The Role of Oral Antibiotic Preparation in Elective Colorectal Surgery: A Meta-analysis

Objectives To compare the impact of the use of oral antibiotics (OAB) with or without mechanical bowel preparation (MBP) on outcome in elective colorectal surgery. Summary Background Data Meta-analyses have demonstrated that MBP does not impact upon postoperative morbidity or mortality, and as such it should not be prescribed routinely. However, recent evidence from large retrospective cohort and database studies has suggested that there may be a role for combined OAB and MBP, or OAB alone in the prevention of surgical site infection (SSI). Methods A meta-analysis of randomized controlled trials and cohort studies including adult patients undergoing elective colorectal surgery, receiving OAB with or without MBP was performed. The outcome measures examined were SSI, anastomotic leak, 30-day mortality, overall morbidity, development of ileus, reoperation and Clostridium difficile infection. Results A total of 40 studies with 69,517 patients (28 randomized controlled trials, n = 6437 and 12 cohort studies, n = 63,080) were included. The combination of MBP+OAB versus MBP alone was associated with a significant reduction in SSI [risk ratio (RR) 0.51, 95% confidence interval (CI) 0.46–0.56, P < 0.00001, I2 = 13%], anastomotic leak (RR 0.62, 95% CI 0.55–0.70, P < 0.00001, I2 = 0%), 30-day mortality (RR 0.58, 95% CI 0.44–0.76, P < 0.0001, I2 = 0%), overall morbidity (RR 0.67, 95% CI 0.63–0.71, P < 0.00001, I2 = 0%), and development of ileus (RR 0.72, 95% CI 0.52–0.98, P = 0.04, I2 = 36%), with no difference in Clostridium difficile infection rates. When a combination of MBP+OAB was compared with OAB alone, no significant difference was seen in SSI or anastomotic leak rates, but there was a significant reduction in 30-day mortality, and incidence of postoperative ileus with the combination. There is minimal literature available on the comparison between combined MBP+OAB versus no preparation, OAB alone versus no preparation, and OAB versus MBP. Conclusions Current evidence suggests a potentially significant role for OAB preparation, either in combination with MBP or alone, in the prevention of postoperative complications in elective colorectal surgery. Further high-quality evidence is required to differentiate between the benefits of combined MBP+OAB or OAB alone.

rates. When a combination of MBP+OAB was compared with OAB alone, no significant difference was seen in SSI or anastomotic leak rates, but there was a significant reduction in 30day mortality, and incidence of postoperative ileus with the combination. There is minimal literature available on the comparison between combined MBP+OAB versus no preparation, OAB alone versus no preparation, and OAB versus MBP.
Conclusions-Current evidence suggests a potentially significant role for OAB preparation, either in combination with MBP or alone, in the prevention of postoperative complications in elective colorectal surgery. Further high-quality evidence is required to differentiate between the benefits of combined MBP+OAB or OAB alone.
Keywords anastomotic leak; colorectal; mechanical bowel preparation; oral antibiotics; surgery; surgical site infection Surgical site infection (SSI) is a major burden for patients undergoing elective colorectal surgery. It adds significantly to the cost of health care, and administration of preoperative bowel preparation has been proposed to reduce the incidence of SSI. The role of mechanical bowel preparation (MBP) with polyethylene glycol or sodium phosphate has been studied in randomized controlled trials (RCTs), with perceived benefits including ease of manipulation of the bowel, reduced spillage and resultant contamination, reduced luminal pressure, and lesser bacterial load. However, a recent metaanalysis1 of 36 RCTs and cohort studies, and an earlier one2 of 14 RCTs found that that the administration of MBP did not impact upon postoperative morbidity or mortality. This, in combination with high rates of patient dissatisfaction and fluid and electrolyte disturbances, has led to the conclusion that MBP should not be prescribed routinely. This is reflected in Guidelines from the Enhanced Recovery After Surgery Society,3,4 the National Institute of Health and Care Excellence,5 and the American Society for Enhanced Recovery,6 all of which suggest that MBP should not be administered routinely. However, although the American Society for Enhanced Recovery guidelines suggest that MBP should not be given in isolation, they recommend routine use of an isosmotic bowel preparation and combined oral antibiotic prior to elective colorectal surgery.6 The use of oral antibiotic (OAB) prophylaxis, in the form of nonabsorbable luminal antibiotics, was first proposed in 1971 by Rosenberg et al7 in a RCT of 150 patients undergoing large bowel surgery receiving MBP alone, or MBP in combination with phthalylsulphathiazole or phthalylsulphathiazole and neomycin. The combination of MBP +OAB was associated with a significant reduction in SSI (23% vs. 40%), anastomotic leak rates (24% vs. 52%), and sepsis rates (37.3% vs. 64.4%). 6 Although several studies provided evidence for the role of oral antibiotics in elective colorectal surgery, the regimens included large volume preparations,8-10 prolonged preoperative hospital admission, and in the setting of prolonged preoperative starvation protocols, dehydration, and electrolyte disturbances were commonplace.11,12 Decreased compliance and inconsistent bowel cleansing resulted in a reduced intervention effect and, this, combined with reduced preoperative admission times, resulted in the practice of combined MBP+OAB dwindling in favor of more restrictive MBP regimens alone. However, recently there has been resurgent interest in the use of OAB in colorectal surgery,13,14 particularly in light of a large number of retrospective cohort and database studies, many of which originated from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) targeted colectomy database.15-20 Evidence for the role of OAB has been summarized in several narrative reviews21,22 as well as meta-analyses,23-25 which have supported a reduction in SSI associated with combined MBP, OAB, and parenteral antibiotics over MBP and parenteral antibiotics alone. However, the most recent of these studies have been flawed in their inclusion of multiple studies based on the NSQIP database which have large degrees of cross-over of the same study population and have mostly focused upon SSI alone rather than other postoperative outcomes. In addition, recent studies18,26 have suggested that OAB alone may provide equivalent prophylaxis in terms of SSI and anastomotic leak rates when compared with a combined regimen of MBP+OAB.
The aims of this meta-analysis of RCTs and observational cohort studies in patients undergoing elective colorectal surgery were to:

•
Compare the impact of OAB with or without MBP in elective colorectal surgery in terms of SSI, anastomotic leak, 30-day mortality, overall morbidity, development of ileus, reoperations, and Clostridium difficile infection.
• Compare evidence derived from RCTs and cohort studies.
• Compare the role of administration of OAB with and without MBP in the setting of laparoscopic versus open surgery.

Search Strategy
The PubMed, Google Scholar, MEDLINE, and the Cochrane Library databases were searched to identify studies evaluating the effect of OAB in adults undergoing elective colorectal surgery published between January 1, 1981 and May 30, 2018. This date restriction was imposed as recommendations that parenteral antibiotics should be administered routinely for prophylaxis against SSI in colorectal surgery were made in 198127 and it was felt that all studies considering the role of oral antibiotic prophylaxis should include parenteral antibiotic prophylaxis, to reflect current perioperative care. The search terms used were: (oral antibiotic OR oral antibacterial) AND (colon OR rectal OR colorectal) AND surgery. The bibliographies of all studies which met the inclusion criteria, and previous systematic reviews and meta-analyses on the subject were reviewed to ensure study inclusion was as complete as possible. Non-English-language papers were translated for inclusion. The meta-analysis was conducted in accordance with the PRISMA statement. 28

Selection of Articles
Articles were screened for suitability on the basis of title and abstract by 2 independent researchers (K.E.R. and H.J.-E. , and as such only the more comprehensive study including a larger number of clinical outcomes was included.41 The third study from the Michigan Surgical Quality Collaborative database43 examined a different preparation combination, thus this was included in the meta-analysis. Finally, the national Veterans Affairs Surgical Quality Improvement Program was the basis for 2 studies44,45 on the same regimen comparison, thus only the largest study was included within the meta-analysis.45 One study46 included a small proportion of patients undergoing emergency colorectal resection within the cohort (311 of a total population of 2240), so any outcomes that included this study were analyzed both with and without it included to discern any difference in results.

Data Extraction
Data were extracted by 2 independent researchers (K.E.R. and H.J.-E.) and any discrepancies were resolved by a senior author (D.N.L.). The primary outcome measure was SSI, with secondary outcome measures including anastomotic leak, 30-day mortality, overall morbidity, development of ileus, reoperation, and Clostridium difficile infection. Data were also collected on patient demographics (age, sex), surgical variables (type of resection, open vs. laparoscopic, underlying disease necessitating resection), and details of the preparation used, in terms of parenteral and oral antibiotics as well as MBP. Several studies stated that MBP was not used in patients with obstructing masses, which is mirrored in standard clinical practice, thus these papers were included in the meta-analysis.
The risk of bias was assessed for the RCTs included using the Cochrane Collaboration tool within the RevMan software47 which considers random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), and selective reporting (reporting bias).

Statistical Analysis
Data were entered into RevMan 5.3 software.47 Dichotomous variables were calculated as risk ratios (RR) with a 95% confidence interval using the Mantel-Haenszel random effects model. From this, forest plots were derived, with a P value of less than 0.05 on 2-tailed testing representing a statistically significant difference. Data from RCTs and cohort studies were included separately within each forest plot, with a summative analysis of all the evidence performed in addition. Inconsistency and heterogeneity between studies were estimated using the I 2 statistic;48 ≤25% represented low heterogeneity, 25% to 50% represented moderate, and >50% high heterogeneity.

Protocol Registration
The protocol for this meta-analysis was registered with the PROSPERO database (www.crd.york.ac.uk/prospero)-registration number CRD42018098950.

Results
From the 520 studies identified in the initial search,  No data were available on return to theater rates related to anastomotic leaks.

MBP+OAB Versus No Preparation-
The comparison between MBP+OAB versus no preparation in terms of anastomotic leak was considered by just 2 cohort studies,31,46 with combined MBP+OAB being associated with a significant reduction in anastomotic leak rates (RR 0.52, 95% CI 0.45-0.59, P < 0.00001, I 2 = 0%). No data were available on return to theater rates secondary to anastomotic leaks or diverting stoma rates.
Other Comparisons-The comparison of anastomotic leak rates between OAB alone versus no preparation and OAB versus MBP was each only considered by 1 cohort study,31 and as such meta-analysis was not feasible.

MBP+OAB Versus No Preparation-No
RCTs considered the comparison between MBP+OAB versus no preparation, with evidence arising from 2 cohort studies only.31,41 Only 1 study41 provided a definition of ileus. This demonstrated that the combination of MBP+OAB was associated with a significant reduction in ileus (RR 0.72, 95% CI 0.68-0.77, P < 0.00001, I 2 = 0%).
Other Comparisons-The comparison in reoperation rates between OAB alone versus no preparation and OAB versus MBP were each only considered by 1 cohort study,31 thus meta-analysis was not performed.

Reoperation
Insufficient data were available for any of the planned analyses on reoperation rates, with 2 studies including data comparing MBP+OAB versus MBP (1 RCT49 and 1 cohort study31), and just 2 studies comparing MBP+OAB versus OAB alone (again 1 RCT71 and 1 cohort study).31 Thus, no meta-analysis was performed. The comparisons of reoperation rates between MBP+OAB versus no preparation, OAB alone versus no preparation and OAB versus MBP were each only considered by 1 cohort study,31 and as such meta-analysis was not performed. However, the largest cohort study31 showed a significant reduction (P < 0.001) in reoperation rates with combined MBP+OAB (3.2%) compared with OAB alone (4.7%), MBP alone (4.2%), and no preparation (4.5%).

Main Findings
This meta-analysis has provided evidence to suggest that MBP+OAB should be given serious consideration in patients undergoing elective colorectal surgery to reduce the risk of SSI. In addition, it has shown that the combination of MBP+OAB is associated with significant reductions in anastomotic leak rates, 30-day mortality, overall morbidity, and the incidence of postoperative ileus, without increasing the risk of developing C difficile infection (Table 3). Its findings are in contradiction with previous meta-analyses1,2 that did not account for the role of luminal antibiotics and showed that MBP on its own was of no benefit when compared with no bowel preparation or rectal enemas alone.
However, as only 9.3% (6437 patients) of the 69,517 patients included were studied in the context of RCTs, the results must be interpreted with some caution. Hence, when evidence arising from RCTs alone was considered, the combination of MBP+OAB was associated with a significant reduction in SSI alone. The evidence for the combination of MBP+OAB to reduce SSI rates is, thus, strong. European data reporting the results of colorectal surgery in the context of Enhanced Recovery After Surgery protocols where mechanical bowel preparation is not used routinely, have shown SSI rates of >10%,84,85 whereas the US NSQIP studies have shown that SSI rates are approximately 3% with a combination of MBP +OAB, 6% with MBP alone and 7% with no preparation.31 When the combination of MBP+OAB was compared with OAB alone, a significant reduction in 30-day mortality and incidence of postoperative ileus was seen, but no difference was seen between the 2 preparations in RCTs alone. There are no RCTs focusing on the combinations of MBP+OAB versus no preparation, OAB alone versus no preparation or OAB alone versus MBP alone. However, evidence from cohort studies suggests that the combination of MBP+OAB versus no preparation is associated with a significant reduction in SSI, anastomotic leak, 30-day mortality, and postoperative ileus. For OAB versus no preparation, the only significant reduction was in SSI rates, and for OAB versus MBP there was no significant difference in any of the clinical outcome measures. When a planned subgroup analysis of patients undergoing open versus laparoscopic surgery was undertaken, the combination of MBP+OAB versus MBP alone was associated with a significant reduction in SSI rates in patients undergoing open procedures, but not in those undergoing laparoscopic procedures.

Strengths and Weaknesses
The main weakness of this meta-analysis is the inclusion of both RCTs and cohort studies. While this lowers the overall quality of evidence, the decision to include cohort studies and large database studies was made as a large proportion of the recent evidence supporting the potential role of OAB or combined MBP+OAB has arisen from such studies. However, every analysis was conducted separately using evidence from RCTand cohort studies alone, as well as a summative analysis, to provide a more robust interpretation of the data.
The role of parenteral antibiotic prophylaxis is considered a standard of care in current practice, with evidence published in 198127 providing evidence for its benefit in terms of infection prevention and overall mortality and dictating that no further placebo or no intervention trials should be conducted. Definitive support was provided in a Cochrane Review86 demonstrating a significant reduction in SSI in patients receiving parenteral antibiotic prophylaxis versus those receiving no antibiotics or placebo (RR 0.34, 95% CI 0.28-0.41, P < 0.0001).
The practice of mechanical bowel preparation has changed significantly since the early 1980s. The regimen of Lazorthes et al62 included admission 3 days prior to surgery and administration of a low-residue diet and standard mechanical procedures such as enemas and magnesium sulphate purges. In contrast, more modern regimens are typically administered the day before surgery and are less invasive. This is particularly important in the setting of prolonged starvation protocols in vogue prior to the more modern ones, as they resulted in increased preoperative dehydration and electrolyte disturbances which are known to have adverse effects on postoperative complications. It should, however, be considered that each study level comparison between preparation types should have been exposed to the same level of bias, thus making the results more comparable. The OAB agent, dosing, and timing Europe PMC Funders Author Manuscripts as well as the parenteral antibiotic details were also inconsistent between studies, with insufficient data from each differing combination to perform a meaningful analysis. Several included just 1 preoperative dose of OAB, or differing parenteral antibiotic regimens depending upon which preparation regimen the patient received which exerts a potential significant bias. In addition, because of limited data, we have been unable to discern conclusively whether the reduction in morbidity is a result of OAB on their own or in combination with MBP.
The definition of anastomotic leak was not stipulated for inclusion within this meta-analysis, with the data from each individual study included, irrespective of whether this was based upon clinical or radiological diagnosis of anastomotic leak. However, the definition of leak was consistent within individual studies, thus the data from each study were comparable, attenuating this potential weakness.

Conclusion
The present meta-analysis is the largest and most comprehensive to date examining the role of bowel preparation prior to colorectal surgery, and supports a potentially significant benefit for OAB preparation, either in combination with MBP or alone, in the prevention of postoperative complications. While evidence arising from large retrospective cohort and database studies suggests a strong positive benefit, these are tempered when evidence arising from RCTs alone is considered. However, the evidence presented would suggest a benefit from OAB preparation in terms of SSI, which represents a major source of morbidity and increased healthcare costs. Further high-quality evidence is required to differentiate between the benefits of combined MBP+OAB or OAB alone in this setting before more definitive recommendations can be made.

Mini Abstract
This meta-analysis examines the role of oral antibiotic preparation, with and without mechanical bowel preparation in elective colorectal surgery. Combined oral antibiotic and mechanical bowel preparation significantly reduces surgical site infection rates versus mechanical preparation alone, but this effect is similar to that of oral antibiotics alone. Rollins Ann Surg. Author manuscript; available in PMC 2020 July 01.

Figure 1.
Forest plot comparing surgical site infection rate for patients receiving MBP+OAB versus MBP alone, divided by evidence from RCTs and cohort studies. A Mantel-Haenszel random effects model was used to perform the meta-analysis and risk ratios are quoted including 95% confidence intervals. Rollins Ann Surg. Author manuscript; available in PMC 2020 July 01.

Figure 2.
Forest plot comparing surgical site infection rate for patients receiving MBP+OAB versus OAB alone, divided by evidence from RCTs and cohort studies. A Mantel-Haenszel random effects model was used to perform the meta-analysis and risk ratios are quoted including 95% confidence intervals. Rollins Ann Surg. Author manuscript; available in PMC 2020 July 01. Forest plot comparing anastomotic leak rate for patients receiving MBP+OAB versus MBP alone, divided by evidence from RCTs and cohort studies. A Mantel-Haenszel random effects model was used to perform the meta-analysis and risk ratios are quoted including 95% confidence intervals.  Forest plot comparing 30-day mortality rates for patients receiving MBP+OAB versus MBP alone, divided by evidence from RCTs and cohort studies. A Mantel-Haenszel random effects model was used to perform the meta-analysis and risk ratios are quoted including 95% confidence intervals.     Ann Surg. Author manuscript; available in PMC 2020 July 01.