INCREASED ANTIBIOTIC EFFECTIVENESS IN A MODEL OF SURGICAL INFECTION THROUGH CONTINUOUS-INFUSION

As long as infection remains the most common cause of morbidity and mo rtality in severely ill patients, there exists the need for more effec tive anti-infective therapy. The current study was undertaken to deter mine whether continuous infusion (CONT) is superior to intermittent ad ministration (INT) of an equal amount of cefazolin (CEF) in a model of surgical infection. The thigh suture model consists of the surgical p lacement 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 (IF ) 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 IF in jections every 8 hours at 180 mg/kg/day (n=20) for 3 days. All CEF tre ated animals received identical quantities of total CEF, and all group s were followed for 10 days. The control and INT CEF groups had 20% su rvival, whereas the CONT CEF group had 81% survival, (P<0.001), Contin uous CEF yielded constant serum levels of 19+/-1 mu g/mL, whereas INT injections resulted in peak serum level of 74+/-12 mu g/mL at one minu te but declined to 3.9+/-0.9 mu g/mL in 2 hours. Although there was st atistically significant tissue bacterial growth in the INT injection g roup, there was extensive tissue bacterial clearance in the CONT infus ion group. Animals with CONT CEF did not have any bacteremia, whereas We surviving INT injection animals had persistent bacteremia up to 4 d ays 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 bacter ial clearance, and survival. The more practical implication is that su ch clinically relevant models of surgical infection can be used to ove rcome increasing obstacles associated with human clinical trials in th e development of new and more efficacious anti-infective regimens.