Dear Editor,
We commend the authors of the article “Effect of oral antimicrobial prophylaxis on surgical site infection after elective colorectal surgery: multicentre, randomised, double blind, placebo controlled trial” on completing a large multicentre trial, covering an important, hotly debated topic. However, we feel important methodological points were overlooked both within the paper and accompanying editorial.
The methodology surrounding the assessment of the primary outcome is not clear. The authors state the operating surgeon assessed each patient for surgical site infection (SSI) during their inpatient stay. However, there is no description of training of SSI ascertainment or assessment of competence in the manner of the GlobalSurg studies [1, 2]. Primary outcome assessment by independent clinicians or research staff not directly involved in the care of the patient would be more rigorous and less prone to bias. We note that trial staff were involved in the telephone assessment of patients who were discharged prior to day-30, but it is unclear if there was standardisation of the questions asked during this consultation. The Bluebelle wound healing questionnaire is a validated tool that has been used in many SSI related studies. Whilst this tool did not exist at the time of trial development, it does highlight the kind of methodological work into the reporting of the primary outcome measure that should have been completed prior to the study commencing. Additionally, as recently highlighted by the GlobalSurg group, the use of telephone follow-up risks under reporting of SSI rates, when compared to in-person review [3].
The authors describe the trial as pragmatic. When assessing the methodology with the PRECIS-2 toolkit, it scores within the middle range for a number of domains, such as “follow-up” and “setting”. It specifically scores low for “eligibility”, due to the stringent exclusion criteria used (e.g. BMI>35, IBD). Given the increasing prevalence of obesity and IBD worldwide, the external validity of the trial is not only limited by the antibiotic choices as highlighted in the accompanying editorial, but also by the patient group studied.
Failure to optimise the control arm has been associated with over estimation of the effect size of interventions in surgical RCTs [4]. Within the editorial, concern was expressed for the high SSI rate of 22% within the control arm. We would argue that this rate is reflective of contemporaneous colorectal practice. The VINCat Colon Surgery Group prospectively collected the SSI rates across 10 Spanish hospitals, using the same diagnostic CDC criteria. In this prospective study of 3710 patients, the SSI rate for those without pre-operative oral antibiotics was 21.3 % (454/2134), almost identical to the rate reported here.
Some surgeons have argued that evidence-based standards of care should be implemented within trials [4] and in this context the failure to provide optimal intravenous anaerobic antibiotic prophylaxis is noted in the editorial. Furthermore, the implementation of WHO SSI prevention guidelines [5] might reasonably be expected to lower the SSI rate further and rates less than 10% can be achieved [6, 7]. However, fully optimising SSI prevention practice in both arms would necessitate a far greater sample size to detect a clinically significant risk reduction. The question has to be asked whether in this study the effect size of oral ornidazole has been over estimated due to poor practice in the control arm.
We agree with the editorial – high quality RCTs on the use of pre-operative oral antibiotics and SSI rates are desperately needed, and there is certainly scope for sophisticated methodology, such as adaptive trial design, as used in the RECOVERY studies [8-10].
Yours sincerely,
Miss Adele Sayers & Professor Neil Smart,
Royal Devon University Healthcare NHS Foundation Trust
REFERENCES
1. GlobalSurg Collaborative. Determining the worldwide epidemiology of surgical site infections after gastrointestinal resection surgery: protocol for a multicentre, international, prospective cohort study (GlobalSurg 2). BMJ Open. 2017 Jul 21;7(7):e012150. doi: 10.1136/bmjopen-2016-012150.
2. GlobalSurg Collaborative. Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study. Lancet Infect Dis. 2018 May;18(5):516-525. doi: 10.1016/S1473-3099(18)30101-4. Epub 2018 Feb 13.
3. GlobalSurg Annals paper
4. Strobel O, Büchler MW. The problem of the poor control arm in surgical randomized controlled trials. Br J Surg. 2013 Jan;100(2):172-3. doi: 10.1002/bjs.8998. Epub 2012 Nov 23.
5. Global Guidelines for the Prevention of Surgical Site Infection. Geneva: World Health Organization; 2018 (update). Available from: https://www.ncbi.nlm.nih.gov/books/NBK536404/
6. Abbas M, de Kraker MEA, Aghayev E, Astagneau P, Aupee M, Behnke M, Bull A, Choi HJ, de Greeff SC, Elgohari S, Gastmeier P, Harrison W, Koek MBG, Lamagni T, Limon E, Løwer HL, Lyytikäinen O, Marimuthu K, Marquess J, McCann R, Prantner I, Presterl E, Pujol M, Reilly J, Roberts C, Segagni Lusignani L, Si D, Szilágyi E, Tanguy J, Tempone S, Troillet N, Worth LJ, Pittet D, Harbarth S. Impact of participation in a surgical site infection surveillance network: results from a large international cohort study. J Hosp Infect. 2019 Jul;102(3):267-276. doi: 10.1016/j.jhin.2018.12.003. Epub 2018 Dec 7. PMID: 30529703.
7. Falconer R, Ramsay G, Hudson J, Watson A; Highland Colorectal SSI Group. Reducing surgical site infection rates in colorectal surgery – a quality improvement approach to implementing a comprehensive bundle. Colorectal Dis. 2021 Nov;23(11):2999-3007. doi: 10.1111/codi.15875. Epub 2021 Sep 2. PMID: 34396654; PMCID: PMC9293099.
8. RECOVERY Collaborative Group. Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021 Feb 13;397(10274):605-612. doi: 10.1016/S0140-6736(21)00149-5. Epub 2021 Feb 2. PMID: 33545096; PMCID: PMC7884931.
9. RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021 May 1;397(10285):1637-1645. doi: 10.1016/S0140-6736(21)00676-0. PMID: 33933206; PMCID: PMC8084355.
10. RECOVERY Collaborative Group. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial. Lancet. 2021 May 29;397(10289):2049-2059. doi: 10.1016/S0140-6736(21)00897-7. Epub 2021 May 14. PMID: 34000257; PMCID: PMC8121538.
Response to “Effect of oral antimicrobial prophylaxis on surgical site infection after elective colorectal surgery: multicentre, randomised, double blind, placebo controlled trial”