Efficacy of moxifloxacin monotherapy versusgatifloxacin monotherapy, piperacillin-tazobactam combination therapy, and lindamycin plus gentamicin combination therapy: An experimental study in a rat model of intra-abdominal sepsis induced by fluoroquinolone-resistant Bacteroides fragilis.

BACKGROUND: In intra-abdominal infections, the activity of antimicrobial agents against Bacteroides fragilis and phenotypically related organisms, and the increasing resistance of these organisms, are of particular importance and concern to surgeons. In vitro data suggest that moxifloxacin is more active than other quinolones against obligately anaerobic organisms, including Bacteroides spp. OBJECTIVE: The aim of this study was to compare the efficacy of moxifloxacin monotherapy versus gatifloxacin monotherapy and 2 combination therapies (piperacillin-tazobactam and clindamycin plus gentamicin) in a rat model of intra-abdominal sepsis. The end point was marked by the incidence of mortality and intra-abdominal abscesses at necropsy 7 days after bacterial challenge. METHODS: Three different strains of B fragilis with different degrees of resistanceto moxifloxacin (minimum inhibitory concentrations [MICs]: 4, 8, and 16 pg/mL) were added to the challenge inoculum in 3 separate experiments. Groups of 20 animals were used in each experiment. Group 1 served as saline-treated controls; group 2 received moxifloxacin 15 mg QD; group 3 received gatifloxacin 25 mg QD; group 4 received piperacillin-tazobactam 93 mg (-83 mg of piperacillin) QD; and group 5 received a combination of clindamycin 15 mg TID plus gentamicin 2 mg TID. All treatments were given intramuscularly. For all antimicrobials, dose was based on peak and trough serum drug concentrations determined by prior testing, with animal doses adjusted based on the ratio of body surface area to body weight, and comparing these doses and levels with studies in humans. RESULTS: In all 3 experiments, the mortality rate with moxifloxacin was significantlylower or statistically similar compared with antibiotic active comparators (P ≤ 0.024). In addition, there were no significant differences in the incidence of abscess with moxifloxacin versus its comparators or between the 3 moxifloxacin groups across experiments. The best results for moxifloxacin were found in the experiment in which the B fragilis strain with MIC 16 µg/mL was added to the inoculum. CONCLUSION: The results of this study in an animal model of intra-abdominalsepsis induced by fluoroquinolone-resistant B fragilis suggest that moxifloxacin monotherapy performs as well as combination regimens such as piperacillin-tazobactam and clindamycin plus gentamicin, and is as effective as other fluoroquinolones with antianaerobic activity, such as gatifloxacin.

Protective effect of ethyl-3-(3-dimethyl aminopropyl)urea dihydrochloride (EDU) against LPS-induced death in mice.

Evaluation of anti-adhesive gels and bioresorbable films in animal models of intra-abdominal infection has shown that a product of the cross-linking reaction between hyaluronic acid (HA) and CM-cellulose, 1-ethyl-3-(3-dimethyl aminopropyl)urea dihydrochloride (EDU), has immunomodulatory properties. The effects of EDU were evaluated by using an endotoxin-induced shock mouse model. Pre-treatment of mice with EDU (50 mg kg(-1)) in DMSO resulted in a significant reduction in mortality following injection of LPS, compared to vehicle (DMSO) pre-treatment alone. Serum levels of TNF-alpha, IL1beta and IFN-gamma in EDU-treated mice were significantly lower than those in vehicle-treated mice. Nitric oxide (NO) concentrations in the sera of mice after inoculation with LPS were significantly lower in the EDU-treated group than in the vehicle-treated group at various time-points. In contrast, EDU pre-treatment was associated with an enhanced IL10 response after LPS injection, compared to vehicle pre-treatment alone. In vitro studies revealed that IL10 production by RAW 264.7 macrophages, elicited by LPS, was increased significantly when EDU was added to the culture medium. These results suggest that the protective effect of EDU during LPS-induced shock in mice is the result of inhibition of proinflammatory cytokines and NO production and an enhanced IL10 response.

Protection against lethal intra-abdominal sepsis by 1-(3-dimethylaminopropyl)-3-ethylurea.

Sodium hyaluronate-carboxymethylcellulose (HA/CMC) formulations are gels that effectively reduce postoperative adhesions in both animals and humans, when placed in the peritoneal or pelvic cavities concomitant with surgical manipulation. However, it has been suggested that the use of these products may increase the risk of peritoneal infection after contamination with intestinal contents during surgery. Using the rat intra-abdominal sepsis model, we found that administration of HA/CMC gels before bacterial challenge did not increase mortality but did significantly protect rats against lethal infection. This effect was dose and time dependent. Protection was conferred not by the HA/CMC gels themselves but by 1-(3-dimethylaminopropyl)-3-ethylurea (EDU), a small molecule released from the gel complex under physiologic conditions. Our results suggest that the protective effect exhibited by EDU is related to down-regulation of T cell-dependent responses and suppression of the proinflammatory-cytokine cascade associated with mortality during the early phase of disease.