Open Access

Cefepime-induced neurotoxicity in critically ill patients undergoing continuous renal replacement therapy: beware of dose reduction!

Critical Care201519:455

https://doi.org/10.1186/s13054-015-1179-z

Published: 30 December 2015

The original article was published in Critical Care 2013 17:R264

The recently published article by Fugate et al. [1] reminds us of the frequently underappreciated yet deleterious neurotoxic potential of cefepime (CEF) in critically ill patients with pre-existent or acute kidney dysfunction [2]. We do agree with the authors that dose adjustments for renal function are critical to minimize the risk of CEF neurotoxicity. However, we would like to warn of daredevil CEF dose reduction in patients undergoing continuous renal replacement therapy (CRRT). Indeed, approximately one-fifth of the patients studied by Fugate et al. were treated with CRRT and most of them received less than 1 g CEF every 12 h [1]. CEF has a very low protein binding and distribution volume and thus will easily be removed by CRRT [3]. Seyler et al. previously studied whether recommended CEF doses (2 g, twice daily) enabled an appropriate pharmacokinetic/pharmacodynamic (PK/PD) target concentration to be reached for treatment of Pseudomonas aeruginosa (32 mg/L, corresponding to four times the EUCAST minimal inhibitory concentration (MIC)) in patients undergoing CRRT. They observed that none of the patients attained the suggested PK/PD target within the first 48 h of treatment, even when a 2 g CEF bolus dose was given [4]. According to Seyler et al.’s results, the applied CEF regimen would allow 90 % coverage of micro-organisms with a MIC ≤2, implicating that less susceptible bacteria escape treatment. Thus, applying a CEF dose of 2 g or less during CRRT, as suggested by Fugate et al., may decrease the risk of CEF-induced neurotoxicity at the cost of inducing treatment failure or resistance! We strongly argue against dose reduction of CEF during CRRT and even prescribe higher doses (2 g, three times daily) in CRRT patients. Close monitoring of neurotoxicity, preferably using 24-h recording of electrical brain activity, remains imperative. Therapeutic drug monitoring has been advocated but its validity to support dose adaptation of β-lactam antibiotics is questionable and any dose relationship between CEF levels and occurrence of neurotoxicity remains to be proven. If neurotoxicity is detected, other antibiotics (e.g., colistin) must be administered.

Notes

Abbreviations

CEF: 

Cefepime

CRRT: 

Continuous renal replacement therapy

MIC: 

Minimal inhibitory concentration

PK/PD: 

Pharmacokinetic/pharmacodynamics

Declarations

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
ICU Department, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel

References

  1. Fugate JE, Kalimullah EA, Hocker SA, Clark SL, Wijdicks EF, Rabinstein AA. Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy. Crit Care. 2013;17:R264.PubMedPubMed CentralView ArticleGoogle Scholar
  2. Sonck J, Laureys G, Verbeelen D. The neurotoxicity and safety of treatment with cefepime in patients with renal failure. Nephrol Dial Transplant. 2008;23:966–70.PubMedView ArticleGoogle Scholar
  3. Malone RS, Fish DN, Abraham E, Teitelbaum I. Pharmacokinetics of cefepime during continuous renal replacement therapy in critically ill patients. Antimicrob Agents Chemother. 2001;45:3148–55.PubMedPubMed CentralView ArticleGoogle Scholar
  4. Seyler L, Cotton F, Taccone FS, De Backer D, Macours P, Vincent JL, et al. Recommended β-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy. Crit Care. 2011;15:R137.PubMedPubMed CentralView ArticleGoogle Scholar

Copyright

© Honore and Spapen. 2015

Advertisement