What data support a thrice-weekly regimen of ertapenem therapy in patients with end-stage renal disease on intermittent hemodialysis?
Carbapenems are broad-spectrum antimicrobial agents that elude inactivation by most beta-lactamases.1 They are critically important for treating serious, complicated infections resistant to other beta-lactam antibiotics. Such infections include complicated intra-abdominal infections and urinary tract infections, community-acquired pneumonia, acute pelvic infections, and complicated skin and skin structure infections.2,3 Use of these agents in certain patients, however, is associated with neurotoxicity.4 Carbapenem-related neurotoxicity is often observed in patients with renal impairment, which has been identified as an important risk factor for neurological adverse drug events.4,5 Patients with end-stage renal disease (ESRD) are especially predisposed to this toxicity due to decreased renal clearance, electrolyte imbalances, dialysis-induced hypotension, risk of uremia, and in rare cases, dialysis disequilibrium syndrome; consequently, carbapenem dose reductions are recommended when used in this population.6,7 One such agent is ertapenem, which is currently approved for the treatment of various moderate to severe infections in patients with ESRD undergoing hemodialysis (HD).
In adults with normal renal function, the Food and Drug Administration (FDA) dosing guidelines for ertapenem recommend a 1-g intravenous (IV) dose administered once daily.3 In ESRD, however, the guidelines recommend that the normal daily dose be reduced to 0.5 g IV once daily and given at least 6 hours prior to HD; if administered any later, a supplementary post-dialysis dose of 150 mg is recommended to compensate for drug loss (estimated to be 30% in low-flux HD) in the dialysate.8 Despite this adjustment, recent case reports and studies suggest that the current regimen continues to pose neurological risk.9-11 As such, researchers are beginning to explore alternative ertapenem dosing regimens that may mitigate these risks in this patient population.
Current dosing regimen and associated neurotoxicity
The FDA-approved dosing regimen is based on a 2006 open-label study that examined the pharmacokinetics (PK) of a single 1-g IV dose of ertapenem in 26 volunteers with varying degrees of renal impairment.2,8 Of the 26 participants, 7 had ESRD (creatinine clearance [CrCl] < 10 mL/min/1.73 m2) and were receiving intermittent hemodialysis (IHD). Following ertapenem administration on a non-dialysis day, patients with ESRD were observed to have a 2- and 3-fold elevation in total drug exposure compared to those with moderate and mild renal impairment, respectively. Elimination half-life was also markedly increased in patients with ESRD (14.1 h) compared to patients with no renal impairment (4.5 h), mild renal impairment (4.4 h), and moderate renal impairment (6.1 h). Extrapolating from these data, the study authors proposed that a 50% dose reduction – from 1 g IV once daily to 0.5 g IV once daily (plus a supplemental 150 mg if given within 6 h prior to HD) – would sufficiently reduce total drug exposure (and any associated increase in potential adverse effects) without compromising antimicrobial efficacy in the ESRD/IHD population.2,3
Reports of neurotoxicity have nonetheless emerged among dialysis patients who have received the FDA-approved regimen.9,10,12,13 In these patients, toxicity presents as seizures, hallucinations, and, less commonly, encephalopathy.5,9,13 Cases have also occurred in patients with moderate or advanced renal failure not yet on dialysis.14,15 Ertapenem toxicity is thought to be due, at least in part, to the drug’s interference at the gamma-aminobutyric acid (GABA) receptors, permitting excitatory mechanisms of the central nervous system (CNS) to overwhelm GABA-mediated CNS inhibition, resulting in adverse neurological manifestations.5,10 Increased blood-brain barrier permeability due to renal impairment is also thought to contribute to the ertapenem-related CNS toxicities observed in these individuals.
Pharmacokinetics of single-dose ertapenem in IHD
Case reports of ertapenem-associated neurotoxicity have prompted researchers to explore alternative dosing schedules that might mitigate toxicity without impacting efficacy. A recent study (similar in nature to the 2006 open-label study on which the FDA-approved dosing regimen was based) sought to examine the PK profile of a single 1-g IV dose of ertapenem up to 48 hours post-dose in 7 non-infected patients receiving IHD.11 In this study, patients were dosed immediately following a high-flux HD session. Drug concentrations were measured throughout the next 48 hours, the final measurement occurring at 48 hours post-dose – just prior to the patient’s next dialysis session. All through the 48-hour period, ertapenem concentrations were found to remain above the recommended minimum inhibitory concentrations (MICs) for various anaerobes (4 mcg/mL), enterobacteriaceae (2 mcg/mL), and streptococci (1 mcg/mL) against which ertapenem exhibits activity. Based on these findings, the authors suggest that a non-daily ertapenem dosing regimen may be a feasible option for improving safety without negatively impacting antimicrobial activity in patients receiving IHD. Notably, because only a single dose was administered, the potential for toxicity due to possible drug accumulation that might occur with administration of multiple doses, was not studied.
A thrice-weekly dosing strategy
Two alternative non-daily dosing strategies have been reported in the literature, each of which utilizes a thrice-weekly dosing scheme, though with different ertapenem doses.16,17 Unlike previous PK studies that evaluated single-dose therapy in non-infected patients on HD, both thrice-weekly dosing studies described below evaluate multiple doses of ertapenem in ESRD/IHD patients with an existing infection.
A pilot study conducted by Geerlings et al evaluated a thrice-weekly regimen of 1 g in 10 infected patients with ESRD on IHD eligible for ertapenem.16 Patients were dosed immediately following a 4-hour high-flux HD session. Between dialysis session, ertapenem trough levels were maintained above the determined MICs for the microorganisms of interest. An 80% clinical success rate was reported, and no severe adverse events occurred.
A second investigation by Ueng et al also evaluated a thrice-weekly dosing regimen but with the FDA-recommended ESRD/HD dose of 0.5 g as opposed to the 1-g dose utilized by Geerlings et al.17 A total of 22 infected patients with ESRD on IHD were enrolled. Eleven patients were assigned to a control group in which they received the FDA-specified HD regimen of 0.5 g IV once daily; the other 11 patients were assigned to the experimental group in which they also received 0.5 g IV, but thrice weekly and dosed after each dialysis session. Total and free drug concentrations were significantly higher in those receiving the daily regimen as opposed to those receiving the non-daily regimen. Drug concentrations in the experimental group remained above the MIC of 2 mg/L, while those same drug concentrations in the control group far exceeded the MIC, suggesting that once-daily dosing results in ertapenem levels that are unnecessarily high. The results of both studies suggest that replacing a once-daily regimen with a thrice-weekly regimen does not negatively impact efficacy and may come with the added benefits of improved safety and practicality.
Notably, because sample sizes for the aforementioned studies were small, larger cohorts of patients would need to be studied for further evaluation of the proposed dosing alternatives. Additionally, it is possible that the 0.5-g thrice-weekly proposed regimen may underdose patients in North America (who tend to have larger mean body weights than those of the Taiwanese patients studied in Ueng et al), and that the 1-g thrice-weekly proposed regimen may still carry with it the neurotoxicity risk observed with the FDA dosing regimen.10 As such, additional dosing strategies may need to be proposed and evaluated.
Researchers must also consider the impact of various types of dialyzers on ertapenem drug concentrations. The 2006 pilot study that informs the current dosing recommendations utilized a low-flux dialyzer that removed approximately 30% of a 1-g ertapenem dose, whereas the more recent PK studies utilized a high-flux dialyzer thought to reduce ertapenem drug concentrations by 72%.11,14,16 Ueng et al, on the other hand, observed post-dialysis concentration reductions of 50% – though in this case, dialyzer type was not specified.17 Various types of dialysis techniques, in addition to various types of renal impairment, will likely require their own dosing studies in evaluating both the efficacy and safety of a thrice-weekly ertapenem regimen.
Because the proposed thrice-weekly dosing schedule utilizes post-dialysis dosing, such a regimen may eliminate the necessity for outpatient parenteral ertapenem therapy, thereby obviating the need for peripherally inserted central catheters (PICC).2 This would also serve to improve patient safety by minimizing PICC-associated risks, namely, vein occlusion, stenosis, thrombosis, and potentially compromised vascular access for IHD.
Available PK data suggest that the currently-recommended ertapenem dosing regimen of 0.5 g IV once daily in the context of ESRD/IHD may result in drug concentrations that far exceed what is necessary for eradication of infection. Such excess may unnecessarily result in accumulation of drug to potentially toxic levels. While the proposed thrice-weekly dosing schedule is a more convenient and potentially safer option for patients with ESRD receiving IHD, larger studies are needed to assess the efficacy and safety of this regimen.
- Doi Y. Ertapenem, imipenem, meropenem, doripenem, and aztreonam. In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 9th Elsevier; 2020. Accessed September 8, 2021. https://www.clinicalkey.com/#!/content/book/3-s2.0-B9780323482554000229?indexOverride=GLOBAL
- Cimino C, Burnett Y, Vyas N, Norris AH. Post-dialysis parenteral antimicrobial therapy in patients receiving intermittent high-flux hemodialysis. Drugs. 2021;81(5):555-574. doi:10.1007/s40265-021-01469-2
- Invanz. Package insert. Merck & Co, Inc; 2021.
- Sutter R, Rüegg S, Tschudin-Sutter S. Seizures as adverse events of antibiotic drugs: A systematic review. Neurology. 2015;85(15):1332-1341. doi:10.1212/WNL.0000000000002023
- Deshayes S, Coquerel A, Verdon R. Neurological adverse effects attributable to β-lactam antibiotics: a literature review. Drug Saf. 2017;40(12):1171-1198. doi:10.1007/s40264-017-0578-2
- Sazgar M. Kidney disease and epilepsy. J Stroke Cerebrovasc Dis. 2021;30(9):105651. doi:10.1016/j.jstrokecerebrovasdis.2021.105651
- Títoff V, Moury HN, Títoff IB, Kelly KM. Seizures, antiepileptic drugs, and CKD. Am J Kidney Dis. 2019;73(1):90-101. doi:10.1053/j.ajkd.2018.03.021
- Mistry GC, Majumdar AK, Swan S, et al. Pharmacokinetics of ertapenem in patients with varying degrees of renal insufficiency and in patients on hemodialysis. J Clin Pharmacol. 2006;46(10):1128-1138. doi:10.1177/0091270006291839
- Lee KH, Ueng YF, Wu CW, Chou YC, Ng YY, Yang WC. The recommended dose of ertapenem poses a potential risk for central nervous system toxicity in haemodialysis patients – case reports and literature reviews. J Clin Pharm Ther. 2015;40(2):240-244. doi:10.1111/jcpt.12239
- El Nekidy WS, Elrefaei H, St John TJL, et al. Ertapenem neurotoxicity in hemodialysis patients-safe and effective dosing is still needed: a retrospective study and literature review. Ann Pharmacother. 2021;55(1):52-58. doi:10.1177/1060028020938059
- Hsaiky LM, Salinitri FD, Wong J, et al. Pharmacokinetics and investigation of optimal dose ertapenem in intermittent hemodialysis patients. Nephrol Dial Transplant. 2019;34(10):1766-1772. doi:10.1093/ndt/gfy166
- Seto AH, Song JC, Guest SS. Ertapenem-associated seizures in a peritoneal dialysis patient. Ann Pharmacother. 2005;39(2):352-356. doi:10.1345/aph.1E421
- Adams R, Chopra P, Miranda R, Calderon A. Ertapenem-induced encephalopathy. BMJ Case Rep. 2020;13(6):e231875. doi:10.1136/bcr-2019-231875
- Wen MJ, Sung CC, Chau T, Lin SH. Acute prolonged neurotoxicity associated with recommended doses of ertapenem in 2 patients with advanced renal failure. Clin Nephrol. 2013;80(6):474-478. doi:10.5414/CN107247
- Shea YF, Mok MY, Cheng KC, Hon FK, Chu LW. Delayed recovery from ertapenem induced encephalopathy: case-report and a possible mechanism. Int J Clin Pharm. 2013;35(4):535-537. doi:10.1007/s11096-013-9812-x
- Geerlings CJ, de Man P, Rietveld AP, Touw DJ, Cohen Tervaert JW. A practical thrice weekly ertapenem dosage regime for chronic hemodialysis patients?. Clin Nephrol. 2013;80(4):312. doi:10.5414/cn108071
- Ueng YF, Wang HJ, Wu SC, Ng YY. A practical thrice weekly ertapenem in hemodialysis patients. Antimicrob Agents Chemother. 2019;63(12):e01427-19. doi:10.1128/AAC.01427-19
Rosa Macrito, PharmD Candidate Class of 2023
University of Illinois at Chicago College of Pharmacy
Patricia Hartke, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
The information presented is current as of September 8, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.