C54-29 Piperacillin-Tazobactam Depletes Gut Bacterial Metabolites and Suppresses Cytokine Production in Experimental Sepsis

Introduction/Rationale Anti-anerobic antibiotics are widely used in sepsis and have recently been associated with increased mortality and secondary infections; The mechanisms behind this harm are unknown. Piperacillin-tazobactam, depletes gut anaerobes, yet its effects on immunomodulatory bacterial metabolites, such as short-chain fatty acids (SCFAs), and systemic immunity in sepsis are unknown. We used a murine model to test whether piperacillin-tazobactam alters gut bacterial metabolites and cytokine responses during sepsis. Methods Female C57BL/6 mice were pretreated for three days with piperacillin-tazobactam, cefepime (anaerobe-sparing comparator), or vehicle. Sepsis was modeled using systemic endotoxin (5 mg/kg i.p.). Mice were euthanized 24 hours post-injection. Intestinal SCFAs were quantified by LC-MS, and serum CXCL-1, a key neutrophil chemoattractant, was quantified via bead-based immunoassay Results Antibiotic pretreatment had significant, divergent effects on SCFAs. Piperacillin-tazobactam significantly reduced SCFA levels by 100-fold compared to control and cefepime (p < 0.0001) , whereas cefepime increased SCFA levels compared to both groups (p < 0.001). Following endotoxin challenge, piperacillin-tazobactam-treated mice had reduced plasma CXCL-1 levels compared to untreated mice (p < 0.001). Cefepime-treated mice exhibited similar CXCL-1 levels to untreated mice (p > 0.05). Conclusion Piperacillin-tazobactam depleted intestinal metabolites and blunted pro-inflammatory cytokine responses during experimental sepsis, unlike cefepime. These findings suggest anti-anaerobic antibiotics may impair early immune activation during sepsis, through microbiome disruption. In future studies, we test whether SCFA repletion rescues immune responses in piperacillin-tazobactam treated mice, to determine whether metabolite depletion drives immune suppression. This abstract is funded by: None