Most Frequently Isolated Pathogens

Streptococci are traditionally the most common causative agent of infectious endocarditis, but the results of the ICE-PCS show that streptococci had fallen into second place to staphylococci as the leading cause.⁶ However, this apparent temporal shift from predominantly streptococcal to predominantly staphylococcal infective endocarditis may be partly due to recruitment/referral bias in specialized centers, since this trend is not evident in population-based epidemiologic surveys of infective endocarditis.¹⁴ Streptococcus species (mainly Streptococcus mitis, Streptococcus sanguis, Streptococcus mutans), which abound in the mouth and nasopharynx, are associated with dental procedures and diseases. Poor dental hygiene and minor or unrecognized periodontal disease may be the source of Streptococcus viridans infectious endocarditis. Streptococcus gallolyticus (previously S. bovis) may be involved in valve infection of dental or buccal origin. In addition, the association of S. gallolyticus with carcinoma or other lesions of the colon (e.g., diverticulitis, polyps) is well known. Beta-hemolytic streptococci (groups A, B, C, and G) and Streptococcus milleri are isolated from 6% of patients with infectious endocarditis,¹ with the predominant species being group B. The majority of nonpregnant patients with group B streptococcal infectious endocarditis have an underlying condition such as diabetes mellitus, breast cancer, decubitus ulcer, or cirrhosis.¹⁵

Enterococci, mainly Enterococcus faecalis and Enterococcus faecium, account for only 10% of cases of infectious endocarditis.⁶ These pathogens affect older patients, as demonstrated by a description of 93 episodes of enterococcal infectious endocarditis occurring in patients with a mean age of 74 years.¹⁶ The portals of entry are the gastrointestinal and urogenital tracts through a lesion or a procedure (e.g., injection sclerosis of esophageal varices, transurethral prostate resection, urethral dilatation) resulting in transient bacteremia, in which case the infection is healthcare associated.

Staphylococcus aureus is now implicated in approximately 30% of all cases of left-sided native valve infectious endocarditis,⁶ in 23% of PVE,⁹ and is the most common cause of healthcare-associated infections.¹⁵ S. aureus is also the causative agent in most acute infections, with about half of patients having no previously known heart disease. A clinically identifiable focus of infection (e.g., carbuncle, cellulitis, bursitis, ulcer, burn, osteomyelitis) may be present. However, in 50% to 60% of cases, no obvious portal of entry is detected, although the skin is probably the source in many of them. The relationship between S. aureus nasal carriage and infection has been established in specific subsets of patients, especially in IV drug users and patients with diabetes mellitus or on hemodialysis.¹² Methicillin-resistant strains are isolated in healthcare-associated endocarditis, although rare cases of community-acquired methicillin-resistant endocarditis have been reported.

Coagulase-negative staphylococci (CoNS), in a recent international study, were found to cause 16% of 537 cases of definite noninjecting drug use–associated PVE. Nearly 50% of patients with CoNS PVE presented between 60 days and 365 days of valve implantation. Methicillin resistance was present in 68% of CoNS strains.¹⁷ CoNS are also a well-documented, albeit rather rare, cause of native valve infectious endocarditis. Most patients have documented valvular abnormalities, especially mitral valve prolapse. A substantial subset of CoNS infective endocarditis has been identified as being due to Staphylococcus lugdunensis, which causes destructive cardiac lesions; its differentiation from other CoNS species in the laboratory may be difficult.

Overall, staphylococci, streptococci, and enterococci account for more than 80% of microorganisms responsible for infective endocarditis.

Infrequent Pathogens

Enterobacteriaceae and HACEK Group. Despite the high frequency of Enterobacteriaceae bacteremia leading to severe sepsis or septic shock, infectious endocarditis caused by these pathogens is extremely uncommon, probably because gram-negative bacilli adhere less avidly to the endothelium than gram-positive cocci do. Most cases of native valve infectious endocarditis develop in patients with severe comorbidities, including cirrhosis or immunosuppression.¹⁸ Gram-negative bacilli are usually encountered in early and late PVE, but they account only for 2% of the cases. Bacteria of the HACEK group (fastidious organisms) originate from the oropharyngeal or urogenital flora and include Haemophilus aphrophilus or paraphrophilus (H), Actinobacillus actinomycetemcomitans (A), Cardiobacterium hominis (C), Eikenella corrodens (E), and Kingella species (K). These HACEK pathogens are implicated in 2% of cases of infectious endocarditis on either native or prosthetic valves.⁶

Streptococcus pneumoniae infectious endocarditis occurs more commonly in alcoholics, but other patients, such as those with diabetes, malignancy, or chronic obstructive pulmonary disease, may be affected. Approximately 65% to 80% of patients have no known predisposing cardiopathy. The primary infection focus is the lungs, and meningitis is present in 40% to 60% of cases.¹⁹

Fungi are a rare cause of infective endocarditis, being isolated in 2% of cases but in 4% of those patients with prosthetic valve infection. Although injection drug use was traditionally an important risk factor, a recent study showed that patients with Candida infective endocarditis were more likely to have a prosthetic valve, short-term indwelling catheters, and healthcare-associated infections.²⁰ Other fungi such as Aspergillus spp. are even less frequently encountered. Fungi are frequently responsible for mural endocarditis.

Patients with Negative Blood Cultures

Five main points should be emphasized: (1) Abiotrophia spp. (previously classified as nutritionally variant streptococci) are the main cause of culture-negative infectious endocarditis in patients who have recently received antibiotics. (2) Only 5% to 7% of patients who have not recently taken antibiotics have negative blood cultures. Polymerase chain reaction (in blood, excised vegetation, or systemic emboli) can be used to identify the causative organism, such as Bartonella spp., Tropheryma whippelii, or Coxiella burnetii, but also streptococci or other pathogens not isolated from blood cultures.²¹ (3) Serologic tests are useful to diagnose infectious endocarditis caused by those organisms or by Brucella and Legionella species. (4) HACEK organisms may require prolonged incubation and subculturing. (5) Candida (but not Aspergillus) spp. are usually isolated from routine blood cultures, but in some cases, fungi are recovered only from excised vegetations or peripheral emboli.