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Table 2 PK/PD studies of beta-lactams in patients with sustained low-efficiency dialysis or extended daily dialysis

From: Pharmacokinetics–pharmacodynamics issues relevant for the clinical use of beta-lactam antibiotics in critically ill patients

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

  1. 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