Beta-lactam dose reductions in critically ill patients with acute kidney injury: a scoping review

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M.B. Horstink, W. J.R. Rietdijk, D. R. Geel, P. E. Deetman, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7156465/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Dec, 2025 Read the published version in Critical Care → Version 1 posted 16 You are reading this latest preprint version Abstract Background Acute kidney injury is a common complication in critically ill patients, often coinciding with the need for antibiotic therapy. The dose of beta-lactam antibiotics is frequently adjusted and often reduced based on estimated Glomerular Filtration Rate. However, early dose reductions may lead to underdosing, especially during the critical first 48 hours of infection treatment, when AKI may be transient and adequate antibiotic treatment is critical. While some reviews suggest delaying dose reductions improves clinical outcomes, evidence remains limited. This scoping review evaluates the current literature on beta-lactam dosing strategies in critically ill patients with acute kidney injury, focusing on pharmacological and clinical outcomes. Methods We conducted a systematic scoping review following PRISMA-ScR guidelines. We searched Medline, Embase, Web of Science, Cochrane CENTRAL, and Google Scholar from database inception through March 24, 2025. Two reviewers independently screened all articles and assessed study quality using ROB-2 and ROBINS-E tools. Eligible studies included critically ill adult patients with acute kidney injury, receiving beta-lactams, and reporting clinical or pharmacological outcomes. Data were extracted using a standardized template and categorized by pharmacological or clinical outcomes. Further stratification by antibiotic type or patient characteristics was not feasible. Results Out of the 1,436 screened articles, 11 studies involving 25,381 patients were included. The risk of bias was high in most studies. Most studies were observational; one was a randomized controlled trial. Seven studies reported beta-lactam plasma concentrations. Higher concentrations were generally observed in patients with acute kidney injury, even though dosages were oftentimes already reduced. One study associated early dose reductions with decreased neurotoxicity. One study reported increased treatment failure with early dose reductions and three studies linked delayed dose reductions to reduced mortality. Conclusions Current evidence on beta-lactam dose reduction in critically ill patients with acute kidney injury is limited and of low quality. Delaying reductions may improve clinical outcomes, but further prospective studies are urgently needed. Intensive Care Acute Kidney Injury Beta-lactam antibiotics Scoping Review Figures Figure 1 Figure 2 Background Acute kidney injury (AKI) is one of most common complications of critical illness, with reported incidences ranging from 20 to 75% [ 1 – 4 ]. The severity of AKI is typically classified based on an increase in serum creatinine and/or a decrease in urine output, although specific criteria vary across definitions [ 5 – 7 ]. At the same time, around 50% of all patients admitted to the intensive care unit (ICU) have an infection that requires antibiotic treatment [ 8 ]. Delay in initiating therapy is strongly associated with increased mortality [ 9 ], underscoring the critical importance of timely and appropriate antimicrobial management in this population. Beta-lactam antibiotics are amongst the most commonly prescribed antibiotics in the ICU setting due to their broad-spectrum activity against both Gram-positive and Gram-negative bacteria [ 10 , 11 ]. Since beta-lactam antibiotics are predominantly cleared by the kidneys, dosing regimens are often adjusted based on renal function. In practice, this means patients with acute or chronic kidney dysfunction typically receive reduced dosages. However, most dosing guidelines are derived from studies involving patients with chronic kidney disease and pharmacodynamic (PD) models, while evidence specific to those with AKI remains limited. Since critically ill patients are a heterogeneous population with rapid, dynamic changes in physiology, achieving target antibiotic concentrations is challenging [ 12 , 13 ]. Factors such as augmented renal clearance, organ dysfunction, fluctuations in albumin levels, and increased volume of distribution all contribute to altered pharmacokinetics. Observational studies have shown that PD targets are often not achieved, meaning that underdosing of beta-lactam antibiotics is common in the ICU population [ 12 , 13 ]. Taking into consideration that the first 48 hours are critical in the treatment of infections [ 14 ], that beta-lactam antibiotics have a broad therapeutic window and that a significant proportion of AKI cases resolve within the first 24 to 48 hours of ICU admission (i.e., rapidly reversible or transient AKI) [ 15 – 17 ], it is reasonable to question whether initial dose reductions based on (temporary) kidney dysfunction are necessary. Moreover, the diagnosis of AKI is typically based on rising serum creatinine levels, despite the frequent absence of reliable baseline values. Therefore, serum creatinine alone is a delayed and imprecise marker of renal function, which further complicates early dosing decisions [ 18 ]. The underlying cause of AKI also plays a crucial role in determining the optimal treatment strategy. For instance, patients with pre-renal AKI may be hyperdynamic and require aggressive fluid resuscitation, potentially diluting antibiotic concentrations. In contrast, post-renal AKI often resolves swiftly once the obstruction is relieved, making early dose reductions potentially unnecessary or even counterproductive. Some narrative reviews have suggested that dose reductions of antibiotics with a broad therapeutic window should be postponed until 48 hours after initiation of therapy, when the trajectory of renal function is more clearly defined. It has been argued that the risk of toxicity with this approach is low, thereby optimizing the risk–benefit balance [ 17 , 19 ]. However, these reviews are mostly based on expert opinion, and fail to provide a systematic overview of available evidence. Therefore, we conducted a scoping review to evaluate the availability and quality of evidence on the achievement of PD targets and clinical outcomes when adjusting beta-lactam dosages in critically ill patients with AKI. Methods A systematic scoping review was conducted to evaluate the existing literature on beta-lactam dose reductions in critically ill patients with AKI. This review followed the Preferred Reporting of Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines [ 20 ]. The PICO framework guiding this review was defined as follows: Patients Critically ill patients with acute kidney injury Intervention Dose reductions of beta-lactam antibiotics based on kidney function Comparator No dose reductions of beta-lactam antibiotics Outcomes Mortality, treatment failure, adverse events, hospital or ICU length of stay, and pharmacodynamic target attainment Search strategy A comprehensive literature search was performed across Medline, Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar from database inception through March 24th, 2025. The search strategy, developed by a medical librarian (M.E., see acknowledgements) in collaboration with the research team (M.H.), included a combination of keywords and subject headings related to: Beta-lactam antibiotics Critical illness/Intensive care Acute kidney injury/Acute renal impairment The full search strategy is detailed in Appendix 1. Only articles published in English were considered for inclusion. A total of 2,097 records were retrieved. After removing duplicates, 1,439 unique records remained. These were uploaded into Covidence for further screening, where an additional 3 duplicates were identified and removed, leaving 1,436 articles for initial review. Title/abstract and full-text screenings were conducted independently by two reviewers (M.H. and W.R.), with discrepancies resolved by a third reviewer (C.U.). Reference lists of included articles were also screened for additional relevant studies. Inclusion and Exclusion criteria The inclusion criteria were primary studies that included critically ill, adult patients with AKI (as defined by the articles) and reported clinical or pharmacological data of beta-lactam antibiotic dosages and/or reductions, as well as kidney function. Exclusion criteria included patients with chronic kidney disease (as defined by the authors), patients on renal replacement therapy, case reports, conference abstracts and (systematic) reviews. Quality Assessment Assessment of risk of bias in individual studies was conducted by two independent authors (M.H. and W.R.) using the Cochrane Risk of Bias tool for randomized trials (ROB-2) or non-randomized exposure (ROBINS-E) studies depending on the study design [ 21 , 22 ]. Disagreements were resolved through discussion and consensus. Data-extraction Data extraction was performed using a predefined template by one reviewer and cross-checked by the other reviewer (M.H. and W.R.). Clinical outcomes were classified into treatment failure (including mortality) and adverse events. There were no data available regarding hospital and ICU length of stay. Pharmacological outcomes were divided into those observed within the first 48 hours after antibiotic initiation and those reported beyond this period. This method was chosen because AKI oftentimes resolves within this time period, while adequate antibiotic therapy is most crucial at the initial phase of sepsis and infection. Although it was initially intended to further classify the articles based on the type of antibiotic and patient characteristics, this was not feasible due to the limited number of available studies. Results Of the 1,436 articles screened for eligibility, 1400 were excluded based on title and abstract screening, leaving 36 articles for full-text review. Next, 26 studies were excluded because they included non-ICU patients (n = 9), included no beta-lactam antibiotic (n = 1), were case reports, reviews or conference abstracts (n = 5), did not report on beta-lactam antibiotic dosages (n = 4), did not report on kidney function (n = 4) or compared other, non-antibiotic interventions (n = 3). One article was included through citation tracking [ 23 ]. In total 11 articles including 25,381 patients, of which 24,650 were from Luo et al., were included in the final analysis [ 23 – 33 ]. A detailed summary of the study selection process is provided in the PRISMA flow diagram (Fig. 1 ). Of the included studies 10 were observational (5 prospective and 5 retrospective cohort studies) and 1 was a randomized controlled trial. Study and patient characteristics are provided in Table 1 and Table 2 , respectively. Table 1 Study characteristics Study Year Country Journal Study design Patients analysed AKI definition Investigated agents Intervention/ exposure Primary outcome Conclusion with regard to kidney function and dose reduction Aldardeer et al. 2024 Kingdom of Saudi Arabia Open Forum Infect Dis Prospective observational cohort 224 KDIGO criteria Piperacillin/ tazobactam Meropenem Imipenem/ cilastatin Ceftazidime Cefepime A reduced beta-lactam dosage based on kidney function 24 h from sepsis recognition. In-hospital mortality within the first 90 days of follow-up In patients with AKI delaying antibiotic dose reduction beyond 24 hours of sepsis recognition decreases mortality. Fugate et al. 2013 United States of America Crit Care Retrospective observational cohort 100 1.5-fold increase from baseline creatinine or absolute increase in creatinine by ≥ 0.3 mg/dL Cefepime 2 g cefepime 2x/24 h Dose reductions: CrCl 30–60 2g 1x/24 h CrCl 11–29 1 gr 1x/24 h Development of cefepime neurotoxicity AKI is not an univariate risk indicator for cefepime neurotoxicity. Hassanpour et al. 2021 Iran Eur J Clin Pharmacol Randomized Controlled trial 16 AKIN and/or RIFLE criteria Meropenem First 48 h: 3 gr meropenem/24 h. Then randomization to dose reduction based on kidney function versus no dose reduction. Percentage of T > 4x MIC (8 mg/l) In patients with AKI, standard doses of meropenem fail to achieve the pharmacodynamic target of ≥ 80%fT > 4xMIC. Heinemeyer et al. 1990 Germany Intensive Care Med Prospective observational cohort 12 CrCl < 50 ml/min/1.73m2 Ceftriaxone 7 days of 2 gr ceftriaxone/24 h. Exploring ceftriaxone pharmacokinetics In patients with AKI, the elimination of ceftriaxone is strongly delayed. Therefore, dosages should be reduced. Luo et al. 2024 Researchers from China, Data from the USA Front Pharmacol Retrospective observational cohort 24,650 KDIGO criteria Amoxicillin Amoxicillin versus no-amoxicillin Subgroup analysis with ≥ 875 mg/ amoxicillin/24 h versus < 875 mg/24 h. 30-day all-cause mortality In patients with AKI an amoxicillin dosage of ≥ 875mg/day shows more mortality reduction than a dosage of < 825 mg/day. Passon et al. 2023 Germany Life Sci Retrospective observational cohort 50 KDIGO criteria Ampicillin/ sulbactam Loading dose of 2/1 gr ampicillin/sulbactam followed by a continuous infusion of 8/4 g per 24 h. Achievement of the MIC (8 mg/l) Patients with AKI exhibit higher ampicillin concentrations and exceed the 4-fold MIC breakpoint more often. Chabert et al. 2022 France Ann Intensive Care Retrospective observational cohort 41 NR Cefoxitin Loading dose 2 gr cefoxitin, followed by a median continuous administration of 6 gr/24 h. Achievement of the modelled serum concentration of 100%fT > MIC on the second day of therapy Cefoxitin dosages may be based on eGFR for dosage individualization. Mitton et al. 2022 South Africa S Afr Med J Prospective observational cohort 68 NR Imipenem/ cilastatin Imipenem dosages eGFR > 70: 1000 mg 4x/24 h eGFR 41–70: 750 mg 3x/24 h eGFR 21–40: 500 mg 3x/24 h eGFR < 21: 500 mg 2x/24 h Explore correlation between eGFR and through plasma levels When dosages are adjusted for kidney function, there is no correlation between eGFR and imipenem plasma concentrations. Kitzes-Cohen et al. 2002 Israel Int J Antimicrob Agents Prospective observational cohort 14 CrCl 50 ml/min (Group I) 1 gr 3x/24 h CrCl < 50 ml/min (Group II) 1 gr 2x/24 h Explore meropenem pharmacokinetics When dose reductions were made based on kidney function (group II), the AUC of meropenem is still higher. Taccone et al. 2010 Belgium Crit Care Prospective observational cohort 80 NR Meropenem Ceftazidime Cefepime Piperacillin/ tazobactam Meropenem Loading dose 1 gr CrCl > 80: 1gr 3x/24 h CrCl 50–80: 1gr 2x/24 h CrCl 10–50: 0.5gr 2x/24 h CrCl 80: 2gr 3x/24 h CrCl 50–80: 2gr 2x/24 h CrCl 10–50: 1gr 2x/24 h CrCl 50: 4/0.5 gr 4x/24 h CrCl 10–50: 4/0.5 gr 3x/24 h CrCl 4x MIC Patients with renal dysfunction (acute and chronic) had a significantly higher probability of having adequate drug concentrations than patients with normal renal function. Even when dosages were reduced based on kidney function. Camargo et al. 2019 Brazil Eur J Clin Pharmacol Retrospective observational cohort 126 NR All antimicrobials, including carbapenems. Not further specified. No reduced dosage, versus a reduced dosage based on kidney function. Treatment failure Mortality rate Antibiotic dose reductions in patients with renal impairment (acute and chronic combined) increase the risk of treatment failure and death. Abbreviations: KDIGO, Kidney Disease Improving Global Outcomes; AKI, Acute Kidney Injury; CrCl, Creatinine Clearance; AKIN, Acute Kidney Injury Network; RIFLE, Risk of renal dysfunction, Injury to kidney, Failure or Loss of kidney function, and End-stage kidney disease; T, Time; MIC, Minimally Inhibitory Concentration; NR, Not Reported; (e)GFR, (estimated) Glomerular Filtration Rate; AUC, Area Under the Curve Table 2 Patient characteristics Study Inclusion Criteria Exclusion Criteria Age BMI/Weight Gender Male (%) Patients with Sepsis SOFA Aldardeer et al., 2024 - Admitted to the ICU - Aged ≥ 18 years - AKI - Sepsis (Sepsis-3 criteria) - Received an initial full dose of antipseudomonal beta-lactam antibiotics - Unknown baseline renal function - Received the initial dose of beta-lactam adjusted for renal function - Were started on non-antipseudomonal beta-lactams - End-stage renal disease or receiving dialysis - Initiated on RRT within 48 hours of sepsis recognition - Confirmed diagnosis of coronavirus disease 2019 - Transferred from outside hospitals - Insufficient data in the medical record - Died within 48 hours of sepsis recognition 62.7 ± 16.8 Weight(kg) 75.6 ± 20.4 139 (62%) 224 (100%) 9 [ 7 – 11 ] Fugate et al., 2013 - Admitted to the ICU - Aged ≥ 18 years - Treated with intravenous cefepime for at least 3 days NR 65.8 ± 12.7 NR 61 (61%) 100 (100%) NR Hassanpour et al., 2021 - Admitted to the ICU - Aged ≥ 18 years - AKI - Treated with standard dose of meropenem (1 gr 3x/24h) based on the physician in charge decision - Chronic Kidney Disease - Renal Replacement Therapy - Pregnancy or lactation - Receiving an adjusted dose of meropenem before recruitment Standard dose 62.4 ± 14.3 Adjusted dose 54.8 ± 24.4 Standard dose weight (kg) 67.4 ± 12.2 Adjusted dose 64.4 ± 9.7 Standard dose 4 (57%) Adjusted dose 5 (56%) 16 (100%) NR Heinemeyer et al., 1990 - Admitted to the surgical ICU - Placed on ceftriaxone at the onset of a bacterial infection of the bronchial tract - Sensitivities verified by an antibiogram NR Mean 53.9 ± 20.1 Weight 73.1 ± 10.5 4 (33.3%) NR NR Luo et al., 2024 - Admitted to the ICU - Aged ≥ 18 years - AKI - Hospitalized for more than 48 h - >5% of their individual data were missing - Baseline values exceeded the median ± 1.5 times the interquartile range Amoxicillin 67.8 ± 17.2 Non-amoxicilin 67.9 ± 15.5 NR Amoxicilin 393 (58.1%) Non-amoxicilin 13.906 (58.0%) Amoxicilin 464 (68.6%) Non-amoxicilin 14.096 (58.8%) Amoxicilin 5 [ 3 – 7 ] Non-amoxicilin 5 [ 3 – 8 ] Passon et al., 2023 - Admitted to the ICU - A continuous infusion regime with ampicillin/sulbactam - Monitored by ampicillin concentration measurements NR 71.5 ± 15.3 BMI 28.7 ± 9.6 24 (48%) 38 (76.0%) 4.8 ± 3.2 Chabert et al., 2022 - Admitted to the ICU - Aged ≥ 18 years - Infection with cefoxitin-susceptible ESBL-PE - Treatment with cefoxitin during ≥ 24 h as a definitive antibiotherapy - Cefoxitin TDM with at least one serum concentration measured during therapy - Refusal to participate - Included in the study during a previous ICU stay 59.0 [53.0–74.0] BMI 65.0 [59.0–83.0] 31 (76%) 36 (88%) At admission 7.0 [5.0–12.0] At inclusion 8.0 [6.0–12.0] Mitton et al., 2022 - Admitted to the surgical ICU - Aged ≥ 18 years - Imipenem/cilastatin therapy - Refusal to participate 47 (range 18–81) Weight (kg): 78 (range 40–140) 43 (63%) 30 (44%) NR Kitzes-Cohen et al., 2002 - Admitted to the ICU - Severe sepsis - Blood or other cultures growing bacteria sensitive to meropenem NR Group 1: 73.6 ± 9.7; Group 2: 72.8 ± 6.2 NR 9 (64%) 13 (93%) NR Taccone et al., 2010 - Admitted to the ICU - Severe sepsis or septic shock - Treatment with a broad-spectrum beta-lactam antibiotic - Age 85 years - Pregnancy or lactation - Previous administration of any of the investigated antibiotics - Chronic renal failure requiring dialysis - Allergy to any of the investigated antibiotics 63 ± 13 BMI: 24.8 ± 4.8 51 (64%) 80 (100%) 8 [IQR 5–10] Camargo et al, 2019 - Admitted to the ICU for > 24 h - Aged ≥ 18 years - Missing data did not allow the calculation of the eGFR or the evaluation of treatment results (success/failure) - Prescribed dose did not match the recommendations of the used guidelines Dose reduction 56.8 ± 21.2 No dose reduction 57.68 ± 17.3 NR 64 (50,7%) 69 (54.8%) NR Data are presented as number (percentage), mean ± SD, or median [IQR] unless stated otherwise. Abbreviations: AKI, Acute Kidney Injury; (e)GFR, (estimated) Glomerular Filtration Rate; RRT, Renal Replacement Therapy; NR, Not Reported; BMI, Body Mass Index; ICU, Intensive Care Unit; TDM, Therapeutic drug monitoring; ESBL-PE, Extended-Spectrum Beta-Lactamase Producing Enterobacteriaceae Risk of bias assessment A Risk of Bias assessment, conducted using the ROB2 or ROBINS-E tool based on each study's design, showed an overall high risk of bias in eight studies [ 23 , 25 – 27 , 29 , 31 – 33 ] and some concerns in three [ 24 , 28 , 30 ]. Additional details regarding this assessment are provided in Fig. 2 and Appendix 3. AKI definitions Definitions of AKI varied considerably across the included studies. Three studies defined AKI according to the KDIGO criteria [ 5 , 24 , 28 , 29 ] one study applied the AKIN and/or RIFLE criteria [ 3 , 7 , 26 ]. Heinemeyer et al. [ 27 ], and Kitzes-Cohen et al. [ 32 ]used an estimated creatinine clearance below 50 ml/min as a threshold. In contrast, Fugate et al. [ 25 ] defined AKI as a 1.5-fold increase from baseline or an absolute increase in serum creatinine of ≥ 0.3 mg/dL. Notably, four studies did not report on any AKI definition. Clinical outcomes – Treatment failure Three studies reported on treatment failure, including mortality. All three reported less treatment failure and mortality when delaying dose reductions or administering higher initial dosages of antibiotics in AKI patients. Camargo et al. [ 23 ] studied multiple groups of antibiotics in a retrospective cohort study. Dose reductions were commonly made after 24 hours of treatment. Treatment failure, defined by the persistence of infection, clinical deterioration, or death, occurred more frequently in the reduced-dose group compared to those who received standard dosing (59.3% vs. 38.9%, p = 0.023). When isolating mortality as an outcome, the difference remained significant (74.1% vs. 55.5%, p = 0.033), suggesting that dose reductions may be associated with worse clinical outcomes. Based on this study it seems that postponing dose reductions for at least 24 hours could potentially improve survival in this patient population. As this result was aggregated across various antibiotics, it remains unclear whether this finding is applicable to beta-lactam antibiotics specifically. In the study by Aldardeer et al. [ 24 ], patients in the late dose reduction group (> 24 h) had a lower in-hospital mortality compared to those in the early reduction group (< 24 h) (HR 0.588, 95% CI: 0.355–0.974). However, this finding may have been confounded by the fact that patients in the early reduction group had worse kidney function and higher APACHE scores, indicating a greater overall severity of illness. Luo et al. [ 28 ] conducted a retrospective cohort study in patients with AKI. Patients were categorized into three groups: those not receiving amoxicillin, those receiving a low dose (< 875 mg/day), and those receiving a high dose (≥ 875 mg/day). The incidence of sepsis was 58.8% and 68.6% in respectively the non-amoxicillin and amoxicillin group. The HR for 30-day mortality was higher in the low dose group compared to the high dose group (0.61 vs. 0.46), suggesting a potential survival benefit with higher dosing. However, both low dose and high dose groups were compared only to the non-amoxicillin group, making direct statistical comparisons between the two dosing strategies not possible. Clinical outcomes – Adverse events In addition to potential clinical benefits, the safety of administering higher antibiotic dosages, delayed or no dose reductions, might raise concerns. Only one study has examined the incidence of adverse effects in this context. Fugate et al. [ 25 ] investigated the incidence of beta-lactam-associated neurotoxicity in ICU patients. This retrospective cohort study looked for neurologic symptoms consisting of encephalopathy, including decreased level of alertness, myoclonus, seizures, or any combination of these in patients that received cefepime. The symptoms needed to have a clear temporal relationship to the administration of cefepime and no alternative cause for neurological deterioration could be present. A total of 15 out of 100 patients developed these symptoms. The authors found that those who developed neurotoxicity were significantly less likely to have received appropriate dose reductions based on renal function compared to those who did not (28.6% vs. 75.3%, p = 0.001). However, patients with neurotoxicity were also more likely to have underlying chronic kidney disease, complicating the interpretation of these findings in populations with AKI. Secondly, dose reductions were made throughout the entire duration of therapy, making the effect of early dose reductions unclear. Finally, it also needs to be pointed out that ruling out other causes of neurological decline in ICU patients remains difficult, given the high incidence of delirium and encephalopathy associated with sepsis-related organ dysfunction. Pharmacological outcomes – 0 to 48 hours Seven studies reported plasma concentration data for beta-lactam antibiotics in critically ill patients, with four of these including sampling within this crucial early timeframe. Sampling strategies varied between studies. Passon et al. [ 29 ] assessed steady-state trough concentrations of ampicillin at a median of 29 hours after treatment initiation. Mitton et al. [ 31 ] collected meropenem trough levels after at least four doses. In contrast, Taccone et al. [ 33 ] conducted multiple samples of different beta-lactams (piperacillin/tazobactam, ceftazidime, cefepime and meropenem) within the first 28 hours of therapy. Among those four studies, three reported higher antibiotic concentrations in patients with acute kidney injury. Passon et al. [ 29 ] demonstrated that patients with AKI exhibited significantly higher ampicillin levels (81.1 ± 37.7 mg/L) compared to those without AKI (38.2 ± 24.8 mg/L; p < 0.001). Additionally, patients with AKI exceeded the 4× MIC threshold (set at 32 mg/L) more frequently (92.0% vs. 44.0%; p < 0.001). This was also the case in the report of Taccone et al. [ 33 ] who reported that patients with decreased renal function at ICU were more likely to achieve the desired target even when dose reductions were made. However, in these patients with lower renal function a substantial proportion was still underdosed (median percentage of T > MIC : 57% for meropenem, 45% for ceftazidime, 34% for cefepime, and 33% for piperacillin/tazobactam), suggesting standard antibiotic regimens are inadequate, but that dose reductions might be beneficial. Chabert et al. [ 30 ] developed a pharmacokinetic model for cefoxitin (median sampling time 19 hours after antibiotic initiation). In this model, renal function significantly influenced dosing requirements. The model showed that standard dose (6 g/24 h) achieved target concentrations only in patients with severe renal impairment (creatinine clearance < 30 mL/min), suggesting that patients with severe AKI need reduced dosages, but that standard regimens may be inadequate in patients with preserved renal function or slight renal impairment. Contradicting these results, Mitton et al. [ 31 ] found no correlation between kidney function and plasma concentrations of imipenem/cilastatin. However, as dosing was individualized according to renal function, the study design limits the ability to assess the impact of renal function on plasma concentrations. As such, definitive conclusions regarding pharmacokinetic variability in relation to renal function cannot be drawn from this study. Pharmacological outcomes – after 48 hours A total of three studies measured antibiotic concentrations after 48 hours. Heinemeyer et al. [ 27 ] evaluated ceftriaxone clearance from day 2 up to day 7 in patients with acute kidney injury, Kitzes-Cohen et al. [ 32 ] collected samples ≥ 48 hours after meropenem initiation and Hassanpour et al. [ 26 ] measured at 48 and 72 hours after the first antibiotic dose. In concordance with the studies that mentioned early antibiotic concentrations, the first two studies concluded that renal impairment is correlated with delayed drug elimination and that even when dosages are reduced based on kidney function, patients with a lower kidney function exhibit higher concentrations end are more likely to achieve the desired target (T > 4×MIC 50–100% in patients with eGFR > 50 vs 75–100% when eGFR < 50) [ 27 , 32 ]. The third study was the only randomized controlled trial [ 26 ]. In this trial patients with AKI received 3 grams of meropenem per day for the first 48 hours, after which plasma concentrations were measured. Only 1 out of 10 patients (10%) achieved the pharmacodynamic target of 100% fT > 4×MIC. Patients were then randomized to either continue full dosing or undergo dose reduction based on renal function. By 72 hours, target attainment remained low (1 of 15 patients, 6.7%), with no significant difference between the dosing strategies. A limitation of this study was the small sample size which limits the generalizability of these findings. Discussion To date, this scoping review is the first to structurally evaluate the availability and quality of evidence regarding the effect of beta-lactam dose reductions on the achievement of PD targets and clinical outcomes in critically ill patients with AKI The availability of evidence was low, and the quality even lower, underscoring the need for robust studies on this topic. A majority of the included studies were observational in nature and carried a high risk of bias, limiting the strength of any conclusions that can be drawn from them. However, when looking at the available evidence, the majority of studies have shown that, unsurprisingly, antibiotic concentrations are higher in patients with acute kidney injury. Furthermore, it has also been shown that delaying or withholding dose reductions of beta-lactam antibiotics is associated with lower mortality and less treatment failure. Several limitations were identified across the studies. There was considerable heterogeneity in study designs, including retrospective cohorts, pharmacokinetic modeling, and small randomized trials. Sampling times for plasma concentrations varied widely, from within the first 24 hours to several days after antibiotic initiation. Definitions of AKI also differed, making it difficult to compare results across studies or generalize findings to the broader ICU population. Accurate diagnosis of AKI in the early phase of hospital and ICU admission presents its own challenges. AKI definitions rely on eGFR or serum creatinine, which are known to be unreliable in critically ill patients [ 18 ]. Creatinine clearance may be influenced by prehospital factors such as diuretic administration, and AKI definitions often depend on dynamic changes in creatinine levels while baseline values are often unknown. These difficulties may lead to both over- and underestimation of kidney function, affecting dose reduction decisions and observed concentrations. The pharmacodynamic targets used to evaluate beta-lactam exposure were also inconsistent. While some studies used thresholds such as 100%fT > MIC, others used more aggressive targets like 100% fT > 4×MIC. The clinical significance of these different targets remains uncertain, and the evidence linking target attainment to improved patient outcomes is limited. Lastly, it is important to recognize that antibiotic concentrations are influenced not only by renal function but also by various patient-specific factors, such as body weight, serum albumin levels, and the underlying pathophysiology of the disease. Similarly, although all beta-lactam antibiotics are primarily eliminated by the kidneys, their pharmacokinetic properties differ across agents. These inter-agent differences may affect systemic drug exposure, thereby influencing both the risk of toxicity and the likelihood of achieving therapeutic targets. However, due to the limited available evidence, it was not possible to identify specific patient characteristics that significantly impact antibiotic concentrations in this population. Despite the limitations inherent to the quality of available evidence, this is the first study to systematically examine the association of dose reductions on clinical and pharmacological outcomes in critically ill patients with AKI receiving beta lactam antibiotics. Current clinical practice is largely guided by expert opinion and PD models. However, these models often rely on eGFR or serum creatinine levels, without adequately accounting for the underlying pathophysiological mechanisms in AKI or chronic kidney disease. As a result, their applicability to this specific, but substantial patient group may be limited. This review highlights a critical gap in our knowledge of infectious treatment in the critically ill population and underscores the need for further clinical research to inform evidence-based dosing strategies. Conclusion In conclusion, the available evidence for beta-lactam dose reductions based on kidney function in critically ill patients with acute kidney injury is limited and of low quality. While some clinical studies and expert opinion based reviews suggest a potential benefit from delaying dose reductions for at least 24–48 hours, definitive recommendations cannot yet be made. Further prospective research is needed to guide optimal dosing strategies in this population. Abbreviations AKI Acute Kidney Injury eGFR Estimated Glomerular Filtration Rate ICU Intensive Care Unit MIC Minimally Inhibitory Concentration PD Pharmacodynamics PRISMA-ScR Preferred Reporting of Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews ROB-2 Risk of Bias tool for randomized trials ROBINS-E Risk of Bias tool for non-randomized exposure Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials Not applicable. Competing interests The authors declare that they have no competing interests. Funding No funding was received for writing this review. Authors' contributions M.H. and W.R. conducted the screening of all titles, abstracts, and full-text articles where necessary. C.U. resolved any discrepancies. M.H. drafted the manuscript. All authors reviewed and approved the final version of the manuscript. Acknowledgements The authors wish to thank Maarten Engel from the Erasmus MC Medical Library for developing and updating the search strategies. References Koeze J, Keus F, Dieperink W, van der Horst IC, Zijlstra JG, van Meurs M. Incidence, timing and outcome of AKI in critically ill patients varies with the definition used and the addition of urine output criteria. BMC Nephrol. 2017;18(1):70. Nisula S, Kaukonen KM, Vaara ST, Korhonen AM, Poukkanen M, Karlsson S, et al. Incidence, risk factors and 90-day mortality of patients with acute kidney injury in Finnish intensive care units: the FINNAKI study. Intensive Care Med. 2013;39(3):420–8. Ostermann M, Chang RW. Acute kidney injury in the intensive care unit according to RIFLE. Crit Care Med. 2007;35(8):1837–43. quiz 52. Kellum JA, Sileanu FE, Murugan R, Lucko N, Shaw AD, Clermont G. Classifying AKI by Urine Output versus Serum Creatinine Level. J Am Soc Nephrol. 2015;26(9):2231–8. Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120(4):c179–84. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, Acute Dialysis Quality Initiative w. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8(4):R204-12. Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302(21):2323–9. Tang F, Yuan H, Li X, Qiao L. Effect of delayed antibiotic use on mortality outcomes in patients with sepsis or septic shock: A systematic review and meta-analysis. Int Immunopharmacol. 2024;129:111616. Goncalves-Pereira J, Povoa P. Antibiotics in critically ill patients: a systematic review of the pharmacokinetics of beta-lactams. Crit Care. 2011;15(5):R206. Sinnollareddy MG, Roberts MS, Lipman J, Roberts JA. beta-lactam pharmacokinetics and pharmacodynamics in critically ill patients and strategies for dose optimization: a structured review. Clin Exp Pharmacol Physiol. 2012;39(6):489–96. Abdulla A, Dijkstra A, Hunfeld NGM, Endeman H, Bahmany S, Ewoldt TMJ, et al. Failure of target attainment of beta-lactam antibiotics in critically ill patients and associated risk factors: a two-center prospective study (EXPAT). Crit Care. 2020;24(1):558. Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, et al. DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014;58(8):1072–83. Lee CC, Lee CH, Hong MY, Tang HJ, Ko WC. Timing of appropriate empirical antimicrobial administration and outcome of adults with community-onset bacteremia. Crit Care. 2017;21(1):119. Kellum JA, Sileanu FE, Bihorac A, Hoste EA, Chawla LS. Recovery after Acute Kidney Injury. Am J Respir Crit Care Med. 2017;195(6):784–91. Federspiel CK, Itenov TS, Mehta K, Hsu RK, Bestle MH, Liu KD. Duration of acute kidney injury in critically ill patients. Ann Intensive Care. 2018;8(1):30. Crass RL, Rodvold KA, Mueller BA, Pai MP. Renal Dosing of Antibiotics: Are We Jumping the Gun? Clin Infect Dis. 2019;68(9):1596–602. Kadivarian S, Heydarpour F, Karimpour H, Shahbazi F. Measured versus estimated creatinine clearance in critically ill patients with acute kidney injury: an observational study. Acute Crit Care. 2022;37(2):185–92. Matuszkiewicz-Rowinska J, Malyszko J, Wojtaszek E, Kulicki P. Dosing of antibiotics in critically ill patients: are we left to wander in the dark? Pol Arch Med Wewn. 2012;122(12):630–40. Tricco AC, Lillie E, Zarin W, O'Brien KK, Colquhoun H, Levac D, et al. PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. Ann Intern Med. 2018;169(7):467–73. Sterne JAC, Savovic J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. Higgins JPT, Morgan RL, Rooney AA, Taylor KW, Thayer KA, Silva RA, et al. A tool to assess risk of bias in non-randomized follow-up studies of exposure effects (ROBINS-E). Environ Int. 2024;186:108602. Camargo MS, Mistro S, Oliveira MG, Passos LCS. Association between increased mortality rate and antibiotic dose adjustment in intensive care unit patients with renal impairment. Eur J Clin Pharmacol. 2019;75(1):119–26. Aldardeer NF, Alshreef MM, Alharbi EA, Aljabri AK, Aljawadi MH, Almangour TA, et al. Early Versus Late Antipseudomonal beta-Lactam Antibiotic Dose Adjustment in Critically Ill Sepsis Patients With Acute Kidney Injury: A Prospective Observational Cohort Study. Open forum infect dis. 2024;11(3):ofae059. Fugate JE, Kalimullah EA, Hocker SE, Clark SL, Wijdicks EF, Rabinstein AA. Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy. Crit Care. 2013;17(6):R264. Hassanpour R, Ziaie S, Kobarfard F, Kouchek M, Miri M, Ahmadi Koomleh A, et al. Evaluation of pharmacokinetic and pharmacodynamic parameters of meropenem in critically ill patients with acute kidney disease. Eur J Clin Pharmacol. 2021;77(6):831–40. Heinemeyer G, Link J, Weber W, Meschede V, Roots I. Clearance of ceftriaxone in critical care patients with acute renal failure. Intensive Care Med. 1990;16(7):448–53. Luo X, Zhou W, Wan D, Peng J, Liao R, Su B. Association between amoxicillin administration and outcomes in critically ill patients with acute kidney injury. Front Pharmacol. 2024;15:1409654. Passon SG, Schmidt AR, Wittmann M, Velten M, Baehner T. Evaluation of continuous ampicillin/sulbactam infusion in critically ill patients. Life Sci. 2023;320:121567. Chabert P, Provoost J, Cohen S, Dupieux-Chabert C, Bitker L, Ferry T et al. Pharmacokinetics, efficacy and tolerance of cefoxitin in the treatment of cefoxitin-susceptible extended-spectrum beta-lactamase producing Enterobacterales infections in critically ill patients: a retrospective single-center study. Ann Intensive Care. 2022;12(1). Mitton B, Paruk F, Gous A, Chausse J, Milne M, Becker P, Said M. Evaluating the usefulness of the estimated glomerular filtration rate for determination of imipenem dosage in critically ill patients. S Afr Med J. 2022;112(9):765–8. Kitzes-Cohen R, Farin D, Piva G, De Myttenaere-Bursztein SA. Pharmacokinetics and pharmacodynamics of meropenem in critically ill patients. Int J Antimicrob Agents. 2002;19(2):105–10. Taccone FS, Laterre PF, Dugernier T, Spapen H. Insufficient β-lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care. 2010;14(4):R126. Additional Declarations No competing interests reported. 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Horstink","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5ElEQVRIiWNgGAWjYFACHijJw3wAWdiCkBYDoBa2BGRhCYJagDSPAXFadBt4Dz6u+PNHxpznzMfHFTV10QbnTyd+YNyBW4vZAb5kw7NtBjyWvb2bDc8cO5y74UbuZgnGM/i08JhJNjYY8Bic590m2cB2AKiFdxsDYxsBLQ1/QFp4nv9s+FeXu+H8WWK0sAG1nO1hY2xsY87dcCCXgJbDPMaGjW3GPAZnjhlLNvYdzp0J8ksiPi3HewwfNvyRszc4k/zwY8O3uty+82c3fvjYZoNTCwMzVtEE3BpGwSgYBaNgFBABAOMLU7QgWmSXAAAAAElFTkSuQmCC","orcid":"","institution":"Maasstad Hospital","correspondingAuthor":true,"prefix":"","firstName":"M.","middleName":"M.B.","lastName":"Horstink","suffix":""},{"id":493555312,"identity":"41561102-004e-41db-b1f3-2700fd6b011a","order_by":1,"name":"W. J.R. Rietdijk","email":"","orcid":"","institution":"Erasmus MC","correspondingAuthor":false,"prefix":"","firstName":"W.","middleName":"J.R.","lastName":"Ri","suffix":"J.R."},{"id":493555314,"identity":"f45961d9-132e-4a3e-b56b-85c46dd402ce","order_by":2,"name":"D. R. Geel","email":"","orcid":"","institution":"Erasmus MC","correspondingAuthor":false,"prefix":"","firstName":"D.","middleName":"R.","lastName":"Geel","suffix":""},{"id":493555316,"identity":"451bf529-0f58-4116-9b97-86e3a40437dc","order_by":3,"name":"P. E. Deetman","email":"","orcid":"","institution":"Albert Schweitzer Hospital","correspondingAuthor":false,"prefix":"","firstName":"P.","middleName":"E.","lastName":"Deetman","suffix":""},{"id":493555318,"identity":"65823b5d-5546-4d9f-86f2-a88fee922ea7","order_by":4,"name":"H. Endeman","email":"","orcid":"","institution":"Erasmus MC","correspondingAuthor":false,"prefix":"","firstName":"H.","middleName":"","lastName":"Endeman","suffix":""},{"id":493555319,"identity":"e30fe9b7-7934-400c-99ae-37ad224c08cd","order_by":5,"name":"B. C.P. 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A. den Uil","email":"","orcid":"","institution":"Maasstad Hospital","correspondingAuthor":false,"prefix":"","firstName":"C.","middleName":"A. den","lastName":"Uil","suffix":""}],"badges":[],"createdAt":"2025-07-18 10:08:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7156465/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7156465/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13054-025-05736-6","type":"published","date":"2025-12-02T15:57:56+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":88102617,"identity":"04c71d9b-99fd-4719-bc81-ceb6a5c64ac9","added_by":"auto","created_at":"2025-08-01 11:41:25","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":88631,"visible":true,"origin":"","legend":"\u003cp\u003ePrisma Flow Diagram\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7156465/v1/d1168050cead209a5328da26.jpg"},{"id":88102619,"identity":"339133b7-ba67-4412-a7f3-50a1adf7845c","added_by":"auto","created_at":"2025-08-01 11:41:25","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":51335,"visible":true,"origin":"","legend":"\u003cp\u003eROB assessments summary\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7156465/v1/1ec5527342d0b6e97e3ee616.jpg"},{"id":97724617,"identity":"de42e680-e1d1-4e08-93c5-3db063d3823f","added_by":"auto","created_at":"2025-12-08 16:12:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1020574,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7156465/v1/d5d8ff06-7afb-44e9-9ebb-ee90ae9a4372.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Beta-lactam dose reductions in critically ill patients with acute kidney injury: a scoping review","fulltext":[{"header":"Background","content":"\u003cp\u003eAcute kidney injury (AKI) is one of most common complications of critical illness, with reported incidences ranging from 20 to 75% [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The severity of AKI is typically classified based on an increase in serum creatinine and/or a decrease in urine output, although specific criteria vary across definitions [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAt the same time, around 50% of all patients admitted to the intensive care unit (ICU) have an infection that requires antibiotic treatment [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Delay in initiating therapy is strongly associated with increased mortality [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], underscoring the critical importance of timely and appropriate antimicrobial management in this population. Beta-lactam antibiotics are amongst the most commonly prescribed antibiotics in the ICU setting due to their broad-spectrum activity against both Gram-positive and Gram-negative bacteria [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Since beta-lactam antibiotics are predominantly cleared by the kidneys, dosing regimens are often adjusted based on renal function. In practice, this means patients with acute or chronic kidney dysfunction typically receive reduced dosages. However, most dosing guidelines are derived from studies involving patients with chronic kidney disease and pharmacodynamic (PD) models, while evidence specific to those with AKI remains limited.\u003c/p\u003e\u003cp\u003eSince critically ill patients are a heterogeneous population with rapid, dynamic changes in physiology, achieving target antibiotic concentrations is challenging [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Factors such as augmented renal clearance, organ dysfunction, fluctuations in albumin levels, and increased volume of distribution all contribute to altered pharmacokinetics. Observational studies have shown that PD targets are often not achieved, meaning that underdosing of beta-lactam antibiotics is common in the ICU population [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Taking into consideration that the first 48 hours are critical in the treatment of infections [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], that beta-lactam antibiotics have a broad therapeutic window and that a significant proportion of AKI cases resolve within the first 24 to 48 hours of ICU admission (i.e., rapidly reversible or transient AKI) [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], it is reasonable to question whether initial dose reductions based on (temporary) kidney dysfunction are necessary. Moreover, the diagnosis of AKI is typically based on rising serum creatinine levels, despite the frequent absence of reliable baseline values. Therefore, serum creatinine alone is a delayed and imprecise marker of renal function, which further complicates early dosing decisions [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The underlying cause of AKI also plays a crucial role in determining the optimal treatment strategy. For instance, patients with pre-renal AKI may be hyperdynamic and require aggressive fluid resuscitation, potentially diluting antibiotic concentrations. In contrast, post-renal AKI often resolves swiftly once the obstruction is relieved, making early dose reductions potentially unnecessary or even counterproductive.\u003c/p\u003e\u003cp\u003eSome narrative reviews have suggested that dose reductions of antibiotics with a broad therapeutic window should be postponed until 48 hours after initiation of therapy, when the trajectory of renal function is more clearly defined. It has been argued that the risk of toxicity with this approach is low, thereby optimizing the risk\u0026ndash;benefit balance [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eHowever, these reviews are mostly based on expert opinion, and fail to provide a systematic overview of available evidence. Therefore, we conducted a scoping review to evaluate the availability and quality of evidence on the achievement of PD targets and clinical outcomes when adjusting beta-lactam dosages in critically ill patients with AKI.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eA systematic scoping review was conducted to evaluate the existing literature on beta-lactam dose reductions in critically ill patients with AKI. This review followed the Preferred Reporting of Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The PICO framework guiding this review was defined as follows:\u003c/p\u003e\u003cp\u003e\u003cstrong\u003ePatients\u003c/strong\u003e\u003cp\u003eCritically ill patients with acute kidney injury\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e\u003cp\u003eDose reductions of beta-lactam antibiotics based on kidney function\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eComparator\u003c/strong\u003e\u003cp\u003eNo dose reductions of beta-lactam antibiotics\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003cp\u003eMortality, treatment failure, adverse events, hospital or ICU length of stay, and pharmacodynamic target attainment\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eSearch strategy\u003c/em\u003e\u003c/p\u003e\u003cp\u003eA comprehensive literature search was performed across Medline, Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar from database inception through March 24th, 2025. The search strategy, developed by a medical librarian (M.E., see acknowledgements) in collaboration with the research team (M.H.), included a combination of keywords and subject headings related to:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eBeta-lactam antibiotics\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eCritical illness/Intensive care\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eAcute kidney injury/Acute renal impairment\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003cp\u003eThe full search strategy is detailed in Appendix 1. Only articles published in English were considered for inclusion.\u003c/p\u003e\u003cp\u003eA total of 2,097 records were retrieved. After removing duplicates, 1,439 unique records remained. These were uploaded into Covidence for further screening, where an additional 3 duplicates were identified and removed, leaving 1,436 articles for initial review. Title/abstract and full-text screenings were conducted independently by two reviewers (M.H. and W.R.), with discrepancies resolved by a third reviewer (C.U.). Reference lists of included articles were also screened for additional relevant studies.\u003c/p\u003e\u003cp\u003e\u003cem\u003eInclusion and Exclusion criteria\u003c/em\u003e\u003c/p\u003e\u003cp\u003eThe inclusion criteria were primary studies that included critically ill, adult patients with AKI (as defined by the articles) and reported clinical or pharmacological data of beta-lactam antibiotic dosages and/or reductions, as well as kidney function. Exclusion criteria included patients with chronic kidney disease (as defined by the authors), patients on renal replacement therapy, case reports, conference abstracts and (systematic) reviews.\u003c/p\u003e\u003cp\u003e\u003cem\u003eQuality Assessment\u003c/em\u003e\u003c/p\u003e\u003cp\u003eAssessment of risk of bias in individual studies was conducted by two independent authors (M.H. and W.R.) using the Cochrane Risk of Bias tool for randomized trials (ROB-2) or non-randomized exposure (ROBINS-E) studies depending on the study design [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Disagreements were resolved through discussion and consensus.\u003c/p\u003e\u003cp\u003e\u003cem\u003eData-extraction\u003c/em\u003e\u003c/p\u003e\u003cp\u003e Data extraction was performed using a predefined template by one reviewer and cross-checked by the other reviewer (M.H. and W.R.). Clinical outcomes were classified into treatment failure (including mortality) and adverse events. There were no data available regarding hospital and ICU length of stay. Pharmacological outcomes were divided into those observed within the first 48 hours after antibiotic initiation and those reported beyond this period. This method was chosen because AKI oftentimes resolves within this time period, while adequate antibiotic therapy is most crucial at the initial phase of sepsis and infection. Although it was initially intended to further classify the articles based on the type of antibiotic and patient characteristics, this was not feasible due to the limited number of available studies.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eOf the 1,436 articles screened for eligibility, 1400 were excluded based on title and abstract screening, leaving 36 articles for full-text review. Next, 26 studies were excluded because they included non-ICU patients (n\u0026thinsp;=\u0026thinsp;9), included no beta-lactam antibiotic (n\u0026thinsp;=\u0026thinsp;1), were case reports, reviews or conference abstracts (n\u0026thinsp;=\u0026thinsp;5), did not report on beta-lactam antibiotic dosages (n\u0026thinsp;=\u0026thinsp;4), did not report on kidney function (n\u0026thinsp;=\u0026thinsp;4) or compared other, non-antibiotic interventions (n\u0026thinsp;=\u0026thinsp;3). One article was included through citation tracking [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In total 11 articles including 25,381 patients, of which 24,650 were from Luo et al., were included in the final analysis [\u003cspan additionalcitationids=\"CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. A detailed summary of the study selection process is provided in the PRISMA flow diagram (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Of the included studies 10 were observational (5 prospective and 5 retrospective cohort studies) and 1 was a randomized controlled trial. Study and patient characteristics are provided in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, respectively.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eStudy characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"11\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eYear\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCountry\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eJournal\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eStudy design\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePatients analysed\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eAKI definition\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eInvestigated agents\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eIntervention/ exposure\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePrimary outcome\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003eConclusion with regard to kidney function and dose reduction\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAldardeer et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eKingdom of Saudi Arabia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOpen Forum Infect Dis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eProspective observational cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e224\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eKDIGO criteria\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePiperacillin/ tazobactam\u003c/p\u003e\u003cp\u003eMeropenem\u003c/p\u003e\u003cp\u003eImipenem/ cilastatin\u003c/p\u003e\u003cp\u003eCeftazidime\u003c/p\u003e\u003cp\u003eCefepime\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eA reduced beta-lactam dosage based on kidney function\u0026thinsp;\u0026lt;\u0026thinsp;24 h of sepsis recognition, versus a reduced dosage \u0026gt;24 h from sepsis recognition.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eIn-hospital mortality within the first 90 days of follow-up\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eIn patients with AKI delaying antibiotic dose reduction beyond 24 hours of sepsis recognition decreases mortality.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFugate et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2013\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnited States of America\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCrit Care\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRetrospective observational cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.5-fold increase from baseline creatinine or absolute increase in creatinine by \u0026ge;\u0026thinsp;0.3 mg/dL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCefepime\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e2 g cefepime 2x/24 h\u003c/p\u003e\u003cp\u003eDose reductions:\u003c/p\u003e\u003cp\u003eCrCl 30\u0026ndash;60 2g 1x/24 h\u003c/p\u003e\u003cp\u003eCrCl 11\u0026ndash;29 1 gr 1x/24 h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDevelopment of cefepime neurotoxicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eAKI is not an univariate risk indicator for cefepime neurotoxicity.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHassanpour et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIran\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eEur J Clin Pharmacol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRandomized Controlled trial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eAKIN and/or RIFLE criteria\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMeropenem\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eFirst 48 h: 3 gr meropenem/24 h.\u003c/p\u003e\u003cp\u003eThen randomization to dose reduction based on kidney function versus no dose reduction.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePercentage of T\u0026thinsp;\u0026gt;\u0026thinsp;4x MIC\u003c/p\u003e\u003cp\u003e(8 mg/l)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eIn patients with AKI, standard doses of meropenem fail to achieve the pharmacodynamic target of \u0026ge;\u0026thinsp;80%fT\u0026thinsp;\u0026gt;\u0026thinsp;4xMIC.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHeinemeyer et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1990\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGermany\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIntensive Care Med\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eProspective observational cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCrCl\u0026thinsp;\u0026lt;\u0026thinsp;50 ml/min/1.73m2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCeftriaxone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e7 days of 2 gr\u003c/p\u003e\u003cp\u003eceftriaxone/24 h.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eExploring ceftriaxone pharmacokinetics\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eIn patients with AKI, the elimination of ceftriaxone is strongly delayed. Therefore, dosages should be reduced.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLuo et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eResearchers from China, Data from the USA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFront Pharmacol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRetrospective observational cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e24,650\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eKDIGO criteria\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAmoxicillin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAmoxicillin versus no-amoxicillin\u003c/p\u003e\u003cp\u003eSubgroup analysis with \u0026ge;\u0026thinsp;875 mg/ amoxicillin/24 h versus\u003c/p\u003e\u003cp\u003e\u0026lt;\u0026thinsp;875 mg/24 h.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e30-day all-cause mortality\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eIn patients with AKI an amoxicillin dosage of \u0026ge;\u0026thinsp;875mg/day shows more mortality reduction than a dosage of \u0026lt;\u0026thinsp;825 mg/day.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePasson et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGermany\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLife Sci\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRetrospective observational cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eKDIGO criteria\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAmpicillin/ sulbactam\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eLoading dose of 2/1 gr ampicillin/sulbactam followed by a continuous infusion of 8/4 g per 24 h.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eAchievement of the MIC\u003c/p\u003e\u003cp\u003e(8 mg/l)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePatients with AKI exhibit higher ampicillin concentrations and exceed the 4-fold MIC breakpoint more often.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eChabert et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFrance\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAnn Intensive Care\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRetrospective observational cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eCefoxitin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eLoading dose 2 gr cefoxitin, followed by a median continuous administration of 6 gr/24 h.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eAchievement of the modelled serum concentration of 100%fT\u0026thinsp;\u0026gt;\u0026thinsp;MIC on the second day of therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eCefoxitin dosages may be based on eGFR for dosage individualization.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMitton et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSouth Africa\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eS Afr Med J\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eProspective observational cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eImipenem/ cilastatin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eImipenem dosages\u003c/p\u003e\u003cp\u003eeGFR\u0026thinsp;\u0026gt;\u0026thinsp;70: 1000 mg 4x/24 h\u003c/p\u003e\u003cp\u003eeGFR 41\u0026ndash;70: 750 mg 3x/24 h\u003c/p\u003e\u003cp\u003eeGFR 21\u0026ndash;40: 500 mg 3x/24 h\u003c/p\u003e\u003cp\u003eeGFR\u0026thinsp;\u0026lt;\u0026thinsp;21: 500 mg 2x/24 h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eExplore correlation between eGFR and through plasma levels\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eWhen dosages are adjusted for kidney function, there is no correlation between eGFR and imipenem plasma concentrations.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eKitzes-Cohen et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIsrael\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eInt J Antimicrob Agents\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eProspective observational cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCrCl\u0026thinsp;\u0026lt;\u0026thinsp;50 ml/min\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMeropenem\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMeropenem dosages\u003c/p\u003e\u003cp\u003eCrCl\u0026thinsp;\u0026gt;\u0026thinsp;50 ml/min (Group I)\u003c/p\u003e\u003cp\u003e1 gr 3x/24 h\u003c/p\u003e\u003cp\u003eCrCl\u0026thinsp;\u0026lt;\u0026thinsp;50 ml/min (Group II)\u003c/p\u003e\u003cp\u003e1 gr 2x/24 h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eExplore meropenem pharmacokinetics\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eWhen dose reductions were made based on kidney function (group II), the AUC of meropenem is still higher.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTaccone et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBelgium\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCrit Care\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eProspective observational cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMeropenem\u003c/p\u003e\u003cp\u003eCeftazidime\u003c/p\u003e\u003cp\u003eCefepime\u003c/p\u003e\u003cp\u003ePiperacillin/ tazobactam\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMeropenem\u003c/p\u003e\u003cp\u003eLoading dose 1 gr\u003c/p\u003e\u003cp\u003eCrCl\u0026thinsp;\u0026gt;\u0026thinsp;80: 1gr 3x/24 h\u003c/p\u003e\u003cp\u003eCrCl 50\u0026ndash;80: 1gr 2x/24 h\u003c/p\u003e\u003cp\u003eCrCl 10\u0026ndash;50: 0.5gr 2x/24 h\u003c/p\u003e\u003cp\u003eCrCl\u0026thinsp;\u0026lt;\u0026thinsp;10: 0.5 gr 1x/24 h\u003c/p\u003e\u003cp\u003eCeftazidime or Cefepime\u003c/p\u003e\u003cp\u003eLoading dose 2 gr\u003c/p\u003e\u003cp\u003eCrCl\u0026thinsp;\u0026gt;\u0026thinsp;80: 2gr 3x/24 h\u003c/p\u003e\u003cp\u003eCrCl 50\u0026ndash;80: 2gr 2x/24 h\u003c/p\u003e\u003cp\u003eCrCl 10\u0026ndash;50: 1gr 2x/24 h\u003c/p\u003e\u003cp\u003eCrCl\u0026thinsp;\u0026lt;\u0026thinsp;10: 0.5 gr 1x/24 h\u003c/p\u003e\u003cp\u003ePiperacillin/tazobactam\u003c/p\u003e\u003cp\u003eLoading dose 4/0.5 gr\u003c/p\u003e\u003cp\u003eCrCl\u0026thinsp;\u0026gt;\u0026thinsp;50: 4/0.5 gr 4x/24 h\u003c/p\u003e\u003cp\u003eCrCl 10\u0026ndash;50: 4/0.5 gr 3x/24 h\u003c/p\u003e\u003cp\u003eCrCl\u0026thinsp;\u0026lt;\u0026thinsp;10: 4/0.5 gr 2x/24 h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePercentage of T\u0026thinsp;\u0026gt;\u0026thinsp;4x MIC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003ePatients with renal dysfunction (acute and chronic) had a significantly higher probability of having adequate drug concentrations than patients with normal renal function. Even when dosages were reduced based on kidney function.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCamargo et al.\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBrazil\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eEur J Clin Pharmacol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRetrospective observational cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e126\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAll antimicrobials, including carbapenems.\u003c/p\u003e\u003cp\u003eNot further specified.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNo reduced dosage, versus a reduced dosage based on kidney function.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eTreatment failure\u003c/p\u003e\u003cp\u003eMortality rate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eAntibiotic dose reductions in patients with renal impairment (acute and chronic combined) increase the risk of treatment failure and death.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"11\"\u003eAbbreviations: KDIGO, Kidney Disease Improving Global Outcomes; AKI, Acute Kidney Injury; CrCl, Creatinine Clearance; AKIN, Acute Kidney Injury Network; RIFLE, Risk of renal dysfunction, Injury to kidney, Failure or Loss of kidney function, and End-stage kidney disease; T, Time; MIC, Minimally Inhibitory Concentration; NR, Not Reported; (e)GFR, (estimated) Glomerular Filtration Rate; AUC, Area Under the Curve\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eInclusion Criteria\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eExclusion Criteria\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBMI/Weight\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eGender Male (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePatients with Sepsis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSOFA\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAldardeer et al., 2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e- Admitted to the ICU\u003c/p\u003e\u003cp\u003e- Aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years\u003c/p\u003e \u003cp\u003e- AKI\u003c/p\u003e\u003cp\u003e- Sepsis (Sepsis-3 criteria)\u003c/p\u003e\u003cp\u003e- Received an initial full dose of antipseudomonal beta-lactam antibiotics\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e- Unknown baseline renal function\u003c/p\u003e \u003cp\u003e- Received the initial dose of beta-lactam adjusted for renal function\u003c/p\u003e\u003cp\u003e- Were started on non-antipseudomonal beta-lactams\u003c/p\u003e\u003cp\u003e- End-stage renal disease or receiving dialysis\u003c/p\u003e\u003cp\u003e- Initiated on RRT within 48 hours of sepsis recognition\u003c/p\u003e\u003cp\u003e- Confirmed diagnosis of coronavirus disease 2019\u003c/p\u003e \u003cp\u003e- Transferred from outside hospitals\u003c/p\u003e\u003cp\u003e- Insufficient data in the medical record\u003c/p\u003e\u003cp\u003e- Died within 48 hours of sepsis recognition\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e62.7\u0026thinsp;\u0026plusmn;\u0026thinsp;16.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWeight(kg)\u003c/p\u003e\u003cp\u003e75.6\u0026thinsp;\u0026plusmn;\u0026thinsp;20.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e139 (62%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e224 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e9 [\u003cspan additionalcitationids=\"CR8 CR9 CR10\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFugate et al., 2013\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e- Admitted to the ICU\u003c/p\u003e\u003cp\u003e- Aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years\u003c/p\u003e \u003cp\u003e- Treated with intravenous cefepime for at least 3 days\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e65.8\u0026thinsp;\u0026plusmn;\u0026thinsp;12.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e61 (61%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e100 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHassanpour et al., 2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e- Admitted to the ICU\u003c/p\u003e\u003cp\u003e- Aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years\u003c/p\u003e \u003cp\u003e- AKI\u003c/p\u003e\u003cp\u003e- Treated with standard dose of meropenem (1 gr 3x/24h) based on the physician in charge decision\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e- Chronic Kidney Disease\u003c/p\u003e\u003cp\u003e- Renal Replacement Therapy\u003c/p\u003e\u003cp\u003e- Pregnancy or lactation\u003c/p\u003e\u003cp\u003e- Receiving an adjusted dose of meropenem before recruitment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eStandard dose 62.4\u0026thinsp;\u0026plusmn;\u0026thinsp;14.3 Adjusted dose 54.8\u0026thinsp;\u0026plusmn;\u0026thinsp;24.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eStandard dose\u003c/p\u003e\u003cp\u003eweight (kg) 67.4\u0026thinsp;\u0026plusmn;\u0026thinsp;12.2\u003c/p\u003e\u003cp\u003eAdjusted dose 64.4\u0026thinsp;\u0026plusmn;\u0026thinsp;9.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eStandard dose 4 (57%)\u003c/p\u003e\u003cp\u003eAdjusted dose 5 (56%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e16 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHeinemeyer et al., 1990\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e- Admitted to the surgical ICU\u003c/p\u003e\u003cp\u003e- Placed on ceftriaxone at the onset of a bacterial infection of the bronchial tract\u003c/p\u003e \u003cp\u003e- Sensitivities verified by an antibiogram\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMean\u003c/p\u003e\u003cp\u003e53.9\u0026thinsp;\u0026plusmn;\u0026thinsp;20.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWeight 73.1\u0026thinsp;\u0026plusmn;\u0026thinsp;10.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4 (33.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLuo et al., 2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e- Admitted to the ICU\u003c/p\u003e\u003cp\u003e- Aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years\u003c/p\u003e \u003cp\u003e- AKI\u003c/p\u003e\u003cp\u003e- Hospitalized for more than 48 h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e- \u0026gt;5% of their individual data were missing\u003c/p\u003e \u003cp\u003e- Baseline values exceeded the median\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5 times the interquartile range\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAmoxicillin 67.8\u0026thinsp;\u0026plusmn;\u0026thinsp;17.2\u003c/p\u003e\u003cp\u003eNon-amoxicilin 67.9\u0026thinsp;\u0026plusmn;\u0026thinsp;15.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAmoxicilin\u003c/p\u003e\u003cp\u003e393 (58.1%)\u003c/p\u003e\u003cp\u003eNon-amoxicilin 13.906 (58.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eAmoxicilin\u003c/p\u003e\u003cp\u003e464 (68.6%)\u003c/p\u003e\u003cp\u003eNon-amoxicilin 14.096 (58.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAmoxicilin\u003c/p\u003e\u003cp\u003e5 [\u003cspan additionalcitationids=\"CR4 CR5 CR6\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eNon-amoxicilin 5 [\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePasson et al., 2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e- Admitted to the ICU\u003c/p\u003e\u003cp\u003e- A continuous infusion regime with ampicillin/sulbactam\u003c/p\u003e \u003cp\u003e- Monitored by ampicillin concentration measurements\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e71.5\u0026thinsp;\u0026plusmn;\u0026thinsp;15.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBMI 28.7\u0026thinsp;\u0026plusmn;\u0026thinsp;9.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e24 (48%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e38 (76.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e4.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChabert et al., 2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e- Admitted to the ICU\u003c/p\u003e\u003cp\u003e- Aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years\u003c/p\u003e \u003cp\u003e- Infection with cefoxitin-susceptible ESBL-PE\u003c/p\u003e\u003cp\u003e- Treatment with cefoxitin during \u0026ge;\u0026thinsp;24 h as a definitive antibiotherapy\u003c/p\u003e \u003cp\u003e- Cefoxitin TDM with at least one serum concentration measured during therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e- Refusal to participate\u003c/p\u003e \u003cp\u003e- Included in the study during a previous ICU stay\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e59.0 [53.0\u0026ndash;74.0]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBMI 65.0 [59.0\u0026ndash;83.0]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e31 (76%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e36 (88%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAt admission 7.0 [5.0\u0026ndash;12.0]\u003c/p\u003e\u003cp\u003eAt inclusion 8.0 [6.0\u0026ndash;12.0]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMitton et al., 2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e- Admitted to the surgical ICU\u003c/p\u003e\u003cp\u003e- Aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years\u003c/p\u003e \u003cp\u003e- Imipenem/cilastatin therapy\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e- Refusal to participate\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e47 (range 18\u0026ndash;81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWeight (kg): 78 (range 40\u0026ndash;140)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e43 (63%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e30 (44%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKitzes-Cohen et al., 2002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e- Admitted to the ICU\u003c/p\u003e\u003cp\u003e- Severe sepsis\u003c/p\u003e \u003cp\u003e- Blood or other cultures growing bacteria sensitive to meropenem\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eGroup 1: 73.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.7; Group 2: 72.8\u0026thinsp;\u0026plusmn;\u0026thinsp;6.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e9 (64%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e13 (93%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTaccone et al., 2010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e- Admitted to the ICU\u003c/p\u003e\u003cp\u003e- Severe sepsis or septic shock\u003c/p\u003e\u003cp\u003e- Treatment with a broad-spectrum beta-lactam antibiotic\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e- Age\u0026thinsp;\u0026lt;\u0026thinsp;18 years or \u0026gt;\u0026thinsp;85 years\u003c/p\u003e\u003cp\u003e- Pregnancy or lactation\u003c/p\u003e\u003cp\u003e- Previous administration of any of the investigated antibiotics\u003c/p\u003e\u003cp\u003e- Chronic renal failure requiring dialysis\u003c/p\u003e\u003cp\u003e- Allergy to any of the investigated antibiotics\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e63\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBMI: 24.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e51 (64%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e80 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e8 [IQR 5\u0026ndash;10]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCamargo et al, 2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e- Admitted to the ICU for \u0026gt;\u0026thinsp;24 h\u003c/p\u003e \u003cp\u003e- Aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e- Missing data did not allow the calculation of the eGFR or the evaluation of treatment results (success/failure)\u003c/p\u003e \u003cp\u003e- Prescribed dose did not match the recommendations of the used guidelines\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDose reduction 56.8\u0026thinsp;\u0026plusmn;\u0026thinsp;21.2\u003c/p\u003e\u003cp\u003eNo dose reduction 57.68\u0026thinsp;\u0026plusmn;\u0026thinsp;17.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e64 (50,7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e69 (54.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNR\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003eData are presented as number (percentage), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, or median [IQR] unless stated otherwise.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003eAbbreviations: AKI, Acute Kidney Injury; (e)GFR, (estimated) Glomerular Filtration Rate; RRT, Renal Replacement Therapy; NR, Not Reported; BMI, Body Mass Index; ICU, Intensive Care Unit; TDM, Therapeutic drug monitoring; ESBL-PE, Extended-Spectrum Beta-Lactamase Producing Enterobacteriaceae\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eRisk of bias assessment\u003c/em\u003e\u003c/p\u003e\u003cp\u003eA Risk of Bias assessment, conducted using the ROB2 or ROBINS-E tool based on each study's design, showed an overall high risk of bias in eight studies [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] and some concerns in three [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Additional details regarding this assessment are provided in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Appendix 3.\u003c/p\u003e\u003cp\u003e\u003cem\u003eAKI definitions\u003c/em\u003e\u003c/p\u003e\u003cp\u003eDefinitions of AKI varied considerably across the included studies. Three studies defined AKI according to the KDIGO criteria [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] one study applied the AKIN and/or RIFLE criteria [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Heinemeyer et al. [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], and Kitzes-Cohen et al. [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]used an estimated creatinine clearance below 50 ml/min as a threshold. In contrast, Fugate et al. [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] defined AKI as a 1.5-fold increase from baseline or an absolute increase in serum creatinine of \u0026ge;\u0026thinsp;0.3 mg/dL. Notably, four studies did not report on any AKI definition.\u003c/p\u003e\u003cp\u003e\u003cem\u003eClinical outcomes \u0026ndash; Treatment failure\u003c/em\u003e\u003c/p\u003e\u003cp\u003eThree studies reported on treatment failure, including mortality. All three reported less treatment failure and mortality when delaying dose reductions or administering higher initial dosages of antibiotics in AKI patients. Camargo et al. [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] studied multiple groups of antibiotics in a retrospective cohort study. Dose reductions were commonly made after 24 hours of treatment. Treatment failure, defined by the persistence of infection, clinical deterioration, or death, occurred more frequently in the reduced-dose group compared to those who received standard dosing (59.3% vs. 38.9%, p\u0026thinsp;=\u0026thinsp;0.023). When isolating mortality as an outcome, the difference remained significant (74.1% vs. 55.5%, p\u0026thinsp;=\u0026thinsp;0.033), suggesting that dose reductions may be associated with worse clinical outcomes. Based on this study it seems that postponing dose reductions for at least 24 hours could potentially improve survival in this patient population. As this result was aggregated across various antibiotics, it remains unclear whether this finding is applicable to beta-lactam antibiotics specifically.\u003c/p\u003e\u003cp\u003eIn the study by Aldardeer et al. [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], patients in the late dose reduction group (\u0026gt;\u0026thinsp;24 h) had a lower in-hospital mortality compared to those in the early reduction group (\u0026lt;\u0026thinsp;24 h) (HR 0.588, 95% CI: 0.355\u0026ndash;0.974). However, this finding may have been confounded by the fact that patients in the early reduction group had worse kidney function and higher APACHE scores, indicating a greater overall severity of illness.\u003c/p\u003e\u003cp\u003eLuo et al. [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] conducted a retrospective cohort study in patients with AKI. Patients were categorized into three groups: those not receiving amoxicillin, those receiving a low dose (\u0026lt;\u0026thinsp;875 mg/day), and those receiving a high dose (\u0026ge;\u0026thinsp;875 mg/day). The incidence of sepsis was 58.8% and 68.6% in respectively the non-amoxicillin and amoxicillin group. The HR for 30-day mortality was higher in the low dose group compared to the high dose group (0.61 vs. 0.46), suggesting a potential survival benefit with higher dosing. However, both low dose and high dose groups were compared only to the non-amoxicillin group, making direct statistical comparisons between the two dosing strategies not possible.\u003c/p\u003e\u003cp\u003e\u003cem\u003eClinical outcomes \u0026ndash; Adverse events\u003c/em\u003e\u003c/p\u003e\u003cp\u003eIn addition to potential clinical benefits, the safety of administering higher antibiotic dosages, delayed or no dose reductions, might raise concerns. Only one study has examined the incidence of adverse effects in this context. Fugate et al. [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] investigated the incidence of beta-lactam-associated neurotoxicity in ICU patients. This retrospective cohort study looked for neurologic symptoms consisting of encephalopathy, including decreased level of alertness, myoclonus, seizures, or any combination of these in patients that received cefepime. The symptoms needed to have a clear temporal relationship to the administration of cefepime and no alternative cause for neurological deterioration could be present. A total of 15 out of 100 patients developed these symptoms. The authors found that those who developed neurotoxicity were significantly less likely to have received appropriate dose reductions based on renal function compared to those who did not (28.6% vs. 75.3%, p\u0026thinsp;=\u0026thinsp;0.001). However, patients with neurotoxicity were also more likely to have underlying chronic kidney disease, complicating the interpretation of these findings in populations with AKI. Secondly, dose reductions were made throughout the entire duration of therapy, making the effect of early dose reductions unclear. Finally, it also needs to be pointed out that ruling out other causes of neurological decline in ICU patients remains difficult, given the high incidence of delirium and encephalopathy associated with sepsis-related organ dysfunction.\u003c/p\u003e\u003cp\u003e\u003cem\u003ePharmacological outcomes \u0026ndash; 0 to 48 hours\u003c/em\u003e\u003c/p\u003e\u003cp\u003eSeven studies reported plasma concentration data for beta-lactam antibiotics in critically ill patients, with four of these including sampling within this crucial early timeframe. Sampling strategies varied between studies. Passon et al. [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] assessed steady-state trough concentrations of ampicillin at a median of 29 hours after treatment initiation. Mitton et al. [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] collected meropenem trough levels after at least four doses. In contrast, Taccone et al. [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] conducted multiple samples of different beta-lactams (piperacillin/tazobactam, ceftazidime, cefepime and meropenem) within the first 28 hours of therapy.\u003c/p\u003e\u003cp\u003eAmong those four studies, three reported higher antibiotic concentrations in patients with acute kidney injury. Passon et al. [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] demonstrated that patients with AKI exhibited significantly higher ampicillin levels (81.1\u0026thinsp;\u0026plusmn;\u0026thinsp;37.7 mg/L) compared to those without AKI (38.2\u0026thinsp;\u0026plusmn;\u0026thinsp;24.8 mg/L; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Additionally, patients with AKI exceeded the 4\u0026times; MIC threshold (set at 32 mg/L) more frequently (92.0% vs. 44.0%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). This was also the case in the report of Taccone et al. [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] who reported that patients with decreased renal function at ICU were more likely to achieve the desired target even when dose reductions were made. However, in these patients with lower renal function a substantial proportion was still underdosed (median percentage of T\u0026thinsp;\u0026gt;\u0026thinsp;MIC : 57% for meropenem, 45% for ceftazidime, 34% for cefepime, and 33% for piperacillin/tazobactam), suggesting standard antibiotic regimens are inadequate, but that dose reductions might be beneficial.\u003c/p\u003e\u003cp\u003eChabert et al. [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] developed a pharmacokinetic model for cefoxitin (median sampling time 19 hours after antibiotic initiation). In this model, renal function significantly influenced dosing requirements. The model showed that standard dose (6 g/24 h) achieved target concentrations only in patients with severe renal impairment (creatinine clearance\u0026thinsp;\u0026lt;\u0026thinsp;30 mL/min), suggesting that patients with severe AKI need reduced dosages, but that standard regimens may be inadequate in patients with preserved renal function or slight renal impairment.\u003c/p\u003e\u003cp\u003eContradicting these results, Mitton et al. [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] found no correlation between kidney function and plasma concentrations of imipenem/cilastatin. However, as dosing was individualized according to renal function, the study design limits the ability to assess the impact of renal function on plasma concentrations. As such, definitive conclusions regarding pharmacokinetic variability in relation to renal function cannot be drawn from this study.\u003c/p\u003e\u003cp\u003e\u003cem\u003ePharmacological outcomes \u0026ndash; after 48 hours\u003c/em\u003e\u003c/p\u003e\u003cp\u003eA total of three studies measured antibiotic concentrations after 48 hours. Heinemeyer et al. [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] evaluated ceftriaxone clearance from day 2 up to day 7 in patients with acute kidney injury, Kitzes-Cohen et al. [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] collected samples\u0026thinsp;\u0026ge;\u0026thinsp;48 hours after meropenem initiation and Hassanpour et al. [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] measured at 48 and 72 hours after the first antibiotic dose.\u003c/p\u003e\u003cp\u003eIn concordance with the studies that mentioned early antibiotic concentrations, the first two studies concluded that renal impairment is correlated with delayed drug elimination and that even when dosages are reduced based on kidney function, patients with a lower kidney function exhibit higher concentrations end are more likely to achieve the desired target (T\u0026thinsp;\u0026gt;\u0026thinsp;4\u0026times;MIC 50\u0026ndash;100% in patients with eGFR\u0026thinsp;\u0026gt;\u0026thinsp;50 vs 75\u0026ndash;100% when eGFR\u0026thinsp;\u0026lt;\u0026thinsp;50) [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe third study was the only randomized controlled trial [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In this trial patients with AKI received 3 grams of meropenem per day for the first 48 hours, after which plasma concentrations were measured. Only 1 out of 10 patients (10%) achieved the pharmacodynamic target of 100% fT\u0026thinsp;\u0026gt;\u0026thinsp;4\u0026times;MIC. Patients were then randomized to either continue full dosing or undergo dose reduction based on renal function. By 72 hours, target attainment remained low (1 of 15 patients, 6.7%), with no significant difference between the dosing strategies. A limitation of this study was the small sample size which limits the generalizability of these findings.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo date, this scoping review is the first to structurally evaluate the availability and quality of evidence regarding the effect of beta-lactam dose reductions on the achievement of PD targets and clinical outcomes in critically ill patients with AKI\u003c/p\u003e\u003cp\u003eThe availability of evidence was low, and the quality even lower, underscoring the need for robust studies on this topic. A majority of the included studies were observational in nature and carried a high risk of bias, limiting the strength of any conclusions that can be drawn from them. However, when looking at the available evidence, the majority of studies have shown that, unsurprisingly, antibiotic concentrations are higher in patients with acute kidney injury. Furthermore, it has also been shown that delaying or withholding dose reductions of beta-lactam antibiotics is associated with lower mortality and less treatment failure.\u003c/p\u003e\u003cp\u003eSeveral limitations were identified across the studies. There was considerable heterogeneity in study designs, including retrospective cohorts, pharmacokinetic modeling, and small randomized trials. Sampling times for plasma concentrations varied widely, from within the first 24 hours to several days after antibiotic initiation. Definitions of AKI also differed, making it difficult to compare results across studies or generalize findings to the broader ICU population.\u003c/p\u003e\u003cp\u003eAccurate diagnosis of AKI in the early phase of hospital and ICU admission presents its own challenges. AKI definitions rely on eGFR or serum creatinine, which are known to be unreliable in critically ill patients [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Creatinine clearance may be influenced by prehospital factors such as diuretic administration, and AKI definitions often depend on dynamic changes in creatinine levels while baseline values are often unknown. These difficulties may lead to both over- and underestimation of kidney function, affecting dose reduction decisions and observed concentrations.\u003c/p\u003e\u003cp\u003eThe pharmacodynamic targets used to evaluate beta-lactam exposure were also inconsistent. While some studies used thresholds such as 100%fT\u0026thinsp;\u0026gt;\u0026thinsp;MIC, others used more aggressive targets like 100% fT\u0026thinsp;\u0026gt;\u0026thinsp;4\u0026times;MIC. The clinical significance of these different targets remains uncertain, and the evidence linking target attainment to improved patient outcomes is limited.\u003c/p\u003e\u003cp\u003eLastly, it is important to recognize that antibiotic concentrations are influenced not only by renal function but also by various patient-specific factors, such as body weight, serum albumin levels, and the underlying pathophysiology of the disease.\u003c/p\u003e\u003cp\u003eSimilarly, although all beta-lactam antibiotics are primarily eliminated by the kidneys, their pharmacokinetic properties differ across agents. These inter-agent differences may affect systemic drug exposure, thereby influencing both the risk of toxicity and the likelihood of achieving therapeutic targets. However, due to the limited available evidence, it was not possible to identify specific patient characteristics that significantly impact antibiotic concentrations in this population.\u003c/p\u003e\u003cp\u003eDespite the limitations inherent to the quality of available evidence, this is the first study to systematically examine the association of dose reductions on clinical and pharmacological outcomes in critically ill patients with AKI receiving beta lactam antibiotics. Current clinical practice is largely guided by expert opinion and PD models. However, these models often rely on eGFR or serum creatinine levels, without adequately accounting for the underlying pathophysiological mechanisms in AKI or chronic kidney disease. As a result, their applicability to this specific, but substantial patient group may be limited. This review highlights a critical gap in our knowledge of infectious treatment in the critically ill population and underscores the need for further clinical research to inform evidence-based dosing strategies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, the available evidence for beta-lactam dose reductions based on kidney function in critically ill patients with acute kidney injury is limited and of low quality. While some clinical studies and expert opinion based reviews suggest a potential benefit from delaying dose reductions for at least 24\u0026ndash;48 hours, definitive recommendations cannot yet be made. Further prospective research is needed to guide optimal dosing strategies in this population.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAKI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAcute Kidney Injury\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eeGFR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eEstimated Glomerular Filtration Rate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eICU\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eIntensive Care Unit\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMIC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMinimally Inhibitory Concentration\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePharmacodynamics\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePRISMA-ScR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePreferred Reporting of Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eROB-2\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRisk of Bias tool for randomized trials\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eROBINS-E\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRisk of Bias tool for non-randomized exposure\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003ch3\u003eEthics approval and consent to participate\u003c/h3\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch3\u003eConsent for publication\u003c/h3\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch3\u003eAvailability of data and materials\u003c/h3\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch3\u003eCompeting interests\u003c/h3\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003ch3\u003eFunding\u003c/h3\u003e\n\u003cp\u003eNo funding was received for \u0026nbsp; writing this review.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eAuthors' contributions\u003c/h3\u003e\n\u003cp\u003eM.H. and W.R. conducted the screening of all titles, abstracts, and full-text articles where necessary. C.U. resolved any discrepancies. M.H. drafted the manuscript. All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\n\u003ch3\u003eAcknowledgements\u003c/h3\u003e\n\u003cp\u003eThe authors wish to thank Maarten Engel from the Erasmus MC Medical Library for developing and updating the search strategies.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKoeze J, Keus F, Dieperink W, van der Horst IC, Zijlstra JG, van Meurs M. Incidence, timing and outcome of AKI in critically ill patients varies with the definition used and the addition of urine output criteria. BMC Nephrol. 2017;18(1):70.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNisula S, Kaukonen KM, Vaara ST, Korhonen AM, Poukkanen M, Karlsson S, et al. Incidence, risk factors and 90-day mortality of patients with acute kidney injury in Finnish intensive care units: the FINNAKI study. Intensive Care Med. 2013;39(3):420\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOstermann M, Chang RW. Acute kidney injury in the intensive care unit according to RIFLE. Crit Care Med. 2007;35(8):1837\u0026ndash;43. quiz 52.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKellum JA, Sileanu FE, Murugan R, Lucko N, Shaw AD, Clermont G. Classifying AKI by Urine Output versus Serum Creatinine Level. J Am Soc Nephrol. 2015;26(9):2231\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKhwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120(4):c179\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, Acute Dialysis Quality Initiative w. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8(4):R204-12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302(21):2323\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTang F, Yuan H, Li X, Qiao L. Effect of delayed antibiotic use on mortality outcomes in patients with sepsis or septic shock: A systematic review and meta-analysis. Int Immunopharmacol. 2024;129:111616.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGoncalves-Pereira J, Povoa P. Antibiotics in critically ill patients: a systematic review of the pharmacokinetics of beta-lactams. Crit Care. 2011;15(5):R206.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSinnollareddy MG, Roberts MS, Lipman J, Roberts JA. beta-lactam pharmacokinetics and pharmacodynamics in critically ill patients and strategies for dose optimization: a structured review. Clin Exp Pharmacol Physiol. 2012;39(6):489\u0026ndash;96.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAbdulla A, Dijkstra A, Hunfeld NGM, Endeman H, Bahmany S, Ewoldt TMJ, et al. Failure of target attainment of beta-lactam antibiotics in critically ill patients and associated risk factors: a two-center prospective study (EXPAT). Crit Care. 2020;24(1):558.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRoberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, et al. DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014;58(8):1072\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLee CC, Lee CH, Hong MY, Tang HJ, Ko WC. Timing of appropriate empirical antimicrobial administration and outcome of adults with community-onset bacteremia. Crit Care. 2017;21(1):119.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKellum JA, Sileanu FE, Bihorac A, Hoste EA, Chawla LS. Recovery after Acute Kidney Injury. Am J Respir Crit Care Med. 2017;195(6):784\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFederspiel CK, Itenov TS, Mehta K, Hsu RK, Bestle MH, Liu KD. Duration of acute kidney injury in critically ill patients. Ann Intensive Care. 2018;8(1):30.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCrass RL, Rodvold KA, Mueller BA, Pai MP. Renal Dosing of Antibiotics: Are We Jumping the Gun? Clin Infect Dis. 2019;68(9):1596\u0026ndash;602.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKadivarian S, Heydarpour F, Karimpour H, Shahbazi F. Measured versus estimated creatinine clearance in critically ill patients with acute kidney injury: an observational study. Acute Crit Care. 2022;37(2):185\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMatuszkiewicz-Rowinska J, Malyszko J, Wojtaszek E, Kulicki P. Dosing of antibiotics in critically ill patients: are we left to wander in the dark? Pol Arch Med Wewn. 2012;122(12):630\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTricco AC, Lillie E, Zarin W, O'Brien KK, Colquhoun H, Levac D, et al. PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. Ann Intern Med. 2018;169(7):467\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSterne JAC, Savovic J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHiggins JPT, Morgan RL, Rooney AA, Taylor KW, Thayer KA, Silva RA, et al. A tool to assess risk of bias in non-randomized follow-up studies of exposure effects (ROBINS-E). Environ Int. 2024;186:108602.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCamargo MS, Mistro S, Oliveira MG, Passos LCS. Association between increased mortality rate and antibiotic dose adjustment in intensive care unit patients with renal impairment. Eur J Clin Pharmacol. 2019;75(1):119\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAldardeer NF, Alshreef MM, Alharbi EA, Aljabri AK, Aljawadi MH, Almangour TA, et al. Early Versus Late Antipseudomonal beta-Lactam Antibiotic Dose Adjustment in Critically Ill Sepsis Patients With Acute Kidney Injury: A Prospective Observational Cohort Study. Open forum infect dis. 2024;11(3):ofae059.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFugate JE, Kalimullah EA, Hocker SE, Clark SL, Wijdicks EF, Rabinstein AA. Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy. Crit Care. 2013;17(6):R264.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHassanpour R, Ziaie S, Kobarfard F, Kouchek M, Miri M, Ahmadi Koomleh A, et al. Evaluation of pharmacokinetic and pharmacodynamic parameters of meropenem in critically ill patients with acute kidney disease. Eur J Clin Pharmacol. 2021;77(6):831\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHeinemeyer G, Link J, Weber W, Meschede V, Roots I. Clearance of ceftriaxone in critical care patients with acute renal failure. Intensive Care Med. 1990;16(7):448\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLuo X, Zhou W, Wan D, Peng J, Liao R, Su B. Association between amoxicillin administration and outcomes in critically ill patients with acute kidney injury. Front Pharmacol. 2024;15:1409654.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePasson SG, Schmidt AR, Wittmann M, Velten M, Baehner T. Evaluation of continuous ampicillin/sulbactam infusion in critically ill patients. Life Sci. 2023;320:121567.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChabert P, Provoost J, Cohen S, Dupieux-Chabert C, Bitker L, Ferry T et al. Pharmacokinetics, efficacy and tolerance of cefoxitin in the treatment of cefoxitin-susceptible extended-spectrum beta-lactamase producing Enterobacterales infections in critically ill patients: a retrospective single-center study. Ann Intensive Care. 2022;12(1).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMitton B, Paruk F, Gous A, Chausse J, Milne M, Becker P, Said M. Evaluating the usefulness of the estimated glomerular filtration rate for determination of imipenem dosage in critically ill patients. S Afr Med J. 2022;112(9):765\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKitzes-Cohen R, Farin D, Piva G, De Myttenaere-Bursztein SA. Pharmacokinetics and pharmacodynamics of meropenem in critically ill patients. Int J Antimicrob Agents. 2002;19(2):105\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTaccone FS, Laterre PF, Dugernier T, Spapen H. Insufficient β-lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care. 2010;14(4):R126.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"critical-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cric","sideBox":"Learn more about [Critical Care](http://ccforum.biomedcentral.com/)","snPcode":"13054","submissionUrl":"https://submission.nature.com/new-submission/13054/3","title":"Critical Care","twitterHandle":"@Crit_Care","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Intensive Care, Acute Kidney Injury, Beta-lactam antibiotics, Scoping Review","lastPublishedDoi":"10.21203/rs.3.rs-7156465/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7156465/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eAcute kidney injury is a common complication in critically ill patients, often coinciding with the need for antibiotic therapy. The dose of beta-lactam antibiotics is frequently adjusted and often reduced based on estimated Glomerular Filtration Rate. However, early dose reductions may lead to underdosing, especially during the critical first 48 hours of infection treatment, when AKI may be transient and adequate antibiotic treatment is critical. While some reviews suggest delaying dose reductions improves clinical outcomes, evidence remains limited. This scoping review evaluates the current literature on beta-lactam dosing strategies in critically ill patients with acute kidney injury, focusing on pharmacological and clinical outcomes.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003e We conducted a systematic scoping review following PRISMA-ScR guidelines. We searched Medline, Embase, Web of Science, Cochrane CENTRAL, and Google Scholar from database inception through March 24, 2025. Two reviewers independently screened all articles and assessed study quality using ROB-2 and ROBINS-E tools. Eligible studies included critically ill adult patients with acute kidney injury, receiving beta-lactams, and reporting clinical or pharmacological outcomes. Data were extracted using a standardized template and categorized by pharmacological or clinical outcomes. Further stratification by antibiotic type or patient characteristics was not feasible.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eOut of the 1,436 screened articles, 11 studies involving 25,381 patients were included. The risk of bias was high in most studies. Most studies were observational; one was a randomized controlled trial. Seven studies reported beta-lactam plasma concentrations. Higher concentrations were generally observed in patients with acute kidney injury, even though dosages were oftentimes already reduced. One study associated early dose reductions with decreased neurotoxicity. One study reported increased treatment failure with early dose reductions and three studies linked delayed dose reductions to reduced mortality.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eCurrent evidence on beta-lactam dose reduction in critically ill patients with acute kidney injury is limited and of low quality. Delaying reductions may improve clinical outcomes, but further prospective studies are urgently needed.\u003c/p\u003e","manuscriptTitle":"Beta-lactam dose reductions in critically ill patients with acute kidney injury: a scoping review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-01 11:41:20","doi":"10.21203/rs.3.rs-7156465/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-13T13:11:51+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-07T19:05:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-06T16:44:07+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-05T20:19:30+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-05T11:42:42+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-31T06:43:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"282454536697688202353405284560151037188","date":"2025-07-29T12:56:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"281001552531214050198273528840267090822","date":"2025-07-29T09:23:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"330463463245148996838837806199278315455","date":"2025-07-29T08:23:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"17475955712218485360320453168766566204","date":"2025-07-28T16:56:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"98442214489470546349788960018131737603","date":"2025-07-28T14:39:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"139660952544980498599118062795113181011","date":"2025-07-28T14:27:58+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-28T14:00:06+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-25T00:50:26+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-25T00:49:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"Critical Care","date":"2025-07-18T09:53:54+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"critical-care","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cric","sideBox":"Learn more about [Critical Care](http://ccforum.biomedcentral.com/)","snPcode":"13054","submissionUrl":"https://submission.nature.com/new-submission/13054/3","title":"Critical Care","twitterHandle":"@Crit_Care","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f8ad9ea3-451b-486c-bc4a-f4d71183ffab","owner":[],"postedDate":"August 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-08T16:09:30+00:00","versionOfRecord":{"articleIdentity":"rs-7156465","link":"https://doi.org/10.1186/s13054-025-05736-6","journal":{"identity":"critical-care","isVorOnly":false,"title":"Critical Care"},"publishedOn":"2025-12-02 15:57:56","publishedOnDateReadable":"December 2nd, 2025"},"versionCreatedAt":"2025-08-01 11:41:20","video":"","vorDoi":"10.1186/s13054-025-05736-6","vorDoiUrl":"https://doi.org/10.1186/s13054-025-05736-6","workflowStages":[]},"version":"v1","identity":"rs-7156465","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7156465","identity":"rs-7156465","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}