Pathogenesis of Gram-Negative Bacteremia

Abstract

Gram-negative bacteremia is a devastating public health threat, with high mortality in vulnerable populations and significant costs to the global economy. Concerningly, rates of both Gram-negative bacteremia and antimicrobial resistance in the causative species are increasing. Gram-negative bacteremia develops in three phases. First, bacteria invade or colonize initial sites of infection. Second, bacteria overcome host barriers, such as immune responses, and disseminate from initial body sites to the bloodstream. Third, bacteria adapt to survive in the blood and blood-filtering organs. To develop new therapies, it is critical to define species-specific and multispecies fitness factors required for bacteremia in model systems that are relevant to human infection. A small subset of species is responsible for the majority of Gram-negative bacteremia cases, including Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii The few bacteremia fitness factors identified in these prominent Gram-negative species demonstrate shared and unique pathogenic mechanisms at each phase of bacteremia progression. Capsule production, adhesins, and metabolic flexibility are common mediators, whereas only some species utilize toxins. This review provides an overview of Gram-negative bacteremia, compares animal models for bacteremia, and discusses prevalent Gram-negative bacteremia species.

Keywords: Acinetobacter; Escherichia coli; Gram-negative bacteria; Klebsiella; Pseudomonas aeruginosa; bacteremia; bloodstream infections; pathogenesis; sepsis.

FIG 1

Gram-negative species are adapted to colonize or infect diverse initial sites, which may progress to secondary bacteremia.

FIG 2

Gram-negative bacteremia pathogenesis broadly involves three phases. (Step 1) Invasion. Bacteria must invade initial sites of colonization or infection and evade host immune responses using mechanisms such as capsule production (K. pneumoniae) and secretion of exotoxins (P. aeruginosa). Initial-site specificity varies by species, with certain bacteria being adapted for invasion at specific sites. (Step 2) Dissemination. After invasion, bacteria penetrate host epithelial barriers to access the blood. Dissemination requires factors such as adhesins and exotoxins (P. aeruginosa) or activation of specific pathways in epithelial cells (HIF-1α for K. pneumoniae). (Step 3) Survival. Once in the blood, species must survive a new environment through metabolic flexibility (C. freundii and S. marcescens) and evade immune clearance with capsule production. Each bacteremia phase must be investigated to better comprehend pathogenesis at both species-specific and multispecies levels.