Table 1 Main features of the included studies
Study reference | Stud design | Country | Time period | No. of enrolled patients | Age (mean or median)a | Sex (Male) | Severity index | Beta-lactam and mode of administration | Type of infections | Isolated pathogens | Aggressive PK/PD taret (reference MIC value) | Timing of PK/PD target assessment |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
PICO 1—Clinical efficacy of attaining aggressive vs. conservative beta-lactams PK/PD targets | ||||||||||||
Wong et al. [20] | Prospective observational monocentric | Australia | 2012–2013 | 369 | 53.4 ± 17.7 | 66% | RRT 13.8% Median APACHE II 22 (16–27) | Ceftriaxone, cefazolin, meropenem, ampicillin, benzylpenicillin, flucloxacillin and piperacillin CI 4.3% | VAP 35.0% BSI 16.8% IAI 9.2% | NA | 100fT>4 x MIC (MIC value of the clinical isolate in case of targeted therapy; EUCAST clinical breakpoint in case of empirical therapy) | NS |
Carriè et al.b [21] | Prospective observational monocentric | France | 2016–2017 | 79 | 52 (33–68) | 78% | SAPS II 40 (27–47) Vasopressors 52% ARDS 19% | Cefazolin, cefotaxime, piperacillin/tazobactam, cefepime, ceftazidime, meropenem CI 100.0% | VAP 72% IAI 13% BSI 11% UTI 9% | Enterobacteriaceae 66% Non-fermenting GNB 11% | 100fT>4 x MIC (MIC value of the clinical isolate in case of targeted therapy; EUCAST clinical breakpoint in case of empirical therapy) | At 24 h, 48 h, and 72 h |
Abdulla et al.b [22] | Prospective observational multicentric | Netherlands | 2016–2017 | 147 | 63 (56–70) | 61.9% | Median SOFA 11 (7–15) Median APACHE II 23 (18–27) RRT 19% | Amoxicillin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, meropenem CI 0.0% | NA | NA | 100fT>4 x MIC (EUCAST clinical breakpoint) | At 48 h |
Alshaer et al. [23] | Retrospective observational monocentric | USA | 2016–2018 | 206 | 59 (46–69) | 62% | Median SOFA 5 (2–8) Median APACHE II 17 (12–22) RRT 15% | Ampicillin, ceftriaxone, cefazolin, cefepime, meropenem, piperacillin CI 0.0% | VAP 57.3% BSI 31.1% UTI 12.6% SSTI 12.6% IAI 6.8% CNS 2.4% | P. aeruginosa 44.2% K. pneumoniae 19.9% E. cloacae 14.6% E. coli 14.1% | 100fT>4 x MIC (MIC value of the clinical isolate being all targeted therapies) | NS |
Taccone et al. [24] | Retrospective observational monocentric | Belgium | 2010–2016 | 70 | 55 (41–61) | 49% | Lung transplant recipients 100.0% Median SOFA 9 (7–11) Median APACHE II 14 (12–19) RRT 13% ECMO 23% MV 59% Vasopressors 43% | Cefepime, piperacillin, meropenem CI 0.0% | VAP 42.9% UTI 2.9% IAI 1.4% CR-BSI 1.4% | P. aeruginosa 11.4% E. cloacae 7.1% K. aerogenes 7.1% E. coli 5.7% S. maltophilia 4.3% | 100fT>4 x MIC (EUCAST clinical breakpoint for P. aeruginosa) | NS |
Gatti et al. [7] | Retrospective observational monocentric | Italy | 2020–2021 | 116 | 66 (56–73) | 69.8% | Vasopressors 53.5% MV 87.1% RRT 22.4% | Ceftazidime, meropenem, piperacillin/tazobactam CI 100.0% | VAP 49.1% BSI 28.1% UTI 11.2% IAI 1.7% BJI 0.9% CNS 0.9% | K. pneumoniae 25.7% P. aeruginosa 23.7% E. coli 19.4% Enterobacter spp 10.1% P. mirabilis 5.0% Other 16.6% | Css/MIC > 5 (MIC value of the clinical isolate being all targeted therapies) | Within 72 h |
Chua et al. [25] | Prospective observational multicentric | Singapore | 2016–2018 | 85 | 61.3 ± 14.8 | 80.0% | Median APACHE II 25 (20–31) RRT 44% MV 82% Vasopressors 56% ECMO 18% | Meropenem, piperacillin/tazobactam CI 1% EI (over 3-4 h) 60.9% | VAP 69% BSI 21% IAI 8% | NA | 100fT>5 x MIC (MIC value of the clinical isolate in case of targeted therapy; EUCAST clinical breakpoint for P. aeruginosa in case of empirical therapy) | Within 48 h |
Zhao et al. [26] | Prospective observational monocentric | China | 2019 | 64 | 64 (51–71) | 73.4% | Median APACHE II 17 (12–23) | Meropenem CI 0.0% (6.3% EI > 2 h) | NA | NA | Cmin/MIC > 4 Punctual MIC values (all targeted therapies) | Within 48 h |
Alshaer et al. [27] | Retrospective observational monocentric | USA | 2016–2021 | 840 | 56 ± 20 | 61% | Mean SOFA 6 ± 4 RRT 21% | Meropenem, cefepime, piperacillin/tazobactam CI 0.0% | HAP/VAP 100.0% | P. aeruginosa 44.3% Enterobacter spp 6.8% K. pneumoniae 6.2% S. marcescens 5.0% E. coli 4.9% A. baumannii 3.8% | 100fT>4 x MIC Punctual MIC values (all targeted therapies) | At 24 h, at day 10, and at the end of therapy |
Gatti et al. [28] | Retrospective observational monocentric | Italy | 2021–2023 | 58 | 62.5 (55.5–73.8) | 62.1% | RRT 25.9% ARC 10.3% | Ceftazidime/avibactam CI 100.0% | BSI 41.4% VAP 19.0% VAP + BSI 17.2% IAI + BSI 12.1% IAI 5.2% Other 5.1% | KPC-Kp 31.0% OXA-48-producing Enterobacterales 27.6% DTR-PA 24.1% | fCss/MIC > 4 (ceftazidime) fCss/CT > 1 (avibactam) (MIC value of the clinical isolate being all targeted therapies) | At 72 h for first assessment |
Alshaer et al. [6] | Retrospective observational monocentric | USA | 2016–2021 | 213 | 58 ± 16 | 57.0% | Mean SOFA 8 ± 4 RRT 24% | Cefepime, meropenem, piperacillin/tazobactam CI 0.0% | BSI 100.0% CI 11% | P. aeruginosa 36.2% E. coli 19.2% K. pneumoniae 16.0% Other 28.6% | 100fT>4 x MIC (MIC value of the clinical isolate being all targeted therapies) | At 24 h and at day 7 |
Gatti et al. [29] | Retrospective observational monocentric | Italy | 2021–2023 | 43 | 69 (57–74) | 58.1% | Median SOFA 8 (4–11) MV 81.4% Vasopressors 62.8% RRT 25.6% ARC 7.0% | Piperacillin/tazobactam CI 100.0% | BSI 55.8% VAP 37.2% VAP + BSI 7.0% | E. coli 37.5% P. aeruginosa 29.0% K. pneumoniae 12.5% Other 21.0% | fCss/MIC > 4 (piperacillin) fCss/CT > 1 (tazobactam) (MIC value of the clinical isolate being all targeted therapies) | NS |
PECO 2—Predictive factors for failure in attaining aggressive beta-lactams PK/PD targets | ||||||||||||
Udy et al. [30] | Retrospective observational monocentric | Australia | NA | 52 | 52.9 ± 20.9 | 70.8% | Mean APACHE II 20.3 ± 6.8 Mean SAPS II 39.6 ± 16.1 MV 85% Vasopressors 25% | Ampicillin, dicloxacillin, penicillin, flucloxacillin, piperacillin, cephalothin, cefazolin, ceftriaxone, ceftazidime, cefepime, meropenem, ertapenem CI 0.0% | VAP 52% | Enterobacterales 29.1% Pseudomonas spp 3.6% Acinetobacter spp 1.8% Empirical therapy 30.9% | 100fT>4 x MIC (MIC value of the clinical isolate in case of targeted therapy; EUCAST clinical breakpoint in case of empirical therapy) | NS |
Hites et al. [31] | Retrospective observational monocentric | Belgium | 2009–2011 | 68 | 59 (24–79) | 55% | Median APACHE II 18 (8–32) Median SOFA 10 (1–19) RRT 50% MV 47% Vasopressors 72% | Cefepime, meropenem, piperacillin/tazobactam CI 0.0% | VAP 37% IAI 31% SSTI 27% UTI 6% | P. aeruginosa 29% Enterobacterales 29% Non-fermenting GNB 18% | 100fT>4 x MIC (EUCAST clinical breakpoint for P. aeruginosa) | NS |
Alobaid et al. [32] | Retrospective observational multicentric | Australia, Germany, Spain | NA | 1400 | 67 (52–76) | 65% | BMI > 30 27.1% | Piperacillin/tazobactam, meropenem CI 54.6% | NA | NA | 100fT>4 x MIC (EUCAST clinical breakpoint for P. aeruginosa) | NS |
Damen et al. [33] | Prospective observational monocentric | Belgium | 2016–2018 | 356 | 66 (55–74) | 66.6% | Median APACHE II 23.0 (20.8–26.0) Median SOFA 6.0 (2.5–9.0) ARC 41.9% | Piperacillin/tazobactam CI 100.0% | NA | NA | 100fT>4 x MIC (EUCAST clinical breakpoint for P. aeruginosa) | 21.1% at 24 h, 35.1% at 48 h, 43.8% after > 48 h |
Dhaese et al. [34] | Prospective observational monocentric | Belgium | NA | 253 | 62.2 ± 15.0 | 64.8% | Mean APACHE II 23.5 ± 8.4 Median SOFA 5 (0–9) Vasopressors 1% | Piperacillin/tazobactam, meropenem CI 100.0% | NA | NA | 100fT>4 x MIC (EUCAST clinical breakpoint for P. aeruginosa) | At 48 h |
Fillatre et al. [35] | Prospective observational multicentric | France | NA | 42 | 60 (49–66) | 81% | Median SAPS II 50 (40–65) Median SOFA 11 (9–14) ECMO 50% | Piperacillin/tazobactam EI 4 h 100.0% | NA | Enterobacterales 26.2% P. aeruginosa 11.9% Empirical therapy 40.5% | 100fT>4 x MIC (EUCAST clinical breakpoint for P. aeruginosa) | NS |
Guilhaumou et al. [36] | Prospective observational multicentric | France | 2015–2017 | 196 | 56 (53.6–58.4) | 64.7% | Median SAPS II 39 (38.5–51) Median SOFA 4 (2–5) RRT 6% | Cefepime, cefotaxime, ceftazidime, meropenem CI 100.0% | VAP 51.5% BSI 25.7% UTI 15.7% CNS 2.2% IAI 0.7% | E. coli 26.1% P. aeruginosa 17.0% K. pneumoniae 13.7% | 100fT>4 x MIC (EUCAST clinical breakpoint) | At 24 h, at day 4, and at day 7 |
Gatti et al. [15] | Retrospective observational monocentric | Italy | 2021–2023 | 100 | 57 (51–63) | 63.6% | Orthotopic liver transplant recipients 100.0% Median SOFA 6.5 (3.75–9.25) MV 46.8% Vasopressors 64.9% RRT 36.4% ARC 19.5% | Meropenem, piperacillin/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam CI 100.0% | VAP 39.5% IAI 25.6% BSI 20.9% IAI + BSI 9.3% VAP + BSI 4.7% | K. pneumoniae 31.3% E. cloacae 15.7% E. coli 13.7% P. aeruginosa 13.7% | fCss/MIC > 4 (piperacillin; meropenem; ceftazidime) fCss/CT > 1 (tazobactam; avibactam) fAUC/CT > 24 (vaborbactam) (MIC value of the clinical isolate in case of targeted therapy; EUCAST clinical breakpoint in case of empirical therapy) | NS |
Tournayre et al. [37] | Retrospective observational monocentric | France | 2019–2020 | 70 | 69 (60–74) | 69% | Median SAPS II 54 (41–67) Median SOFA 8 (6–10) Septic shock 56% RRT 19% ARC 17% | Meropenem CI 52.9% EI 47.1% | VAP 53% UTI 19% IAI 13% BSI 10% | NA | Cmin or Css/MIC > 5 (EUCAST clinical breakpoint for P. aeruginosa) | At 48 h |