Why Antibiotic Treatment Is Not Enough for Sepsis Resolution: an Evaluation in an Experimental Animal Model

Abstract

Sepsis remains a major health problem at the levels of mortality, morbidity, and economic burden to the health care system, a condition that is aggravated by the development of secondary conditions such as septic shock and multiple-organ failure. Our current understanding of the etiology of human sepsis has advanced, at least in part, due to the use of experimental animal models, particularly the model of cecum ligation and puncture (CLP). Antibiotic treatment has been commonly used in this model to closely mirror the treatment of human septic patients. However, whether their use may obscure the elucidation of the cellular and molecular mechanisms involved in the septic response is questionable. The objective of the present study was to determine the effect of antibiotic treatment in the outcome of a fulminant model of CLP. Various dosing strategies were used for the administration of imipenem, which has broad-spectrum coverage of enteric bacteria. No statistically significant differences in the survival of mice were observed between the different antibiotic dosing strategies and no treatment, suggesting that live bacteria may not be the only factor inducing septic shock. To further investigate this hypothesis, mice were challenged with sterilized or unsterilized cecal contents. We found that exposure of mice to sterilized cecal contents also resulted in a high mortality rate. Therefore, it is possible that bacterial debris, apart from bacterial proliferation, triggers a septic response and contributes to mortality in this model, suggesting that additional factors are involved in the development of septic shock.

Blocking ADAM17 Function with a Monoclonal Antibody Improves Sepsis Survival in a Murine Model of Polymicrobial Sepsis

“…We again examined peritoneal levels of neutrophils at 24 h post-CLP for both treatment groups, which was significantly increased in the MEDI3622 plus ertapenem-treated mice ( Figure 2C). treatment alone had a marginal though not significant effect on sepsis survival (Figure 2A), similar to other studies [28]. Interesting is that when MEDI3622 was administered pre-CLP followed by ertapenem post-CLP, survival was dramatically increased compared to mice that received ertapenem alone (Figure 2A).…”

Chronic Critical Illness and the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome

“…However, the mechanism(s) driving the process in mice are likely different from those seen in CCI and PICS, because survivors of CLP have a necrotic cecum in addition to an indeterminate nidus of infection. High-dose antibiotics have been attempted to sterilize the peritoneal cavity, but accomplishment of sterility has rarely been demonstrated ( 51 ). With that said, some investigators have looked at the long-term outcomes in murine survivors of CLP sepsis, and demonstrating myeloid cell expansion, inflammation, and immune suppression ( 52 – 54 ).…”

Antecedent Dietary Glutamine Supplementation Benefits Modulation of Liver Pyroptosis in Mice with Polymicrobial Sepsis

“…We duplicated the measurement of each sample and the number of the sample in each group is at least six. There is no significantly different in the expression (Ct value) of GAPDH in all groups [28].…”