Epidemiology, Pathogenesis, Clinical Features, and Management of Non-HACEK Gram-Negative Infective Endocarditis

Background/Objectives: Non-HACEK Gram-Negative Infective Endocarditis (NHGNIE) is a rare but increasingly recognized condition associated with high morbidity and mortality. Its incidence is rising among people who inject drugs (PWID), patients with prosthetic valves or cardiac devices, and those with significant healthcare exposure. We aimed to provide a comprehensive review of the epidemiology, pathogenesis, diagnosis, clinical features, and management of NHGNIE. Methods: We conducted a narrative synthesis of published cohort studies, case series, guideline documents, and recent registry data addressing NHGNIE. Evidence was extracted and critically appraised with emphasis on epidemiological patterns, microbial etiology, diagnostic frameworks, therapeutic strategies, and outcomes. Special focus was given to pathogen-specific differences and the impact of antimicrobial resistance. Results: NHGNIE accounts for approximately 1.5–10.7% of IE cases worldwide, with marked geographical variability. Pseudomonas aeruginosa, Serratia marcescens, Klebsiella pneumoniae, and Escherichia coli are the predominant pathogens, with clinical profiles differing between younger, PWID-based populations and older, comorbidity-affected cohorts. Advances in molecular diagnostics and imaging have improved case identification, though pathogen-specific diagnostic performance remains limited. Outcomes are poor, with in-hospital mortality up to 41%. Antimicrobial therapy is complicated by biofilm formation and potential for multidrug resistance; evidence for combination therapy versus monotherapy is conflicting. Surgical intervention appears to improve outcomes when performed according to guideline-based indications, but results are heterogeneous across studies. Conclusions: NHGNIE is a clinically significant form of IE with complex epidemiology, diagnostic challenges, and limited evidence to guide treatment. Effective management requires individualized care coordinated within a multidisciplinary “endocarditis team”.