Antibiotic Timing and Survival After Immune Checkpoint Inhibitor Initiation in Patients With Cancer

Importance

While gut dysbiosis is known to impair response to immune checkpoint inhibitors (ICIs), the relative clinical impact of antibiotic timing (pre-vs. post-ICI initiation) remains unclear.

Objective

To evaluate whether antibiotic timing differentially influences overall survival (OS) in a large, multi-institutional pan-cancer cohort.

Design, Setting, and Participants

This retrospective cohort study utilized deidentified electronic health record data from six academic medical centers within the University of California Health system. We included 21,108 adults with any malignancy who received PD-1, PD-L1, or CTLA-4 inhibitors between January 2014 and December 2024.

Exposures

Antibiotic exposure windows were categorized as pre-only (−60 to −1 days), post-only (+1 to +60 days), both windows, or none.

Main Outcomes and Measures

The primary outcome was overall survival (OS) calculated from the first ICI dose. Multivariable Cox proportional hazards models adjusted for demographics, tumor type, line of therapy, and baseline health indicators (albumin, NLR, and recent hospitalization).

Results

Among 21,108 patients, 17.3% had pre-only exposure, 13.3% had post-only exposure, and 60.6% had no exposure. In the multivariable model, post-only exposure (HR, 1.27; 95% CI, 1.20–1.35) and combined pre- and post-exposure (HR, 1.31; 95% CI, 1.23–1.40) were significantly associated with higher mortality. Pre-only exposure was not significantly associated with OS (HR, 1.04; 95% CI, 0.99–1.10). Subgroup analyses by tumor type showed consistent trends across major malignancies, including head and neck (Post HR, 1.46) and renal cell carcinoma (Post HR, 1.26).

Conclusions and Relevance

In contrast to some smaller studies, this large-scale analysis indicates that antibiotic exposure after ICI initiation carries a greater risk than exposure prior to treatment. These findings highlight the need for rigorous antibiotic stewardship strategies specifically during the early phases of immunotherapy treatment.

Key Points

Question

Does the timing of antibiotic administration relative to immune checkpoint inhibitor (ICI) initiation differentially affect overall survival across a pan-cancer cohort?

Findings

In this retrospective cohort study of 21,108 patients, antibiotic exposure within 60 days after starting ICIs was associated with a 27% increased risk of death (HR, 1.27; 95% CI, 1.20-1.35). Conversely, exposure occurring only before ICI initiation showed no significant long-term survival association in adjusted models (HR, 1.04; 95% CI, 0.99-1.10).

Meaning

Clinical focus should shift toward antibiotic stewardship during the active phase of immunotherapy, as post-initiation exposure appears to be a more critical driver of poor outcomes than pre-treatment exposure.