aeruginosa with retained susceptibility to cefepime. An infectious disease specialist recommended the use of high-dose cefepime for healthcare-associated infection and coverage of P. aeruginosa. Based on the patient’s renal function (estimated glomerular filtration rate of 43 mL/minute/1.73 m², calculated using the Modification of Diet in Renal Disease equation), we adjusted the dose to 2 g every 12 hours. After cefepime administration, the patient’s fever, weakness, and overall health improved. After 1 week of cefepime therapy, however, the patient developed recurrence of an altered mental status accompanied by seizures. Comprehensive diagnostic assessments were performed, including a blood examination with a septic workup, electrolyte evaluation, endocrinology tests, and brain computed tomography. Throughout the administration of cefepime, no significant change in renal function occurred. Subsequent electroencephalography (EEG) revealed the following three abnormalities: diffuse background slowing, predominant at 4 to 6 Hz; intermittent abundant slowing at 1 to 2 Hz in the bilateral hemispheres; and frequent generalized periodic discharges at 1 Hz, maximal in the frontal region. The patient had been using multiple medications for an extended period to manage her chronic diseases with no noticeable side effects. After admission, the primary addition to the medication regimen was antibiotic therapy for a urinary tract infection. Following an assessment of the patient’s clinical symptoms and EEG findings as well as discussions with the neurologist, we confirmed the presence of cefepime-induced encephalopathy with moderate to severe cerebral dysfunction. Discontinuation of cefepime for several days led to gradual improvement in the patient’s level of consciousness with no subsequent seizures. No anti-epileptic drugs were prescribed.

We have de-identified all patient details in this report. The reporting of this study conforms to the CARE guidelines. ¹⁰

Discussion

Cefepime is a widely used fourth-generation cephalosporin with broad-spectrum effects against gram-positive and gram-negative pathogens. The drug was first approved in the United States in 1996.^11,12 The potential neurotoxic effects of cefepime were first reported in 1999 in a patient with end-stage renal disease undergoing hemodialysis. The patient developed an altered mental status, myoclonus, and generalized tonic–clonic seizures with an elevated serum cefepime concentration.^12,13 The possible mechanism of cefepime-induced neurotoxicity (CIN) is thought to be related to concentration-dependent inhibition of the gamma-aminobutyric acid receptor secondary to the accumulation of cefepime.^14,15 The awareness of CIN has recently increased. However, the incidence has been highly variable among different reports, ranging from 4% to 23% in diverse settings. ¹⁶

Because most of the cefepime that is administered (approximately 85% of the dose) is excreted through the urine, CIN is often associated with impaired renal function. This leads to high plasma concentrations of cefepime and increased penetration of the drug through the blood–brain barrier.^11,17,18 Although renal dysfunction and excessive cefepime doses are the most important and common risk factors for CIN, the condition has also been reported in patients with normal renal function or properly adjusted doses (approximately 25%). Apart from renal dysfunction and overdose, factors such as old age, pre-existing brain injuries, and diseases that increase central nervous system penetration and disrupt the blood–brain barrier (such as critical illness) can also contribute to CIN.^14,19

Neurological symptoms or signs can manifest within 1 to 10 days following cefepime administration (up to 14 days according to some reports), with a median onset period of 4 days (2 days according to some reports).^20–22 Moreover, CIN presents with various symptoms that may be challenging to diagnose. Systematic reviews and cohort studies have indicated that common symptoms include decreased or altered consciousness (such as drowsiness, stupor, coma, disorientation, confusion, hallucinations, or agitation), aphasia, tremor, myoclonus, seizures, and non-convulsive status epilepticus.^14,19–21

The diagnostic criteria for CIN are the emergence of neurological symptoms a few days after initiating cefepime treatment; identification of EEG findings consistent with generalized periodic discharges demonstrating a triphasic appearance; resolution of symptoms; abnormal EEG findings within several days after discontinuing cefepime; absence of any other factors likely to be responsible for the patient’s symptoms, such as metabolic or toxic encephalopathy; and abnormally high concentrations of cefepime, if measurable.^12,23 In addition to identifying neurological symptoms and signs possibly related to cefepime, the clinician can also perform EEG to gather additional relevant information. Notably, EEG findings may vary greatly because of the severity of encephalopathy and the timing of the study. The most common EEG findings are generalized slowing of the background rhythm, multifocal sharp waves, and generalized periodic discharges with or without a triphasic morphology.^{12,16,19,23–25}

Some prior studies have explored the relationship between the cefepime concentration and the incidence of CIN, and others have examined the correlation between reduction of the cefepime concentration and clinical improvement of CIN. Most of these studies only reported trough thresholds.^11,18,20 A recent retrospective cohort study demonstrated a significant association between higher cefepime plasma trough concentrations and the risk of neurotoxicity. In that study, every individual with a cefepime plasma trough concentration of >38.1 mg/L developed CIN. Additionally, those with presumed CIN exhibited significantly lower renal function and a higher in-hospital mortality rate.^16,20 In another recent retrospective review, a cefepime trough concentration of 36 mg/L was the optimal threshold for distinguishing between patients who did and did not develop neurotoxicity.^16,26 Other reports have suggested trough concentrations exceeding 35 mg/L and 49 mg/L as potential thresholds for neurotoxicity. Considering the variability in pharmacokinetics and analytical factors among individuals, the neurotoxic threshold might lie within the range of 35 to 49 mg/L. ¹¹

It should be noted that comparisons across studies are hindered by limitations such as the retrospective nature of the studies, variability in defining neurotoxicity, exclusive focus on trough concentrations in measurements or analyses, and potential technical variability in analytical methods. Consequently, target serum trough concentrations of cefepime with substantial discriminatory ability have not yet been definitively established. Future research endeavors should investigate alternative measures to address drug accumulation, such as the cumulative area under the concentration–time curve from time zero to infinity.^11,12 Additionally, therapeutic drug monitoring may be valuable in preventing neurotoxicity, especially in patients undergoing high-dose therapy, with renal dysfunction, or receiving continuous renal replacement therapy. ¹² Although the serum cefepime concentration was not evaluated in our patient, its monitoring is recommended, especially in patients with renal dysfunction.

After cessation of cefepime, most patients (approximately 90%) experience clinical improvement or resolution of symptoms within a median duration of 2 days (range, 1–19 days). The initial and definitive treatment approaches involve either discontinuing treatment with cefepime or reducing the dosage of the drug.^14,19,23,27 However, hemodialysis is recommended to rapidly enhance the elimination of cefepime from both the bloodstream and cerebrospinal fluid, especially in life-threatening scenarios. This is attributed to the ability of dialysis to remove cefepime, enabling extraction of up to 70% of a given dose during a 3-hour hemodialysis session. Reliable data strongly support the early initiation of hemodialysis to expedite removal of cefepime from the circulation, leading to accelerated recovery and a favorable prognosis.^{12,19,23,28,29}

Anticonvulsant therapy, primarily consisting of benzodiazepines along with alternatives such as phenobarbital, phenytoin, levetiracetam, and valproic acid, is occasionally administered to patients with CIN. However, benzodiazepines do not lead to immediate or permanent restoration of patients’ mental state or EEG patterns, although EEG studies have demonstrated temporary suppression of generalized periodic discharges following benzodiazepine injection. Clinical and EEG improvements typically occur within 2 to 3 days, mainly due to discontinuation of cefepime; thus, anticonvulsant therapy is essential primarily for patients experiencing convulsive seizures or exhibiting definite non-convulsive status epilepticus.^{12,14,19,23,30}

Conclusions

The incidence of cefepime-induced encephalopathy may be higher than expected in older individuals, particularly those with polypharmacy or renal insufficiency, potentially leading to increased mortality and complications. Therefore, careful consideration is warranted when prescribing cefepime.