Excerpt from HACEK Group Infections

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Background

The acronym HACEK refers to a grouping of gram-negative bacilli; Haemophilus species (H parainfluenzae, H aphrophilus, and H paraphrophilus), Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella species. These organisms share an enhanced capacity to produce endocardial infections. They are responsible for 5-10% of cases of infective endocarditis (IE) involving native valves and are the most common cause of gram-negative endocarditis among persons who do not abuse intravenous drugs. All are part of the normal oropharyngeal flora, are slow growers, and prefer a carbon dioxide–enriched atmosphere. Because of their fastidious growth requirements, they have been a frequent cause of culture-negative endocarditis.

In addition to valvular infections, they also produce other infections such as bacteremias, various types of abscesses, peritonitis, otitis media, conjunctivitis, pneumonia, septic arthritis, osteomyelitis, peritonitis, urinary tract infections, wound infections, brain abscess, and periodontal infections. Because of its significance and challenging nature, both diagnostic and therapeutic, this review focuses on IE due to the HACEK group.

Pathophysiology

When introduced into healthy tissue, the HACEK group organisms have the potential for abscess formation and invasive disease. In addition, many examples produce luxuriant vegetations on infected cardiac valves that are complicated by macroemboli. These vegetations are due to the intrinsic properties of the organisms themselves, the significant delay in diagnosis, or to a combination of these 2 factors. Sixty percent of cases of HACEK IE are associated with various types of dental pathology.

Haemophilus species are pleomorphic gram-negative coccobacilli that require X (hemin) and/or V (nicotinamide adenine dinucleotide) factors for isolation. These substances are found naturally in red blood cells. They are responsible for 0.5-1% of all cases of IE. Of those, 40% are due to H aphrophilus, followed by H parainfluenzae. H influenzae rarely causes IE despite its frequency of being involved in bacteremias. Ten percent of cases involve a second pathogen, usually an alpha-hemolytic Streptococcus or Staphylococcus aureus. Endocarditis due to H parainfluenzae has been increasing in frequency. Of these cases, 45% are associated with oral pathology and 10% are associated with upper respiratory tract infections. In 67% of cases, the mitral valve is involved, and in 17%, the aortic valve is involved. Fifty percent of patients have underling valvular disease.

Thirty-three percent of cases of H aphrophilus IE are due to dental disease, and 20% are due to sinusitis or otitis media. The mitral valve is involved in 56% of patients, and the aortic valve is involved in 33%. Eighty-eight percent of individuals have underlying cardiac disease. Arterial embolization occurs in 31% of cases of IE caused by H aphrophilus.

A actinomycetemcomitans was first isolated in 1912 from skin lesions associated with Actinobacillus israelii. Growth of this bacillus occurs in trypticase soy broth, where it forms granules that float on top or stick to the container. It is the etiologic agent of localized juvenile periodontitis, one manifestation of early-onset periodontitis (EOP).

EOP includes a spectrum of entities in which severe periodontal attachment loss occurs in children, adolescents, and young adults. The ability of this organism to produce gingivitis is based in great part on its production of a leukotoxin and its ability to invade gingival cells. A actinomycetemcomitans, on its own, can mimic most of the clinical syndromes caused by A israelii. Of patients with IE caused by this pathogen, 86% have underlying heart disease and 25% have infection of a prosthetic valve (usually aortic). The aortic valve is involved in 65%, and the mitral valve is involved in 30%. Arterial embolization occurs in 43% of cases.

As opposed to the other members of the group, C hominis has been isolated almost exclusively from patients with endocarditis. In addition to being part of the normal flora of the mouth and upper airway, it is isolated from the large bowel. However, most bloodstream infections are secondary to oral pathology. They are gram-negative or gram-variable pleomorphic rods with bulbous swelling of both ends that are characteristically grouped in chains, clusters, or rosettes. Seventy-five percent of cases have underlying heart disease; 43% involving the mitral valve and 36% the aortic valve. Arterial embolization is documented in 40% of patients.

E corrodens takes its name from its ability to corrode (or pit) the agar during growth. It is a gram-negative pleomorphic, often coccobacillary, rod that exudes a chlorine bleach odor. It is facultatively anaerobic. It is part of the oral flora and many other mucosal surfaces.

E corrodens usually is isolated to other organisms, especially strains of streptococci. This organism is a well-recognized cause of cellulitis resulting from human bites and clenched-fist injuries. It also has been found to be a common cause of soft-tissue infections and endocarditis in drug users. This association may arise from the habit of intravenous drug abusers to lick their needles for good luck. These infections often are complicated by osteomyelitis of the underlying bones. It may produce a variety of pulmonary infections (eg, empyema, pneumonia, septic emboli) that mimic those caused by strict anaerobes. Most patients with endocarditis caused by this organism have underlying valve lesions. Compared to cases of IE caused by the other members of the HACEK group, the valvular infections of E corrodens usually are due to intravenous drug abuse.

Kingella species are small gram-negative organisms whose shapes range from those of cocci to those of coccobacilli. This organism also can cause pitting of the agar. The Kingella genus includes 3 species: Kingella kingae, Kingella denitrificans, and Kingella indologenes. IE usually is caused by K kingae. Only approximately 20 cases of endocarditis have been described. Unlike the other HACEK organisms, IE caused by this organism progresses quite rapidly.

Frequency

United States

In a study performed in 1982, the HACEK organisms were found to be responsible for 57% of endocarditis due to gram-negative organisms. This represents approximately 5-10% of native-valve endocarditis in patients who are not intravenous drug users. More recently, increased awareness of fastidious organisms by clinicians and microbiology laboratory personnel suggests these organisms probably are more frequently recognized today, although recent data are not available.

International

Although cases of endocarditis caused by the HACEK organisms have been reported in other countries, the precise incidence of infection with these organisms is not known.

Mortality/Morbidity

Endocarditis caused by the HACEK organisms characteristically develops on a subacute or chronic basis. At the time of presentation, valvular vegetations typically are larger than those resulting from more rapidly growing bacteria. Embolization is frequent and results in significant morbidity.

• Mortality rates range from 10-40% and are organism specific. The lowest mortality rate is observed in infections produced by H parainfluenzae. The rate observed with other examples usually ranges from 30-40%.
• Infectious endocarditis caused by Haemophilus species carries an arterial embolization rate of approximately 50%. That of other members of the group varies from 30-40%.
• Congestive heart failure (CHF) occurs in only 10% of cases of IE due to H parainfluenzae. Approximately 50% of patients with valvular infections due to the other examples of the HACEK group develop significant cardiac failure.

Race

• No racial differences have been reported in endocarditis caused by the HACEK organisms.

Sex

• In general, males develop HACEK endocarditis more often than females, except in the case of Haemophilus species, which favor middle-aged women.

Age

• The great majority of IE caused by HACEK organisms has been reported in older adults.

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