Who Are the HACEK Organisms?

Feb. 11, 2019

The acronym “HACEK” is common in clinical microbiology, although its pronunciation may be somewhat controversial (hay-sek or hah-sek?). The acronym stands for Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, and Kingella: all HACEK members are fastidious Gram-negative bacteria associated with infective endocarditis.

HACEK Organisms are Associated with Infective Endocarditis

The HACEK group is not based on taxonomic relationships but on the organisms’ propensity to cause endocarditis. All HACEK organisms are commensals of the human oropharynx but how they travel to distal sites to cause disease is not fully established. One hypothesis is that they spread hematogenously following introduction into the blood during tooth brushing, dental cleanings, or subsequent to oral diseases such as periodontitis.
 
Most endocarditis is caused by Gram-positive bacteria (most commonly Staphylococcus or Streptococcus) with a minority caused by Gram-negatives or fungi. A recent multinational study attributed 1.4% of cases of endocarditis to HACEK organisms. Here, we will review the most common species isolated from the HACEK group.
 
Haemophilus parainfluenzae is one of the most common HACEK organisms associated with endocarditis. In contrast, H. influenzae, the otherwise best known and most commonly isolated member of the genus, is rarely associated with infective endocarditis.
 
H. parainfluenzae was originally described in 1922 by Thomas M. Rivers, who isolated it from influenza patients. He differentiated it from H. influenzae based on its requirement for NAD (V factor) but not hemin (X factor) in contrast to H. influenzae which requires both. Rivers initially hypothesized that it was a cause of influenza, although we now know that this disease is caused by the influenza virus.
 
His isolation of H. parainfluenzae from influenza patients was likely incidental as it is a commensal of the human oropharynx. It is not a cause of oral diseases such as dental caries or periodontitis and is preferentially isolated from dental plaque from healthy teeth. Outside the oral cavity, H. parainfluenzae is capable of causing a variety of infections such as otitis media, abscesses, and pneumonia, although it is an uncommon cause of these infections.
 
Aggregatibacter actinomycetemcomitans was originally isolated by R. Klinger in 1912 from an actinomycotic lesion and its species name means “occurring with actinomycetes”. Its original genus name, “Actinobacillus”, referred to the internal star shapes formed by colonies on solid media. In 2006, the genus was renamed Aggregatibacter, reflecting the propensity of organisms in this genus to grow as discrete clumps (aggregates) in broth culture.
 
Although best known for its role in infective endocarditis, A. actinomycetemcomitans is also an etiologic agent of periodontal disease. It is specifically associated with localized aggressive periodontitis (LAP), a form of periodontal disease that afflicts adolescents. This form of disease progresses from symptom onset to tooth loss in a matter of months as opposed to years as seen in adult periodontitis.
 
Colonization with virulent strains of A. actinomycetemcomitans is most common in individuals of African descent but relatively rare in most other ethnic groups. Among African-American adolescents, colonization rates can be up to 16.7% with a subset of carriers (up to 20%) progressing to LAP.

Figure 1. Aggregatibacter actinomycetemcomitans colonies develop a star-shaped structure after prolonged incubation.

Cardiobacterium hominis was first described in 1962 and was isolated from patients with endocarditis. Like other HACEK organisms, C. hominis is found in the oropharynx but rarely the gastrointestinal tract. It is infrequently isolated from oropharyngeal specimens however, potentially due to overgrowth by other commensals. Unlike the other members of the HACEK group, C. hominis is very rarely implicated in diseases other than endocarditis.
 
Eikenella corrodens is named in honor of M. Eiken, the microbiologist who first discovered the organism. The species name indicates that it pits (or corrodes) into the surface of solid agar media. This pitting is associated with the presence of pilins, which may be important for adhesion to host tissue. It is a member of the Neisseriaceae family but cannot be recovered on selective media for Neisseria spp. such as Thayer-Martin agar.
 
Among the HACEK organisms, Eikenella is a rarer cause of endocarditis but has the ability to cause disease at other sites. Along with A. actinomycetemcomitans, it is among the few organisms linked to periodontal disease. Additionally, E. corrodens is associated with infection following traumatic inoculation from the oral cavity and is found in up to 42% of abscesses from human bite wounds.
 
Figure 2. Eikenella corrodens exhibits a spreading colony morphology. The colonies themselves may pit or corrode into the agar.

Kingella kingae was discovered by and later named for Elizabeth King, a microbiologist who characterized many novel species while working at the Centers for Disease Control and Prevention. Like Eikenella, it is a member of the Neisseriaceae but unlike Eikenella, it can usually be recovered on Thayer-Martin agar.
 
In comparison to others in the HACEK group, K. kingae is infrequently isolated from endocarditis. However, it is a significant cause of osteomyelitis/septic arthritis in children aged 6 months-3 years. The organism may also be transmitted person to person by respiratory droplets and caused a 2004 outbreak of septic arthritis in children attending daycare. 

Clinical Identification of HACEK organisms

Previously, HACEK organisms were implicated in endocarditis from which no pathogen could be isolated (so called “culture-negative endocarditis”). This was attributed to slow growth in old formulations of blood culture bottles and resulted in recommendations for extended incubation (>5 days) when the presence of these organisms was suspected. However, modern blood culture instruments reliably detect HACEK organisms within a 5-day incubation period.
 
HACEK organisms can be isolated on routinely used non-selective media, often growing better on chocolate agar than on blood agar. They cannot be isolated from selective media designed for enterics such as MacConkey agar. Identification can be performed by automated systems but performance may be suboptimal. As with many other organisms, MALDI-TOF is emerging as a potential identification technology for the HACEK group.

Susceptibility Testing and Treatment of HACEK organisms

Clinical and Laboratory Standards Institute (CLSI) guidelines are available for HACEK organisms in the M45 (Aggregatibacter, Cardiobacterium, Eikenella, and Kingella) or M100 (Haemophilus) documents.  Despite standardized methods, susceptibility testing is difficult and these organisms fail to grow in broth-dilution panels 60% of the time.
 
However, susceptibility testing may not always be necessary since the major resistance mechanism in this group is expression of one or more beta lactamases, for which CLSI recommends routine testing using chromogenic substrates. Resistance to cephalosporins is rare and current Infectious Diseases Society of American (IDSA) guidelines on endocarditis suggest ceftriaxone for treatment.

Conclusion

The HACEK group comprises commensal organisms of the human oropharynx. Although most notable for causing infective endocarditis, they are significant causes of other diseases including periodontitis, abscesses, and septic arthritis.
 
Members of this group have been known for anywhere between 60-100 years but have historically been difficult to culture and identify. However, modern advances in blood culture instrumentation and MALDI-TOF mass spectrometry have facilitated growth and identification. Susceptibility testing is still challenging but rarely necessary due to near universal susceptibility to cephalosporins.
 

Author: Kenneth (K.P.) Smith

Kenneth (K.P.) Smith
Dr. Kenneth (K.P.) Smith is a postdoctoral fellow at Beth Israel Deaconess Medical Center. His research interest is in development of drugs and diagnostics for multidrug-resistant gram-negative bacteria.