Table 2.

PK/PD studies of beta-lactams in patients with sustained low-efficiency dialysis or extended daily dialysis

Study	Endpoints	Antibiotic	Design	Results	Conclusions
Kielstein et al. [82]	To evaluate PK of meropenem in critically ill patients with renal failure undergoing EDD	Meropenem	Prospective clinical study Adult ICU patients with anuric acute renal failure being treated with EDD and receiving meropenem (n = 10) Meropenem administered as 1 g dose, as an intravenous infusion over a period of 30 mins, 6 h before EDD was started Blood samples were drawn before administration of the drug; at 0.5, 1, 2, 4, and 6 h after its administration; before EDD; during EDD, at time points 2, 4, and 6 h; at the end of EDD; and at 0.5, 1, 3, and 8 h after EDD. Additional blood samples were drawn pre- and post-dialyzer in order to calculate the dialyzer clearance	The average (mean ± SD) dialysis time during the study was 480 ± 6 min, and mean blood and countercurrent dialysate flow was 160 ± 3 mL/min T1/2off was 8.7 h [4.7–30] T1/2on was 3.7 h [2.1–4.7] Vd was 0.72 L/kg [0.35–2.78] CLoff 5.01 L/h [2.44–11.15] CLdial was 2.3 L/h [0.7–3.7] (estimated from the drug amount recovered in the dialysate) and 5.1 L/h [4.3–5.7] (estimated from drug concentrations before and after application of the dialysis membrane)	Meropenem is significantly eliminated by EDD. Compared with PK results in the literature for intermittent dialysis and CRRT, dosing regimens cannot be used for critically ill septic patients with renal failure being treated with EDD EDD eliminates meropenem at least to an extent similar to CVVH. Thus, physicians run the risk of underdosing. A dose of 0.5 to 1.0 g meropenem every 8 h is recommended. The exact dose should be tailored according to weight and severity of illness as well as to the current MIC against the incriminated bacteria. Whenever possible, therapeutic drug monitoring should be performed
Lorenzen et al. [83]	The aims of this study were to evaluate the PK of ampicillin/sulbactam in critically ill patients with AKI undergoing extended dialysis and to establish a dosing recommendation for this treatment method	Ampicilin-sulbactam	Prospective, open-label, observational study 12 adult ICU patients with anuric AKI PK after a single dose of ampicillin/sulbactam (2 g/1 g) over a period of 30 min was obtained in 12 patients. Multiple-dose PK after 4 days of twice-daily ampicillin/sulbactam (2 g/1 g) was obtained in three patients. The average dialysis time was 442 ± 77 min and mean blood and counter current dialysate flow was 162 ± 6 mL/min, resulting in a mean urea reduction ratio of 50.1% ± 2.7%. ED was started 3 h after the end of the ampicillin/sulbactam infusion	Cmax 280.9 ± 174.9 mg/L Tmax 0.5 h AUClast 847.5 ± 499.5 mg.h/L t1/2 2.8 ± 0.8 Vd (L) 13.1 ± 11.1 CLtot 61.1 ± 55.2 mL/min CLdial 80.1 ± 7.7 mL/min	Ampicillin/sulbactam is eliminated by ED Current dosing recommendations from patients undergoing IHD (3 g every 24 h) would cause a significant underdosing of the drug in patients treated with ED Ampicillin/sulbactam concentrations exceeded MIC90 values of Enterobacteriaceae, such as Escherichia coli or Klebsiella pneumoniae (MIC90 < 2.0 mg/L) or Enterococcus faecalis (MIC90 = 2.0 mg/L), only for 8 h (approximately 30% of the dosing interval for patients on intermittent hemodialysis) after start of infusion. A dosage of 3 g every 12 h in patients undergoing ED does not lead to a significant accumulation of the drug
Burkhardt et al. [84]	To evaluate PK of ertapenem, with once-daily dosing, in critically ill patients with anuric acute renal failure undergoing EDD	Ertapenem	Prospective, open-label study 6 adult ICU patients undergoing EDD treated with 1 g ertapenem as a single intravenous dose Blood samples were collected before ertapenem infusion and 0.5, 1, 2, 4, 6, 8 h after the end of the infusion and also 2, 4, 6, and 8 h after the start of EDD. Additional blood samples were drawn pre- and post-dialysis in order to calculate the dialyzer clearance. To study post-EDD PK, samples were drawn 0.5, 1, 3, and 8 h after the end of EDD	Cmax 81.3 ± 12.1 mg/L AUC0-inf 687.4 ± 212.0 mg.h/L T1/2off 18.9 ± 5.4 h T1/2on 6.7 ± 0.4 h Vd (L) 15.9 ± 3.2 CLoff 19.3 ± 11.4 mL/min CLdial 49.5 ± 10.9 mL/min T > MIC was 100% (MIC90 ≤ 1 mg/L) and 85% (MIC90 ≤ 2 mg/L)	1 g ertapenem per day to critically ill patients with ARF in the ICU that undergo EDD is necessary to ensure optimal free concentrations of ertapenem. A reduction of the dose is not supported by our data. Further dosing recommendations for patients with renal failure in the ICU treated with such effective modes of renal replacement therapy should be developed to avoid excess mortality due to under-dosing of life-saving medication
Tamme et al. [85]	To describe the PK of piperacillin and tazobactam during extended high volume hemodiafiltration to define optimal dosing	Piperacilin-tazobactam	Prospective, observational study 10 adult ICU patients with sepsis and AKI requiring CRRT A single dose of 4000 mg of piperacillin and 500 mg tazobactam was administered as a 30-min intravenous infusion 1 h after the start of HVHDF Blood samples of 4 mL were collected before and immediately after the end of piperacillin/tazobactam infusion and 60, 90, 120, 150, 180, 240, 300, 360, 420, and 480 min after the start of drug administration	The plasma concentration–time profiles of piperacillin and especially tazobactam demonstrated high interindividual variability For piperacilin CL (range) 6.9 L/h (6.1–7.9) Vd central compartment (range) 9.0 L (7.4–11.0) Vd peripheral compartment (range) 11.2 L (8.9–14.2) For tazobactam CL (range) 5.1 L/h (4.1–6.3) Vd central compartment (range) 8.6 L (6.9–10.7) Vd peripheral compartment (range) 8.9 L (6.6–12.0) Using Monte Carlo simulation, the probability of 100% fT > MIC target attainment for piperacillin/tazobactam 4.5 g dosed every 6 and 8 h as 4-h infusion were 88.6% and 61.0%, respectively, for MIC 16 mg/l	Application of extended HVHDF for the treatment of AKI in septic shock patients results in considerable clearance of piperacillin and tazobactam Piperacillin/tazobactam doses of 4.5 g, administered every 8 h as 0.5-h infusion during HVHDF, ensured more than 80% probability of attaining the 50% fT > MIC target for intermediately susceptible bacteria (MIC 16 mg/l) While aiming for 100% fT > MIC of 16 mg/l, increasing doses to 4.5 g every 6 h and prolonging the infusion time to 4 h would be necessary

AKI acute kidney injury, ARF acute renal failure, CLdial dialysis clearance, CLoff drug clearance without dialysis, EDD extended daily dialysis, ICU intensive care unit, SD standard deviation, SLED sustained low-efficiency dialysis, T1/2off half-life before/after EDD, T1/2on half-life during EDD, Vd volume of distribution