Ertapenem Neurotoxicity in Hemodialysis Patients—Safe and Effective Dosing Is Still Needed: A Retrospective Study and Literature Review

Abstract

<jats:p> Background: The approved dosing of ertapenem in patients with chronic kidney disease stage 5 utilizing dialysis (CKD-5D) is 0.5 g intravenous daily. Several reports associated this dosing strategy with neurotoxicity. Objective: The purpose of this study is to identify the incidence of neurotoxicity in this population and the risk factors associated with this toxicity. The secondary objective was to review the literature and discuss a safer/cost-effective dosing strategy based on available data. Methods: A retrospective study was conducted screening all patients who received ertapenem and hemodialysis at our quaternary hospital between May 2015 and March 2019. Patients’ demographics, comorbidities, concomitant drugs (known to induce neurotoxicity), and seizure history were collected. Results: A total of 99 eligible patients were identified; 10 of them (10%) developed neurotoxicity. The patients who developed neurotoxicity were all male; mean age was 74 ± 9 years as compared with 68.9 ± 13 years in the sample. Bivariate relationships between all predictors and the seizures (dichotomously coded) were estimated to investigate the risk factors. The following were the significant predictors of seizures: male sex (17%; P = 0.014), dementia (27%; P = 0.012), and concomitant use of β-lactams, aminoglycosides, or fluoroquinolones (19.6%; P = 0.042). Conclusion and Relevance: The currently approved ertapenem dose imposes a risk of developing neurotoxicity in patients with CKD-5D. Utilizing the published data in this population, alternative post-dialysis dosing strategies administered through dialysis access such as 1 g loading dose, followed by either 0.5 g (for the 48 hours interdialytic time) or 1 g (for the 72 hours interdialytic time) might warrant further investigation for efficacy and safety. </jats:p>

Ertapenem-induced neurotoxicity in an end-stage renal disease patient on intermittent haemodialysis: a case report

“…In a study on the AUC0-∞ of 1 g daily ertapenem in CKD 5D patients, it was found that the free drug concentration was five folds higher than in patients with mild renal impairment at eGFR > 30 [ 2 ]. This could be excessive as identified in our case and several other case reports [ 1 , 10 ]. A recent pharmacokinetic study of the effects of ertapenem when administered as a 500 mg dose three times weekly found that a plasma concentration above 2 mg/L was maintained (selected based on the MIC90 and the CLSI/FDA susceptibility breakpoint) [ 11 ].…”

“…This difference in the onset of symptoms may be due to lack of awareness of the symptoms, and other contributing factors in our patient such as older age, low albumin and morbid obesity. In a retrospective study of ertapenem-induced seizures among CKD 5D patients, male sex, dementia and concomitant use of antibiotics were found to be the main predictors of seizure [ 1 ].…”

“…use of antibiotics were found to be the main predictors of seizure [1]. The current approved ertapenem dosing guidelines recommend an adjusted dose for CKD 5D patients.…”

“…Carbapenems are a group of antibiotics with bactericidal activity towards both aerobic and anaerobic gram positive and negative organisms [ 1 ]. Ertapenem is a parenteral carbapenem with long-acting properties that is highly protein bound with a mean half-life of 3.8 to 4.4 hours [ 2 ].…”

Ertapenem neurotoxicity in patients with kidney damage: A case report

“…Lee et al measured blood ertapenem levels and demonstrated that even this dose can cause toxicity in routine hemodialysis patients, despite the fact that up to 70% is eliminated by hemodialysis (4). Again, in the study of El Nekidy et al, it was emphasized that the neurotoxic effects could continue in CKD-5D patients at a dose of 500 mg/day and it was stated that alternative dosage or administration strategies should be developed (8). Central nervous system toxicity with ertapenem use generally occurs in the geriatric population.…”