Target-controlled dialysis for antibiotics (TCD-ABx)

Abstract

Background: Effective antimicrobial therapy is an essential part of intensive care medicine and renal replacement therapy is an important and common intervention which significantly affects the pharmacokinetics of many antimicrobials. This is especially critical for substances with a narrow therapeutic range, creating a dilemma of weighing the risk of toxicity from increased drug exposure against risk of ineffective treatment and promotion of antimicrobial resistance. To address this problem, we investigate a target-controlled dialysis by in vitro experiments - a novel technique in which drug is spiked into the dialysis solution to make use of the physicochemical properties of renal replacement therapy for solute transport, with the goal to reduce the risk of inadequate drug exposure.

Methods: Five antibiotics (ceftazidime, meropenem, piperacillin/tazobactam, vancomycin, flucloxacillin) were dialyzed in an in vitro model of continuous veno-venous hemodialysis using 1 L of bovine serum albumin solution as simulated patient plasma compartment. This was done with and without antibiotics in target concentrations added to the dialysis solution, mimicking three clinically relevant scenarios: (i) target-controlled dialysis in a subject with sub-therapeutic drug levels, (ii) target-controlled dialysis in a subject with supra-therapeutic drug levels, and (iii) traditional dialysis of drugs starting at the target concentration. Drug levels were quantified by high-performance liquid chromatography. Additionally, the stability over 24 h of all antibiotics in two typical dialysis solutions was assessed.

Results: Our data shows that with target-controlled dialysis, antibiotic concentrations will change in the desired direction towards the target concentration, depending on the patients' unbound drug levels in relation to the concentration in the dialysis solution. The desired target concentrations can be induced and maintained, regardless of the initial concentration. Furthermore, the stability tests revealed only a minor and clinically irrelevant loss in drug concentration (all < 10.2%) after 12 h.

Conclusions: We outlined the mechanistic plausibility and provided experimental evidence of the feasibility of the target-controlled dialysis concept, which could help to maintain therapeutic concentrations of many time-dependent antibiotics in critically ill patients under renal replacement therapy. The required stability in dialysis solutions was shown for a set of important antibiotics. The next step will be the prudent application of this concept to patients in clinical trials.

Keywords: Antibiotics; Hemodialysis; Intensive care; Renal replacement therapy; Target-controlled dialysis; Therapeutic drug monitoring.

Fig. 1

Representation of the experimental setup with a MultiFiltratePRO^® hemodialysis unit in continuous veno-venous mode (CVVHD), setup with a hemofilter in counterflow of 1 L simulated patient reservoir (SPR) against dialysis solution (DS) from four parallel 5 L multiBic^® dialysis solution bags. SPR flow (“blood flow”) $Q_{\text{SPR}}$ was set at 200 mL/min, dialysate flow $Q_{\text{DS}}$ at 66.67 mL/min, and net ultrafiltration $Q_{\text{UF}}$ at 0 mL/min

Fig. 2

Experimental setup with a MultiFiltratePRO^® hemodialysis unit in continuous veno-venous hemodialysis mode, primed and with both in- and outlet tubing attached to a simulated patient reservoir stored in an Erlenmeyer flask (see red rectangle) with continuous mixing by a magnetic stirrer and a heating unit. An obstacle was the machine’s blood detection sensor blocking the initiation of circulation, which was overcome by using a customized piece of cellulose-based fabric (see red arrow)

Fig. 3

Image of MultiBic^® dialysis solution bags, highlighting the standard Luer–Lock access ports, which can be used for safe and simple addition of substances for target-controlled dialysis

Fig. 4

Concentration-time profiles of ceftazidime (A), piperacillin (B), vancomycin (C), and meropenem (D) during three sequential phases of an in vitro hemodialysis experiment: phase 1 simulates an antibiotic-naive subject receiving antibiotic through target-controlled dialysis (TCD), phase 2 simulates administration of a high dose of antibiotic with subsequent TCD, and phase 3 shows traditional dialysis. The dashed horizontal line represents the TCD target concentration, i.e., the concentration in the dialysis solution during phases 1 and 2

Fig. 5

Concentration-time profile of flucloxacillin, an antibiotic highly bound to albumin, during three sequential phases of an in vitro hemodialysis experiment: phase 1 simulates an antibiotic-naive subject receiving antibiotic through target-controlled dialysis (TCD), phase 2 simulates administration of a high dose of antibiotic with subsequent TCD, and phase 3 shows traditional dialysis. The dashed horizontal line represents the TCD target concentration, i.e., the concentration of flucloxacillin in the dialysis solution during phases 1 and 2

Fig. 6

Stability of piperacillin (PIP), tazobactam (TAZ), ceftazidime (CAZ) meropenem (MEM), vancomycin (VAN), and flucloxacillin (FXN) was tested in two typical dialysis solutions: multiBic^® (A) and Ci–Ca^® K2 (B), as well as in 0.9% NaCl over 24 h (C). Solid lines depict the relative loss (degradation) of drug concentration, and dashed lines pH levels during an incubation period of 24 h. The typical duration of use of dialysis solution bags during continuous veno-venous renal replacement therapy of 10 h is shown by a dotted vertical, and the 10% degradation limit as dotted horizontal line