Prolonged versus intermittent vancomycin infusion in critically ill patients with sepsis: A systematic review and meta-analysis

doi:10.21203/rs.3.rs-3555370/v1

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Prolonged versus intermittent vancomycin infusion in critically ill patients with sepsis: A systematic review and meta-analysis

https://doi.org/10.21203/rs.3.rs-3555370/v1

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Background

Vancomycin is often used empirically as a first-line drug for methicillin-resistant Staphylococcus aureus therapy in patients with sepsis. This review aimed to clarify the clinical efficacy and safety of prolonged vancomycin infusion compared to intermittent infusion in adult patients with acute severe infection.

Methods

Potentially eligible trials were identified by searching the MEDLINE, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi (ICHUSHI) online databases. We selected randomized controlled trials and observational studies in which the clinical outcomes of adult patients with sepsis or septic shock were compared between prolonged and intermittent vancomycin infusion strategies. Two investigators independently screened the search results and extracted data. The primary outcome was all-cause mortality at the maximum follow-up. Secondary outcomes included the attainment of the target plasma concentration, clinical cure, and adverse events, such as nephrotoxicity.

Results

Sixteen studies were identified for the analysis of baseline characteristics. A total of 214 patients from three randomized trials and 1999 patients from 13 observational studies were included. Mortality rates of patients receiving prolonged infusion and patients receiving intermittent infusion were similar (pooled risk ratios, 1.05; 95% confidence intervals, 0.63–1.74; P = 0.85 in randomized controlled trials and pooled risk ratios, 1.07; 95% confidence intervals, 0.74–1.55; P = 0.71 in observational studies). Patients treated with prolonged infusion had a significantly higher attainment of the target plasma concentration compared with patients receiving intermittent infusion (pooled risk ratios, 5.62; 95% confidence intervals, 2.09–15.07; P < 0.001 in randomized controlled trials and pooled risk ratios, 2.27; 95% confidence intervals, 1.393.71; P = 0.001 in observational studies). No significant difference was detected in the other outcomes.

Conclusions

Our findings revealed that, compared with intermittent administration, prolonged infusion of vancomycin may be advantageous for controlling blood vancomycin levels.

vancomycin

prolonged infusion

continuous infusion

sepsis

Sepsis is associated with a high fatality rate and there is an urgent need to improve the treatment of sepsis. Antimicrobial therapy is the cornerstone of sepsis treatment. Methicillin-resistant Staphylococcus aureus (MRSA) accounts for approximately 14% of sepsis-causing bacteria [1], and vancomycin is often empirically used as a first-line drug for anti-MRSA therapy. In sepsis, owing to increased vascular permeability, augmented cardiac output, and changes in blood protein concentration, the volume of distribution increases [2]. Furthermore, acute kidney injury and augmented renal clearance change the excretory ability and cause extreme fluctuations in the blood concentration of drugs [3]. Vancomycin exhibits concentration-dependent nephrotoxicity and therapeutic effects that are indicative of its narrow pharmacokinetic target exposure range. Therefore, balancing the achievement of appropriate pharmacokinetic/pharmacodynamic (PK/PD) targets for vancomycin with the adverse effects of vancomycin in the treatment of sepsis is challenging.

Current guidelines recommend the intermittent infusion of vancomycin as a standard strategy [4]. However, in terms of PK/PD, a prolonged infusion strategy may be more effective, and the efficacy and tolerability of prolonged vancomycin infusions have recently received increased attention [5]. Similar to vancomycin, β-lactams have time-dependent antibacterial activity and evidence has already been accumulated regarding the efficacy of prolonged β-lactams infusion. Despite insufficient evidence of improved clinical prognosis with prolonged vancomycin infusion, this strategy confers an advantage in reducing renal dysfunction and achieving target blood levels, with similar results in critically ill patients [5].

Nonetheless, the optimal dose of vancomycin for patients with sepsis remains unclear. This review was performed to determine the clinical efficacy and safety of prolonged or intermittent vancomycin infusion in adult patients with sepsis by analyzing findings from newly published studies.

Data Sources and Search Strategies

To identify eligible trials, we searched the MEDLINE database via PubMed, the Cochrane Central Register of Controlled Trials, and the Igaku Chuo Zasshi (ICHUSHI) online database [6]. The search was performed on November 29, 2022, and was not restricted by date of publication or sample size, although only reports published in English and Japanese were included. The search terms are presented in Additional file 1. A systematic review and meta-analysis were conducted in accordance with the PRISMA guidelines [7] and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines [8], which do not require ethical approval. The PRISMA 2020 checklist is presented in additional file 2. The protocol was registered with the International Prospective Register of Systematic Reviews (ID: CRD42022371727).

Study Selection

Titles and abstracts of the search results were retrieved from the databases. After excluding duplicate studies, two investigators (YM and AK) independently screened titles and abstracts for potential eligibility. In case of disagreement between the reviewers, a full-text report was used to determine study eligibility. Disagreements were resolved by consensus, although a third reviewer (YK) was consulted if a consensus could not be reached. The full texts of potentially eligible articles were independently reviewed by two investigators (YM and AK), and a final decision regarding eligible studies was made with the consensus of all the authors.

We included randomized controlled trials (RCT) and observational studies (OS) that compared the clinical outcomes of prolonged and intermittent vancomycin infusion in the acute-phase management of critically ill adult patients. Prolonged infusion was defined as infusion with longer time than normally required for intermittent infusion, or continuous infusion with or without loading doses. We set the overall mortality as the primary outcome during the observation period. The secondary outcomes included attainment of the target plasma concentration, clinical cure, and adverse events, including nephrotoxicity.

Data Extraction

Data extraction was conducted independently by two investigators (YM and AK), and a consensus was reached to resolve any disagreements. The extracted data included the author, year of publication, study design, number of study participants, patient demographics, outcome measures, and inclusion and exclusion criteria.

Assessment of Methodological Quality: Risk-of-Bias Assessment and GRADE Approach

We adapted the Cochrane Risk of Bias tool (RoB2) for RCTs and the Risk Of Bias In Non-randomized Studies – of Interventions assessment tool (ROBINS-I) for OS to assess the quality of the included studies [9, 10]. Moreover, we graded the quality of evidence for each finding based on the criteria established by the GRADE working group [11]. The quality of the study methodology was independently classified by two investigators (YM and YK) as high, moderate, low, or very low based on the study design, risk of bias, indirectness, inconsistency, imprecision, and publication bias. Publication bias was assessed visually using funnel plots.

Statistical Analysis

Using the Der Simonian–Laird random-effects model, we pooled eligible patients for each outcome and calculated the risk ratios (RR) and corresponding 95% confidence intervals (CI). The weights were calculated using the inverse variance-weighted method. Interstudy heterogeneity was evaluated using I² statistics (I² > 50% indicated severe heterogeneity). All statistical analyses were performed using Review Manager version 5.4.1, for Windows (Cochrane Systematic Review Software, The Nordic Cochrane Centre, the Cochrane Collaboration, Copenhagen, Denmark).

Sensitivity analysis

Sensitivity analysis was performed to assess the potential risk of bias, and studies with a high risk of reporting bias were excluded.

Search Results

We identified 741 studies from the electronic databases after eliminating duplicates, and only 22 studies were assessed for eligibility based on the title and abstract. After a review of the full-text articles, three RCTs and 13 OSs were included in this review (Fig. 1).

Study Characteristics and Risk-of-Bias Assessment

The 16 studies [12–27] included 2,213 patients (Table 1). In the RCTs, 109 and 105 patients were assigned to the prolonged and intermittent vancomycin infusion groups, respectively. In the OS, 1,198 and 801 patients were assigned to the prolonged and intermittent vancomycin infusion groups, respectively. All prolonged infusions were in the continuous infusion style in the included studies. The risk of bias regarding the primary outcome of the RCTs and OSs is shown in the risk-of-bias summary (Fig. 2A, 2B). Deviations from intended interventions were categorized as having a high risk of bias in RCTs owing to the nature of the intervention. Bias in the selection of the reported results was categorized as serious in one of the OS because the results varied depending on the analysis method. The risk of bias assessment for all results were presented in additional file 3.

Table 1

Baseline characteristics of eligible studies
References	Type of study	Intervention/Target of each group	Site of infection	Inclusion criteria for renal injury or renal replacement therapy
Wysocki and Delatour, 2001	RCT	Group 1 (n = 61): 15 mg/kg infused, followed by a continuous infusion and adjusted. / plateau of 20 to 25 mg/liter. Group 2 (n = 58): 15 mg/kg infused every 12 h and adjusted. / trough of 10 to 15 mg/liter.	endocarditis, septicemia, catheter-related infections, pneumonia, mediastinitis, meningitis, miscellaneous infections.	serum creatinine < 2.3 mg/dl.
Eldemiry, 2013	RCT	Group 1 (n = 20): continuous infusion. / steady-state concentrations of 15 to 20 µg/mL. Group 2 (n = 20): intermittent infusion based on actual body weight and CLCr. / steady-state concentrations of 15 to 20 µg/mL.	pneumonia	serum creatinine > 1.4 mg%, and oliguria < 0.5 mL/kg/h for 6 h, not underwent dialysis.
Schmelzer, 2013	RCT	Group 1 (n = 28): 20 mg/kg infused, followed by a continuous infusion and adjusted. / serum concentration of 15 to 25 mg/mL forty-eight hours after initiating treatment. Group 2 (n = 27): 15 mg/kg vancomycin intravenously every 12 hours and adjusted. / serum concentration of 15 to 25 mg/mL forty-eight hours after initiating treatment.	VAP	Without abnormal renal function (defined as creatinine clearance less than 60 mL/min)
Wysocki, 1995	Prospective Cohort	Group 1 (n = 13): 15 mg/kg infused, followed by a continuous infusion and adjusted. / plateau of 20 and 30 mg/L. Group 2 (n = 13): 15 mg/kg infused over 1h twice a day and adjusted. / peak of 20 to 40 mg/L and trough of 5 to 10 mg/L	pneumonia, bacteraemia	serum creatinine concentration ≦ 320µM/L
Di Filippo 1998	Retrospective Cohort	Group 1 (n = 11): continuous infusion of 83 mg/h after initial bolus of 0.5 g. / NR. Group 2 (n = 14): 0.5 g infused every 6 h. / NR.	NR	NR
Hutschala 2009	Retrospective Cohort	Group 1 (n = 119): 20 mg/kg infused, followed by a continuous infusion and adjusted. / plateau of 20 to 25 mg/l. Group 2 (n = 30): 20 mg/kg infused and adjusted. / through concentration of 15 mg/l. .	wound infection, sternal infection, mediastinitis, catheter-related infection, hospital-acquired pneumonia, infection with bacteremia	Preoperative creatinine concentration > 1.5 mg/dl, no preoperative period of acute or chronic renal failure, no preoperative renal replacement therapy.
Akers 2012	Retrospective Cohort	Group 1 (n = 44): 3 g per 24 hours and adjusted. / steady-state levels of 20 to 25 µg/mL. Group 2 (n = 44): 1g every 8 hours and adjusted. / trough of 15 to 20 µg/mL.	bacteremia, sepsis without bacteremia, pneumonia	CVVH and Non-CVVH
Saugel 2013	Retrospective Cohort	Group 1 (n = 94): after a loading dose, 40 or 60 mg per hour and adjusted. / plateau of 15 to 25 mg/L. Group 2 (n = 52): intermittent infusion and adjusted. / trough of 5 to 10 mg/L.	NR	Include patients who need for renal replacement therapy when vancomycin was started.
Hanrahan 2014	Retrospective Cohort	Group 1 (n = 653): Continuous infusion. NR in detail. / NR. Group 2 (n = 390): Intermittent infusion. NR in detail. / NR.	NR	NR
Lin 2015	Retrospective Cohort	Group 1 (n = 14): After a loading dose of 25 mg/kg, 1,500 mg (60 mg/hr) daily and adjusted. / serum concentration of 15 mcg/ml to 25 mcg/ml every 24 hours. Group 2 (n = 45): 1,000 to 2,000 mg daily and adjusted / trough of 15 mcg/ml to 20 mcg/ml.	NR	Undergoing CVVH.
Tafelski 2015	Prospective Cohort	Group 1 (n = 76): Initiation of therapy with1g infused, followed by 2g/24h or 1g/24h in patients with impaired renal function. / drug levels 24 to 36 after administration of 15 to 20mg/L. Group 2 (n = 49): 500mg vancomycin every 6h or 1g every12h. / trough of 10 to 15mg/L or 15 to 20mg/L for severe infection.	pneumonia, endocarditis, urogenital, ZNS, abdomen, catheter-related, bones and joints, soft tissues, unknown focus.	NR
Duszynska 2016	Prospective Cohort	Group 1 (n = 21): Initial daily dose of 30 mg/kg infused, followed by continuous infusion and adjusted. / AUC24/MIC > 400 Group 2 (n = 21): 25 mg/kg followed by maintenance daily dose. / AUC24/MIC > 400.	peritonitis, CLA-BSI, SSTI, CNS infection, HAP/VAP, others.	Without chronic renal failure requiring hemodialysis (HD), AKI already treated by renal replacement therapy (CRRT).
Maarseveen 2016	Prospective Cohort	Group 1 (n = 44): 1000 mg infused, followed by a continuous infusion. / plateau of 15 to 20 mg/L. Group 2 (n = 27): 15 mg/kg infusion every 12 hours. / trough of 8 to 12 mg/L.	sepsis, pneumonia, endocarditis and so on.	Without renal replacement therapy.
Bissell 2020	Retrospective Cohort	Group 1 (n = 75): 20 mg/kg infused, followed by a continuous infusion of 30 mg/kg/d and adjusted. / 48-hour level of 15 to 25 mg/dL. Group 2 (n = 75): NR in detail. / trough of 15 to 20 mg/dL.	pneumonia, meningitis, empiric, bacteremia, skin and soft tissue, abdominal.	With a creatinine clearance over 50 mL/min and without renal replacement therapy.
Yamada 2020	Prospective Cohort	Group 1 (n = 11): loading dose of 30 mg/kg followed by 30 mg/kg / concentration of 15 to 25 µg/mL. Group 2 (n = 13): loading dose of 30 mg/kg followed by 15 mg/kg q12 h. / NR in detail.	lungs, central nervous system, skin or soft tissue, abdominal, catheter related, others	Without renal dysfunction (serum creatinine ≥ 2.5 mg/dl or estimated creatinine clearance ≤ 40 mL/min).
Xu 2022	Prospective Cohort	Group 1 (n = 23): 20–25 mg/kg infused, followed by a continuous infusion. / trough concentration of 15 to 20mg/mL. Group 2 (n = 28): (1) 20 to 25 mg/kg followed by a maintenance dose of 7.5 to 10 mg/kg q12h for patients on CVVH with EFR of 20 to 25 mL/kg/h; (2)10 to 13 mg/kg q12h for those undergoing CVVH with EFR at 25 to 40 mL/kg/h, and 13 to 15 mg/kg q12h for EFR more than 40 mL/kg/h. / steady-state concentration of 15 to 25mg/dL.	lung, bloodstream, urinary tract, Intra-abdominal, skin and soft-tissue, infective endocarditis, ≥ 2 sites of infection	Having AKI requiring CVVH, and anuria (24-h urine volume < 100 mL) during CVVH.
RCT, randomized control trial; NR, not reported; VAP, ventilator-associated pneumonia; CVVH, continuous venovenous hemofiltration; ZNS, Zentralnervensystem; SSTI, skin and soft tissue infection; CLA-BSI, central line-associated bloodstream infection; HAP, hospital-acquired pneumonia; HD, hemodialysis; AKI, acute kidney injury; EFR, effluent flow rate.
Group 1: prolonged infusion group, Group 2: intermittent infusion group

Heterogeneity

For the primary outcome (overall mortality), heterogeneity was observed among the studies in the OS analysis (I² = 57%, χ2 = 18.59, P = 0.02; Fig. 3B). Furthermore, heterogeneity was observed in other outcomes (Figs. 4B, 5B, and 6B).

Publication Bias and Quality of Evidence

We analyzed the presence of publication bias (Additional file 4). Visual inspection of the funnel plots suggested publication biases in the RCTs for adverse events and in the OSs for the attainment of the target plasma concentration. The quality of the evidence was rated as very low for the effect of prolonged infusion on primary outcomes in the RCTs, with the grade being lowered owing to the risk of bias and imprecision. For other outcomes, the certainty of the evidence was considered low or very low for almost all outcomes in the RCTs and OSs. A summary of this evidence is presented in Table 2.

Table2. Summary table of findings
Outcomes	Anticipated absolute effects (95%CI)		Relative effect (95%CI)	Number of participants (studies)	Certainty of the evidence (GRADE)
	Risk with intermittent infusion	Risk with prolonged infusion

Mortality (RCTs)	328 per 1,000	344 per 1,000 (206 to 570)	RR 1.05 (0.63 to 1.74)	119 (1 RCT)	Very low

Mortality (OSs)	186 per 1,000	199 per 1,000 (138 to 289)	RR 1.07 (0.74 to 1.55)	1715 (9 OSs)	Very low

Attainment of target plasma concentration (RCTs)	85 per 1,000	478 per 1,000 (178 to 1,000)	RR 5.62 (2.09 to 15.07)	95 (2 RCTs)	Low

Attainment of target plasma concentration (OSs)	267 per 1,000	606 per 1,000 (371 to 991)	RR 2.27 (1.39 to 3.71)	544 (6 OSs)	Low

Clinical cure (RCTs)	810 per 1,000	786 per 1,000 (656 to 940)	RR 0.97 (0.81 to 1.16)	119 (1 RCT)	Low

Clinical cure (OSs)	510 per 1,000	668 per 1,000 (347 to 1000)	RR 1.31 (0.68 to 2.51)	93 (2 OSs)	Very low

Adverse event (RCTs)	162 per 1,000	113 per 1,000 (55 to 230)	RR 0.70 (0.34 to 1.42)	214 (3 RCTs)	Very low

Adverse event (OSs)	235 per 1,000	174 per 1,000 (124 to 246)	RR 0.74 (0.53 to 1.05)	1869 (11 OSs)	Moderate

Outcomes

Mortality

One RCT with 119 patients (one study) reported overall mortality as the primary outcome in 61 and 58 patients in the prolonged and intermittent vancomycin infusion groups, respectively (Fig. 3A). Of these, 21 (34.4%) and 19 (32.8%) in the prolonged and intermittent vancomycin infusion groups, respectively, died. The pooled RR of mortality was not statistically significant (pooled RR, 1.05; 95% CI, 0.63–1.74) (Fig. 3A).

The OSs that included 1,715 patients (nine studies) reported overall mortality as a primary outcome, with 1028 and 687 patients in the prolonged and intermittent vancomycin infusion groups, respectively (Fig. 3B), among whom 249 (24.2%) and 128 (18.6%), respectively, died. The pooled RR of mortality was not statistically significant (pooled RR, 1.07; 95% CI, 0.74–1.55) (Fig. 3B).

Attainment of the target plasma concentration

When comparing secondary outcomes, two studies on the attainment of the target plasma concentration were included, and the pooled RR significantly favored prolonged infusion (pooled RR, 5.62; 95% CI, 2.09–15.07) (Fig. 4A).

In the OSs, six studies were included, and the pooled RR significantly favored prolonged infusion (pooled RR, 2.27; 95% CI, 1.39–3.71) (Fig. 4B).

Clinical cure and Adverse event

For clinical cure and adverse event, there was no significant difference between the prolonged and intermittent vancomycin infusion groups in the RCTs (clinical cure: pooled RR, 0.97; 95% CI, 0.81–1.16, adverse events: pooled RR, 0.70; 95% CI, 0.34–1.42) (Fig. 5A and 6A).

In OSs, there was no significant difference between the prolonged and intermittent vancomycin infusion groups (clinical cure: pooled RR, 1.31; 95% CI, 0.68–2.51, adverse event: pooled RR, 0.74; 95% CI, 0.53–1.05) (Fig. 5B and 6B).

Sensitivity analysis

The results of the sensitivity analysis are shown in Fig. 7. After excluding the studies that are at high risk of reporting bias, the RR for mortality was less pronounced in OSs (pooled RR, 0.90; 95% CI, 0.68–1.20); however, the analyses were not statistically significant. In contrast, for adverse events, a significant reduction in adverse events was observed in the prolonged vancomycin infusion group (pooled RR, 0.69; 95% CI, 0.52–0.91) (Fig. 7A and 7B).

In this systematic review, the effects of prolonged vs. intermittent vancomycin infusion in adult patients with sepsis were evaluated based on recent studies. In the included studies, all prolonged infusions compared to intermittent infusions were continuous infusions. Hence, in effect, a comparison between continuous infusion and intermittent infusion was evaluated. The results showed that continuous infusion of vancomycin is advantageous in achieving target blood levels and that there was no increase in side effects; this indicates that continuous vancomycin infusion may be a safer, more controlled treatment for critically ill patients. However, there was no significant intergroup difference in important outcomes, such as mortality or clinical cure.

Several meta-analyses have been conducted to determine the efficacy of continuous vancomycin infusions. Cataldo et al. performed a meta-analysis and suggested that continuous infusion of vancomycin was associated with a significantly lower risk of nephrotoxicity than intermittent infusion [28]. Hao et al. reported that continuous infusion was safer than intermittent infusion, although the clinical efficacy did not differ significantly [29]. Chu et al. showed that continuous infusion made it easier to achieve the target concentration and safer than intermittent infusion [30]. Flannery et al. conducted a systematic review and meta-analysis for the first time in critically ill patients on this issue and showed that nephrotoxicity was reduced by continuous infusion in their analysis [5]. However, to date, there is no evidence that continuous drug administration is effective in terms of mortality or clinical cure.

Therefore, comparing the clinical efficacy of different vancomycin infusion methods is challenging. Vancomycin, a key antimicrobial agent often used to treat sepsis, is often initiated in combination with other antimicrobial agents, which complicates the situation. In addition, when considering the safety and efficacy of antimicrobials in critically ill patients, appropriate targeting should be performed, and sufficient doses of antimicrobials should be administered in each case. Regarding dosage, the importance of additional dosing was noted [31]. Furthermore, vancomycin-induced kidney injury has other known risk factors [32] besides the effects of vancomycin itself, such as blood vessel levels, which must be eliminated as much as possible. It should be noted that while many studies have addressed renal dysfunction as an adverse effect, each study has different criteria for the participants’ baseline renal function, with some including only patients with normal renal function at the start of treatment and others including only patients with renal dysfunction or under continuous venovenous hemofiltration. These differences in baseline characteristics may have affected our results. Thus, comparative studies that consider these aspects are desirable in the future.

This meta-analysis had several limitations. First, only one RCT was analyzed for the primary outcome. Thus, given the inherent limitations of observational studies, our results should be interpreted cautiously. Second, most of the analyses showed a considerable degree of statistical heterogeneity. This may be partially due to differences in the criteria for grouping and the baseline characteristics of each included participant. The literature search targeted patients with sepsis and extended to include acutely managed critically ill patients requiring vancomycin. Statistical heterogeneity was managed using random-effects models. Third, the certainty of evidence for most outcomes was judged to be low to very low owing to the risk of bias and imprecision in both the RCTs and OSs. Fourth, the target concentrations were not consistent across the studies. In the studies included in the present systematic review, the targets generally plateaued at blood levels for continuous infusion and trough values for intermittent infusion. The dosing design for vancomycin should be based on the ratio of the total Area Under the Curve to Minimum Inhibitory Concentration (AUC/MIC). The latest Infectious Diseases Society of America guidelines [4] recommend an AUC/MIC of 400–600 for vancomycin. Trough-guided therapy may significantly exceed the target AUC, and an AUC-guided approach has a lower risk of nephrotoxicity [33]. Thus, a comparative study of the efficacy and safety of prolonged and intermittent infusion therapy based on AUC-guided dosing is warranted.

The pooled results of our meta-analysis suggest that prolonged vancomycin infusion might increase the rate of achievement of target blood levels and reduce complications in critically ill patients with sepsis. However, because the certainty of evidence for most outcomes is considered low to very low, it is an oversimplification to say that prolonged infusion of vancomycin is more clinically useful. Therefore, further confirmation using prospective, well-designed RCTs is required.

RCT

randomized controlled trial

observational studies

inverse variance-weighted method

confidence interval.

Ethics approval and consent to participate: Not applicable.

Consent for publication: Not applicable.

Availability of data and material: The data used for this meta-analysis are obtained in our list of references.

Competing interests: The authors declare that they have no conflicts of interest.

Funding: None

Authors’ contributions

All authors were involved in designing the study. YM, AK, K. Kano, K. Kubo, ME, and YK identified the studies for inclusion in the meta-analysis and then analyzed the data. YM drafted the manuscript and YK supervised the drafting of the manuscript. All authors were involved in data interpretation and discussion. All the authors have read and approved the final version of the manuscript.

Acknowledgements

We thank all the members of the committees that formulated the Japanese Clinical Practice Guidelines for the Management of Sepsis and Septic Shock 2024 (J-SSCG 2024) and Editage (www.editage.jp) for English language editing.

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No competing interests reported.

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Prolonged versus intermittent vancomycin infusion in critically ill patients with sepsis: A systematic review and meta-analysis

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Abstract

Background

Methods

Results

Conclusions

Figures

BACKGROUND

METHODS

Data Sources and Search Strategies

Study Selection

Data Extraction

Assessment of Methodological Quality: Risk-of-Bias Assessment and GRADE Approach

Statistical Analysis

Sensitivity analysis

RESULTS

Search Results

Study Characteristics and Risk-of-Bias Assessment

Heterogeneity

Publication Bias and Quality of Evidence

Outcomes

Mortality

Attainment of the target plasma concentration

Clinical cure and Adverse event

Sensitivity analysis

DISCUSSION

CONCLUSIONS

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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