P0952 - Incidence and Risk Factors for Cefepime Induced Neurotoxicity in Patients with Cirrhosis

Sunday, October 22, 2023

3:30 PM – 7:00 PM PT

Location: Exhibit Hall

Presenting Author(s)

Frances Lee, MD

California Pacific Medical Center
San Francisco, CA

Frances Lee, MD¹, Vishwajit Kode, MD², Todd Frederick, MD²
¹California Pacific Medical Center, San Francisco, CA; ²CPMC, San Francisco, CA

Introduction: Cirrhosis may increase the risk of adverse side effects from medications, including those that are renally excreted due to portal hypertension, portosystemic shunting, and loss of protein binding capacity with hypoalbuminemia. Cefepime is a fourth-generation cephalosporin frequently used due to its broad-spectrum of activity. However, cefepime may induce cefepime induced neurotoxicity (CIN), defined as alterations in neurologic and psychologic function within 4-6 days of initiation that resolve within 48 hours of antibiotic withdrawal. While this is often described in patients with renal insufficiency, we aimed to review the frequency and associations of this phenomenon in patients with cirrhosis.

Methods: This is a single center retrospective case control study of hospitalized patients with cirrhosis exposed to cefepime in a tertiary care center in San Francisco between January 2018 to November 2022. Based on two independent reviewers, we stratified our patients into four different groups – “CIN Unlikely,” “CIN Possible,” “CIN Probable,” and “CIN Likely.” For the purposes of statistical analysis, “CIN probable” and “CIN likely” were combined into the positive outcome, while “CIN unlikely” and “CIN possible” were our null outcome.

Results: 104 patients with cirrhosis and at least 3 days of exposure to cefepime were included in this study. 82 or 79% patients were deemed “CIN Unlikely;” 9 or 9% patients “CIN Possible;” 4 or 4% of patients “CIN Probable;” and 9 or 9% patients “CIN Likely.” Factors associated with “CIN Probable-Likely” designation include MELD (OR 1.07, p=0.01), MELD-Na (OR 1.06, p= 0.037), Creatinine (OR 1.5, p=0.041), Bilirubin (OR 1.04, p=0.093), Albumin (OR 0.4, p=0.045), dialysis use (OR 8.8, p=0.0001), and cefepime exposure within 30 days of transplant (OR 8.8, p =0.004). (Table 1)

Discussion: Cefepime induced neurotoxicity was a common phenomenon in our case control study. Patients with higher MELD scores, higher bilirubin, lower albumin, higher creatinine, those on dialysis, and those within peri-transplant period are at higher risk of developing CIN. It is critically important for clinicians caring for patients with cirrhosis to be aware of and recognize the signs and symptoms of CIN to appropriately discontinue the medication. This study can inform clinicians in their choice of antibiotic use within the context of local antibiotic resistance patterns and severity of liver decompensation.

	Total N=104	CIN Unlikely-Possible N=91	CIN Possible-Probable N=13	Odds Ratio (95% CI)	P value
Age at admission, mean ± SD	61.5 ± 12.6	62.2± 12.6	56.2 ± 11.4	0.9 (0.9-1.01)	0.11
Sex, n (%)
Female	51 (49%)	45 (49%)	6 (46%)	0.9 (0.3-2.8)	0.82
Male	53 (51%)	46 (51%)	7 (54%)	Reference
Race, n (%)
White	55 (53%)	51 (56%)	4 (31%)	Reference
Black	10 (9.6%)	9 (9.9%)	1 (7.7%)	1.4 (0.14-14.2)	0.77
Asian	19 (18.3%)	15 (16.5%)	4 (30.8%)	3.4 (0.76-15.2)	0.11
Other	20 (19.2%)	16 (17.6%)	4 (30.8%)	3.12 (0.7-14.2)	0.13
Liver Disease, n (%)
Alcohol	56 (54%)	49 (54%)	7 (54%)	1 (0.26-3.9)	1.0
NASH/NAFLD	15 (14%)	14 (15%)	1 (7.7%)	0.45 (0.01-3.6)	0.46
Autoimmune (AIH,PSC,PBC)	9 (9%)	7 (8%)	2 (15%)	2.2 (0.2-13.5)	0.35
HCV	17 (16.4%)	16 (17.6%)	1 (7.7%)	0.39 (0.009-3.04)	0.37
HBV	5 (4.8%)	4 (4.4%)	1 (7.7%)	1.8 (0.03-20.3)	0.60
Other	2 (1.9%)	2 (2.2%)	0	0 (0-14.2)	0.59
Peri-transplant cefepime exposure, n (%)	6 (5.8%)	3 (3%)	3 (23%)	8.8 (1.0-72.3)	0.004
Cefepime stopped before transplant, n (%)	2 (1.9%)	0 (0%)	2 (15.3%)	0	0.34
Cefepime stopped after transplant, n (%)	4 (3.8%)	3 (3.2%)	1 (7.7%)	Reference
Death at discharge, n (%)	20 (19.2%)	17 (18.7%)	3 (23%)	1.3 (0.2-5.8)	0.71
Days on cefepime, mean ± SD	5.8 ± 4.7	5.7 ± 4.5	7 ± 6.1	1.05 (0.9-1.2)	0.41
MELD, mean ± SD	21.2± 10.1 N=96	20.1± 9.7 N=83	28± 10.6 N=13	1.07 (1.01-1.1)	0.014
MELD-Na, mean ± SD	21.8 ± 10.4 N=96	20.8 ± 10 N=83	27.5 ± 11.1 N=13	1.06 (1.004-1.1)	0.037
Sodium, mean ± SD	135.7 ± 5.1	135.7 ± 4.8	135.8± 6.8	1.0	0.91
Creatinine, mean ± SD	1.7 ± 1.2	1.6 ± 1.2	2.84± 1.6	1.5 (1.12-2.2)	0.041
INR, mean ± SD	1.9 ± 1.0 N=96	1.9 ± 1.1 N=83	1.85± 0.9 N=13	0.95	0.88
Bilirubin, mean ± SD	5.1 ± 8.9	4.5±7.4	9.4± 15.8	1.04	0.093
Albumin, mean ± SD	2.8 ± 0.8	2.9 ± 0.8	2.4 ± 0.8	0.4 (0.2-0.9)	0.045
GFR , mean ± SD	59.5 ± 33.9 N=99	61.2 ± 33.3 N=86	48.2 ± 37.1 N=13	0.99 (0.97-1.01)	0.19
Dialysis, n (%)	22 (21%)	14 (15.4%)	8 (61.5%)	8.8 (2.1-38.5)	0.0001
Benzodiazepine use, n (%)	46 (44%)	39 (42.9%)	7 (53.9%)	1.5 (0.41-6.06)	0.33
Opiate Use, n (%)	94 (90%)	82 (90%)	12 (92.3%)	1.3 (0.16-62.5)	0.64
Lactulose Use, n (%)	26 (25%)	22 (24.2%)	4 (30.8%)	1.4 (0.3-5.6)	0.42
Rifaximin Use, n (%)	16 (15.4%)	13 (14.3%)	3 (53.9%)	1.8 (0.3-8.3)	0.32

Table: Table 1. Demographic, laboratory values, medication use, and their odds ratios associated with cefepime induced neurotoxicity in hospitalized patients with cirrhosis.

Disclosures:

Frances Lee indicated no relevant financial relationships.

Vishwajit Kode indicated no relevant financial relationships.

Todd Frederick: Astra Zeneca – Investigator. Mallinckrodt – Consultant, Investigator. River 2 Renal – Investigator. Salix/Bausch Health – Investigator. Seal Rock Therapeutics – Consultant. Tremor Therapeutics – Consultant.

Frances Lee, MD¹, Vishwajit Kode, MD², Todd Frederick, MD². P0952 - Incidence and Risk Factors for Cefepime Induced Neurotoxicity in Patients with Cirrhosis, ACG 2023 Annual Scientific Meeting Abstracts. Vancouver, BC, Canada: American College of Gastroenterology.