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META-ANALYSES

Intraoperative Redosing of Surgical Antibiotic Prophylaxis in Addition to Preoperative Prophylaxis Versus Single-dose Prophylaxis for the Prevention of Surgical Site Infection

A Meta-analysis and GRADE Recommendation

Wolfhagen, Niels MD; Boldingh, Quirine J. J. MD; de Lange, Mats MD; Boermeester, Marja A. MD, PhD; de Jonge, Stijn W. MD

Author Information
doi: 10.1097/SLA.0000000000005436

Abstract

Surgical site infections (SSI) are a common postoperative complication associated with increased hospital stay, morbidity and mortality.1–4 Surgical antibiotic prophylaxis (SAP) is an effective intervention for the prevention of SSI in indicated procedures.5 However, administration of antibiotics also has a dose and duration dependent association with adverse effects including the emergence of antibiotic resistance.6 Therefore, SAP strategies aim to be both optimally effective and restrictive on the amount of antibiotics administered. Administration of SAP before incision is advised but postoperative continuation is discouraged.7–9

Evidence of the effect of timely preoperative administration of SAP suggest that adequate tissue concentration is needed at the time of incision and throughout the procedure for SAP to be effective.10–12 Similarly, inadequate antibiotic tissue concentration upon wound closure is associated with increased risk of SSI13 and the redundancy of postoperative continuation of antibiotics depends on timely preoperatively administration and intraoperative redosing.14 Tissue concentration depends on pharmacokinetics, pharmacodynamics, the initial dose, and the time passed since the initial dose.15,16 Long procedure duration or excessive blood loss may decrease antibiotic tissue levels, potentially below effective concentrations.15,16 Intraoperative redosing of SAP increases tissue concentration and has been suggested during longer procedures or after excessive blood loss to help prevent SSI.5 There is some clinical evidence to support this hypothesis.17,18

Recent guidelines have assessed redosing of SAP either as out of scope,7 deemed too few randomized trials available for proper analysis and recommendation8 or recommend to give a repeat dose if the surgical procedure is longer than the half-life of the antibiotic.9 However, the latter recommendation is presented without support of evidence.9,19 An earlier guideline on SAP by the American Society of Hospital Pharmacists (ASHP) recommended redosing of SAP in long procedures defined as exceeding 2 half-lives of the antimicrobial agent or procedures with excessive blood loss.5 Local SAP protocols, such as the American Surgical Care Improvement Programme, also advise redosing of SAP in surgical procedures lasting longer than 2 times the half-life of the antibiotic given.20,21 Unfortunately, reported compliance is low.22,23 The conflicting recommendations leave patients and practitioners in uncertainty and inevitably lead to suboptimal care in some cases. To our knowledge no systematic review on the effect of SAP redosing on SSI risk has been performed.

We performed a systematic review and meta-analysis to assess the effect of intraoperative redosing in addition to preoperative SAP compared to a single dose of preoperative SAP on the incidence of SSI. We hypothesized that intraoperative redosing of SAP reduces the risk of SSI.

METHODS

Search Strategy and Selection Criteria

We performed a systematic review with meta-analysis according to our pre-registered PROSPERO protocol (CRD42021229035). We report according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.24

We searched MEDLINE (PubMed), Embase, CINAHL, CENTRAL databases from inception until June 25, 2021. The terms “surgical site infection," “antibiotic prophylaxis," “drug administration schedule," “redosing," and “perioperative care” were used. A clinical librarian aided the literature search. We performed backward and forward citation tracking to identify additional eligible studies. There were no restrictions on study type, publication date, or language. The search strategy is available in supplementary Appendix 1, https://links.lww.com/SLA/D732.

We included randomized controlled trials (RCTs) that compared the effect intraoperative redosing in addition to preoperative SAP (intervention) to a single dose of preoperative SAP (control) on the incidence of SSI in adult patients undergoing elective surgery and observational studies that aimed to estimate the effect [odds ratio (OR) or relative risk (RR)] of additional intraoperative redosing compared to a single dose of preoperative SAP. Intraoperative redosing was defined as the administration of any intraoperative dose of antibiotics after initial preoperative SAP. There were no restrictions on the protocol of redosing concerning timing and dosage. We excluded studies that did not clearly state administration of preoperative SAP or did not clearly distinguish between intraoperative or postoperative redosing or studies that investigated the effects of topical antibiotics. Two authors (N.W. and Q.B.) independently screened all titles and abstracts through Rayyan QCRI.25 Full texts articles of eligible studies were obtained. Articles that fulfilled the inclusion criteria were included. Disagreements were resolved by consensus with a third author. The reference lists of the included articles were cross-checked for additional potential eligible studies.

Outcomes

The primary outcome was (adjusted) OR for SSI after receiving preoperative SAP with additional intraoperative redosing (intervention) compared to a single dose of preoperative SAP (control). Secondary outcomes included SSI related mortality, length of hospital stay, adverse events related to the use of antibiotics such as allergic reactions or Clostridium difficile infections.

Data Synthesis

Two authors (N.W. and Q.B.) independently extracted study data following a predefined data extraction form. Data included study type, publication date, country of publication, type of surgery, wound class following the CDC-classification,26 minimum surgery length, antibiotic used, half-life of antibiotic regimen, preoperative SAP, intraoperative redosing strategy, and its definition in analysis of observational studies, postoperative SAP duration, SSI definition, reported adverse events, number of patients, incidence of SSI, and reported estimated effect. Authors were contacted if insufficient detail of the before mentioned data was reported.

For RCTs, the ORs for SSI were calculated based the SSI incidence in the control and intervention group. For observational studies, we used the reported OR for the participants that received redosing compared to the group that did not receive redosing. To account for confounding in observational studies, we used the reported adjusted. If an adjusted RR was reported and the incidence of the outcome was low (< 10%), we assumed the adjusted RR to be equal to the OR.27

Statistical Analysis

Meta-analyses were stratified per study type. For binary outcomes, we calculated pooled effect estimates as ORs with corresponding 95% confidence intervals (CIs) using a generic invariance random-effects model (DerSimonian and Laird). No continuous outcomes were identified. Heterogeneity was expressed using the I2 statistic.

The following subgroup analyses were conducted: studies that administered redosing within 2 half-lives after SAP, as this is the most widely recommended regimen5; Studies that did continue prophylaxis postoperatively versus studies that did not, as postoperative continuation of SAP might mask a potential benefit of intraoperative redosing.14 Furthermore, a sensitivity analysis was performed for studies that used a cefazolin-based protocol versus studies that used other agents, as cefazolin is the most widely recommended agent for SAP.5,28 When at least ten studies per variable were identified, formal meta-regression and subgroup analysis were conducted. Otherwise, exploratory subgroup analysis was performed without-meta regression analysis.

Statistical analysis was performed using R version 4.0.3 [R Core Team (2016) R: A language and environment for statistical computing; R Foundation for Statistical Computing, Vienna, Austria R; https://www.R-project.org/].

Risk of Bias and Certainty of Evidence

We used the Cochrane Risk of Bias tool for randomized trials (RoB2)29 to assess bias in randomized trials and the Risk Of Bias In Non-randomized Studies—of Interventions (ROBINS-I) tool for cohort studies.30 A funnel plot was constructed to assess publication bias.31 If appropriate, trim-and-fill analysis was performed to analyze the effect on the effect estimate of any potential publication bias. Certainty of evidence was determined following the Grade of Recommendations Assessment, Development and Evaluation (GRADE) method.32

RESULTS

Study Selection

Figure 1 depicts the article selection process. The search yielded 6095 potential studies. We removed 1324 duplicates. A total of 27 full texts were reviewed. Reasons for exclusion are listed in supplementary Appendix 2, https://links.lww.com/SLA/D732. We included 2 randomized controlled studies33,34 and 8 observational studies.17,18,22,23,35–38 One study was retrieved through backward citation tracking.23 The included studies had 9470 participants and were published between 1997 and 2019.

F1
FIGURE 1:
PRISMA flow diagram.

Study Characteristics

Study characteristics of the included studies are listed in Table 1. Five studies were conducted in a mixed population of multiple different surgical expertise.22,23,34,35,37 Most studies were performed with patients undergoing abdominal,35–37 orthopedic/trauma,22,23,34,35 cardiothoracic,18,34,38 gynecologic,22,23,33 or general surgery.17,23,34

TABLE 1 - Study Characteristics
Author, Year No. of patients Type of Surgery Minimal Length Surgery Antibiotic Class Antibiotic Regimen Redosing Strategy (RCT) or Analysis Definition of Redosing (OBS) & t1/2 SAP Timing (Min. pre-incision) Postoperative SAP Reported Primary Outcome Covariates Adjusted For
Randomized controlled trials
 Colombo et al, 199833 448 Gynecologic surgery 120 min Penicillin Ampicillin (2 g) and sulbactam (1 g) 120 min after incision (t1/2: 0.8–1.3) 15 None C: 32/223I: 20/225
 Scher, 199734 296 Urology, otorhinolaryngology, general, thoracic surgery 180 min First-generation cephalosporin Cefazolin (1g) 180 min after initial dose (t1/2: 1.2–2.2) 15–30 None C: 9/147I: 2/149
Prospective observational cohort studies
 de Jonge et al, 202123 671 General, orthopedic and gynecologic surgery 240 min Cephalosporin, quinolone Cefuroxime and clindamycin, cefuroxime, cefamandole, other Redose after 2 times t1/2 or >1.5 L blood loss. (t1/2: 1–2) < 120 (96%)Other (4%) None aOR: 0.60 (0.32–1.12) Diabetes, use immunosuppressant, wound class, implantations
 Steinberg et al, 200922 512 Cardiac, orthopedic, gynecologic surgery 240 min Cephalosporin, macrolide, quinolone, glycopeptide Cephalosporin, cephalosporin and vancomycin, vancomycin, fluoroquinolones 240 min after start but before the end of surgery (t1/2: 1.2–2.2) < 60 Varying from none up to 48 h 1) aOR: 0.32 (0.08–1.36)2) aOR: 1.02 (0.23–4.54) Hospital, period of measurement, group status, procedure type, procedure duration, ASA score
Retrospective observational cohort studies
 Bertschi, 201935 593 Abdominal, vascular and trauma surgery 240 min Cephalosporin, other Cefuroxime (1.5 g) with/without metronidazole (0.5 g) Any intraoperative administration before wound closure (t1/2: 1–2) <120 None aOR: 0.60 (0.37–0.96) Wound class, ASA, elective vs emergency
 Kasatpibal et al, 201717 4001 General surgery n.a. First-generation cephalosporin, Macrolide, Quinolone Cefazolin, cefazolin and metronidazole, ciprofloxacin and metronidazole, clindamycin, other Redose after 1–2 times t1/2 (t1/2: 1.2–2.2) <60 None aRR: 0.22 (0.06–0.75) Sex, race, in-patient status, origin status, smoking, serum albumin, ASA classification, Emergency surgery, Operative procedure, incision classification, duration of surgery, multiple procedures, antibiotic agent, insulin, crystalloids, colloids, transfusion, blood loss
 Morita et al, 200536 96 Colorectal surgery 240 min after SAP Cephalosporin Cephalosporin (1 g) 240 min after initial SAP (t1/2: 1.2–2.2) <60 Yes, unspecified aOR: 0.09 (0.02–0.53) Protocol of administration, DM, procedure, operating time
 Zanetti et al, 200118 1548 Cardiac surgery 240 min First-generation cephalosporin Cefazolin (1 g) Any intraoperative administration before wound closure (t1/2: 1.2–2.2) < 90 6 additional gifts 1) aOR: 1.27 (0.80–2.02)2) aOR: 0.44 (0.23–0.85) Procedure duration, surgeon
 Zhang, 201537 547 Colorectal or hepatobiliary surgery 240 min First-generation cephalosporin, macrolide, glyco -peptide, other Cefazolin (2 g) (and metronidazole [0.5 g]), gentamycin (2 mg/kg), and clindamycin (0.6 g), gentamycin (2 mg/kg), and metronidazole (0.5 g) Every 3 to 12 ho depending on SAP, based on initial timing of preoperative dose (t1/2: 1.2–2.2) n.a. None aOR: 0.65 (0.35 – 1.22) Age, operating time
 Zhang et al, 201938 1840 Cardiothoracic, orthopedic, vascular, abdominal, and neurosurgery. All patients had diabetes 240 min First-generation cephalosporin Most commonly; cefazolin 240 min After initial dose (t1/2: 1.2–2.2) < 60 n.a. aOR: 0.43 (0.24–0.78) Sex, ASA, operation location, hypertension, blood glucose control, WBC
Agent with shortest t1/2.
Both antibiotics double dosage if patients weigh >80 kg, In cases of known or suspected allergies to these antibiotics, vancomycin (1 g), gentamicin (4 mg/Kg), and metronidazole or clindamycin (300 mg) with or without ciprofloxacin (400 mg) were used as alternative treatments.Time between closure and first gift.aOR indicates adjusted odds ratio; aRR, adjusted relative risk; C, control; I, intervention; min, minutes; n.a., not available; t1/2, half-life.

Redosing Protocols

There was substantial variation in choice of antibiotic regimen and redosing protocols. The majority of the studies included surgical procedures with a minimal duration of 240 minutes.22,23,35–38 Two studies only used cefazolin,18,34 1 study used ampicillin and sulbactam,33 and the other studies reported several regimens with some including cefazolin. Antibiotic classes and half-lives of the respective antibiotic agents are summarized in Table 2. Preoperative timing varied from within 120 minutes,23,35 to 90 minutes,18 60 minutes,17,22,36,38 30 minutes,34 or 15 minutes33 preoperatively. Three studies continued prophylaxis postoperatively until up to 48 hours18,22,36 and 5 other studies reported to have refrained from this.17,23,33–35 Two studies did not provide sufficient information to assess this;37,38 we tried contacting those authors, but they did not respond.

TABLE 2 - Half-Life of Antibiotics in Adults With a Normal Renal Function5
Antibiotic Antibiotic Class Recommended Dose Half–Life, h
Ampicillin + sulbactam Penicillin 3 g 0.8–1.3
Cefazolin First-generation cephalosporin 2 g 1.2–2.2
Cefuroxime Second-generation cephalosporin 1.5 g 1–2
Cefotaxime Third-generation cephalosporin 1 g 0.9–1.7
Cefoxitin Second-generation cephalosporin 2 g 0.7–1.1
Clindamycin Macrolide 900 mg 2–4
Ciprofloxacin Quinolone 400 mg 3–7
Levofloxacin Quinolone 500 mg 6–8
Piperacillin-tazobactam Penicillin 3.375 g 0.7–1.2
Vancomycin Glycopeptide 15 mg/kg 4–8
Metronidazole Other 1 g 6–8

Redosing in the 2 RCTs was formalized as intervention at 2 hours after incision33 and 3 hours after the initial dose.34 Most observational studies described a local protocol for redosing and differences in compliance permitted analysis of its effectiveness. Absent a formal intervention, adequate redosing was defined in the analysis. This definition varied from any subsequent intraoperative dose after initial preoperative SAP administration18,35 to strict definitions based on the half-life of the administered agent17,23 or a set time for any agent. One study also included blood loss exceeding 1500 ml in the definition.23 Like with the RCTs, set point for timing of redosing varied between initial preoperative SAP administration17,18,23,36,38 or timing of incision.22,35 One study did not report on the set point for timing of redosing.37 Six studies reported redosing strategies that resulted in administration within 2 half-lives after initial SAP administration,17,23,33,34,36,38 3 did not,18,22,35 and 1 study provided insufficient information for this assessment.37

The number of covariates adjusted for in the analysis of observational studies ranged from 237 to 18.17 Most studies adjusted for complexity of the procedure (operating time, procedure type, ASA). One study reported 2 models. We used the model based on covariates from baseline characteristics similar to the other studies. One study compared redosing to no redosing or late redosing.17 Late redosing constituted 1.46% of the study population.

Primary and Secondary Outcomes

All included articles reported a quantitative analysis of the effect of redosing on the incidence of SSI. Several observational studies reported >1 effect estimate because of interaction or subgroup differences.18,22 All investigated subpopulations met our inclusion criteria and were included in the primary analysis with their combined estimate when available, or as 2 separate estimates when a combined estimate was not reported. No study reported any of the secondary outcomes set for this systematic review.

Meta-Analyses

Forest plots are presented in Figure 2. Meta-analyses were stratified per study types. Meta-analysis of 2 RCTs resulted in a pooled OR of 0.47 (95% CI: 0.19–1.16. I2 = 36%) for SSI for patients that received redosing. Meta-analysis of 8 observational studies resulted in a pooled OR for SSI of 0.55 (95% CI: 0.38–0.79, I2 = 56%). Given the similarity in effect estimates, the data were combined and resulted in an OR of 0.54 (95% CI: 0.40–0.74. I2 = 50%).

F2
FIGURE 2:
Forest plot of meta-analysis. Footprint Figure 2: Two studies reported 2 [A and B) effect estimates because of interaction or subgroup differences.

Subgroup and Sensitivity Analyses

Subgroup of studies that administered redosing within 2 half-lives after initial administration showed a pooled OR for SSI of 0.43 (95% CI: 0.28–0.65, I2 = 31%) versus an OR of 0.69 (95% CI: 0.41–1.14, I2 = 59%) for studies that reported redosing without this strict interval. Analysis comparing studies that did, and those that did not continue postoperative prophylaxis resulted in a pooled OR for SSI of 0.58 (95% CI: 0.44–0.77, I2 = 0%) for studies that did not continue SAP after surgery, and 0.47 (95% CI: 0.22–1.02, I2 = 71%) for studies that did. Pooled OR for SSI for studies that used a cefazolin-based protocol was 0.58 (95% CI: 0.22–1.55, I2 = 36%). Plots of these additional analyses are shown in the Appendix 4, https://links.lww.com/SLA/D732 (S1–S5).

Timing of Redosing

Two studies attempted to investigate the effect of timing of redosing on SSI. One study found no difference between patients that received redosing between 120 and 240 minutes after initial SAP and patients that received redosing either earlier or later than that interval.35 Another study found a significant slope toward less SSI when no redosing, redosing >240 minutes and redosing within 240 minutes were compared,18 favoring redosing within 240 minutes.

Risk of Bias

Results of the risk of bias evaluation are presented in Figure 2. The RCTs showed serious risk of bias. Five observational studies were assessed at moderate risk of bias, 1 at serious risk of bias and 2 studies at critical risk of bias. The scores for the individual domains for risk of bias assessment are presented in supplementary Appendix 3, https://links.lww.com/SLA/D732.

Too few RCTs were available to plot a funnel plot. For the observational studies, the funnel plot showed some asymmetry favoring the intervention indicating possible publication bias. Subsequent trim-and-fill analysis imputated 3 studies and resulted in a slightly smaller effect estimate (OR: 0.55 vs OR: 0.65). The funnel and funnel plot after trim-and-fill analysis is presented in the supplementary Appendix 4, https://links.lww.com/SLA/D732 S6-S7.

Certainty of Evidence

The GRADE approach was used for RCTs and cohort studies separately. The summary of findings table is presented in Table 3. There was some risk of bias in the included studies. For RCTs, there was no inconsistency of results, with low heterogeneity (I2 = 36%). There was no indirectness of evidence. Publication bias could not be assessed for RCTs. We downgraded the certainty due to imprecision and risk of bias. We assessed the certainty of evidence for RCTs as low. For the cohort studies, we observed serious risk of bias and possible publication bias. We found no indirectness and little inconsistency or imprecision. Residual confounding may cause underestimation of the effect. We deemed certainty of evidence for observational studies very low. Overall, we assessed the certainty of evidence of this systematic review as low.

TABLE 3 - GRADE Summary of Findings Table
Certainty Assessment no of Participant Effect
No. of studies Study Design Risk of Bias Inconsistency Indirectness Imprecision Other Biases SSI Additional Intraoperative Redosing of SAP SSI Preoperative Single-dose Prophylaxis Relative Effect (95% CI) Absolute Effect (95% CI) Certainty of Evidence (GRADE) Importance
Surgical site infections—randomized controlled trials
 2 Randomized controlled trials Serious No No Serious No other biases 22/372 (5.9%) 41/270 (15.2%) OR 0.47 (0.19–1.16) 74 Fewer per 1.000 (119 fewer to 20 more) ⊕⊕ LOW CRUCIAL
Surgical site infections—observational cohort studies
 8 Observational cohort studies Serious No No No Publication bias suspected; residual confounding may cause underestimation NA NA OR 0.55 (0.38–0.79) NA ⊕ VERY LOW CRUCIAL

DISCUSSION

In this systematic review and meta-analysis, we evaluated the effect of intraoperative redosing in addition to a single dose of preoperative surgical antibiotic prophylaxis (SAP) versus a single dose of preoperative surgical antibiotic prophylaxis on the incidence of SSI. Meta-analysis of 2 RCTs and 8 observational studies resulted in a clear effect in favor of redosing. This effect was most pronounced among studies that administered redosing within 2 half-lives of the administered agent after initial SAP administration and studies that discontinued SAP after surgery. The certainty of evidence was low due to risk of bias and imprecision. Overall, present meta-analysis shows that intraoperative antibiotic redosing in addition to preoperative SAP may reduce the incidence of SSI compared to a single dose of preoperative prophylaxis.

To our knowledge, this is the first systematic review and meta-analysis on the effect of intraoperative redosing of SAP and the risk of SSI. Current World Health Organization7 and Centers for Disease Control and Prevention8 guidelines on SSI prevention do not provide a recommendation on intraoperative redosing due to limited clinical evidence. The recent National Institute health and Care Excellence guidelines recommend redosing in surgery taking longer than the half-life of the antibiotic regimen, but this recommendation is presented without evidence.9 An earlier guideline by the ASHP recommended intraoperative redosing after 2 half-lives of the administered agent have passed since initial SAP administration. This recommendation was based on pharmacokinetic principles and evidence that adequate tissue- and plasma concentrations of antibiotics are necessary throughout the surgical procedure to prevent surgical site infection.11–13 The present systematic review and meta-analysis provides clinical evidence to this context. The effect was more pronounced in studies that provided redosing based on the half-lives of administered agents. Our findings are therefore in line with the existing ASHP recommendation.5 Although the evidence is formally of low certainty, our findings likely render a sufficiently powered placebo controlled RCT unethical. This leaves little room for further improvement of certainty. Previous research has shown that after adequately timed SAP and intraoperative redosing, postoperative continuation of SAP is obsolete.14 This aligns with our finding that the effect of redosing is more pronounced in studies that did not continue SAP postoperatively. Future protocols for SAP and quality improvement initiatives should therefore focus on intraoperative redosing after timely preoperative administration.

The exact optimal redosing interval remains unclear and may depend on pharmacokinetic and pharmacodynamics (PK/PD) properties such as the agent, initial dose, blood loss, and protein binding. Further research should focus on optimization of dosing strategies of commonly used agents such as cefazolin and metronidazole) and include PK/PD outcomes such as serum- and tissue levels throughout surgery alongside clinical outcomes.28 Until then, a pragmatic recommendation such as formulated by the ASHP seems very reasonable.5

There are some limitations to consider. The amount of available evidence is limited. We identified only 2 small RCTs that both seem underpowered based on their individual effect estimates. Similarly, there were only 8 observational studies, most of which were small. Observational studies are at risk of confounding due to the lack of randomization of the intervention. Outside of RCTs, redosing typically does not occur at random and reflects long procedure duration, blood loss, or other concerns on infection risk. To account for this, we used adjusted ORs as causal estimates from observational studies. However, residual confounding could still lead to underestimation of the effect. When stratified analysis revealed similar effect estimates of observational studies and RCTs, we combined the 2 in 1 meta-analysis to optimize statistical power with the limited amount of available data. Although this increased confidence in our effect estimate, the underlying quality and quantity of data remain limited. Subgroup analyses should be considered exploratory and interpreted with caution. Funnel plot and trim-and-fill analysis indicated there was some evidence of publication bias in favor of redosing, suggesting the true effect may be slightly smaller than our estimated effect. Although there was some statistical heterogeneity, almost all variation was in the size and precision of a beneficial effect of redosing. Only 1 observational study indicated potential harm of redosing in shorter procedures but, in the absence of another plausible explanation of redosing of SAP causing infection, this likely represents residual confounding by factors that led the surgeon to administer the second dose.

Although this meta-analysis indicates that intraoperative redosing in addition to preoperative SAP reduces the incidence of SSI when compared to a single dose of preoperative prophylaxis, the certainty of evidence is low. A sufficiently powered placebo controlled RCT examining intraoperative redosing may be unethical given the present findings. The optimal redosing protocol remains unclear and should be the focus of future research.

Acknowledgments

The authors thank F. van Etten—Jamaludin for her advice on the search strategy.

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Keywords:

anesthesia; antibiotics; meta-analysis; prevention; surgery; surgical site infections

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