Epidemiology, Pathogenesis, Clinical Features, and Management of Non-HACEK Gram-Negative Infective Endocarditis
Abstract
1. Introduction
2. Epidemiology and Etiology
3. Pathogenesis
3.1. Adhesion and Biofilm Formation in Gram-Negative Bacteria
3.2. Pseudomonas aeruginosa
3.3. Serratia marcescens
3.4. Klebsiella pneumoniae
3.5. Escherichia coli
Pathogen | Entry and Source | Adhesion and Colonization | Biofilm Features | Other Pathogenesis Notes |
---|---|---|---|---|
Pseudomonas aeruginosa | Healthcare-associated infections Device-related infections | Type IV pili, flagella, adhesins Alginate enhances binding | Complex (flat or tower/mushroom) Alginate and rhamnolipids matrix QS-regulated (las, rhl systems) Architecture influenced by environmental factors | Toxins (exotoxin A, elastases, alkaline protease, hemolytic phospholipase C) Dispersal triggered by environment |
Serratia marcescens | Injection drug use Healthcare-associated infections Device-related infections | Type I fimbriae (fimA, fimC) Extracellular polymeric substances aids device adhesion | Porous, filamentous QS-regulated Serrawettin-enhanced development Nutrient-dependent | QS controls proteases, lipases, hemolysins, prodigiosin and motility Injection equipment colonization in IDU |
Klebsiella pneumoniae | Healthcare-associated infections | Type I/III fimbriae Capsular polysaccharides Adhesins | High prevalence of biofilm producers QS for intra- and interspecies communication | Multidrug resistance enzymes (ESBL, carbapenemases) Toxin production (hemolysins, cytotoxins) Antibiotic recalcitrance |
Escherichia coli | Urinary tract infections | Poor cardiac endothelium adhesion Type I fimbriae ExPEC adherence proteins | High biofilm production in uropathogenic strains Increased in serum-resistant and MDR | ExPEC (especially B2 strains): siderophores, toxins Immune evasion |
4. Diagnosis
4.1. Evolution of Diagnostic Criteria for Infective Endocarditis
4.2. Advances in Microbiological and Molecular Diagnostics
4.2.1. Expanded List of Typical Pathogens
4.2.2. Diagnostic Criteria and Imaging Updates
4.2.3. New Molecular Techniques
4.3. Comparative Performance of Diagnostic Criteria: Sensitivity and Specificity
4.4. Focus on NHGNIE in Recent Studies
5. Clinical Features and Outcomes
5.1. Fever
5.2. Valvular Vegetations and Intra-Cardiac Abscesses
5.3. Heart Failure
5.4. Embolic Events
5.5. Septic Shock
5.6. Relapses and Recurrences
5.7. Mortality
5.8. Pathogen-Specific Profiles in NHGNIE
5.8.1. Pseudomonas spp.
5.8.2. Serratia spp.
5.8.3. Other Enterobacterales
6. Management
6.1. Antimicrobial Treatment
6.2. Surgical Treatment
7. Future Directions and Unmet Needs
7.1. Improved Epidemiological Understanding
7.2. Diagnostic Advances
7.3. Antimicrobial Strategies and Surgical Managment
- What should be considered as the first-line treatment of choice?
- Is there a role for combination therapy (especially in selected populations, e.g., patients with PVE or P. infections)?
- What is the most appropriate treatment duration?
- Is there a role for transition to oral therapy?
- Should patients with PVE not undergoing surgery receive suppressive antimicrobial treatment?
7.4. Translational Science and Novel Therapeutic Adjuncts
8. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
NHGNIE | Non-HACEK Gram-Negative Infective Endocarditis |
IE | Infective Endocarditis |
PWID | people who inject drugs |
PVE | prosthetic valve endocarditis |
MDR | multidrug-resistant |
EPS | extracellular polymeric substances |
QS | quorum sensing |
ExPEC | Extraintestinal Pathogenic Escherichia coli |
UTI(s) | urinary tract infection(s) |
ESC | European Society of Cardiology |
ISCVID | International Society for Cardiovascular Infectious Diseases |
CIED | cardiovascular implantable electronic device |
PET/CT | positron emission tomography/computed tomography |
18F-FDG | Fluorine-18 Fluorodeoxyglucose (radiotracer used in PET scans) |
WBC SPECT/CT | white blood cell single-photon emission-computed tomography/computed tomography |
CT | computed tomography |
BCNIE | blood-culture-negative infective endocarditis |
PCR | polymerase chain reaction |
ESBL(s) | extended-spectrum beta-lactamase(s) |
NVE | native valve endocarditis |
CNS | central nervous system |
MRSA | methicillin-resistant Staphylococcus aureus |
VRE | vancomycin-resistant Enterococcus |
AHA | American Heart Association |
BL | beta-lactams |
AG | aminoglycosides |
FQ | fluoroquinolones |
p-value | p |
aOR | Adjusted Odds Ratio |
CI | Confidence Interval |
IDU | injection drug use |
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Study | Year | Country, Setting | Cases | Median Age | Median Charlson | Previous IE | Nosocomial or Healthcare-Associated Acquisition | PWID | Source of Infection | Right-Sided IE | PVE |
---|---|---|---|---|---|---|---|---|---|---|---|
International | |||||||||||
Morpeth et al. 2007 [1] | 2000–2005 | International, multicenter | 49/2761 (1.8%) | 63 | 8% | Nosocomial 39% Healthcare-associated 17% | 4% | Genitourinary 22% Gastrointestinal 13% Skin 9% | 12% | 59% | |
North America | |||||||||||
Shah et al. 2023 [2] | 2010–2021 | USA, multicenter | 123 | 49 | 1 | 23% | 52% | 23% | 17% | ||
Lorenz et al. 2021 [3] | 2011–2019 | USA, monocenter | 60/1036 (5.8%) | 50 | 3 | 40% | IVDU-related 35% Gastrointestinal 18% Genitourinary 17% CVC 5% | 25% | |||
Veve et al. 2020 [4] | 2011–2019 | USA, monocenter | 43 | 40 | 67% | Healthcare-associated 49% | 93% | 63% | 30% | ||
South America | |||||||||||
de Sousa et al. 2023 [5] | 2006–2019 | Brazil, multicenter | 38/1154 (3.3%) | 57 | 8% | Nosocomial 53% Healthcare-associated 26% | 0% | CVC 29% Genitourinary 5% Gastrointestinal 5% | 11% | 47% | |
Burgos et al. 2019 [6] | 1998–2016 | Argentina, monocenter | 31/452 (6.9%) | 72 | Healthcare-associated 70% | 0% | 46% | ||||
Europe | |||||||||||
Dorfler et al. 2025 [7] | 2015–2021 | Germany, monocenter | 19/1093 (1.7%) | 69 | 4 | 15% | Nosocomial 42% | 0% | Genitourinary 50% CVC 31% Gastrointestinal 25% | 0% | 37% |
Al Janabi et al. 2025 [8] | 2008–2023 | Sweden, multicenter | 114/7426 (1.5%) | 69 | 16% | Nosocomial 9% Healthcare-associated 5% | 20% | 9% | 21% | ||
Sebillotte et al. 2023 [9] | 2007–2020 | France, multicenter | 77/3230 (2.4%) | 69 | 2 | 8% | Healthcare-associated 36% | 8% | Genitourinary 33% Gastrointestinal 17% Skin 13% | 8% | 23% |
Loubet et al. 2015 [10] | 2009–2014 | France, monocenter | 12 (4%) | 51 | 33% | Healthcare-associated 33% | 17% | Genitourinary 25% Gastrointestinal 25% | 33% | 67% | |
Calderón-Parra et al. 2021 [11] | 2008–2018 | Spain, multicenter | 104/3910 (2.6%) | 71 | 5 | Nosocomial 48% Healthcare-associated 5% | 4% | Venous catheter 26% Genitourinary 22% Gastrointestinal 6% | 12% | 33% | |
Noureddine et al. 2011 [12] | 1984–2008 | Spain, multicenter | 24/961 (2.5%) | 63 | 4 | Nosocomial 29% | 0% | 4% | 17% | ||
Ertugrul Mercan et al. 2019 [13] | 2007–2016 | Turkey, multicenter | 26 | 53 | 4% | 0% | 19% | 19% | |||
Falcone et al. 2018 [14] | 2004–2011 | Italy, multicenter | 58/1722 (3.4%) | 70 | Healthcare-associated 41% Nosocomial 3% | 9% | Genitourinary 28% Skin 14% Gastrointestinal 16% | 28% | |||
Asia | |||||||||||
Arora et al. 2021 [15] | 2010–2020 | India, monocenter | 11/199 (5.5%) | 55% | 45% | 18% | |||||
Thomas et al. 2020 [16] | 2006–2016 | India, monocenter | 27/256 (10.7%) | 49 | 35% | ||||||
Tran et al. 2017 [17] | 2005–2014 | Vietnam, monocenter | 6/189 (3.2%) | 17% | 33% |
Study | Fever | Complications | Vegetations | Heart Failure | Cardiac Abscesses | Embolic Events | Septic Shock | Recurrence/Relapse | Mortality |
---|---|---|---|---|---|---|---|---|---|
Dorfler et al. 2025 [7] | 74% | 32% | 32% | 11% | In hospital 21% 1 year 44% | ||||
Al Janabi et al. 2025 [8] | 31% | In hospital 17% | |||||||
Shah et al. 2023 [2] | 61% | >10 mm 60% | 34% | 66% | 9 months 15% | In hospital 14% 90 days 20% | |||
de Sousa et al. 2023 [5] | 58% | Median size 11 mm | 47% | 3% | 55% | 50% | |||
Sebillotte et al. 2023 [9] | 88% | 16% | 5% | 31% | 20% | 5% | 1 year 36% | ||
Arora et al. 2021 [15] | In hospital 36% | ||||||||
Calderón-Parra et al. 2021 [11] | 76% | 69% | 33% | 17% | 20% | 21% | 1% | In hospital 37% 1 year 42% | |
Lorenz et al. 2021 [3] | 72% >10 mm 38% | 42% | In hospital 6% 60 days 20% | ||||||
Thomas et al. 2020 [16] | 100% | 51% | In hospital 30% | ||||||
Veve et al. 2020 [4] | 65% | 40% | In hospital 5% 1 year 30% | ||||||
Burgos et al. 2019 [6] | 84% | 21% | 19% | 3% | 10% | In hospital 21% | |||
Ertugrul Mercan et al. 2019 [13] | 77% | 88% Median size 11 mm | 38% | 23% | In hospital 23% | ||||
Falcone et al. 2018 [14] | 86% Median size 14 mm | 26% | 5% | 24% | 3% | In hospital 14% 1 year 31% | |||
Loubet et al. 2015 [10] | 92% | 58% | 92% | 8% | 42% | 58% | 8% | In hospital 0% 1 year 8% | |
Noureddine et al. 2011 [12] | 91% | 92% | 46% | 50% | 20% | 0% | In hospital 41% | ||
Morpeth et al. 2007 [1] | 92% | 80% | 37% | 25% | 33% | In hospital 24% |
European Society of Cardiology Guidelines [79] | American Heart Association Guidelines [99] | |
---|---|---|
Antibiotic therapy | β-lactams in combination with aminoglycoside, sometimes with additional fluoroquinolones or cotrimoxazole. | Combination antibiotic therapy with β-lactams and either aminoglycosides or fluoroquinolones. |
Duration of antibiotic therapy | 6 weeks | 6 weeks |
Surgical therapy | Always recommended, as early as possible. | Cardiac surgery is reasonable for most patients, particularly when left-side valves are involved. |
Other recommendations | Consultation with endocarditis team when available. In vitro bactericidal tests and monitoring of serum antibiotic concentrations. | Consultation with infectious diseases specialist is recommended. In vitro susceptibility testing. |
Study | Number of Patients | Pathogen | Combination Therapy | Therapy | Outcomes of Combination vs. Monotherapy |
---|---|---|---|---|---|
Shah et al. 2023 [2] | 123 | Serratia marcescens 41% Pseudomonas aeruginosa 21% Escherichia coli 10% Klebsiella pneumoniae 9% | 43% | BL + AG 45% BL + FQ 42% Other 13% | No overall benefit of combination therapy Serratia and Enterobacterales: Clinical failure 10% vs. 26% (p = 0.09) 90-day mortality 15% vs. 41% (p = 0.037) Pseudomonas aeruginosa: Clinical failure 37% vs. 0% (p = 0.134) 90-day mortality 21% vs. 0% |
Calderon-Parra et al. 2021 [11] | 104 | Escherichia coli 38% Pseudomonas aeruginosa 30% Serratia spp. 8% Klebsiella spp. 7% | 79% | BL + AG 45% BL + FQ 30% Other 25% | In-hospital mortality (BL + FQ) aOR 0.29, CI 0.09–0.96 |
Lorenz et al. 2021 [3] | 60 | Pseudomonas aeruginosa 37% Escherichia coli 17% Serratia spp. 12% Klebsiella pneumoniae 10% | 43% | BL + AG 38% BL + FQ 58% Other 4% | Composite outcome (60-day mortality/readmission/recurrence) aOR 0.45 (CI 0.13–1.6) Bacteremia recurrence 19% vs. 9% (p = 0.28) Readmission 31% vs. 41% (p = 0.36) Mortality 19% vs. 21% (p = 0.9) Adverse events 19% vs. 0% (p = 0.012) |
Veve et al. 2020 [4] | 43 | Pseudomonas aeruginosa 68% Serratia marcescens 20% Klebsiella spp. 2% | 76% | BL + AG 50% BL + FQ 34% Other 16% | No overall benefit of combination therapy BL + FQ: 90-day mortality/readmission aOR 6.7 (CI 1.4–30.4) 12-month readmission aOR 33.9 (CI 2.7–429.9) |
Falcone et al. 2018 [14] | 58 | Escherichia coli 31% Pseudomonas aeruginosa 19% Klebsiella pneumoniae 10% Serratia marcescens 4% | 86% | Non-carbapenem BL + AG 28% Non-carbapenem BL + FQ 16% Carbapenem + AG or FQ 8% Non-carbapenem BL + carbapenems ± AG or FQ 14% | Higher survival with penicillin/cephalosporin-based vs. carbapenem-based regimens (univariate analysis) |
Morpeth et al. 2007 [1] | 49 | Escherichia coli 29% Pseudomonas aeruginosa 22% Klebsiella spp. 10% Serratia spp. 8% | 63% | BL + AG 57% BL + FQ 30% BL + AG and FQ 7% Other 6% | In-hospital mortality 27% vs. 22% (p = 0.73) |
Meena et al. 2024 [93] | 218 (systematic review) | Pseudomonas aeruginosa | 77% | Penicillin/cephalosporins + AG 54% Carbapenem + AG 13% FQ-based combination 15% Polymyxin-based combination 11% Other 7% | Mortality OR 0.64 (CI 0.34–1.20) |
Shah et al. 2024 [91] | 48 | Pseudomonas aeruginosa | 69% | BL + AG 61% BL + FQ 33% Other 6% | No benefit in response rate or survival Adverse events leading to discontinuation 21% vs. 0% (p = 0.08) |
Walczak et al. 2023 [92] | 15 | Pseudomonas aeruginosa | 60% | BL + AG 67% BL + FQ 33% | 1-year mortality 36% vs. 75% (p = 0.282) |
McCrary et al. 2025 [95] | 159 | Serratia spp. | 43% | BL + AG 43% BL + FQ 54% Other 1% | In-hospital mortality aOR 0.15 (CI 0.03–0.74) |
Shah et al. 2023 [96] | 75 | Serratia spp. | 48% | BL + AG 33% BL + FQ 56% Other 11% | Clinical failure aOR 0.17 (CI 0.03–0.86) Microbiological failure 0% vs. 15% (p = 0.026) 90-day all-cause mortality 11% vs. 31% (p = 0.049) Adverse events leading to discontinuation 36% vs. 8% (p = 0.058) |
Study | Number of Patients | Indication for Surgery | Surgery | Outcomes of Surgery vs. No Surgery |
---|---|---|---|---|
Dorfler et al. 2025 [7] | 19 | 10 (53%) | 8 (42%) | In-hospital mortality 25% vs. 18% (p = 1.0) 1-year mortality 25% vs. 45% (p = 0.633) |
Shah et al. 2023 [2] | 123 | 84 (68%) | 49 (40%) | No surgery despite indication: Clinical failure aOR 7.44 (CI 2.37–23.4) 90-day mortality aOR 14.6 (CI 4.62–45.9) |
De Sousa et al. 2023 [5] | 38 | 8 (21%) | Mortality 42% vs. 58% (not significant) | |
Sebillotte et al. 2023 [9] | 77 | 12 (16%) | No difference in 1-year mortality (p = 0.29) | |
Calderón Parra et al. 2021 [11] | 104 | 64 (62%) | 47 (45%) | No surgery despite indication: In-hospital mortality aOR 3.60 (CI 1.17–11.05) |
Veve et al. 2020 [4] | 43 | 10 (23%) | No difference in 90-day or 1-year mortality (p = 0.29) | |
Burgos et al. 2019 [6] | 24 | 9 (38%) | No difference in in-hospital mortality | |
Ertugrul Mercan et al. 2019 [13] | 26 | 10 (38%) | In-hospital mortality 20% vs. 25% (not significant) | |
Falcone et al. 2018 [14] | 58 | 25 (43%) | Patients with complications (cardiac abscess, fistula, dehiscence, valve perforation, heart failure): mortality 18% vs. 60% (p = 0.049) | |
Morpeth et al. 2007 [1] | 49 | 25 (51%) | In-hospital mortality 24% vs. 25% (p = 0.94) | |
McCrary et al. 2025 [95] | 159 (Serratia spp.) | 57 (36%) | Mortality aOR 0.14 (CI 0.03–0.64) | |
Shah et al. 2023 [96] | 75 (Serratia spp.) | 58 (77%) | 34 (45%) | No surgery despite indication: Clinical failure aOR 3.84 (CI 4.5–105) |
Shah et al. 2024 [91] | 48 (Pseudomonas spp.) | 30 (63%) | 17 (35%) | No difference in clinical failure |
Meena et al. 2024 [93] | 218 (Pseudomonas spp, systematic review) | 125 (57%) | Mortality aOR 0.41 (CI 0.20–0.82) |
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Monardo, R.; Papaioannu Borjesson, R.; Ponta, G.; Castagna, A.; Ripa, M. Epidemiology, Pathogenesis, Clinical Features, and Management of Non-HACEK Gram-Negative Infective Endocarditis. Antibiotics 2025, 14, 980. https://doi.org/10.3390/antibiotics14100980
Monardo R, Papaioannu Borjesson R, Ponta G, Castagna A, Ripa M. Epidemiology, Pathogenesis, Clinical Features, and Management of Non-HACEK Gram-Negative Infective Endocarditis. Antibiotics. 2025; 14(10):980. https://doi.org/10.3390/antibiotics14100980
Chicago/Turabian StyleMonardo, Roberta, Rebecka Papaioannu Borjesson, Giacomo Ponta, Antonella Castagna, and Marco Ripa. 2025. "Epidemiology, Pathogenesis, Clinical Features, and Management of Non-HACEK Gram-Negative Infective Endocarditis" Antibiotics 14, no. 10: 980. https://doi.org/10.3390/antibiotics14100980
APA StyleMonardo, R., Papaioannu Borjesson, R., Ponta, G., Castagna, A., & Ripa, M. (2025). Epidemiology, Pathogenesis, Clinical Features, and Management of Non-HACEK Gram-Negative Infective Endocarditis. Antibiotics, 14(10), 980. https://doi.org/10.3390/antibiotics14100980