Female Sex and Mortality in Patients With Gram-Negative Bacteremia: A Systematic Review and Meta-Analysis

TL;DR

This study finds that female patients with gram-negative bloodstream infections are not at higher risk of death compared to males, unlike in Staphylococcus aureus infections.

Contribution

The study is the first to systematically investigate sex-based mortality differences in gram-negative bloodstream infections.

Findings

Female patients with gram-negative bloodstream infection had no increased mortality risk compared to males.

No subgroups showed sex-specific mortality differences after adjusting for confounding factors.

Unadjusted analysis suggested a decreased mortality risk for females, but this was not consistent after adjustment.

Abstract

This systematic review and meta-analysis explores whether there is an association between biological sex and mortality among patients with gram-negative bloodstream infection.

Are female patients with gram-negative bloodstream infection at increased risk of death relative to male patients?

In this systematic review and meta-analysis that included 16 350 patients from 25 studies in the primary analysis, female sex was not associated with increased mortality. No patient subgroups with sex-specific differences in mortality were identified in the adjusted analyses.

Findings suggest that in contrast to female patients with Staphylococcus aureus bloodstream infection, those with gram-negative bloodstream infection are not at increased risk of death relative to male patients.

Female sex has been identified as a risk factor for mortality in Staphylococcus aureus bloodstream infection (SA-BSI). It is unknown whether this association extends to bloodstream infections with other bacterial species.

To investigate whether female sex is associated with increased mortality risk among patients with gram-negative bloodstream infection (GN-BSI).

MEDLINE, Embase, and Web of Science were searched from inception to January 8, 2025.

Study inclusion criteria were randomized or observational studies assessing adults with GN-BSI that included at least 100 patients and reported mortality at or before 90 days following GN-BSI, with mortality stratified by sex and, when applicable, by gram-negative bacterial species. Studies with polymicrobial GN-BSI were excluded. For inclusion in the primary analysis, studies must have stratified or statistically adjusted for confounding variables between female and male patients with GN-BSI. A secondary analysis included studies that reported sex-stratified unadjusted mortality.

One reviewer conducted extraction and quality assessment, which was verified by a second reviewer. Risk of bias and quality were assessed with the Newcastle-Ottawa Quality Assessment Scale. Mortality data were combined as odds ratios (ORs). The study followed the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline.

Mortality at or before 90 days following GN-BSI, stratified by sex.

From 9752 studies retrieved, 25 (16 350 patients; 4017 female [25%], 12 333 male [75%]) were included in the primary analysis. Female patients with GN-BSI did not have increased risk of mortality relative to male patients (pooled OR, 0.98 [95% CI, 0.81-1.17]). No publication bias was identified. Subset analyses based on medical comorbidities, timing of mortality end point, bacterial species group, antibiotic resistance phenotype, and publication date did not reveal a set of patients with differences in sex-stratified mortality. A total of 321 studies (147 810 patients) that reported unadjusted mortality were included in a secondary analysis. In this analysis, female sex was associated with decreased risk of mortality (pooled OR, 0.90 [95% CI, 0.86-0.94]).

In this systematic review and meta-analysis, female patients with GN-BSI were not at higher risk than male patients of mortality after statistical adjustment. GN-BSI and SA-BSI thus differ in sex-specific mortality outcomes, highlighting the need for further research into the immunological, pathophysiological, and clinical management factors that may be associated with sex disparities in SA-BSI but not in GN-BSI.

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