Pharmacodynamic modelling of intravenous antibiotic prophylaxis in elective colorectal surgery

Surgical-site infections are the leading cause of post-operative morbidity and mortality as well as increased costs following colorectal surgery. The purpose of this study was to evaluate different β-lactam antimicrobial dosing regimens currently used for prophylaxis in elective colorectal procedures with the aim of identifying optimal antibiotics and dosing regimens. Serum pharmacokinetic (PK) parameters specific to each drug for use in pharmacodynamic (PD) modelling were obtained from the published literature. Susceptibility data for Escherichia coli, Bacteroides fragilis and Staphylococcus aureus for use in modelling simulations were obtained from the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Monte Carlo simulation was used to evaluate the influence of dose and dosing frequency of tested antibiotics to achieve a prophylaxis target fT>MIC (time during which the free drug concentration exceeds the pathogen minimum inhibitory concentration) of 100% for up to 4h. Ertapenem 1g, cefuroxime 1.5 g and cefazolin 2 g were the only antibiotic regimens that consistently yielded target fT>MIC of 100% for the entire 4-h post-dose interval and against all targeted organisms more than 90% of the time. In contrast, cefoxitin, cefotetan and ampicillin/sulbactam yielded very poor predicted PK/PD performances. In conclusion, this study demonstrates the value of, and need for, applied PD research in the area of surgical prophylaxis. Whether cefoxitin, cefotetan or ampicillin/sulbactam should continue to be advocated as first-line agents for prophylaxis during elective colorectal surgery, particularly at the standard doses currently being used, is debatable.