Abstract 2806: A single dose of perioperative cefazolin disrupts the gut microbiome and immunity in patients (pts) with early-stage melanoma

Abstract

Abstract Background: Perioperative antibiotic prophylaxis is routinely utilized to reduce surgical site infections (SSIs). However, the rate of SSIs following a clean surgical procedure is <3%. Overuse of antibiotics is associated with potential adverse effects, including disruption of the composition and function of the native gut microbiota. Numerous studies have shown a negative impact of antibiotics on response and survival in patients with cancer treated with immune checkpoint blockade. The primary objective of this study was to determine the impact of a single dose of perioperative cefazolin on the gut microbiome and immunity. Methods: In this pilot trial (NCT04875728), 22 eligible pts diagnosed with clinical stage I or II melanoma undergoing wide excision with or without sentinel lymph node biopsy were enrolled between October 2021 and January 2023. Pts were randomized 1:1 to receive a single dose of cefazolin as standard-of-care (ABX, n=11) or no antibiotics (No ABX, n=11) at the time of surgery. Stool samples were collected before surgery, on post-operative day (POD) 14 and POD90 for metagenomic sequencing (WMS). Bulk RNA-sequencing of peripheral blood mononuclear cells (PBMCs) collected at the same timepoints was performed and data processed using DESeq2, log-transformed, and standardized for subsequent analysis. Immune pathway enrichment scores were calculated using GSVA for each sample with gene lists from 3 immune pathways (ADAPTIVE_IMMUNE_SYSTEM, INNATE_IMMUNE_SYSTEM, and CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM) from REACTOME (https://reactome.org) and immune cell gene signatures from Danaher P et al, 2017. Results: Treatment with a single dose of perioperative cefazolin was associated with a decrease in the alpha diversity of the gut microbiome 2 weeks postoperatively in pts who received perioperative cefazolin versus those who did not receive antibiotics (p=0.057, R2=0.0526); this persisted to POD90 (p=0.021, R2=0.0948). WMS showed prominent and persistent decreases in Akkermansia muciniphila (POD14: Log2FC=-8.38, q<0.001) and Alistipes communis (POD90: Log2FC=-4.47, q<0.001) in the ABX group compared to No ABX, respectively. RNA-seq analysis of PBMCs from pts revealed differences in immune subsets at POD90 between ABX and No ABX groups including decreased IFN-γ signatures (p=0.02) in pts who received perioperative cefazolin. Conclusions: Perioperative antibiotic prophylaxis is associated with profound and persistent reduction in microbiome diversity and composition, particularly of bacterial species associated with protective metabolic and inflammatory effects. Further studies will seek to assess the functional impact of this reduction on the immune response in a murine model, evaluate the generalizability of our findings across broader cohorts of patients undergoing surgery, and apply these findings to guide clinical management decisions. Citation Format: Estefania Fernandez, Samuel Cass, Yongwoo D. Seo, Ashish V. Damania, Xiaolong Meng, Pranoti V. Sahasrabhojane, Jiun Sheng Liu, Wenbin Liu, Yulong Chen, Roland L. Bassett, Samuel Shelburne, Hsiu-Yin Chang, Kinjal R. Somaiya, Kristi S. Mungovan, Jared C. Malke, Brenna Matejka, Sarah B. Fisher, Anthony Lucci, Jeffrey E. Lee, Merrick I. Ross, Jeffrey E. Gershenwald, Padmanee Sharma, Nadim J. Ajami, Christina L. Roland, Jennifer A. Wargo, Emily Z. Keung. A single dose of perioperative cefazolin disrupts the gut microbiome and immunity in patients (pts) with early-stage melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2806.