Table 3.
Pharmacokinetic parameters of novel agents retrieved in patients undergoing continuous renal replacement therapy
| Novel agent (study reference) | Dose |
Cmax (mg/L) |
Cmin (mg/L) |
Vd (L) |
CLtot (L/h) |
CLCRRT (L/h) |
CLCRRT/total CL ratio |
t½ (h) |
AUC (mg × h/L) |
Sieving or saturation coefficient | PK/PD target attainment |
|---|---|---|---|---|---|---|---|---|---|---|---|
|
Ceftolozane–tazobactam (Sime et al. 2019 [24]) |
1.5 g q8h (1-h infusion) |
LOZ: 54 (47–78) TAZ: 17.5 (16.4–20.2) |
LOZ: 28 (21-42) TAZ: 6.1 (5.5–6.7) |
LOZ: 73.4 ± 39.0 TAZ: 77.2 ± 32.3 |
LOZ: 3.52 ± 0.6 TAZ: 6.1 ± 0.8 |
LOZ: 2.92 ± 0.6 TAZ: 2.85 ± 0.6 |
LOZ: 83.0% TAZ: 46.7% |
LOZ: 14.5 TAZ: 8.8 |
LOZ: 284.1 TAZ: 82.0 |
LOZ: 0.94 ± 0.24 TAZ: 1.08 ± 0.3 |
3 g LD followed by 0.75 g q8h achieved a PK/PD target of 100%fT>MIC according to the CRRT setting of the study |
|
Ceftolozane–tazobactam (Kuti et al. [28]) |
3 g q8h (1-h infusion) |
LOZ: 127.2 TAZ: 40.6 |
LOZ: 43.3 LOZ: 6.7 (ELF) TAZ: 8.4 TAZ: 1.7 (ELF) |
LOZ: 17.9 TAZ: 19.2 |
LOZ: 2.6 TAZ: 4.9 |
NA | NA |
LOZ: 4.7 TAZ: 2.7 |
LOZ: 1153.8c TAZ: 612.2c |
NA |
LOZ: 100%fT>57.7×MICb TAZ: 100%T>4 mg/Lb LOZ (ELF): 100%T>8.93×MIC |
|
Ceftolozane–tazobactam (Bremmer et al.) [32] |
3 g q8h (1-h infusion) |
LOZ: 163.9 TAZ: 35.9 |
LOZ: 79.4 TAZ: 13.1 |
LOZ: 55.7c TAZ: 92.0c |
LOZ: 2.9 TAZ: 7.5 |
LOZ: 2.4 TAZ: 2.72 |
LOZ: 82.8% TAZ: 36.3% |
LOZ: 13.3 TAZ: 8.5 |
LOZ: 689 TAZ: 132.5 |
NA |
LOZ: 100%fT>39.7×MICb TAZ: 100%T>4 mg/Lb |
|
Ceftolozane–tazobactam (Oliver et al. [27]) |
1.5 g q8h (EI 4 h) |
LOZ: 38.57 TAZ: 10.94 |
LOZ: 31.63 TAZ: 7.81 |
LOZ: 153.0c TAZ: 273.9c |
LOZ: 3.52c TAZ: 6.76c |
NA | NA |
LOZ: 30.7 TAZ: 28.1 |
LOZ: 284.4 TAZ: 74.0 |
NA |
LOZ: 100%fT>21.1×MICb TAZ: 100%T>4 mg/Lb |
|
Ceftolozane–tazobactam (Aguilar et al. [30]) |
3 g q8h (1-h infusion) |
LOZ: 53.0 TAZ: 14.5 |
LOZ: 25.8 TAZ: 5.1 |
LOZ: 97.5 TAZ: 194.2 |
LOZ: 5.4 TAZ: 17.4 |
NA | NA |
LOZ: 12.6 TAZ: 7.8 |
LOZ: 373 TAZ: 57.6 |
NA |
LOZ: 100%fT>6.4×MICd TAZ: 100%T>4 mg/L |
|
Ceftolozane–tazobactam (Carbonell et al. [29]) |
3 g q8h (3-h infusion) |
LOZ: 112.7 | LOZ: 51.44 | LOZ: 24.0 | LOZ: 3.39 | NA | NA | LOZ: 5.3 | LOZ: 589 | NA | LOZ: 100%fT>12.86×MICd |
|
Ceftolozane–tazobactam (Butragueño-Laiseca et al. [33]) |
30 mg/kg q8h | LOZ: 75.8 | LOZ: 18.1 | LOZ: 1.91 | NA | LOZ: 0.39 | NA | LOZ: 3.51 | LOZ: 448.72 |
LOZ: 0.99–1.14 |
LOZ: 100%fT>4.53×MICb |
|
Ceftolozane–tazobactam (Mahmoud et al. [31]) |
3 g q8h CI |
LOZ (Css mean): 44.9 TAZ (Css mean): 18.9 |
NA |
LOZ: 5.6 TAZ: 6.6 |
LOZ: 4.15 TAZ: 4.27 |
LOZ: 74.1% TAZ: 64.7% |
NA |
LOZ: 359 TAZ: 151 |
LOZ: 0.88 ± 0.02 TAZ: 0.9 ± 0.02 |
LOZ: 100%fT>17.96×MIC TAZ: 100%T>4 mg/L |
|
|
Ceftazidime–avibactam (Wenzler et al. [35]) |
1.25 g q8h (2-h infusion) |
CAZ: 61.1 AVI: 14.5 |
CAZ: 32.0 AVI: 8.45 |
CAZ: 27.23 AVI: 30.81 |
CAZ: 2.87 AVI: 2.92 |
CAZ: 1.51 AVI: 1.52 |
CAZ: 57.1% AVI: 54.3% |
CAZ: 6.07 AVI: 6.78 |
CAZ: 347.9 AVI: 85.7 |
CAZ: 0.96 AVI: 0.93 |
CAZ: 100%T>5.33×MICb AVI: 100%T>4 mg/Lb |
|
Ceftazidime–avibactam (Soukup et al. [34]) |
2.5 g q8h (2-h infusion) |
CAZ: 152.39 AVI: 35.83 |
CAZ: 70 AVI: 17.2 |
CAZ: 11.51 AVI: 12.44 |
CAZ: 1.54 AVI: 1.45 |
NA | NA |
CAZ: 5.17 AVI: 5.92 |
CAZ: 1295.4 AVI: 343.4 |
NA |
CAZ: 100%T>8.75×MICb AVI: 100%T>4 mg/Lb |
|
Meropenem–vaborbactam (Kufel et al. [36]) |
1 g/1 g q8h (3-h infusion) |
MER: 35.0 VAB: 44.1 |
MER: 7.5 VAB: 17.2 |
MER: 50.28c VAB: 83.9c |
MER: 5.48c VAB: 3.44c |
NA | NA |
MER: 6.38 VAB: 16.81 |
MER: 182.42 VAB: 290.65 |
NA |
MER: 100%T>79.8×MICb VAB: AUC/MIC = 36.33b |
|
Fosfomycin (Gattringer et al. [26]) |
8 g q12h | 442.7 ± 124 | 103.1 ± 36.6 | 33.7 ± 12.7 | 6.4 ± 7.7 | 1.1 ± 0.2 | 76.7% ± 6.2% | 12.1 ± 5.2 | 2159.4 ± 609.8 | 0.7 ± 0.1 | 100%T>4×MIC achieved for MIC up to 16 mg/L |
|
Ceftaroline (Kalaria et al. [25]) |
300–600 mg q12h (1-h infusion) |
12.5 ± 2.4 | 2.86 ± 1.62 | 41.8 ± 16.1 | 6.68 ± 1.04 | 2.52 ± 0.60 | 35.3% ± 5.8% | 4.13 ± 1.59 | 58.3 ± 18.2 | 0.81 ± 0.1 | 100%T>MIC achieved in 75% of patients; none achieved an aggressive target of 100%T>4–5×MICb |
|
Ceftobiprole (Cojutti et al. [37]) |
250 mg q12h (2-h infusion) |
9.21 | 2.82 | 21.17 | 2.98 | NA | NA | 4.93c | 83.89c | NA | 100%T>1.41×MICb |
|
Dalbavancina (Corona et al. [38]) |
1500 mg single dose | 55.1 | NA | 27.2 | 0.334 | NA | NA | 56.8c | 4491 | NA | AUC/MIC = 89,820b |
Considering 20% protein binding for ceftolozane: 100%fT> 46.19 × MIC, 100%fT> 31.76 × MIC, 100%fT> 16.9 × MIC, and 100%fT> 3.62 × MIC []; considering 22% protein binding for tazobactam: 100%fT > 6.55 mg/L [], 100%fT > 6.01 mg/L [], 100%fT > 10.21 mg/L []. Considering 10% protein binding for ceftazidime: 100%fT> 4.79 × MIC [], and 100%fT> 7.88 × MIC []; considering 8% protein binding for avibactam: 100%fT > 7.77 mg/L [], and 15.8 mg/L []. Considering 2% protein binding for meropenem: 100%fT> 78.19 × MIC; considering 33% protein binding for vaborbactam: AUC/MIC = 24.34. Considering 20% protein binding for ceftaroline: the target of 100%fT> MIC was achieved in only 50% of cases. Considering 16% protein binding for ceftobiprole: 100%fT> 1.18 × MIC. Considering 93% protein binding for dalbavancin: fAUC/MIC = 6287 (optimal PK/PD target achieved)
AUC area under the concentration-time curve, AVI avibactam, CAZ ceftazidime, CI continuous infusion, CL clearance, CLCRRT continuous renal replacement therapy clearance, CLtot total clearance, Cmax peak concentration, Cmin trough concentration, CRRT continuous renal replacement therapy, Css mean mean concentration at steady state, EI extended infusion, ELF epithelial lining fluid, LD loading dose, LOZ ceftolozane, MER meropenem, MIC minimum inhibitory concentration, PK/PD pharmacokinetic/pharmacodynamic, qxh every x h, TAZ tazobactam, t½ half-life, VAB vaborbactam, Vd volume of distribution
aPK analysis was performed at day 8 after dalbavancin administration
bFree concentration was not calculated
cNot provided in original articles and calculated according to the formulae reported in the Methods section
dConsidering an MIC of 4 mg/L (clinical breakpoint) in the absence of isolates