We have read the recent letter by Honore et al.  about our findings published in this journal regarding the influence of continuous renal replacement therapy (CRRT) on the pharmacokinetics of ceftolozane-tazobactam (C/T) . In our report, we decided to administer a 3 g/iv dose every 8 h taking into account two previous studies referenced in our paper  and another one which showed CRRT to be an independent predictor of clinical failure (OR 4.5, 95% CI 1.18–17.39, p = 0.02) when C/T is administered at 1.5 g every 8 h .
As Honore et al. explain in their paper, the C/T eliminitation was assumed by hemodiafiltration and the adsorption was not assessed . However, there is a misunderstanding in this letter , because we used a polysulphone membrane (Fresenius, Germany) instead of an acrylonitrile 69 Multiflow (AN-69-M). In contrast to highly adsorptive membranes (HAM; e.g., AN69 surface-treated, AN69-ST), the antibiotic adsorption with polysulphone ones is negligible, which facilitates antibiotic adaptation during CRRT .
Our data should not be extrapolated to other clinical scenarios, as noted by Honore et al. . In our report, ceftolozane and tazobactam plasma concentrations remained above the minimal inhibitory concentration (MIC), for MICs of up to 8 μg/mL, but we estimated that the administration of standard doses of 1 g/0.5 g, even with polysulphone membranes, could compromise the effectiveness of C/T for not reaching adequate tazobactam concentrations. Thus, the use of HAM would represent a real risk factor of clinical failure when a C/T dose of 1.5 g every 8 h is administered, especially in multidrug-resistant infections . Therefore, we agree with Honore et al.  that therapeutic drug monitoring (TDM) is critical when using C/T for patients receiving CRRT, especially when MICs of bacteria like multidrug-resistant (MDR) Pseudomonas aeruginosa are considered very high. However, the recommendation of continuous (over 24 h) vs extended (over 2 to 4 h) or intermittent (over 30 to 60 min) infusion of beta-lactams is still under debate .
Availability of data and materials
Acrylonitrile 69 Multiflow
Continuous renal replacement therapy
Highly adsorptive membranes
Minimal inhibitory concentration
Honore PM, Mugisha A, Gutierrez LB, Redant S, Kaefer K, Gallerani A, De Bels D. Optimizing ceftolozane-tazobactam dosage during continuous renal replacement therapy: additional insights. Crit Care. 2019;23(1):406.
Aguilar G, Ferriols R, Martínez-Castro S, Ezquer C, Pastor E, Carbonell JA, Alós M, Navarro D. Optimizing ceftolozane-tazobactam dosage in critically ill patients during continuous venovenous hemodiafiltration. Crit Care. 2019;23(1):145.
Bassetti M, Castaldo N, Cattelan A, Mussini C, Righi E, Tascini C, et al. Ceftolozane/tazobactam for the treatment of serious P. aeruginosa infections: a multicenter nationwide clinical experience. Int J Antimicrob Agents. 2019 Apr;53(4):408–15.
Honore PM, Spapen HD. What a clinician should know about a renal replacement membrane? J Transl Intern Med. 2018;6:62–5.
Lee YR, Miller PD, Alzghari SK, Blanco DD, Hager JD, Kuntz KS. Continuous infusion versus intermittent bolus of beta-lactams in critically ill patients with respiratory infections: a systematic review and meta-analysis. Eur J Drug Metab Pharmacokinet. 2018;43(2):155–70.
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This reply refers to the comment available at: https://doi.org/10.1186/s13054-019-2692-2.
About this article
Cite this article
Aguilar, G., Ferriols, R., Martínez-Castro, S. et al. Optimizing ceftolozane-tazobactam dosage during continuous renal replacement therapy: some nuances. Crit Care 24, 11 (2020). https://doi.org/10.1186/s13054-019-2724-y