Oral and Parenteral vs. Parenteral Antibiotic Prophylaxis for Patients Undergoing Laparoscopic Colorectal Resection: An Intervention Review with Meta-Analysis

This study aims to systematically assess the efficacy of parenteral and oral antibiotic prophylaxis compared to parenteral-only prophylaxis for the prevention of surgical site infection (SSI) in patients undergoing laparoscopic surgery for colorectal cancer resection. Published and unpublished randomized clinical trials comparing the use of oral and parenteral prophylactic antibiotics vs. parenteral-only antibiotics in patients undergoing laparoscopic colorectal surgery were collected searching electronic databases (MEDLINE, CENTRAL, EMBASE, SCIENCE CITATION INDEX EXPANDED) without limits of date, language, or any other search filter. The outcomes included SSIs and other infectious and noninfectious postoperative complications. Risk of bias was assessed using the Cochrane revised tool for assessing risk of bias in randomized trials (RoB 2). A total of six studies involving 2252 patients were finally included, with 1126 cases in the oral and parenteral group and 1126 cases in the parenteral-only group. Meta-analysis results showed a statistically significant reduction of SSIs (OR 0.54, 95% CI 0.40 to 0.72; p < 0.0001) and anastomotic leakage (OR 0.55, 95% CI 0.33 to 0.91; p = 0.02) in the group of patients receiving oral antibiotics in addition to intravenous (IV) antibiotics compared to IV alone. Our meta-analysis shows that a combination of oral antibiotics and intravenous antibiotics significantly lowers the incidence of SSI compared with intravenous antibiotics alone.


Introduction
Surgical site infection (SSI) is defined as an infection of superficial or deep tissue or organs at the surgical site or related to the site of the surgical procedure [1]. SSI is quite common in people undergoing colorectal surgery and is related to increased length of stay and costs and poor quality of life [2][3][4]. Risk factors for wound infection include male sex, advanced age, previous chemotherapy, conversion from laparoscopic to open technique, and reintervention within the first 30 postoperative days [2][3][4]. Antibiotic prophylaxis has been shown to have a pivotal role for preventing SSIs in patients undergoing elective colorectal surgery [5][6][7]. In several studies, authors reported evidence regarding the effect of oral and parenteral prophylaxis in colorectal surgery [8][9][10], but none of them referred to laparoscopic surgery. In fact, laparoscopic surgery can achieve similar oncological outcomes as compared with open surgery [11,12] and showed potential advantages, including less bleeding, faster postoperative recovery, less pain, and less wound-related complications [13][14][15][16]. However, further research is needed on the effectiveness of pre-operative oral antibiotic regimen in patients undergoing elective laparoscopic colon surgery.
Another frequent postoperative complication of laparoscopic colon surgery is anastomotic leakage (AL) [17]. AL, which is defined as a defect of the intestinal wall at the anastomotic site, is represented by a communication between the intra-and extraluminal 1.
Types of studies All randomized clinical trials (RCTs). Nonrandomized and quasirandomized trials were excluded. Studies where it was not possible to obtain the complete manuscript were excluded.

2.
Types of participants Patients undergoing laparoscopic colorectal surgery.

3.
Types of interventions and comparison Oral and parenteral antibiotic prophylaxis vs. parenteral-only prophylaxis.

4.
Types of outcome measures Primary outcomes: SSIs. Secondary outcomes: other infectious and noninfectious postoperative complications. Studies with no outcome of interest were excluded.

Search Strategy
The Peer Review of Electronic Search Strategies (PRESS) Guideline [28] was consulted for the search strategy development process. The electronic databases MEDLINE, The Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, and Science Citation Index Expanded (SCI-EXPANDED) were searched without limits of date, language, or any other search filter. Searches started on the 1 May 2021 and were updated on 6 December 2021. Searches were performed by two reviewers (G.S. and M.V.) independently. Search strategies with the time span of the searches are showed in Appendix A. Other electronic searches that were performed included trial registers for ongoing and registered trials such as ClinicalTrials.gov (clinicaltrials.gov) and World Health Organization (WHO). Additionally, reference lists of included articles were hand-searched and experts in the field were contacted to obtain additional data.

Selection Process
The review was conducted according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions 6.2 [29]. Two reviewers (G.S. and M.V.) independently selected studies according to the inclusion and exclusion criteria. An initial screening of the titles and abstracts was performed. Full texts of all potentially eligible studies were retrieved and examined to decide whether the studies were eligible for inclusion Antibiotics 2022, 11, 21 3 of 18 in the review. Disagreements were resolved through discussion or by a third review author (A.B.). No automation tools were used in the process.

Data Collection Process
Two reviewers (G.S. and M.V.) independently extracted the data from eligible studies using a data preformatted form designed by the review authors. Any discrepancies in results were resolved by repeating data extraction and discussion. Data extracted included: characteristics of study (first author, year of publication, study design), number of participants, types of surgical resection, outcome data, and details of antibiotic regimes administered.

Risk of Bias Assessment
Review authors (G.S. and M.V.) independently assessed the included studies for risk of bias using the Cochrane revised tool for assessing risk of bias in randomized trials (RoB 2) [30] to assess five domains:
Bias due to deviations from intended interventions; 3.
Bias due to missing outcome data; 4.
Bias in measurement of the outcome; 5.
Bias in selection of the reported result.
Trials with low risk of bias were considered those trials having "low risk of bias" in all of the above specified individual domains. Trials with high risk of bias were considered those trials that were judged as trials having "uncertain risk of bias" or "high risk of bias" in one or more of the above specified individual domains. Disagreements were resolved by repeating the RoB assessment or by discussion with a third review author (A.B.).

Statistical Analysis
Dichotomous data were analyzed calculating the odds ratio (OR) for each trial, expressing the uncertainty with 95% confidence intervals (CI). Comparisons were made between trials evaluating oral and intravenous against intravenous-only antibiotic prophylaxis prior to elective laparoscopic surgery. The statistical package Review Manager 5.4 provided by The Cochrane Collaboration was used [31]. There were not any continuous variables in this review. The homogeneity among the included studies was assessed using the I 2 statistic and the chi-squared test. An I 2 value greater than 50% indicated substantial heterogeneity [29]. The fixed effects model was performed for studies with low heterogeneity (I 2 ≤ 50%). In the presence of significant heterogeneity (I 2 > 50%), the random effect model was used to pool the data. The pooled results were expressed by forest plots.

Certainty Assessment
Certainty (quality of evidence) of the body of evidence was assessed for each outcome of interest using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach and creating a Summary of Findings (SoF) table using the GRADEpro Guideline Development tool (GRADEpro GDT) [32]. The quality of evidence was classified according to the GRADE handbook [33] in one of four grades: (1) high, (2) moderate (3), low, or (4) very low. The quality of evidence could be downgraded by one (serious concern) or two levels (very serious concern) for the following reasons: risk of bias, inconsistency, indirectness, and imprecision.

Study Selection
A total of 137 studies were retrieved by the primary search. After deleting duplicates, records were screened. Following title and abstract screen, 102 clearly irrelevant records were excluded, leaving 35 potentially eligible studies of which full texts were retrieved. Twenty-nine studies were excluded because they did not meet the set criteria. Finally, The studies randomized a total of 2252 patients, of whom 1126 were in the oral + intravenous (Oral+IV) group and 1126 were in the intravenous-only (IV) group. All trials reported data about SSI, which was defined according to the guidelines issued by the Centers for Disease Control and Prevention [7] and classified as being either incisional or organ/space infection. Incisional SSIs were infections occurring at the incisional site within 30 days after the procedure and involving the skin, subcutaneous tissue, muscle and fascia but not the organ/space. The organ/space SSIs involved any part of the anatomy other than the incised body wall layers that had been opened or manipulated during the surgery [34,35].
Study characteristics, baseline data of patients, types of interventions, outcomes, and the details of antibiotic regimes administered are listed in Table 1. The studies randomized a total of 2252 patients, of whom 1126 were in the oral + intravenous (Oral + IV) group and 1126 were in the intravenous-only (IV) group. All trials reported data about SSI, which was defined according to the guidelines issued by the Centers for Disease Control and Prevention [7] and classified as being either incisional or organ/space infection. Incisional SSIs were infections occurring at the incisional site within 30 days after the procedure and involving the skin, subcutaneous tissue, muscle and fascia but not the organ/space. The organ/space SSIs involved any part of the anatomy other than the incised body wall layers that had been opened or manipulated during the surgery [34,35].
Study characteristics, baseline data of patients, types of interventions, outcomes, and the details of antibiotic regimes administered are listed in Table 1.

Risk of Bias Assessment
One trial was at low risk of bias [34]. Two trials [35,37] showed some concerns, whereas three trials [36,38,39] were at high risk of bias according to RoB 2 [30]. The risk of bias assessment is reported in Appendix A Table A1.

Surgical Site Infections
All six studies involving 2252 patients reported available data on the overall SSIs and low heterogeneity was observed among the trials (I 2 = 43%). Therefore, the fixed effect model was used to pool the data. SSI occurred in 72 of 1126 patients in the intervention group (6.4%) vs. 127 of 1126 patients in the control group (11.3%). Meta-analysis results showed a statistically significant reduction of SSIs in the group of patients receiving Oral antibiotics in addition to IV antibiotics (OR 0.54, 95% CI 0.40 to 0.72; Figure 2).

Risk of Bias Assessment
One trial was at low risk of bias [34]. Two trials [35,37] showed some concerns, whereas three trials [36,38,39] were at high risk of bias according to RoB 2 [30]. The risk of bias assessment is reported in Appendix A Table A1.

Surgical Site Infections
All six studies involving 2252 patients reported available data on the overall SSIs and low heterogeneity was observed among the trials (I 2 = 43%). Therefore, the fixed effect model was used to pool the data. SSI occurred in 72 of 1126 patients in the intervention group (6.4%) vs. 127 of 1126 patients in the control group (11.3%). Meta-analysis results showed a statistically significant reduction of SSIs in the group of patients receiving Oral antibiotics in addition to IV antibiotics (OR 0.54, 95% CI 0.40 to 0.72; Figure 2).

Risk of Bias Assessment
One trial was at low risk of bias [34]. Two trials [35,37] showed some concerns, whereas three trials [36,38,39] were at high risk of bias according to RoB 2 [30]. The risk of bias assessment is reported in Appendix A Table A1.

Surgical Site Infections
All six studies involving 2252 patients reported available data on the overall SSIs and low heterogeneity was observed among the trials (I 2 = 43%). Therefore, the fixed effect model was used to pool the data. SSI occurred in 72 of 1126 patients in the intervention group (6.4%) vs. 127 of 1126 patients in the control group (11.3%). Meta-analysis results showed a statistically significant reduction of SSIs in the group of patients receiving Oral antibiotics in addition to IV antibiotics (OR 0.54, 95% CI 0.40 to 0.72; Figure 2).

Risk of Bias Assessment
One trial was at low risk of bias [34]. Two trials [35,37] showed some concerns, whereas three trials [36,38,39] were at high risk of bias according to RoB 2 [30]. The risk of bias assessment is reported in Appendix A Table A1.

Surgical Site Infections
All six studies involving 2252 patients reported available data on the overall SSIs and low heterogeneity was observed among the trials (I 2 = 43%). Therefore, the fixed effect model was used to pool the data. SSI occurred in 72 of 1126 patients in the intervention group (6.4%) vs. 127 of 1126 patients in the control group (11.3%). Meta-analysis results showed a statistically significant reduction of SSIs in the group of patients receiving Oral antibiotics in addition to IV antibiotics (OR 0.54, 95% CI 0.40 to 0.72; Figure 2).

Anastomotic Leakage
Five studies [34][35][36][37][38] involving 1768 patients reported available data on anastomotic leak and no heterogeneity was observed among the trials (I 2 = 0%). Therefore, the fixed effects model was performed to pool the data. Anastomotic leakage occurred in 25 out of 884 patients in the intervention group (2.8%) vs. 44 out of 884 patients in the control group (4.9%). Meta-analysis of the included studies showed a statistically significant protective effect in the group of patients receiving oral antibiotics in addition to IV antibiotics vs. IV antibiotic prophylaxis alone (OR 0.55, 95% CI 0.33 to 0.91; Figure 5).

Anastomotic Leakage
Five studies [34][35][36][37][38] involving 1768 patients reported available data on anastomotic leak and no heterogeneity was observed among the trials (I 2 = 0%). Therefore, the fixed effects model was performed to pool the data. Anastomotic leakage occurred in 25 out of 884 patients in the intervention group (2.8%) vs. 44 out of 884 patients in the control group (4.9%). Meta-analysis of the included studies showed a statistically significant protective effect in the group of patients receiving oral antibiotics in addition to IV antibiotics vs. IV antibiotic prophylaxis alone (OR 0.55, 95% CI 0.33 to 0.91; Figure 5).

Enteritis/Colitis
Four studies [34][35][36]38] involving 1313 patients reported available data on enteritis/colitis. Low heterogeneity was observed among the trials (I 2 = 39%). Therefore, the fixed effects model was performed to pool the data. Meta-analysis of the included studies showed no significant difference between the oral + IV and IV-only groups (OR 0.67, 95% CI 0.30 to 1.48; Figure 6).

Pneumonia
Four studies [35][36][37][38] involving 1257 patients reported available data on pneumonia and no heterogeneity was observed among the trials (I 2 = 0%). Therefore, the fixed effects model was performed to pool the data. Meta-analysis of the included studies showed no significant difference between the oral + IV and IV-only groups (OR 0.75, 95% CI 0.39 to 1.45; Figure 7).

Enteritis/Colitis
Four studies [34][35][36]38] involving 1313 patients reported available data on enteritis/colitis. Low heterogeneity was observed among the trials (I 2 = 39%). Therefore, the fixed effects model was performed to pool the data. Meta-analysis of the included studies showed no significant difference between the oral + IV and IV-only groups (OR 0.67, 95% CI 0.30 to 1.48; Figure 6).

Anastomotic Leakage
Five studies [34][35][36][37][38] involving 1768 patients reported available data on anastomotic leak and no heterogeneity was observed among the trials (I 2 = 0%). Therefore, the fixed effects model was performed to pool the data. Anastomotic leakage occurred in 25 out of 884 patients in the intervention group (2.8%) vs. 44 out of 884 patients in the control group (4.9%). Meta-analysis of the included studies showed a statistically significant protective effect in the group of patients receiving oral antibiotics in addition to IV antibiotics vs. IV antibiotic prophylaxis alone (OR 0.55, 95% CI 0.33 to 0.91; Figure 5).

Enteritis/Colitis
Four studies [34][35][36]38] involving 1313 patients reported available data on enteritis/colitis. Low heterogeneity was observed among the trials (I 2 = 39%). Therefore, the fixed effects model was performed to pool the data. Meta-analysis of the included studies showed no significant difference between the oral + IV and IV-only groups (OR 0.67, 95% CI 0.30 to 1.48; Figure 6).

Pneumonia
Four studies [35][36][37][38] involving 1257 patients reported available data on pneumonia and no heterogeneity was observed among the trials (I 2 = 0%). Therefore, the fixed effects model was performed to pool the data. Meta-analysis of the included studies showed no significant difference between the oral + IV and IV-only groups (OR 0.75, 95% CI 0.39 to 1.45; Figure 7).

Pneumonia
Four studies [35][36][37][38] involving 1257 patients reported available data on pneumonia and no heterogeneity was observed among the trials (I 2 = 0%). Therefore, the fixed effects model was performed to pool the data. Meta-analysis of the included studies showed no significant difference between the oral + IV and IV-only groups (OR 0.75, 95% CI 0.39 to 1.45; Figure 7).

Anastomotic Leakage
Five studies [34][35][36][37][38] involving 1768 patients reported available data on anastomotic leak and no heterogeneity was observed among the trials (I 2 = 0%). Therefore, the fixed effects model was performed to pool the data. Anastomotic leakage occurred in 25 out of 884 patients in the intervention group (2.8%) vs. 44 out of 884 patients in the control group (4.9%). Meta-analysis of the included studies showed a statistically significant protective effect in the group of patients receiving oral antibiotics in addition to IV antibiotics vs. IV antibiotic prophylaxis alone (OR 0.55, 95% CI 0.33 to 0.91; Figure 5).

Enteritis/Colitis
Four studies [34][35][36]38] involving 1313 patients reported available data on enteritis/colitis. Low heterogeneity was observed among the trials (I 2 = 39%). Therefore, the fixed effects model was performed to pool the data. Meta-analysis of the included studies showed no significant difference between the oral + IV and IV-only groups (OR 0.67, 95% CI 0.30 to 1.48; Figure 6).

Pneumonia
Four studies [35][36][37][38] involving 1257 patients reported available data on pneumonia and no heterogeneity was observed among the trials (I 2 = 0%). Therefore, the fixed effects model was performed to pool the data. Meta-analysis of the included studies showed no significant difference between the oral + IV and IV-only groups (OR 0.75, 95% CI 0.39 to 1.45; Figure 7).

Urinary Tract Disorder
Four studies [34,35,37,38] involving 1625 patients reported available data on urinary tract disorder and no heterogeneity was observed among the trials (I 2 = 0%). Therefore, the fixed effects model was performed to pool the data. Meta-analysis of the included studies showed no significant difference between the oral + IV and IV-only group (OR 0.73, 95% CI 0.36 to 1.47; Figure 8).

Urinary Tract Disorder
Four studies [34,35,37,38] involving 1625 patients reported available data on urinary tract disorder and no heterogeneity was observed among the trials (I 2 = 0%). Therefore, the fixed effects model was performed to pool the data. Meta-analysis of the included studies showed no significant difference between the oral + IV and IV-only group (OR 0.73, 95% CI 0.36 to 1.47; Figure 8).

Bowel Obstruction
Three studies [34,35,37] involving 1545 patients reported available data on bowel obstruction and no heterogeneity was observed among the trails (I 2 = 0%). Therefore, the fixed effects model was performed to pool the data. Meta-analysis of the included studies showed no significant difference between the oral + IV and IV-only groups (OR 0.76, 95% CI 0.44 to 1.32; Figure 9).

Certainty Assessment
Certainty (quality of evidence) in the body of evidence was assessed for both primary and secondary outcomes. According to the GRADE Handbook [33], certainty was moderate for all the outcomes except for bowel obstruction. The certainty assessment is detailed in SoF table created with GRADEpro GDT [32] (Table 2).

Bowel Obstruction
Three studies [34,35,37] involving 1545 patients reported available data on bowel obstruction and no heterogeneity was observed among the trails (I 2 = 0%). Therefore, the fixed effects model was performed to pool the data. Meta-analysis of the included studies showed no significant difference between the oral + IV and IV-only groups (OR 0.76, 95% CI 0.44 to 1.32; Figure 9).

Urinary Tract Disorder
Four studies [34,35,37,38] involving 1625 patients reported available data on urinary tract disorder and no heterogeneity was observed among the trials (I 2 = 0%). Therefore, the fixed effects model was performed to pool the data. Meta-analysis of the included studies showed no significant difference between the oral + IV and IV-only group (OR 0.73, 95% CI 0.36 to 1.47; Figure 8).

Bowel Obstruction
Three studies [34,35,37] involving 1545 patients reported available data on bowel obstruction and no heterogeneity was observed among the trails (I 2 = 0%). Therefore, the fixed effects model was performed to pool the data. Meta-analysis of the included studies showed no significant difference between the oral + IV and IV-only groups (OR 0.76, 95% CI 0.44 to 1.32; Figure 9).

Certainty Assessment
Certainty (quality of evidence) in the body of evidence was assessed for both primary and secondary outcomes. According to the GRADE Handbook [33], certainty was moderate for all the outcomes except for bowel obstruction. The certainty assessment is detailed in SoF table created with GRADEpro GDT [32] (Table 2).

Certainty Assessment
Certainty (quality of evidence) in the body of evidence was assessed for both primary and secondary outcomes. According to the GRADE Handbook [33], certainty was moderate for all the outcomes except for bowel obstruction. The certainty assessment is detailed in SoF table created with GRADEpro GDT [32] (Table 2). The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Discussion
Our meta-analysis showed that a combination of oral antibiotics and intravenous antibiotics could significantly lower the incidence of SSI compared with intravenous antibiotics alone in patients undergoing laparoscopic colorectal resection. Several studies concerning the administration route for antibiotics and the number of administrations showed a decrease in surgical site infection after colorectal cancer resection when antibi-otic prophylaxis was applied [5][6][7]26,[40][41][42]. Bellows and colleagues conducted a large meta-analysis of RCTs to compare the effectiveness of combined oral nonabsorbable and intravenous antibiotics to reduce SSIs [26]. The results of this study found that patients receiving a combination of oral and IV antibiotics had decreased SSIs compared to patients receiving only IV antibiotics. Thus, the authors concluded that both oral nonabsorbable and IV antibiotics are necessary. However, this analysis included studies that combined laparoscopic and open surgical procedures. The protocol of antibiotic regiments was not standardized. We have also analyzed whether adding oral antibiotics to intravenous antibiotics had any effect on anastomotic leakage. Our results indicated that patients randomly assigned to an oral antibiotic regimen in addition to intravenous antibiotics had a statistically significant reduced risk of anastomotic leakage compared with participants receiving only intravenous antibiotics. Reduced rates of AL in patients receiving oral antibiotic prophylaxis were shown in earlier studies [43][44][45]; however, indications for surgery varied considerably in these studies and did not only include CRC, but also inflammatory bowel disease (IBD), fistulas and other benign and/or infectious diseases that have a different postoperative complication risk. Furthermore, patients treated for IBD often used immunosuppressive medication, which would influence the incidence on infectious complications and tissue healing. The present meta-analysis comprised of a more homogenous patient group, focusing only on patients undergoing elective laparoscopic resection for colorectal cancer. Furthermore, all the included studies of our meta-analysis were published after 2000, this can ensure the quality of our results because the implementation of enhanced recovery after surgery (ERAS) protocols and laparoscopic surgery in this period have shown to reduce the incidence of postoperative infections [46]. Moreover, most of the previous systematic reviews and meta-analysis mostly focused upon SSI alone, whereas this analysis determined the effect of oral antibiotic prophylaxis on AL as well.
Regarding other infectious and noninfectious postoperative complications (enteritis/colitis, pneumonia, urinary tract disorder, and bowel obstruction), the magnitudes of the pooled effects showed a protective trend, although not statistically significant. The explanation of these results may be due to the fact that only few of the included studies reported data about the mentioned outcomes, therefore we may lack of power to detect true effects. Other explanations could have make these results less generalizable to other patient populations. Iatrogenic ureteral injuries are often reported as a result of laparoscopic surgery [47]; this constitutes an important risk factor associated with postoperative urinary retention that increases the risk of developing urinary tract infection, particularly for geriatric females undergoing the rectal procedure with preoperative steroid use, prolonged duration of the surgery, and under higher classes of anesthesia [48]. A study has shown that laparoscopic and open surgery are equally associated with the development of bowel obstruction [49], and this may be due to several risks factor, such as male sex, emergency surgery, longer duration of surgery, and dysfunctional ileostomy placement [50].
The present study has several limitations. First, there is a wide variation in the type, timing, and dosing of oral antibiotics regimes, both selective [37] and broad-spectrum oral antibiotic prophylaxis have been reported in the included studies. Selective antibiotic prophylaxis is known to target only specific bacteria while leaving indigenous anaerobic, bacteria largely undisturbed [51]. The disadvantage of broad-spectrum oral antibiotic therapy is that it results in a more extensive elimination of bacteria possibly leading to microbial dysbiosis. Therefore, the data supporting the use of universal preoperative oral antibiotic regimens and route of administration for colorectal surgery remains unclear. Second, the use of enhanced recovery protocols is not always documented, which are also known to impact patient outcomes. Third, we did not discriminate between nonabsorbable and absorbable antibiotics given by the oral route. Another important point to discuss is outcome reporting bias. In our study, all of the trials analyzed included data about SSI. However, a certain variability in reporting the secondary outcomes was detected, which supports the moderate certainty of evidence presented in our SoF table and explains the low certainty assessed for the outcome bowel obstruction. Furthermore, it must be highlighted that the three trials [36,38,39] reported as high risk of bias shared concerns in measurement of the outcome and in selection of the reported result, which supports even more these grades of evidence. In many studies, a range of outcome measures is recorded but not all are reported [52]. The choice of outcomes that are reported can be influenced by the results, potentially making published results misleading [53]. Despite these limitations, our study has several key strengths. The main strength of this systematic review and meta-analysis is that, to the best of our knowledge, it is the first study evaluating the role of oral antibiotic prophylaxis in a homogeneous group of patients undergoing elective laparoscopic CRC surgery in a contemporary setting. Even with this focused review, the size of our study was still substantial. We also assessed the risk of bias according to Cochrane Handbook and used GRADE approach to determine the quality of evidence. The methodological quality of included RCTs was not poor. Moreover, the quality of evidence of almost each finding according to the GRADE approach was moderate. Therefore, we can conclude that the use of preoperative oral antibiotics in laparoscopic colorectal surgery should be encouraged.
In conclusion, our results showed that adding an oral antibiotic prophylaxis could have a positive impact in reducing the incidence of SSI after laparoscopic colorectal surgery. However, previous studies have showed that skin preparation, the timing and method of wound closure, patients' comorbidity, intraoperative body temperature, and anatomic location of the colonic resection are significant factors that can also influence the incidence of subsequent infection [54][55][56]. Furthermore, RCTs assessing all the variables that can adversely affect the incidence of infectious complications should be carried out in order to establish the best strategy to decrease SSI after laparoscopic colorectal surgery.

Ishida 2001
Risk of bias arising from the randomization process Some concerns

Risk of bias due to deviations from the intended interventions Low
Bias due to missing outcome data Low

Risk of bias in measurement of the outcome High
Risk of bias in selection of the reported result Some concerns

Kobayashi 2007
Risk of bias arising from the randomization process Low Risk of bias due to deviations from the intended interventions Some concerns