Introduction
Colorectal surgery is a common procedure, with approximately 100,000 operations annually within England, with 18–27% developing a surgical site infection (SSI) [
1‐
6]. SSIs are a major healthcare concern as they are associated with increased morbidity, mortality, and cost [
7]. In an attempt to prevent superficial and deep SSIs, antibiotic prophylaxis is given peri-operatively, normally as a bolus dose within the hour before surgery. Antibiotic prophylaxis is effective; when initially introduced for colorectal surgery, it reduced superficial and deep SSIs rates from 40 to 10% [
8]. Recent data, however, indicate that SSI rates have increased [
2‐
6,
8]. A potential reason for increased SSI rates may be suboptimal dosing of standard antibiotic prophylaxis, secondary to increasing rates of obesity and growing antimicrobial resistance [
9,
10]. In patients undergoing colorectal surgery, one study identified that 20% of patients were colonised with antibiotic resistant Enterobacteriaceae, a genus associated with approximately 80% of SSIs after colorectal surgery [
11]. Furthermore, standard bolus dosing has been reported as not achieving concentrations believed to be effective for preventing SSIs in operations lasting longer than 2 h [
12]. A potential way of improving the effectiveness of prophylaxis is by targeting antibiotic concentrations throughout an operation at concentrations more likely to inhibit the growth of bacteria classified as resistant, by using a bolus dose of antibiotic, followed by a continuous infusion during surgery. We therefore undertook a pilot trial (Colo-Pro) of antibiotic prophylaxis administered as a bolus-continuous infusion, targeting a serum concentration able to inhibit both susceptible and resistant Enterobacteriaceae. The aims of this study were (1) to determine the feasibility of recruiting and following-up colorectal patients in a trial comparing bolus vs. bolus-continuous infusion of prophylactic cefuroxime, and (2) to determine if a bolus-continuous dosing regimen could achieve targeted serum levels of antibiotic through operations without serious adverse reactions, and (3) to describe outcome rates in the recruited study population.
Discussion
We have successfully demonstrated the feasibility of performing a trial of cefuroxime bolus-continuous infusion versus standard bolus cefuroxime antibiotic prophylaxis. This conclusion is based on a recruitment rate of 46%, which we consider good due to the complex and multidisciplinary setting in which recruitment was completed. In this trial, as the treatment was finished by the end of a patient’s surgical procedure, there were no issues related to adherence. Randomisation was successfully completed, and there were only a limited number of patients whose surgical procedures were not carried out. Future studies should aim to randomise at the last available opportunity, and confirm surgical procedures with the most senior member of the surgical team. The single blinding used in the trial was successfully piloted, but future studies should aim to also blind the patients’ clinical teams as well as outcome assessors. There were occasions when a safety concern in relation to low body weight and reduced renal function resulted in non-allocated antibiotic prophylaxis being administered. Guidance within the protocol related to these specific issues could prevent these protocol violations.
In assessing the intervention bolus-continuous dosing regimens, the compartment model–based dosing regimen, which was adjusted for renal function, was the more effective model and achieved target concentrations in > 80% of patients as predicted. This compartment based–dosing regimen is therefore suitable to be used in a clinical trial targeting free serum concentrations of 64 m/L of cefuroxime. The demonstrated feasibility of this trial is important, as it has been shown that antibiotic concentrations at both the start and the end of surgery are important predictors of clinical effectiveness [
24]. The bolus-continuous infusion approach to prophylaxis is a strategy that can achieve desired concentrations of antibiotic throughout surgery, including the end of surgery, across multiple surgical procedures, and for multiple antibiotics, making the bolus-continuous infusion approach highly generalisable.
Rates of SSIs (superficial and deep SSIs) were lower in the intervention group, as were any infections and rates of urinary tract infection. These lower rates are consistent with the aim of the intervention, which is to reduce post-operative infections. As the difference in any infection between intervention groups was higher than the difference between SSIs, infection within 30 days of operation may be considered as the optimal outcome measure in future trials. This approach is supported by previous data that show that antibiotics with a long half-life e.g. ceftriaxone, which act like a continuous infusion of a short half-life antibiotic e.g. cefuroxime, reduce post-operative respiratory tract, surgical site, and urinary tract infections [
25]. However, these long half-life antibiotics are currently avoided in clinical practice over concerns relating to increased risks of
Clostridium difficile infection. All three patients lost-to follow-up at day 30 had an infection identified before their day 30 review. A future study could therefore consider using an intention-to-treat analysis with “the last observation carried forward” method to deal with this as done in this study analysis, or could consider including an outcome measure assessment after a shorter time period e.g. 14 days.
The rate of organ space surgical site infection was higher in the intervention group. Considering known rates of organ space infection it is likely this reflects a lower than expected rate of these events in the standard treatment group [
2]. Alternatively, it has been suggested that antibiotics have the potential to select for bacteria with collagenase activity, with the ability to cause anastomotic leak [
26]. Higher doses of antibiotic associated with the intervention treatment could therefore be consistent with increased selective pressure on the bacteria, and so increased anastomotic leak and subsequent organ space infection. No mortality was seen in the 30 days after the intervention in either treatment group.
The compartment model intervention was successful in obtaining serum concentrations targeted at 64 mg/L for the duration of surgery. This study was performed on a population of patients with high rates of cefuroxime susceptible Enterobacteriaceae colonisation of the colon, with resistance detected in 3–11% of patients, depending on the method of resistance detection used. It is possible that the effectiveness of the intervention may be dependent upon the rate/characteristics of Enterobacteriaceae resistance.
In summary, completion of this feasibility study suggests that a large pragmatic trial into bolus-continuous infusion of cefuroxime prophylaxis can be completed. As rates of antibiotic resistance increase the need for such trials is becoming more urgent.
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