Pharmacokinetics and pharmacodynamics of colistin are complex (Li J, 2006). The issue has become even more relevant in septic shock patients treated by some new RRT approaches, recently proposed to increase the removal of endotoxin, bacterial products and both pro- and anti-inflammatory mediators (Ronco C, 2003; Tetta C, 2002;Livigni S, 2014). These new treatments, including high volume hemofiltration/hemodiafiltration ), coupled plasmafiltration adsorption (CPFA-HF)(Tetta C, 2002;Livigni S, 2014) and hemoperfusion (Cruz DN, 2007) are potentially capable to remove colistin, due to its hydrophobic character and its extensive absorption on many polymeric materials. However, less than 20 cases have been reported so far on conventional continuous RRT (CRRT) accomplished with different membranes (Li j, 2005; Marchand S, 2010; Garonzick SM, 2011; Healy DP, 2011; Markou N, 2012; Karvanen M, 2013; Luque S, 2014), and no data are available for patients treated with sorbent technologies.
Recently, we implemented the quantitative evaluation of colistin A and B using high pressure liquid chromatography-tandem mass spectrometry (HPLC-MS/MS)(Leporati M, 2014). Subsequently, we kept investigating the distribution of colistin between plasma and effluent in further patients treated with CRRT and sorbent technology. The results presented here revealed that sorbent technology is associated to an efficient clearance of colistin through the polysulfone filter and cartridge, and posed the question of colistin maintenance dosage for these patients.
Subjects and methods
Twelve critically ill patients (aged 18-89 years, 58.9±6.89 years, mean ± SEM with septic shock according to current definitions were studied.
All patients presented systemic infection sustained by strain of multiresistant Gram-negative bacteria with only residual sensibility to colistin and suffered from AKI needing RRT.
Out of twelve patients, seven were treated by CVVHDF (Group CVVHDF, n=7 sessions), four by CPFA-HF (Group CPFA-HF, n=4 sessions) and one patient with hemoperfusion cartridge (n=2 sessions).
CVVHDF procedures were carried out with a Multifiltrate apparatus (Fresenius Medical Care AG, Bad Homburg, Germany), equipped with a high flux polysulfone filter (AV1000, Fresenius Medical Care) at blood flow rate of 120 ml/min. Fluid infusion and dialysate flow rates, as well regional citrate anticoagulation was done as previously described (Mariano F, 2010).
CPFA-HF was performed by a five-pump CRRT machine (Lynda, Bellco, Mirandola, (MO), Italy) equipped with a polyethersulfone plasmafilter (0.45 m2, MPS 05, Bellco) placed in series with a highly permeablepolyethersulfone hemodialyzer (1.4 m2, BLS814G, Bellco). The plasma was produced at a rate of 15-20% blood flow, and subsequently underwent absorption on an unselective hydrophobic resin cartridge (Ronco C, 2003; Tetta C, 2002, Mariano F, 2004). For the hemofiltration treatment during CPFA-HF, a sterile bicarbonate-calcium containing solution was infused in postdilution at rate of 1500 ml/hour. The circuit anticoagulation was done by a calcium-free citrate-containing solution infused in predilution mode at 25-30 % blood flow (Mariano F, 2004).
One patient underwent hemoperfusion using a Polymyxin-B Fiber cartridge (Toraymyxin, Toray Industries,Tokyo,Japan) following the manufacture’s instructions (4). The treatment extended for two hours and a further treatment was repeated 24 hours later (QB 120 ml/min, anticoagulation with heparin bolus of 2000 UI).
Colistin methanesulphonate (Colimicina, UCB Pharma SpA, Pianezza (TO), Italy) was administered by i.v. infusion over 60 min at the dose of 4.5 x 106 units (1) in 250 ml of a normal saline solution every 12 hours. All biological samples were collected after the 3rd day of therapy at the steady state condition of colistin pharmacokinetics.
The samples were collected at time 0, 10 min, 1, 3, 6, 12, 24 and 48 hr after the beginning of the CVVHDF session, and at time 0, 1, 3, 6, and 9 hr of CPFA-HF sessions. Infusion of colistin was done during the first hour of CPFA-HF.
Pharmacokinetic parameters including sieving coefficient (SC), effluent clearance (Clear_effl, ml/min), filter clearance (Clear_filter, ml/min) and cartridge clearance (Clear_cartridge, ml/min) were calculated with standard formula (see Supplementary Material in (Mariano F, J Nephrol in press)).
Colistin A and B determination was done by the high pressure liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method described in details in a previous study (Leporati M, 2014).
The software program Statistica (Statistica 6.1, StaSoft Inc, Tulsa, OK, USA) was used for descriptive statistics, ANOVA and Student’s test and graphs. All values are expressed as mean±SEM.
Clinical and dialysis data
The causes of the primary injury, the causative bacteria and the outcome are reported in Table 1. Only four patients survived, out of twelve.
Table 2 shows dialysis flows rates in groups CVVHDF, CPFA-HF and Hemoperfusion. Blood flow rates were significantly higher in CPFA-HF than in CVVHDF (134.0 vs. 103.0 ml/min). In group CPFA-HF the rate of treated plasma reached values higher than 20 ml/min (Table 2).
Colistin handling in group CVVHDF
The SCcvvhdf was significantly lower for colistin A than for colistin B over entire CVVHDF session (Fig. 1a). Figures 1b and 1c show the Clear_effl and Clear_filter for colistin A and B, respectively. Most Clear_filter values overlied Clear_effl values.Declining clearance values were progressively observed, reaching half of the starting values at 48 hours (Fig 1b and 1c).
Colistin handling in group CPFA-HF
During CPFA-HF sessions, the colistin A Cpl_in decreased roughly 4-fold (from basal level of 10.4 to 2.6 mg/L at 9 hour)(Fig. 2a). Colistin A and B precartridge levels were at about 4 and 2 mg/L respectively, representing about 50-60 % of the levels present in systemic plasma. After the cartridge colistin levels were lower than 0.2 mg/L (see Fig. 2a), or not detectable any longer (see Fig. 2b).
The extracorporeal plasma clearance of colistin (the sum of the effluent and cartridge clearance) was slightly higher for colistin B than for colistin A, with values of approximately 40 and 30 ml/min, respectively (Fig. 2C-2D)
In a burn patient (n. 8) treated with colistin for 24 days the systemic levels for colistin A and B on 16th and 17th day of colistin therapy (6th and 7th CPFA-HF sessions) showed an accumulation with peak values of 20 and 4 mg/L respectively (Fig. 3B), doubled in comparison to those determined on the 6st and 7nd day of colistin therapy (1st and 2nd CPFA-HF)(Fig. 3A).
Colistin handling in the patient undergoing hemoperfusion
In the initial part of the 2-hours hemoperfusion session, the postcartridge concentrations for colistin A and B was about 30% lower than those measured before the cartridge (Fig. 4 Panel A). Clearance for both Colistin A and B showed similar patterns, declining to a minimal level of 2-3 ml/min at the end of the 2-hours session (Fig. 4 Panel B).
Blood extracorporeal treatments by CVVHDF, CPFA-HF and hemoperfusion all efficiently remove significant amount of active forms of colistin, the highest clearance values being observed with plasma sorbent technology.
Up to now, no data are available for patients undergoing sorbent technology treatments, such as plasma adsorption or hemoperfusion, and also the present case records on colistin extracorporeal clearance obtained from CVVHDF with polysulfone membrane exceeds the ones as yet reported.
In CVVHDF, the extracorporeal clearance of colistin depends on its elimination through the large exchange area (1.8 mq) of high-flux polysulfone membrane. Polysulfone material is characterized by an anionic surface without significant protein absorption properties, and freely permeable to substances with molecular weight up to 30 kDa (Heilmann K, 2011). An higher SC for colistin B than for colistin A was confirmed (Leporati M, 2014), as colistin A is likely to be more extensively bound to albumin than colistin B due to its longer fatty acid residue (Li J, 2006).
On CPFA-HF the plasma colistin A and B present in the pre-cartridge (after the plasmafilter) were fully adsorbed by cartridge, leaving negligible concentrations in the post-cartridge sampling site, as shown in Fig. 2a and 2b. Thus, the measured cartridge clearance (roughly 15-20 ml/min) added to the effluent clearance of the hemofilter, produces for the 9 hours of treatment a total extracorporeal clearances as extensive as 34 and 43 ml/min for colistin A and B, respectively. These extracorporeal clearance values should be added to the endogenous clearance of both colistin and its prodrug CMS, which are in turn affected by renal failure (Li J, 2006. Even if the decreased renal function implies that a larger fraction of the CMS dose (mainly eliminated by the kidneys) is converted to colistin, renal clearance of colistin represents only a minimal fraction (about 4 %) of its extrarenal clearance of 48.7 ml/min (Couet W, 2011). In effects, in our burn patient on CPFA-HF, after 16-17 days of treatment colistin peaked at 20 mg/L (Fig.3b). On the other hand, the patient responded well to this antibiotic therapy, he survived with a complete recovery of renal function.
Equivalent clearance values of 15 ml/min for colistin A and B were observed at the beginning of the two consecutive hemoperfusion sessions done in a patients with infection by Klebsiella KPC. However, the short time of application (2 hours) likely resulted in a negligible impact of hemoperfusion on the daily total body colistin clearance.
In conclusion, we demonstrated that during CPFA-HF and CVVHDF with high-flux polysulfone filter, colistin A and B were efficiently removed. The extent of this removal, quite well predicted by parameters of dialysis efficiency (volume of effluent, volume of plasmafiltrate) and by free fraction of drug, can counterbalance or overcome the increased bioavailability of colistin due to renal failure.
These data suggest that patients on CVVHDF, and, even more, patients on CPFA-HF should receive unreduced CMS dosage, even if on long term administration plasma levels determination is recommended for the risk of drug accumulation.