Second place winner of the Conrad Jobst Award in the gold medal paper competition. Increased antibiotic effectiveness in a model of surgical infection through continuous infusion.

As long as infection remains the most common cause of morbidity and mortality in severely ill patients, there exists the need for more effective anti-infective therapy. The current study was undertaken to determine whether continuous infusion (CONT) is superior to intermittent administration (INT) of an equal amount of cefazolin (CEF) in a model of surgical infection. The thigh suture model consists of the surgical placement of 1 cm of cotton suture with absorbed K. pneumoniae into the thigh muscle of mice. The experimental groups were: 1) controls (n=20) with thigh suture inoculation and treatment with intraperitoneal (IP) sterile saline; 2) CONT infusion group that received CEF at 60 mg/kg IP 30 minutes before inoculation followed by CONT IP infusion at 180 mg/kg/day (n=22) for 3 days; and 3) INT injection group that received CEF at 60 mg/kg IP 30 minutes before inoculation followed by INT IP injections every 8 hours at 180 mg/kg/day (n=20) for 3 days. All CEF treated animals received identical quantities of total CEF, and all groups were followed for 10 days. The control and INT CEF groups had 20% survival, whereas the CONT CEF group had 81% survival, (P<0.001). Continuous CEF yielded constant serum levels of 19±1 μg/mL, whereas INT injections resulted in peak serum level of 74±12 μg/mL at one minute but declined to 3.9±0.9 μg/mL in 2 hours. Although there was statistically significant tissue bacterial growth in the INT injection group, there was extensive tissue bacterial clearance in the CONT infusion group. Animals with CONT CEF did not have any bacteremia, whereas the surviving INT injection animals had persistent bacteremia up to 4 days after inoculation. We therefore conclude that continuous infusion is superior to intermittent injection of the identical total amount of CEF in achieving continuous serum CEF levels, tissue and blood bacterial clearance, and survival. The more practical implication is that such clinically relevant models of surgical infection can be used to overcome increasing obstacles associated with human clinical trials in the development of new and more efficacious anti-infective regimens