Staphylococcus aureus is now the single most common bacterial cause of infective endocarditis in high-income countries, having overtaken streptococci over the past few decades. But the full roster of organisms that infect heart valves is surprisingly long, stretching from familiar bacteria like strep and enterococci to slow-growing mouth bacteria, zoonotic species carried by cats and livestock, and even fungi. Which organism is responsible in a given case shapes everything from how the infection behaves to how dangerous it is and how doctors treat it.
Staphylococcus Aureus and the Shift in Microbiology
For most of the twentieth century, streptococci were the leading cause of endocarditis. That changed as healthcare became more invasive. The rise of intravenous catheters, implanted cardiac devices, hemodialysis, and surgical prosthetic valves created new entry points for bacteria, and Staphylococcus aureus thrives in exactly those settings. Staphylococci have now overtaken streptococci as the most common cause of the disease globally, a shift driven largely by healthcare contact and invasive procedures.1The Lancet. Infective endocarditis The broader epidemiological picture also shows a growing predominance of enterococci alongside staphylococci, with marked geographic and socioeconomic variation in who gets sick.2PubMed Central. Changing Patterns in Infective Endocarditis: A Contemporary Epidemiological Perspective
S. aureus is aggressive. It can infect previously normal heart valves, unlike many other endocarditis pathogens that tend to target valves already damaged by rheumatic disease, congenital defects, or degenerative changes. One reason for this virulence is the bacterium’s surface proteins. After a valve is even mildly damaged, S. aureus sticks directly to proteins deposited on the injured surface, particularly von Willebrand factor and fibrin. It accomplishes this through surface adhesins like von Willebrand factor-binding protein and Clumping factor A.3PubMed Central. Staphylococcus aureus endocarditis: distinct mechanisms of bacterial adhesion to damaged and inflamed heart valves These sticky surface molecules let the bacterium latch on fast, multiply, and form the clumps of bacteria, immune cells, and clotting material known as vegetations.
Among people who inject drugs, S. aureus dominates even more strikingly. Injecting with non-sterile equipment pushes bacteria directly into the bloodstream, and the infection frequently lands on the tricuspid valve on the right side of the heart, the first valve that venous blood encounters on its way to the lungs.4PubMed Central. Acute endocarditis in intravenous drug users: a case report and literature review Right-sided endocarditis generally carries a better prognosis than left-sided disease, but it still causes serious complications including septic emboli to the lungs.
Coagulase-Negative Staphylococci and Prosthetic Valves
When someone has a prosthetic heart valve, the bacteria that cause endocarditis shift noticeably. Coagulase-negative staphylococci, especially Staphylococcus epidermidis, are common culprits in this setting. These are skin-dwelling bacteria that rarely cause trouble in people with normal anatomy, but they have a particular talent for sticking to artificial surfaces. S. epidermidis produces a capsular polysaccharide/adhesin that helps it colonize prosthetic material. In an animal model, a strain producing this adhesin was estimated to be roughly 42 times more likely to establish endocarditis at any given bacterial dose than a strain lacking it, and the adhesin-positive strain also survived far better in blood when attached to a catheter surface.5PubMed. The pathogenic role of Staphylococcus epidermidis capsular polysaccharide/adhesin in a low-inoculum rabbit model of prosthetic valve endocarditis
This is why prosthetic valve endocarditis within the first year after surgery is often caused by coagulase-negative staph picked up during the procedure or the hospital stay that follows. Later-onset prosthetic valve endocarditis tends to look more like native valve disease, with S. aureus and streptococci playing bigger roles. The distinction matters for treatment: coagulase-negative staph are frequently resistant to methicillin, so antibiotic choices differ from those used against S. aureus.
Streptococci and Their Oral and Gut Origins
Before the staphylococcal takeover, viridans group streptococci were the classic endocarditis bacteria, and they remain a major cause. These bacteria live normally in the mouth. Everyday activities like chewing, flossing, and brushing teeth produce brief episodes of bacteremia, releasing oral streptococci into the bloodstream. In most people this is harmless, but in someone with a vulnerable valve, even these transient episodes can seed an infection. Research from the Brandenburg Endocarditis Registry identified Streptococcus mitis, a typical oral commensal, as a main cause of endocarditis, with bacteremia occurring both during dental treatment and in patients with poor dental hygiene.6PubMed Central. Infectious Endocarditis Is Associated with Dental Treatment or Poor Dental Status—Results from the Brandenburg Endocarditis Registry (B.E.R.)
Streptococcal endocarditis tends to run a more subacute course than staphylococcal disease. Symptoms may build slowly over weeks: low-grade fevers, fatigue, weight loss, night sweats. Because the onset is gradual, diagnosis is sometimes delayed. The bacteria are generally more susceptible to penicillin than staphylococci, which makes treatment somewhat more straightforward when the organism is identified early.
The Streptococcus Gallolyticus and Colorectal Cancer Connection
One streptococcal species deserves its own discussion because of a striking clinical association. Streptococcus gallolyticus (formerly classified under S. bovis) lives in the gut, and when it shows up in the bloodstream or on a heart valve, clinicians take notice. Between a quarter and the vast majority of patients with S. bovis/gallolyticus bacteremia have been found to have coexisting colorectal tumors.7PubMed Central. The association of Streptococcus bovis/gallolyticus with colorectal tumors: the nature and the underlying mechanisms of its etiological role That range is wide because studies vary, but a systematic review and meta-analysis quantified the risk more precisely: patients with S. gallolyticus subspecies gallolyticus bacteremia were about 3.7 times more likely to have a diagnosis of colorectal neoplasia compared with controls.8Open Forum Infectious Diseases. Association of the Streptococcus bovis/Streptococcus equinus Complex With Colorectal Neoplasia: A Systematic Review and Meta-analysis
The implication is practical and important: if someone is diagnosed with S. gallolyticus endocarditis or bacteremia, current clinical practice calls for a colonoscopy to screen for underlying colorectal cancer or precancerous polyps, even if the patient has no gastrointestinal symptoms. The colorectal neoplasia can appear years after the initial bacteremia episode.7PubMed Central. The association of Streptococcus bovis/gallolyticus with colorectal tumors: the nature and the underlying mechanisms of its etiological role The bacterium is often associated with colon tumors in older adults specifically.9PubMed Central. Colorectal cancer-associated Streptococcus gallolyticus: a hidden diversity expose
Enterococcal Endocarditis
Enterococci, particularly Enterococcus faecalis, are the third most common group of bacteria causing endocarditis. They are normal inhabitants of the gastrointestinal and urinary tracts, and they tend to cause endocarditis in older adults, often following urinary or gastrointestinal procedures. In one review, the most commonly identified source of enterococcal bacteremia was urinary (about 20%), followed by catheter-related infections (about 19%), but in more than a third of cases the source remained unknown.10Clinical Infection in Practice. Enterococcus faecalis bacteraemia and infective endocarditis – what are we missing?
Enterococcal endocarditis can lead to serious complications. In one case report, E. faecalis endocarditis caused a large mobile vegetation on the mitral valve that threw off a septic embolus, triggering acute coronary syndrome. Investigation eventually revealed a bowel perforation as the bacterial source.11PubMed Central. Enterococcus faecalis-induced infective endocarditis: an unusual source of infection and a rare clinical presentation This case illustrates a theme with enterococci: because the GI tract is their home turf, clinicians evaluating enterococcal endocarditis often look for an underlying gastrointestinal lesion, including occult malignancy, much like they do with S. gallolyticus.
Treating enterococcal endocarditis is notoriously difficult. Enterococci are intrinsically resistant to several antibiotics, and acquired resistance, including vancomycin resistance in some strains, makes things harder. Treatment typically requires prolonged courses of combination antibiotics.
HACEK Organisms
HACEK is an acronym for five groups of gram-negative bacteria: Haemophilus species, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae. All of them live normally in the mouth and upper respiratory tract.12PubMed Central. Infective endocarditis by HACEK: a review They are uncommon causes of endocarditis, accounting for roughly 1 to 3% of cases, but they punch above their weight in clinical importance because they grow slowly in standard blood culture bottles and can be missed if the lab does not hold cultures long enough.13PubMed. Infective endocarditis caused by HACEK microorganisms
Among the HACEK group, Aggregatibacter species are the most frequently isolated.14PubMed. HACEK infective endocarditis: Epidemiology, clinical features, and outcome: A case-control study HACEK endocarditis tends to present subacutely, with symptoms building over weeks to months. Vegetations can grow large before diagnosis, increasing the risk of embolic events. The good news is that these organisms are generally susceptible to common antibiotics like cephalosporins, and outcomes are often better than for staphylococcal disease when diagnosed and treated appropriately.
Culture-Negative Endocarditis and Hard-to-Grow Pathogens
In a meaningful fraction of endocarditis cases, standard blood cultures come back negative. Sometimes this is because the patient received antibiotics before blood was drawn, suppressing bacterial growth in the lab. But often the culprit is a fastidious organism that simply does not grow well under standard culture conditions. Two of the most important are Bartonella species and Coxiella burnetii, the agent that causes Q fever.15PubMed Central. Detection of fastidious bacteria in cardiac valves in cases of blood culture negative endocarditis
A study from Brazil evaluating community-acquired culture-negative endocarditis found Bartonella species in about 20% of cases and Coxiella burnetii in about 8%, reinforcing that these organisms should be actively looked for rather than assumed absent just because cultures are sterile.16Emerging Infectious Diseases. Bartonella spp. and Coxiella burnetii Associated with Community-Acquired, Culture-Negative Endocarditis, Brazil Bartonella henselae, the species behind cat-scratch disease, is particularly relevant for cat owners. In a series from Algeria, Bartonella quintana, transmitted by body lice, was the dominant zoonotic endocarditis pathogen, accounting for 14 of 18 zoonotic endocarditis cases. Brucella and Coxiella burnetii made up the rest.
Diagnosing these infections requires tools beyond the standard blood culture. Serological testing, PCR on blood or excised valve tissue, and newer molecular methods are essential. The 2023 update to the Duke diagnostic criteria for endocarditis formally incorporated several of these approaches, including enzyme immunoassays for Bartonella, PCR, and metagenomic sequencing, recognizing that blood culture alone misses too many cases.17PubMed Central. The 2023 Duke-International Society for Cardiovascular Infectious Diseases Criteria for Infective Endocarditis: Updating the Modified Duke Criteria
Fungal Endocarditis
Fungi are not bacteria, but they deserve mention because fungal endocarditis is among the most dangerous forms of the disease. It accounts for roughly 1 to 3% of all infective endocarditis and carries a mortality rate above 70%.18PubMed Central. Fungal Endocarditis: Pathophysiology, Epidemiology, Clinical Presentation, Diagnosis, and Management Candida species are responsible for over half of fungal endocarditis cases, followed by Aspergillus and Histoplasma. Risk factors include prosthetic heart valves, prior cardiac surgery, and injection drug use.
Aspergillus endocarditis is especially tricky to diagnose. The fungus has a low tendency to grow in standard blood cultures, so cultures may remain negative even when the infection is raging. Aspergillus also tends to form large vegetations and sometimes infects the walls of the heart rather than the valves themselves, meaning it can be missed on echocardiography if clinicians are only looking at the valves.19PubMed Central. Aspergillus endocarditis Diagnosis is often delayed, and most cases ultimately require surgical intervention in addition to antifungal therapy.
Biofilms and Why Endocarditis Is Hard to Cure
Regardless of which organism is involved, one of the reasons endocarditis requires such long antibiotic courses (typically four to six weeks of intravenous therapy) is that the bacteria do not just float freely in the bloodstream. They embed themselves in vegetations on the valve surface, forming structures that resemble biofilms. Inside these formations, bacteria exist in different states of activity, with some cells metabolically dormant and therefore much less susceptible to antibiotics. Even after appropriate antibiotic therapy, intact microbial aggregates can be found in surgically removed infected heart valves, which helps explain why persistent or recurrent infections occur.20PubMed Central. Anti-biofilm Approach in Infective Endocarditis Exposes New Treatment Strategies for Improved Outcome
This biofilm-like behavior is part of what makes prosthetic valve endocarditis particularly stubborn. Bacteria adhering to artificial materials form even more organized biofilms than on native tissue, and the artificial surface itself is not vascularized, so antibiotics delivered through the bloodstream have trouble penetrating. Surgery to remove the infected prosthesis is frequently necessary when antibiotics alone cannot sterilize the valve.
Antibiotic Prophylaxis Before Dental Work
Because oral streptococci are a well-established cause of endocarditis, and because dental procedures can push these bacteria into the blood, the question of who should take preventive antibiotics before dental work has been debated for decades. Guidelines have narrowed considerably over the years. Where prophylaxis was once recommended for a wide range of cardiac conditions, current guidelines focus it on the highest-risk patients: those with prosthetic heart valves, a history of previous endocarditis, certain congenital heart defects, and cardiac transplant recipients with valve problems.21PubMed Central. Antibiotic Prophylaxis Prior to Dental Procedures
Whether prophylaxis actually works has been hard to prove in randomized trials, but observational data supports the practice in high-risk people. A large study found a significant association between antibiotic prophylaxis use and reduced endocarditis incidence following invasive dental procedures in individuals already at high risk of the disease, supporting American Heart Association recommendations.22PubMed. Antibiotic Prophylaxis Against Infective Endocarditis Before Invasive Dental Procedures For people not in a high-risk category, daily oral hygiene likely matters more than a single antibiotic dose before a dental visit, since bacteremia from routine activities like brushing and chewing happens far more often than from procedures.
Molecular Diagnostics Are Changing the Picture
For culture-negative cases, the diagnostic landscape is shifting rapidly. Metagenomic next-generation sequencing, which reads all the DNA in a sample rather than looking for specific organisms, can identify pathogens that nobody thought to test for. This technology excels at finding Bartonella, Coxiella, and Tropheryma whipplei (the agent behind Whipple disease), all of which are difficult or impossible to grow in standard cultures.23PubMed Central. Unveiling the Future of Infective Endocarditis Diagnosis: The Transformative Role of Metagenomic Next-Generation Sequencing in Culture-Negative Cases In one case, sequencing revealed a mixed infection of Enterococcus faecalis and Granulicatella adiacens in a patient with culture-negative endocarditis following cardiac device implantation, fundamentally changing the treatment approach.
Newer long-read sequencing methods can go even further. In a recent study, nanopore-based long-read sequencing identified the causative organisms in culture-negative endocarditis cases within an hour of starting the sequencing run, and within 18 hours it had reconstructed a complete bacterial genome, providing information about antibiotic resistance genes that would have been impossible to obtain from culture.24PubMed Central. Clinical long-read metagenomic sequencing of culture-negative infective endocarditis reveals genomic features and antimicrobial resistance These are still specialized tools, not yet routine in most hospitals. But they hint at a future where “culture-negative endocarditis” becomes a much rarer diagnostic dead-end.
Microbial cell-free DNA testing on blood samples is another emerging approach, one that can detect pathogen DNA even after a patient has received antibiotics.25PubMed Central. Microbial Cell-Free DNA Identifies the Causative Pathogen in Infective Endocarditis and Remains Detectable Longer Than Conventional Blood Culture in Patients with Prior Antibiotic Therapy This matters because in practice, many patients have already been started on antibiotics by the time endocarditis is seriously suspected, sterilizing the blood cultures and making traditional identification impossible. The broader pattern across all these molecular methods is the same: they catch organisms that standard lab techniques miss, and they work when antibiotics have already muddied the waters.
When the Source of Bacteria Points Somewhere Unexpected
One of the clinically underappreciated aspects of endocarditis is that identifying the causative organism often points doctors toward a source they were not expecting. S. gallolyticus triggers a colonoscopy search for colorectal cancer. Bartonella prompts questions about cat exposure or lice. Enterococcal bacteremia raises concern about occult bowel lesions or urinary tract pathology. Even finding S. aureus in someone with no obvious risk factors may lead to the discovery of an unrecognized abscess or infected intravenous site.
The relationship works in the other direction, too. Clinicians evaluating a patient with known risk factors can sometimes predict the likely organism before cultures return. A person who injects drugs with right-sided valve involvement will most often grow S. aureus. Someone with a recently placed prosthetic valve and early-onset infection will more likely have coagulase-negative staph. A patient with poor dentition and a gradual onset of symptoms points toward viridans streptococci. These clinical clues are not definitive, but they shape initial antibiotic choices while waiting for lab confirmation, and in endocarditis, where delays in effective therapy increase the risk of valve destruction and embolic events, that head start matters.