Due to the premature termination of this multicenter, double-blind, placebo-controlled randomized clinical trial, we were unable to determine the efficacy of OAP in terms of the risk of SSI and other postoperative complications.
The use of oral antibiotic prophylaxis in colorectal surgery is a controversial topic. Several studies demonstrated a reduced risk of SSI when OAP was administered before surgery [23, 24]. However, the question of whether preoperative oral antibiotic prophylaxis is effective without MBP remains unanswered as all RCTs published to date combine OAP with MBP. The best available evidence on OAP efficacy is provided by a recent network meta-analysis that aimed to study the best strategy for bowel preparation. This study also emphasized the knowledge gap on OAP without MBP, as the absence of RCTs that included this strategy as a treatment arm forced the authors to estimate the efficacy of OAP based on indirect comparisons only. Though based on indirect comparisons, a significant reduction in organ/space SSIs was found with OAP only, compared to no preparation (OR 0.13 [95% CrI 0.02–0.55]). This strategy was superior to combining OAP with MBP.
Data on the effectiveness of OAP without simultaneous MBP is also provided by several retrospective observational studies that compared the different bowel preparation strategies. These studies reported conflicting results on effectiveness [25,26,27,28,29,30,31,32,33,34,35,36]. Potential confounding by indication and limited numbers of patients treated with only OAP hamper concluding on the effectiveness of OAP in the absence of MBP and exemplifies the need for well-controlled and adequately powered studies.
We consider the randomized design as a major strength of our study, which facilitated the unbiased assessment of the efficacy of OAP and its potential drug-related side effects. Although the quality of our design is high, selective participation could not be prevented entirely. Unfortunately, not all potential participants were screened. Patients suffering from multiple or more severe comorbidities were not always considered for participation even though they were eligible. This might have had an impact on the generalizability of the study population. Also, multiple other studies were being conducted within this patient population, which competed with our inclusions. Baseline characteristics of our cohort showed potentially relevant differences with those from a historical cohort of patients undergoing colorectal surgery from a different hospital. There are indications that the patients that we included differed from the source population. For example, the percentage of patients with colorectal malignancy in our cohort was higher. A recently implemented national screening program for colorectal cancer led to the detection of malignancies in an earlier stage. In general, these patients are in a better clinical condition, and surgery is less radical, which lowers the risk of SSI.
Treatment with OAP was associated with a significant improvement in perception of quality of life at six months after surgery. At the same time, worsening was seen for patients treated with a placebo. In the absence of an effect of OAP on any of the clinical outcomes that could have been a possible explanation for this improvement, we suggest further investigation to study whether and how OAP might impact the quality of life.
Because of the small sample size, we were unable to study the safety of OAP thoroughly. However, several patients who received OAP reported mild gastrointestinal side effects and an unappealing taste. When OAP is considered for implementation in the future, patients should be informed about these potential side effects and the necessity of completing the entire three-day course of OAP despite these side effects. Another important safety concern is the risk of developing antibiotic resistance. We found the prevalence of colistin and tobramycin resistance at baseline to be 16.7 and 39.4%, respectively. The prevalence of carriage of tobramycin and colistin-resistant species did not increase in both treatment arms. We compared our findings with the results obtained with the implementation of selective decontamination of the digestive tract (SDD), a comparable antibiotic prophylaxis containing tobramycin, colistin, and nystatin that is used in several Dutch ICUs. In a post hoc analysis of two multicenter trials, it was shown that during SDD use, the prevalence of colistin resistance ranged from 1.7 to 2.8%, and of tobramycin resistance from 6.2 to 8.0%, respectively . Other studies on SDD found a comparable prevalence [38,39,40]. The selective culture methods that we used in our study are known to have a higher sensitivity to detect antimicrobial-resistant Gram-negative bacteria , and may explain the higher prevalence observed compared to other studies. Due to the small number of patients, we were unable to exclude that OAP may increase the risk of developing antibiotic resistance.
At the time this trial was initiated, there was no consensus within the Dutch surgical community on whether OAP should be used before colorectal surgery and, as a result, it was not part of clinical care in the vast majority of hospitals. Because of the uncertainty about the efficacy of the intervention, there was clinical equipoise regarding the use of OAP . The shift started when the findings of a single-center before-after study were published. This before-after study was performed in the same setting without routine MBP administration . In contrast to previous observational studies, the risk of confounding by indication was minimized because OAP was implemented as the standard of care and prescribed to all patients who underwent elective colorectal surgery. After implementation, a 42% reduction was observed in the risk of SSI and mortality within 30 days after surgery (aRR 0.58 [95% CI 0.40–0.79)]. Due to the single-center aspect of the study and the risk of residual confounding, a well-controlled study was deemed necessary to confirm the treatment effect.
We faced multiple problems recruiting participants throughout the entire study period despite our efforts to improve the inclusion rate. The unexpectedly low recruitment rate was communicated with the participating hospitals. Supported by the effectiveness found in the observational study, several investigators considered awaiting the trial results unacceptable and decided to implement OAP to reduce SSI rates. We decided to end the trial prematurely, because the assumption of clinical equipoise regarding the administration of OAP was no longer valid, and the use of a placebo was no longer ethically justifiable.
To conclude, we could not evaluate the efficacy of OAP on SSI risk and other postoperative complications after colorectal surgery due to premature termination of this double-blind, placebo-controlled, randomized clinical trial. Due to the loss of clinical equipoise, we will no longer consider the use of placebo in clinical trials on the efficacy of OAP ethics. Considering the current evidence, we recommend the implementation of OAP in clinical practice and the continued monitoring of infection rates and antimicrobial resistance.