Table 1 PK/PD studies of beta-lactams in patients undergoing CRRT

Fish et al. [67]

To more fully characterize PK disposition of imipenem in critically ill adult patients during currently used CVVH or CVVHDF regimens

Imipenem-cilastatin

Prospective open-label study of imipenem-cilastatin administered as the combination product in a fixed 1:1 ratio

Adult ICU patients with CVVH (n = 6 patients) or CVVHDF (n = 6 patients)

Imipenem administered at 0.5 g every 8 to 12 h (total daily doses of 1 to 1.5 g/day) by intravenous infusion over 30 min

Pre- and post-membrane plasma and corresponding ultrafiltrate or dialysate samples were collected at 1, 2, 4, and 8 or 12 h (depending on dosing interval) after completion of the drug infusion

Patients on CVVHDF had significantly higher CLs compared to patients on CVVH (P = 0.01), but this difference was not significant when normalized for total body weight (P = 0.477)

The observed t1/2 was overall similar between both patient groups (P = 0.860)

No significant differzences were found in Vd, S, and Sa, or ultrafiltration rates

Mean Cmax, Cmin, and AUC0–24 values in patients receiving 0.5 g bid during CVVH versus CVVHDF were 17.5 g/mL vs 14.1 g/mL, 1.1 g/mL vs 1.0 g/mL, and 129.5 g·h/mL vs 110.3 g·h/mL, respectively, and in patients receiving 0.5 g tid they were 18.5 g/mL vs 17.1 g/mL, 1.9 g/mL vs 1.1 g/mL, and 183.3 g·h/mL vs 140.6 g·h/mL, respectively

Doses of 0.5 g bid and 0.5 g tid generally provided T > MIC of at least 40 to 50% and 50 to 60%, respectively (MICs of < 2 g/mL) Doses of 0.5 g every 6 h (2.0 g/day) were modeled based on the PK parameters observed in this study and the T > MIC calculated: at 2.0 g/day, organisms with a MIC of < 4 g/mL had a T > MIC of at least 50 to 80%. And for those with MIC < 8 g/mL, T > MIC ranged from 34 to 62%

CVVH and CVVHDF contribute to imipenem clearance to a greater degree than previously reported. Imipenem doses of 1.0 g/day appear to achieve concentrations adequate to treat most common Gram-negative pathogens (MIC up to 2 g/mL) but doses of 2.0 g/day or more may be required to adequately treat and prevent resistance in pathogens with higher MICs (MIC > 4 to 8 g/mL)

Malone et al. [68]

To more fully characterize the

PK disposition of cefepime in critically ill adult ICU patients during CVVH or CVVHDF

Cefepime

Prospective, observational study

12 adult ICU patients receiving CRRT for severe renal failure (5 patients on CVVH, 7 patients on CVVHDF)

Cefepime regimens included either 1 g or 2 g doses administered intravenously every 12 or 24 h (total daily doses of 1 to 4 g/day)

Sampling was performed as soon as possible after initiation of the CRRT and drug therapy. Pre- and post-membrane venous blood samples were obtained 1, 2, 4, and 8 h after the completion of the drug infusion and just before administration of the next dose

Drug clearance during CRRT (CL CRRT) and %CLS were significantly higher (P = 0.002 and 0.018, respectively), and t1/2 was significantly lower (P = 0.005) among patients receiving CVVHDF than in patients receiving CVVH.

The mean cefepime S during CVVH and Sa during CVVHDF were estimated at 0.86 ± 0.04 and 0.78 ± 0.10, respectively, indicating that cefepime is extensively cleared across the CRRT membrane Approximately 40 and 59% of cefepime CLs was attributed to membrane clearance during CVVH and CVVHDF, respectively, indicating that the clearance of cefepime was substantially enhanced during both CRRT techniques

Values for cefepime Vd were also statistically different (P = 0.03) between CVVH and CVVHDF groups, but changes in Vd were only weakly correlated with changes in t1/2 (Spearman’s rank correlation coefficient of 0.641; P = 0.133)

All pathogens isolated from study patients had cefepime MICs of < 4 g/mL, and doses as low as 1 g/day would predictably provide adequate treatment during either CVVH or CVVHDF

Cefepime doses of 2 g/day would be expected to achieve favorable concentrations in serum against susceptible pathogens (MIC < 8 g/mL) with T > MIC greater than 50%. Cefepime (2 g/day) during either CVVH or CVVHDF would also be predicted to achieve favorable T > MIC > 80% against pathogens with intermediate susceptibility (MIC < 16 g/mL)

It appears that CVVHDF is more efficient than CVVH in eliminating cefepime. However, the present study included too few subjects and too much variability was observed within the data to demonstrate this conclusively.

Cefepime regimens of 0.25 to 1.0 g/day as recommended by the manufacturer for anuric patients or those receiving conventional hemodialysis would likely be subtherapeutic against all but the most highly susceptible pathogens when administered to patients receiving CRRT

The authors recommend cefepime doses of 2 g daily under most circumstances in critically ill patients receiving CRRT. However, considering more resistant strains, doses of 4 g/day should be considered for empirical therapy in life-threatening nosocomial infections, while awaiting results of culture and susceptibility testing

Mueller et al. [69]

To determine the PK of piperacillin-tazobactam in critically ill patients with acute anuric renal failure treated by CVVH

Piperacilin-tazobactam

Prospective, observational study

8 adult ICU patients on CVVHD

Doses and dosing schedules were chosen empirically by the attending physicians and were administered intravenously over 15 min

Pre-dialyzer blood samples and dialyzer-outlet dialysate samples were taken before drug administration, at 10 and 30 min after infusion, and at 1, 2, 4, 6, 8, 12, 20, 22, and 24 h after infusion

CVVHD clearance of piperacillin was 37% (median, with a range of 13 to 100%) and the CVVHD clearance of tazobactam was 38% (median, with a range of 32 to 92%) of CLtotal

Vd was 0.31 ± 0.07 and 0.24 ± 0.09 for piperacilin and tazobactam, respectively

t1/2 was 4.3 ± 1.2 and 5.6 ± 1.3 for piperacilin and tazobactam, respectively

Simulations of 4 g of piperacillin and 0.5 g of tazobactam administered every 12 h and 2 g of piperacillin and 0.25 g of tazobactam administered every 8 h resulted in times above MIC of > 50% for piperacillin with susceptible (MIC of piperacillin 16 mg/liter; time above MIC, 48 to 100%) and intermediate susceptible (MIC 32 mg/liter; time above MIC, 17 to 100%) pathogens in seven of eight patients

A relevant contribution of CVVHD to the overall elimination of both drugs has to be taken into account

The estimated Vd values are greater than those of healthy subjects and t1/2 of both drugs were fourfold greater than those of healthy subjects and twofold greater than those with a creatinine clearance < 20 mL/min/1.73 m²

Patients with residual renal function and patients that receive CRRT with higher dialysate flow rates or higher additional hemofiltrate flow rates might have higher CL of piperacillin-tazobactam, resulting in higher dosage needs

Roberts et al. [70]

To assess the variability of antibiotic trough concentrations, the influence of effluent flow rates on such concentrations, and the incidence of suboptimal antibiotic dosage

Meropenem and piperacilin-tazobactam

Prospective, observational, multicenter study, conducted within the multicenter RENAL study. It assessed the effect of post-dilutional higher intensity (40 mL/kg/h effluent rate) or lower intensity (25 mL/kg/h effluent rate) CRRT. Patients were randomized to receive either higher or lower intensity effluent flow rate

24 adult ICU patients with AKI on CVVH. 17 patients were on meropenem and 7 patients on piperacilin-tazobactam

Antibiotic dosing was at the discretion of the treating physician: meropenem 0.5 g every 12 h to 1 g every 8 h; piperacilin 4 g every 12 h to 4 g every 6 h

Blood samples were obtained on more than one occasion on different days and before administration of the antibiotic to determine the trough concentration

There was marked variability in trough concentrations for all antibiotics: 6.7-fold for meropenem; 3.8-fold for piperacillin; 10.5-fold for tazobactam

When investigating trough concentration variability according to effluent flow rate, no statistically significant differences were found using univariate analysis

Meropenem trough concentrations were 10.1 ± 8.7 and 15.0 ± 6.4 for low and high effluent flow rates, respectively

Piperacilin trough concentrations were 83.6 ± 63.8 and 204.0 ± 105.0 for low and high effluent flow rates, respectively

100% T > MIC was achieved with meropenem (for MIC 2 mg/L) and piperacilin-tazobactam (for MIC 16 mg/L)

76% T > MIC was achieved for meropenem (for MIC 8 mg/L)

86% T > MIC was achieved for piperacilin-tazobactam (for MIC 64 mg/L)

It appears that CRRT effluent flow rates cannot be used independently to guide dose adjustment

Trough concentrations failed to achieve the higher therapeutic target in 24% of patients receiving meropenem and 14% of patients receiving piperacillin, which is of concern

Dose-adjusting to achieve a target concentration that exceeds the appropriate MIC but is less than potentially toxic concentrations seems desirable but cannot be reliably achieved with empirical dosing

Banyai et al. [71]

To study the PK of cefpirome in critically ill patients with acute kidney failure treated by CVVH and to develop an optimal dosing regimen in patients with CVVH

Cefpirome

Prospective, observational study

8 adult ICU anuric patients with acute kidney failure on CVVH

All patients received a dosage of 2 g cefpirome over a period of 30 min, every 8 h after starting the hemofiltration

Blood samples were collected from the arterial and venous line of the extracorporeal circuit immediately at baseline and at 60, 120, 180, 240, 300, 360, and 420 min after the start of the first infusion. Additional blood samples were collected immediately before the end and 30 min after the end of each infusion, up to a total study period of 48 h

Ultrafiltration samples were collected from the outlet of the ultrafiltrate compartment of the hemofilter at corresponding times

C_max 14.8 ± 3.2 μg/mL (10.8 to 19.7)

C_min 3.1 ± 0.8 μg/mL

Post hemofiltration to pre-hemofiltration ratio of 0.23 ± 0.10

Total drug removal of 78.0% ± 8.8%

Elimination t1/2 was 2.36 ± 0.59 h (1.6 to 3.2 h). The calculated Vd was 118 ± 36 L

Total body clearance and hemofiltration clearance were 589.1 ± 164.5 mL/min and 43.3 ± 7.8 mL/min, respectively

The calculated AUC was 60.4 ± 16.0 mg/L·h

Highest levels of cefpirome were significantly lower compared with values observed in healthy volunteers and in patients on hemodialysis

Plasma cefpirome concentrations remained above 4 μ g/mL for 62% and above 8 μ g/mL for 25% of the dosing interval, respectively

In patients infected with an intermediate susceptible Pseudomonas aeruginosa (MIC90 ~  8 mg/L), no sufficient antimicrobial efficacy can be expected

Comparable low trough levels of 3.1 ± 0.8 μ g/mL suggest a dosage recommendation of 2 g cefpirome every 8 h

Eyler et al. [72]

To determine the PK of ertapenem in critically ill adults receiving CVVHD or CVVHDF

Ertapenem

Prospective, open-label, first-dose PK study

8 adult ICU patients with suspected or confirmed Gram-negative infections receiving CVVHD (4 patients) or CVVHDF (4 patients)

1 g ertapenem was administered as a half-hour intravenous infusion

Blood samples were collected from the CVVHD circuit at the sampling port, just before the hemodialysis filter at time zero (baseline), 30 min (end of infusion), and 1, 2, 4, 8, 12, 18, and 24 h after the start of the ertapenem infusion. At the same time points, effluent was also collected from the effluent port of the CVVHD/F circuit

CLS, unbound 48 mL/min

VC, unbound 32 l

VP, unbound 21 l

CLdial, unbound 36 mL/min

PTA (40%T > MIC) and fraction of the dosage interval spent above the MIC for different regimens were

For MIC of 0.5 mg/L

500 mg q12h, 1.0 and 0.999

500 mg q24h, 1.0 and 0.999

750 mg q24h, 1.0 and 0.999

1000 mg q24h, 1.0 and 0.999

For MIC of 1 mg/L

500 mg q12h, 1.0 and 0.999

500 mg q24h, 0.99 and 0.916

750 mg q24h, 1.0 and 0.999

1000 mg q24h, 1.0 and 0.999

For MIC of 2 mg/L

500 mg q12h, 1.0 and 0.992

500 mg q24h, 0.962 and 0.563

750 mg q24h, 0.999 and 0.750

1000 mg q24h, 0.999 and 0.917

The unbound fraction (20 to 40%) was markedly increased compared to those reported for healthy volunteers (5 to 15%)

At the effluent rates, ertapenem was cleared to a substantial degree

During the study sampling period, the dose of 1 g every 24 h produced unbound ertapenem concentrations that remained above 2μg/mL for an average of 90% of the dosing interval, achieving the PD targets in all eight patients

Monte Carlo simulations revealed that 99.9% of simulated subjects would achieve unbound ertapenem concentrations above 2μg/mL for at least 40% of the interval, with concentrations remaining above 2μg/mL for a median of 92% (range, 33 to 100%) of the dosing interval

Particularly in patients where organisms with high MICs are suspected, it may be necessary to use doses > 500 mg q24h. Concentrations remained above 2μg/mL for an interquartile range of only 50 to 67% of the dosing interval

Vossen et al. [73]

To characterize the PK profile of 1000 mg doripenem q8h for critically ill patients receiving CRRT

Doripenem

Prospective, open-label, observational study

13 adult ICU patients under CRRT (5 on CVVH, 5 on CVVHD, 3 on CVVHDF)

All patients received 1000 mg every 8 h at a 30-min infusion

Blood and dialysate samples were drawn from the arterial (input), venous (output), and effluent dialysate ports of the dialysis machine before the first administration of doripenem and at 0.5, 1, 2, 3.5, 7, 8, 9, 16, 17, 24, 24.5, 25, 26, 27.5, 31, 32, 33, 40, 41, and 48 h following the start of the first infusion

All patients: AUC0–8 (mg·h/L) 78.58 ± 10.32; Cltot (L/h) 8.07 ± 1.77; Clpre-post filter (mL/min) 36.06 ± 14.27; Sc 0.150 ± 0.053; ClSc (mL/min) 5.20 ± 1.95; Vd total 59.26 ± 26.47; t1/2 (h) 5.39 ± 2.84

Patients on CVVH (n = 3): AUC0–8 (mg·h/L) 87.15 ± 8.13; Cltot (L/h) 6.53 ± 1.00; Clpre-post filter (mL/min) 63.82 ± 5.83; Sc 0.129 ± 0.033; ClSc (mL/min) 6.45 ± 1.81; Vd total 51.05 ± 10.18; t1/2 (h) 5.72 ± 1.96

Patients on CVVHD (n = 5): AUC0–8 (mg·h/liter) 77.59 ± 12.31; Cltot (L/h) 7.48 ± 1.43; Clpre-post filter (mL/min) 34.03 ± 7.22; Sc 0.164 ± 0.067; ClSc (mL/min) 5.63 ± 2.30; Vd total 71.01 ± 34.98; t1/2 (h) 6.80 ± 3.37

Patients on CVVHDF (n = 5): AUC0–8 (mg·h/L) 76.15 ± 4.50; Cltot (L/h) 9.29 ± 1.28; Clpre-post filter (mL/min) 26.99 ± 5.34; Sc 0.145 ± 0.035; ClSc (mL/min) 4.68 ± 1.43; Vd total 50.80 ± 6.34; t1/2 (h) 3.87 ± 0.80

The simulations conducted show that the proposed dose level of 1000 mg every 8 h is superior to lower doses for reaching the desired plasma doripenem concentration of 8 mg/L. Although mean trough concentrations in all dosing regimens exceeded 4 mg/L during steady state, the individual outcomes were highly variable

At a dose of 500 mg every 8 h, only 39.5% of the simulated patients showed trough concentrations that were constantly above the lower threshold (4 mg/L) during steady state. At a dose of 1000 mg every 8 h, plasma concentrations still fell below 8 mg/L, but not lower than 4 mg/L, for 60.5% of the simulated patients

The mean hemofilter clearance rates observed slightly exceeded those reported in the literature

The sieving coefficients observed differed dramatically from those reported previously

The prefilter/postfilter clearance values found in our trial are within the range of values reported previously for imipenem and meropenem

There was an uncharacteristically low clearance for CVVHDF patients, which may be attributed to the larger membrane size and higher membrane kUF employed for the CVVHF and CVVHD groups. The usual expectation for beta-lactam antimicrobials would be quite the opposite: CVVHDF clearance values should be higher than CVVHD or CVVH clearance values. However, this is true only if the same flow rates and membrane materials are chosen.

If the 1-g q8h regimen is used, 39.5% of the patients will reach a trough level of 8 mg/L at the end of each dosing interval. To attain sufficient drug exposure during the first dosing interval the administration of an initial “loading dose” of 20.4 mg/kg of body weight is suggested

The broad therapeutic index of beta-lactams favors higher dosing, providing safety margin for more-effective RRT modalities

Carlier et al. [74]

To describe the PK of cefepime in septic shock patients requiring CRRT and to investigate whether PK/PD targets are achieved with current dosing strategies as well as to investigate the potential advantages of alternative dosing regimens

Cefepime

Prospective, observational study

13 adult ICU patients with septic shock and on CRRT (CVVHF or CVVHDF)

Patients received 2 g q8h or q12h. The dose was administered as a 30-min intravenous infusion

Blood samples were drawn on the day of inclusion and then every second day during CRRT treatment whenever possible. On each sampling day, blood samples were drawn immediately before antibiotic administration (0 h) and then at 1, 2, and 5 h and at 6 or 12 h (depending on the antibiotic regimen) after the start of the infusion

CL (L/h) 4.5

Vd (L) 40.6

PTA at different UFR considering a MIC of 16 mg/L

UFR 1000 mL/h

1 g q12h 100%T > MIC 64% and 60%T > MIC 95%

2 g q12h 100%T > MIC 89% and 60%T > MIC 99%

1 g q8h 100%T > MIC 95% and 60%T > MIC 100%

2 g q8h 100%T > MIC 99% and 60%T > MIC 100%

1 g q6h 100%T > MIC 100% and 60%T > MIC 100%

UFR 1500 mL/h

1 g q12h 100%T > MIC 31% and 60%T > MIC 80%

2 g q12h 100%T > MIC 82% and 60%T > MIC 98%

1 g q8h 100%T > MIC 87% and 60%T > MIC 99%

2 g q8h 100%T > MIC 96% and 60%T > MIC 100%

1 g q6h 100%T > MIC 97% and 60%T > MIC 100%

UFR 2000 mL/h

1 g q12h 100%T > MIC 9% and 60%T > MIC 51%

2 g q12h 100%T > MIC 73% and 60%T > MIC 95%

1 g q8h 100%T > MIC 79% and 60%T > MIC 95%

2 g q8h 100%T > MIC 92% and 60%T > MIC 100%

1 g q6h 100%T > MIC 93% and 60%T > MIC 100%

Antibiotic clearance was proportional to UFR, with important variability between patients both for clearance and Vd

A dose of 2 g q8h or 1 g q6h leads to optimal target attainment (100% T > MIC) whilst minimizing the probability of reaching toxic trough concentrations for patients treated with a high UFR (1500–2000 mL/min). However, the optimal dose for patients treated with lower UFRs (≤ 1000 mL/h) when aiming for the high target was 1 g q8h

Seyler et al. [75]

To evaluate whether the recommended doses of broad-spectrum beta -lactams result in appropriate serum concentrations in ICU patients with severe sepsis and septic shock receiving CRRT

Meropenem

Piperacilin-tazobactam

Cefepime

Ceftazidime

Prospective, open-label study

53 adult ICU patients with severe sepsis or septic shock on CRRT (CVVH, n = 19 or CVVHDF, n = 34)

Meropenem 1 g q12h (n = 17)

Piperacilin-tazobactam 4.5 g q6h (n = 16) Cefepime 2 g q12h (n = 8)

Ceftazidime 2 g q12h (n = 12)

Each antibiotic dose was administered as a 30-min infusion

Serum concentrations of these antibiotics were determined from samples taken before (t = 0) and 1, 2, 5, and 6 or 12 h (depending on the bea-lactam regimen) after the administration of each antibiotic

Series of measurements were separated into those taken during the early phase (< 48 h from the first dose) of therapy and those taken later (> 48 h)

Meropenem

Vd (l/kg) 0.45 (0.20 to 3.03)

Cmax (μg/mL) 26 (15 to 67)

Cmin (μg/mL) 6 (2 to 11)

AUC (mg/h/mL) 134 (61 to 291)

CL (mL/min/kg) 1.15 (0.54 to 3.37)

t1/2 (h) 4.39 (2.61 to 30.5)

Piperacilin-tazobactam

Vd (l/kg) 0.44 (0.22 to 1.72)

Cmax (μg/mL) 138 (36 to 262)

Cmin (μg/mL) 60 (4 to 155)

AUC (mg/h/mL) 527 (62 to 1378)

CL (mL/min/kg) 1.15 (0.27 to 6.26)

t1/2 (h) 4.16 (1.05 to 15.3)

Cefepime

Vd (l/kg) 0.55 (0.33 to 0.94)

Cmax (μg/mL) 43 (28 to 83)

Cmin (μg/mL) 11 (3 to 22)

AUC (mg/h/mL) 379 (148 to 483)

CL (mL/min/kg) 1.04 (0.43 to 2.97)

t1/2 (h) 6.17 (3.30 to 22.9)

Ceftazidime

Vd (l/kg) 0.37 (0.22 to 0.84)

Cmax (μg/mL) 78 (54 to 118)

Cmin (μg/mL) 24 (5 to 46)

AUC (mg/h/mL) 536 (258 to 906)

CL (mL/min/kg) 0.52 (0.13 to 1.61)

t1/2 (h) 7.74 (2.52 to 33.5)

PK/PD target attainment (four times MIC attainment for Pseudomonas spp.)

Meropenem

Day < 48 h (n = 7) 71%

Day > 48 h (n = 15) 87%

Piperacilin-tazobactam

Day < 48 h (n = 12) 66%

Day > 48 h (n = 9) 78%

Cefepime

Day < 48 h (n = 7) 0%

Day > 48 h (n = 4) 0%

Ceftazidime

Day < 48 h (n = 8) 38%

Day > 48 h (n = 7) 71%

The recommended doses for broad-spectrum beta-lactams are generally insufficient to maintain therapeutic serum concentrations greater than four times the MIC of P. aeruginosa

Applying results to other MICs, the observed concentrations for all antibiotics were adequate in 90% of patients only for MICs lower than the clinical breakpoint of Pseudomonas spp., which correspond to MICs of sensitive Enterobacteriaceae

In the first 48 h of treatment, 29%, 34%, 100%, and 62% of our patients treated with meropenem, piperacillin-tazobactam, cefepime and ceftazidime, respectively, never reached the PK target. After 48 h of treatment, the drug concentrations obtained were higher (significantly different only for meropenem), but they remained insufficient in many patients

At the onset of sepsis in patients receiving CRRT, similar beta-lactam doses to those used in the absence of renal failure should be given during the first 48 h of therapy

Dose reduction should be considered thereafter to avoid drug accumulation. Considering the large PK variability, therapeutic drug monitoring of beta-lactams should be performed to optimize antibiotic efficacy

Roberts et al. [76]

To evaluate variability in CL and Vd and to assess the effect of CRRT prescription on extracorporeal and systemic antibiotic CL and Vd in patients treated with CRRT of different intensities

Meropenem

Piperacillin-tazobactam

Nested cohort prospective multicenter observational PK study within a randomized controlled trial of CRRT intensity

Patients were randomly assigned to receive post-dilutional hemodiafiltration as either a higher (40 mL/kg body weight/h effluent flow rate) or lower (25 mL/kg body weight/h effluent flow rate) intensity rate

Sampling occurred each day (1) immediately before antibiotic dosing, (2) after completion of their intravenous infusion, and (3) at 4 h after completion of infusion

It occurred at 65 time points for meropenem and 29 time points for piperacillin-tazobactam in 24 patients

Mean hemodiafiltration clearance of meropenem, piperacillin, and tazobactam did not differ significantly between higher vs lower CRRT intensity: 23 (16–29) vs 21 (15–28), P = 0.4802; 22 (21–31) vs 24 (17–31), P = 0.9091; 37 (34–49) vs 56 (41–66), P = 0.0642, respectively

Systemic clearance and Vd were

Meropenem 38 mL/min (23–95) and 17.5 L

Piperacillin 59 mL/min (37–115) and 18.7 L

Tazobactam 113 mL/min (45–248) and 49.3 L

The prescribed intensity of CRRT did not adequately predict extracorporeal clearance or Sd, CLs, Vd, or half-life

Systemic CL and elimination half-life did not differ according to CRRT dose, and so the CRRT prescription may not be useful for guiding antibiotic prescribing. In many cases, extracorporeal CL accounted for more than 30% of the observed systemic CL for that antibiotic, which is a suggested threshold for adjustment of the dosing regimen

Drug monitoring may be the most practical method for ensuring that antibiotic therapeutic targets are achieved in critically ill patients receiving CRRT

Ohchi et al. [77]

To investigate PK characteristics of doripenem in patients receiving high-flow vs conventional flow intensity CVVHDF

Doripenem

Prospective, observational study

Adult ICU

Two patients with AKI on high-flow CVVHDF. Patients on conventional CVVHDF were described in a previous study

Doripenem administrated as 250 mg single dose infusion over 1 h

Blood samples were collected at 1 (just prior to the end of antibiotic infusion), 2, 3, 4,7, and 12 h after initiating the infusion

High flow CVVHDF parameters: blood flow 100 mL/min; dialysate flow rate 1500 mL/h; filtration flow rate 900 mL/h

Conventional CVVHDF

AUC 74.15 ± 15.5 mg.h/L

Cls 58 ± 12.7 mL/min

Cl dialysis 13.5 ± 1.6 mL/min

t1/2 7.9 ± 3.7 h

High-flow CVVHDF

AUC 35.2 mg.h/L

Cls 118 mL/min

Cl dialysis 41.9 mL/min

t1/2 2.9 h

Extracorporeal clearance increases in proportion with the intensity dialysis rate

The daily dose thus must be increased to 1.0–1.5 g, the same dosage used when creatinine clearance is > 50 mL/min

Arzuaga et al. [78]

To study the PK of piperacillin and tazobactam during CRRT in ICU patients with various degrees of renal impairment.

Piperacilin-tazobactam

Prospective, observational study

14 adult ICU patients on CVVHDF, grouped according to severity (CLCR 10 mL/min, 10 < CLCR < 50 mL/min, and CLCR> 50 mL/min)

Piperacilin 4 g and tazobactam 0.5 g were administrated every 6 or 8 h, by 20-min intravenous infusion

Prefilter blood and ultrafiltrate samples were collected at 0, 0.3, 0.5, 0.75, 1, 3, 6, and 8 h (in case of administration every 8 h) after the administration of the antibiotic. Time 0 was considered just before the beginning of the 20- min infusion

CLCR < 10 mL/min (n = 4)

CLCR: 8.67 ± 2.31 mL/min

UF flow: 27.1 ± 7.8 mL/min

Sc: PIP 0.42 ± 0.25; TZ 0.76 ± 0.26

Cmax: PIP 365.6 ± 232.3; TZ 38.4 ± 13.4 mg/L

t1/2: PIP 7.8 ± 4.2; TZ 7.9 ± 3.0 h

Cls: PIP 50.0 ± 53.0; TZ 50.4 ± 38.3 mL/min

Hemofiltration Cl: PIP 11.45 ± 6.5 1; TZ 20.9 ± 12.6 mL/min

AUC: PIP 76143 ± 49,748; TZ 23218 ± 27,943 mg.h/L

Vd: PIP 21.0 ± 11.7; TZ 18.9 ± 7.1 l

10 < CLCR > 50 mL/min (n = 5)

CLCR 25.20 ± 7.73 mL/min

UF flow: 30.3 ± 4.3 mL/min

Sc: PIP 0.38 ± 0.37; TZ 0.73 ± 0.32

Cmax: PIP 244.5 ± 122.1; TZ 31.5 ± 5.1 mg/L

t1/2: PIP 4.2 ± 2.3; TZ 4.1 ± 0.9 h

Cls: PIP 90.6 ± 29.9; TZ 68.2 ± 26.2 mL/min

Hemofiltration Cl: PIP 12.2 ± 13.2; TZ 21.9 ± 9.6 mL/min

AUC: PIP 45445 ± 25,525; TZ 23218 ± 27,943 mg.h/L

Vd: PIP 26.8 ± 19.8; TZ 21.6 ± 3.0 l.

CLCR> 50 mL/min (n = 5)

CLCR: 82.40 ± 20.03 mL/min

UF flow: 20.0 ± 7.5 mL/min

Sc: PIP 0.23 ± 0.07; TZ 0.86 ± 0.30

Cmax: PIP 160.6 ± 93.2; TZ 15.7 ± 6.6 mg/L

t1/2: PIP 2.6 ± 0.8

TZ 5.0 ± 3.9 h

Cls: PIP 265.2 ± 152.2; TZ 180.1 ± 73.9 mL/min

Hemofiltration Cl: PIP 4.8 ± 3.3; TZ 19.6 ± 15.3 mL/min

AUC: PIP 17,328 ± 11,134; TZ 2098 ± 1030 mg.h/L

Vd: PIP 44.9 ± 20.4; TZ 60.3 ± 34.6 l

t > MIC90 obtained were 100% for all the pathogens in patients with creatinine clearance < 10 mL/min. In patients with a creatinine clearance between 10 and 50 mL/min, t > MIC90 was 100% for pathogens with MIC90 ≤ 32, but only 50% for microorganisms with an MIC90 of 64. However, in patients with creatinine clearance > 50 mL/min, as piperacillin elimination was faster, t > MIC90 was only 55.5% and 16.6% for pathogens with MIC90 values of 32 and 64, respectively

The contribution of the hemofiltration clearance to the total clearance increased with the degree of renal insufficiency. Correct doses of these drugs should take into account this observation to avoid clinical failures due to underdosing

For both drugs, significant differences were documented in the majority of the PK parameters when patients with CLCR > 50 mL/min were compared to patients with CLCR ≤ 10 mL/min

The observed sieving coefficient of piperacillin and tazobactam plus the effluent amount gave a relevant extracorporeal clearance only in the severe renal impairment group, with more than 25% of total clearance for both drugs

To increase the t > MIC90 index, piperacillin-tazobactam combination every 4 h could be a better dosage regimen in patients presenting CLCR > 50 mL/min

Isla et al. [79]

To describe the PK of meropenem in critically ill patients with different degrees of renal impairment undergoing CVVHF or CVVHD

Meropenem

Prospective, observational study

20 adult ICU patients on CVVHF or CVVHDF

Grouped into 3 categories according to the renal function: 7 with severe failure, ClCr less than 10 mL/min (group I); 7 with moderate failure, ClCr 10 to 50 mL/min (group II); and 6 with ClCr greater than 50 mL/min (group III)

Blood flow rate 110–220 mL/min; dialysate flow rate 500 or 1000 mL/min; ultrafiltrate 800–2500 mL/h

Patients received 500, 1000, or 2000 mg of meropenem intravenously every 6 or 8 h and infused over 20 min

Blood was obtained from a prefilter device immediately before dosing, at the end of the infusion, and at 20, 30, and 45 min and 1, 3, and 6 h after the beginning of the infusion. Another sample was collected 8 h after the beginning of the infusion in patients to whom meropenem was administered every 8 h

Simultaneously, dialysate-ultrafiltrate samples were taken directly from the dialysate-ultrafiltrate device

No significant differences depending on renal impairment were found in the Sc. No differences were found in the Sc obtained by CVVHF and the Sa obtained by CVVHD; both membranes showed a similar permeability to meropenem

Total clearance was significantly higher in group III than in the other two groups. This finding could be attributable to the lower t1/2 (1.51 ± 0.52 h in group III versus 2.73 ± 0.68 h and 3.72 ± 0.82 h in groups II and I, respectively) and to the high Vd observed in those patients (1.31 ± 0.90 L/kg in group III, 0.37 ± 0.10 L/kg in group II, and 0.57 ± 0.29 L/kg in group I)

The contribution of CRRT to total clearance diminished in the extent that CLCR increased. Although there were no statistically significant differences between groups I and II, Cl_CRRT was significantly lower in group III

In group I patients, trough plasma concentrations were above 4 μg/mL, with the exception of the only patient who received 500 mg/8 h. In group II, plasma concentrations were above 2 μg/mL during the entire dose interval, except in the patient to whom 1000 mg/8 h was administered

In spite of the higher doses the patients of group III received, 4 of 6 patients showed concentrations below 0.5 μg/mL

Differences in meropenem PK in critically ill patients undergoing CRRT with different degrees of renal impairment have been observed, and they should be taken into account when dosing critically ill patients

In those patients with no renal impairment the risk of underdosing and clinical failure is important, and the administration of meropenem 2000 mg every 8 h did not reach plasma levels to ensure adequate T > MIC values against many bacteria

Ulldemolins et al. [80]

To describe the PKs of meropenem in critically ill patients with septic shock and CRRT, to identify the sources of PK variability in these patients, and to perform different dosing simulations to assess their probability of target attainment by MIC, in order to provide empirical dosing recommendations based on clinical characteristics

Meropenem

Prospective, observational, multicentre study

30 adult ICU patients with septic shock and CRRT, either CVVHF (n = 4) or CVVHDF (n = 26)

Patients were prescribed meropenem at 500 mg q12h over 30 min (n = 1); 500 mg q8h over 30 min (n = 2) or as a 3-h infusion (n = 3); 500 mg q6h as a 3-h infusion (n = 1); 1000 mg

q12h over 30 min (n = 6) as a 3-h infusion (n = 1) or as a 4-h infusion (n = 1); 1000 mg q8h over 30 min (n = 8) as a 3-h infusion (n = 5) or as a 4 h-infusion (n = 1); or 2000 mg q8h over 30 min (n = 1)

Blood samples were collected at 24 h of CRRT and meropenem therapy. For bolus sampling, 6 samples were collected at 10 min pre-dose; at 0, 15, and 60 min and between 3 and 6 h after the end of the infusion; and just before the next dose. For extended infusion sampling, samples were collected at 10 min pre-dose; 0, 60, and 120 min after the end of the infusion; and just before the next dose

CRRT settings: the median intensity on the day of the study was 34.7 mL/kg/h (range, 18.7 to 60.1 mL/kg/h), and the median blood flow was 200 mL/min (range, 130 to 250 mL/min)

The study model failed to identify CRRT intensity to be a significant modifier of meropenem CL, which may lead to the hypothesis that even the lowest CRRT intensities studied may be enough to maximize meropenem clearance and that higher intensities may add little to total meropenem CL

There were no differences between CRRT techniques, likely because of the underrepresentation of CVVHF (4 out of 30 patients) in the study population

For the attainment of a PD target of 100% of the T > MIC, fixed doses would be required, depending on the MIC of the bacteria, but the infusion time would depend on residual diuresis: oligo-anuric patients would benefit from a 30-min bolus, while a 3-h extended infusion would be more appropriate for those patients with preserved diuresis

For the attainment of the classic PD target for carbapenems (40% of the T > MIC), a standard dose of 500 mg q8h as a bolus over 30 min would be sufficient for all cases

For the attainment of a more aggressive target, such as a Cmin/MIC ratio of 5, doses of 1000 mg q8h as a 3-h infusion or higher would be required

Population PK model successfully identified residual diuresis to be a modifier of total meropenem CL

CRRT intensity did not significantly modify meropenem CL, for which dose adjustments based on intensity seem to be unnecessary

Given a certain MIC, simulations showed that meropenem dose titration considering residual diuresis was advantageous for the attainment of 100% of the T > MIC as a PD target. If classic PD targets (40% of the T > MIC) were targeted, a standard dose of 500 mg q8h as a 30-min bolus would be sufficient, regardless of urine output

Bouman et al. [81]

To compare the observed Cl_CVVHF (calculated from measured data) and the predicted Cl_CVVHF (calculated from the F_UP)

To determine whether dose adjustment according to the predicted CVVH removal provides an estimate as reliable as that according to the observed CVVH removal

Amoxicillin

Ceftazidime

Flucloxacillin

Prospective, observational study

45 adult ICU oligoanuric patients on CVVHF

During the sampling period a single antimicrobial drug was administered to 31 patients, two drugs to 9 patients, and a combination of 3 to 5

Dosages were: amoxicilin 1000 mg q6h; ceftazidime 1000 mg q6-12 h; flucloxacillin 2000 mg q4-6 h

Blood flow rate was 150 mL/min and warmed substitution fluids were administered in predilution at a flow rate of 2000 mL/h. If a negative fluid balance was required, the ultrafiltration flow was increased and the substitution flow was constant

Blood samples were collected from the afferent (pre-hemofilter) and efferent (post-hemofilter) line of the extracorporeal circuit and from the ultrafiltrate line. Samples were collected at 2, 4, and 6 h for agents given every 6 h; at 2, 4, and 8 h for agents given every 8 h; and at 2, 6, and 10 h for agents given every 12 or 24 h

All the studied agents were easily filtered (SC > 0.7) with the exception of flucloxacillin

There was a high interindividual variability in the SC values of the studied drugs, in particular for ceftazidime and to a lesser degree for amoxycillin and flucloxacillin

The correlation between observed and predicted clearance was significant (P = 0.003) only when all drugs were combined, not for the individual antimicrobial drugs. Despite the nonsignificant correlation, the difference between predicted and observed clearance for all drugs was small, with the exception of ceftazidime

There was no significant correlation between predicted and observed CVVH drug removal. However, for clinical practice, dose adjustment according to the predicted CVVH removal provides a more reliable estimate than that according to the observed CVVH removal

Although there is interpatient variability between the observed and predicted Cl_CVVHF values for some antibiotics, its effect on dosing strategies is not necessarily clinically relevant: flucloxacillin has an important non-renal elimination route, and therefore the Fr_CVVHF value was extremely low and not affected by the wide interindividual variation in observed Cl_CVVHF. Also, wide therapeutic range, such as with ceftazidime, makes it safe to use the predicted Cl_CVVHF for dose adjustment