Echinocandins and Continuous Renal Replacement Therapies: The Role of Adsorption

The fi rst review [1], that evaluates several articles [37], concludes that the elimination of echinocandins due to adsorption to membrane surfaces is not likely to be clinically relevant, once the concentration in steady state equilibrium is reached. They point out that 20% is lost with the fi rst dose but that it is not relevant, at least it is not important, for anidulafungin and caspofungin because these drugs are prescribed with loading dose to achieve steady state balance on the fi rst day. On the other hand, it indicates that in the case of micafungin, its loss could be relevant due to the lack of loading dose. This drug loss could occur mainly on the fi rst day of TCRR or after fi lter replacement. A new fi lter has a greater adsorptive capacity and even more if the fi lter membranes have a high adsorptive capacity and the ultrafi ltrate fl ows are high. It is also unknown whether repeated coagulation of the fi lter could affect the fungicidal activity of these antifungals. Finally, there are some limitations of these studies regarding the small size of the sample and the heterogeneity of the studied population, as well as a lack of standardization and validation of the determinations to obtain the concentrations of the echinocandins, so that it requires caution in order to evaluate the results of the studies.


Introduction
The following reviews [1,2], about continuous renal replacement therapies (CRRT) and echinocandins conclude that the membranes do not signifi cantly adsorb these antifungals.
The fi rst review [1], that evaluates several articles [3][4][5][6][7], concludes that the elimination of echinocandins due to adsorption to membrane surfaces is not likely to be clinically relevant, once the concentration in steady state equilibrium is reached. They point out that 20% is lost with the fi rst dose but that it is not relevant, at least it is not important, for anidulafungin and caspofungin because these drugs are prescribed with loading dose to achieve steady state balance on the fi rst day. On the other hand, it indicates that in the case of micafungin, its loss could be relevant due to the lack of loading dose. This drug loss could occur mainly on the fi rst day of TCRR or after fi lter replacement. A new fi lter has a greater adsorptive capacity and even more if the fi lter membranes have a high adsorptive capacity and the ultrafi ltrate fl ows are high. It is also unknown whether repeated coagulation of the fi lter could affect the fungicidal activity of these antifungals.
Finally, there are some limitations of these studies regarding the small size of the sample and the heterogeneity of the studied population, as well as a lack of standardization and validation of the determinations to obtain the concentrations of the echinocandins, so that it requires caution in order to evaluate the results of the studies.
The second review [2], evaluates two of the articles already included in the previous review [6,7], and concludes that micafungin can be administered in critically ill patients undergoing TCRR without the need to modify the doses or the recommended intervals. Regarding the different studies selected in both reviews (Table 1), some considerations can be added:

Caspofungin
In the study of Weiler et al. [3], two types of depurative treatment were used in 14 patients. On the one hand, 10%. This decreasing effect may be due to a phenomenon of membrane saturation over time. As occurred with caspofungin, important inter-individual differences were also observed in this study, so that when measuring the AUC of anidulafungin concentrations at the infl ow and outfl ow of the fi lter of several patients (nº1, nº5, nº6 and nº10), the differences were more than 20%. That is, many patients could have lost more than 20% of anidulafungin, and one of them; patient nº 6 would have lost 40% of the drug in the fi lter membrane. In addition, in statistical terms these results are also questionable, so that an average difference of AUC of 20.44 with a standard error of 19.79 would limit its validity.
The other study by Rosa and colleagues [5] only included 2 patients submitted to HFC.

Micafungin
Kishino et al. [6], studied 4 transplanted liver patients who were treated with cellulose membranes, a material that is not commonly used in critically ill patients nowadays in occidental countries, so that the results are not applicable to our patients. Another Japanese study [7], included 4 patients undergoing hemodiafi ltration (HDFC). In this study, polymethylmethacrylate membranes were used, blood fl ows were lower than 100 mL / min and the dialysis fl ow rate was regulated between 500-1000 mL / h. The replacement rate fl ow was not well documented but it seems that the effl uent was It has been suggested that the differences found between the concentration at the infl ow and outfl ow of the hemofi lter found in Leitner study [4], could be due to a post-fi lter replacement dilution effect [7]. However, the difference in concentration from 18% (after 2 hours of CHF) to 9% (after 72 hours of CHF), with no changes in the replacement fl uid rate, is easy to explain due to an adsorption phenomenon and saturation of the membrane over time. Moreover, in the study of Weiler [3], in the HDC group, without any fl uid replacement, the differences between infl ow and outfl ow concentrations of caspofungin, cannot be a consequence of a hemodilution, and instead, it could be explained from the adsorption of the drug by the membrane of the hemofi lter.
Since adsorption is a saturable process, its infl uence on the elimination of a drug will depend on the frequency of fi lter change and the adsorption capacity of the membrane. As In addition, it should be noted that adsorptive capacity of the fi lter membranes used in these studies was low. Membranes with more adsorption capacity like polyacrylonitrile could theoretically adsorb major amount of echinocandins.
Unfortunately, these polyacrylonitrile membranes were not analysed in the studies included in the reviews [1,2], so that we cannot extrapolate the results of these studies and their conclusions if polyacrylonitrile membranes are used, regarding the adsorption of the echinocandins.
A recent study [8], in critically ill patients undergoing HDF, analyses the concentrations of anidulafungin administered with a loading dose of 200 mg / day and a maintenance dose of 100 mg / day. In this study, 1.4 m 2 polysulfone membranes were  in all the samples analysed. Recently, they [9] have also studied caspofungin with polysulfone membranes obtaining similar results [10].
To conclude, even though the reviews [1,2], conclude that echinocandins are not likely to be signifi cantly eliminated by adsorption in patients undergoing CRRT, there is not enough data to be conclusive [10]. In a very recent article [11] these authors have observed that the licensed regimen of caspofungin is insuffi cient to achieve the PK/PD targets in critically ill patients on haemodiafi ltration [11]. It is necessary to design studies with polyacrylonitrile membranes with more adsorption capacity, and also to analyse higher effl uent doses and the effect of frequent fi lter changes.