Antibiotic resistance in Enterobacteriaceae: what impact on the efficacy of antibiotic prophylaxis in colorectal surgery?

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Summary

Antibiotic prophylaxis, introduced in the 1940s, brought in an era of relatively safe colorectal surgery. This was achieved in part due to the prevention of surgical site infections (SSIs) caused by Enterobacteriaceae. Since then, Enterobacteriaceae have become increasingly resistant to the antibiotics commonly used for prophylaxis. The impact of being colonized preoperatively with resistant Enterobacteriaceae on the efficacy of colorectal SSI prophylaxis, if any, is unknown. It is also difficult to predict the likely impact of resistance as the exposure‒response relationships have not been determined for antibiotic surgical prophylaxis. Neither is it known which test for resistance to use; the importance of the concentration of Enterobacteriaceae in the colon, the ability of different species of Enterobacteriaceae to cause SSIs, and the comparative ability of minimum inhibitory concentration or presence of a resistance mechanism in predicting SSI risk have yet to be established. Clinical research is urgently needed to answer these questions.

Introduction

Antibiotic prophylaxis for many types of surgery has been an effective means of reducing surgical site infection (SSI) rates. But the increase in antibiotic resistance in Enterobacteriaceae and the adverse effects this is having on the treatment of infection have raised the question of the impact of this resistance on surgical prophylaxis. To understand what impact resistance in Enterobacteriaceae may have on SSI rates, we have reviewed the literature on SSI prophylaxis in colorectal surgery.

Section snippets

Overview of antibiotic prophylaxis in colorectal surgery

Antibiotic prophylaxis for colorectal surgery was introduced at a time when ‘the stakes were high, with 10% mortality, and 80–90% suppurating wound infections’. In 1938, with Escherichia coli identified from surgical wound infections, sulphonamides were investigated as antibiotic surgical prophylaxis. In 1943, 123 colorectal operations with sulphonamide prophylaxis were reported with 4% mortality, lower than the previously reported 10%. New potential agents continued to be investigated,

Enterobacteriaceae and SSIs

The family Enterobacteriaceae includes a number of clinically relevant species including E. coli, Klebsiella spp., Enterobacter spp., Serratia spp. and Proteus spp. The antimicrobial treatment of infections caused by Enterobacteriaceae is often similar, but this does not mean that these bacteria should be considered equal with respect to their potential to cause SSIs. Most human Enterobacteriaceae infections, including SSIs, are caused by E. coli. This reflects a difference between E. coli and

Enterobacteriaceae antibiotic resistance mechanisms and SSI risk

There are many resistance mechanisms described in Enterobacteriaceae which may impact on the treatment of infections. An example of the range of resistance mechanisms can be seen within resistance to co-amoxiclav, which is commonly used for surgical prophylaxis. Co-amoxiclav may be ineffective against Enterobacteriaceae owing to: hyper-production of class A beta-lactamases such as TEM1, AmpC beta-lactamases, TEM inhibitor-resistant beta-lactamases, OXA beta-lactamases, and extended spectrum

Antibiotic treatment breakpoints in relation to SSI risk

Antimicrobial resistance is defined when the MIC of an antibiotic for a bacterium is above the ‘breakpoint’ for that antibiotic, the MIC above which clinical cure is considered less likely to occur. Setting breakpoints to predict the efficacy of a treatment requires knowledge of the relationship between antibiotic concentrations and their effect on outcomes, so-called exposure‒response relationships. An example of a treatment exposure‒response relationship is fT > MIC [the time during which

Pharmacokinetic/pharmacodynamic modelling to predict the efficacy of antibiotic prophylaxis

In 2013, a Monte Carlo modelling study of antibiotic prophylaxis efficacy, using fT > MIC as the target, was carried out by Moine et al.11 Only a few antibiotics, cefuroxime, cefazolin and ertapenem, achieved fT > MIC targets over a 4 h time-period when the MICs of E. coli reported by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) were considered. Given the clinical data demonstrating equal efficacy between ertapenem, supported by Moine's modelling, and ceftriaxone,

Testing for antibiotic-resistant Enterobacteriaceae colonization

Determining the antibiotic resistance of colonizing Enterobacteriaceae is required if an epidemiological study is planned, if individualized antibiotic prophylaxis is planned, or if research into correlations between resistance and SSI is planned. A number of issues require consideration before undertaking tests to determine resistance. Most published studies have chosen rectal swabs to obtain samples representative of colonic bacteria (Table I).13, 14, 15, 16, 17, 18, 19 Further considerations

Clinical studies into antibiotic resistance and surgical prophylaxis

The impact of antibiotic resistance on SSI rates has not been widely investigated. A few studies have related resistance, using treatment resistance breakpoints, to postoperative infection.13, 14, 15, 16, 18, 19 The main area in which this has been investigated is liver transplantation, presumably because of the potentially high mortality rate associated with postoperative infections. The most informative study, by Bert et al., showed that preoperative colonization with ESBL Enterobacteriaceae

Clinical practice recommendations

The first priority in this time of increasing antibiotic resistance is to ensure that antibiotic resistance is reduced. Therefore any clinician concerned about the efficacy of prophylaxis should first focus on limiting antibiotic use, for example by limiting antibiotic prophylaxis to single doses, and reducing the transmission of resistant bacteria by optimizing hand hygiene, etc. Then modifiable risk factors should be addressed: limit preoperative smoking, increase rates of laparoscopic

Research recommendations

There is a near absence of evidence with which to predict the efficacy of antibiotic prophylaxis. Research is therefore needed to derive an evidence base to guide the selection of regimens for antibiotic prophylaxis. Research recommendations are to:

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    determine exposure‒response relationships relevant to antibiotic prophylaxis of SSIs;

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    determine MIC breakpoints predictive of SSI risk;

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    determine a colonic bacterial concentration threshold relevant to SSIs;

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    determine species-specific SSI potential;

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Conclusion

Antibiotic resistance, as defined by MICs for the treatment of infections, does appear to be impacting on postoperative infection rates in some specific patient groups (liver transplant, prostate biopsy), although evidence of impact outside these areas is mostly absent. In order to optimize surgical antibiotic prophylaxis, further research is needed to elucidate the exposure‒response relationships as well as determinants of resistance relevant to surgical prophylaxis.

Conflict of interest statement

None declared.

Funding sources

None.

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