Anaesthesia induction and maintenance will be performed according to the standard operating procedure of the Asan Medical Center [11]. Cefoxitin will be administered before the skin incision.

Explanation for the choice of comparators

We shall randomly allocate patients to the study group (administration of cefoxitin via TCI method) and the control group (administration of cefoxitin using standard method). We chose standard administration method as the comparator because it is the administration method currently used around the world.

Control group (standard administration method)

Two grams of cefoxitin will be dissolved in 100 ml of normal saline and administered for approximately 10 min. Redosing will be performed every 2 h from the start of the first dose of cefoxitin. The maximum intraoperative dose will be limited to 8 g per day. An additional 2 g of cefoxitin will be administered in the general ward 12 h after the first cefoxitin dose.

Study group (target-controlled infusion method)

Two grams of cefoxitin will be dissolved in 50 ml of normal saline and administered using a commercialised TCI syringe pump until the end of surgery. It will be administered at a target concentration of 80 μg/ml using the total concentration pharmacokinetic model of cefoxitin constructed and validated in previous studies [5, 12]. The TCI syringe pump (PION TCI®; Bionet Co. Ltd., Seoul, Korea) will be connected to a personal computer (PC) by an RS232c cable and controlled by a TCI software (Asan pump, version 2.1.5; Bionet Co. Ltd., Seoul, Korea, https://www.ksap.co.kr/html/, last accessed: December 15, 2023) installed on said PC. Figure 1 shows the operation of the Asan pump program, which is used to administer cefoxitin to a hypothetical patient using the TCI method. Plasma concentration, dose infused, and infusion rate data will be recorded at 10-s intervals and stored in ‘CSV’ format. Twelve hours after starting cefoxitin administration in the operating room, 2 g of cefoxitin will be administered in the general ward using the standard administration method.

Fig. 1

Operation screenshot of the Asan Pump program. Cefoxitin is administered to a hypothetical patient at a target total concentration of 80 μg/ml

Criteria for discontinuing allocated interventions

If the study protocol is violated, intraoperative bleeding exceeds 1.5 L, or the patients withdraw their informed consent, the participants will be dropped from the study.

Strategies to improve adherence to interventions

Not applicable. The designated intervention will be applied only to one method of administration allocated.

Relevant concomitant care permitted or prohibited during the trial

Not applicable. No relevant concomitant care will be permitted or prohibited.

Provisions for post-trial care

The principal investigator (BM Choi) has clinical trial liability insurance. This insurance provides coverage for any damage to the research participants through injury or death caused by the study. Insurance applies to damages that became apparent during the study or within 5 days after the end of the study.

Outcomes and follow-up

The primary outcome will be the incidence of SSI. The secondary outcome will be the administered dose of cefoxitin. The trial endpoint will be established 1 month after the discharge of the last included patient. Each patient will visit the colorectal surgery outpatient clinic 1 month after discharge, and the surgeon in charge will evaluate the patient for the occurrence of surgical site infection.

Participant timeline

The participant timeline is shown in Fig. 2.

Fig. 2

Participant timeline. POD, postoperative day. Patients will be admitted at least 1 day before surgery. After the surgery schedule will be confirmed, informed consent will be obtained from the patients in the general ward the day before surgery. Group allocation will be performed on the morning of surgery after confirming whether cefoxitin will be used as a prophylactic antibiotic. In general, patients who underwent laparoscopic surgery will be discharged on the 5th day after surgery, and patients who underwent open surgery will be discharged on the 7th day after surgery. Approximately 1 month after discharge, the patients will visit the outpatient clinic

Sample size

The primary endpoint of this study is to compare the incidence of SSI between the two groups. Since cefoxitin will be dosed every 2 h during surgery in the standard administration group, the time for which the unbound concentration was maintained above the MIC to inhibit pathogens did not differ from that in the TCI group during surgery. This was confirmed in a stochastic simulation using the pharmacokinetic model of a previous study [5, 12]. Given that there is no difference in the incidence of SSI between the two groups, the sample size in which the TCI group would show a dose reduction of approximately 30% compared to the standard dose administration group was calculated. Using Bonferroni correction, an alpha of 0.025 and a beta of 0.1 were applied. The sample size that satisfied the first condition that fT > MIC would not differ between the two groups was 270 patients per group, and the sample size that satisfied the second condition that the dose in the TCI group would be reduced by approximately 30% was 1187 patients per group. To satisfy both assumptions, a larger sample size must be selected, and considering a dropout rate of 5%, the sample size was determined to be 1247 patients per group.

Recruitment

Patients will be admitted at least 1 day before surgery. After the surgery schedule was confirmed, written informed consent form will be obtained from the patients in the general ward the day before surgery.