eMedicine Specialties > Infectious Diseases > Bacterial Infections

HACEK Group Infections

Author: Isaac P Humphrey, MD, Assistant Professor of Internal Medicine, Uniformed Services University of the Health Sciences; Clinical Assistant Professor of Internal Medicine, Wright State University Boonshoft School of Medicine
Coauthor(s): Mirabelle Kelly, MD, Fellow, Department of Microbiology and Infectious Disease, University of Sherbrooke, Canada; Barnett Gibbs, MD, Assistant Chief, Department of Clinical Trials, Walter Reed Army Institute of Research, Infectious Disease Service, National Capital Consortium; Assistant Professor of Medicine, Uniformed Services University of the Health Sciences; Christian P Sinave, MD, Associate Professor, Department of Medical Microbiology and Infectious Diseases, University of Sherbrooke, Canada
Contributor Information and Disclosures

Updated: Nov 6, 2009

Introduction

Background

The acronym HACEK refers to a grouping of gram-negative bacilli: Haemophilus species (Haemophilus parainfluenzae, Haemophilus aphrophilus, Haemophilus paraphrophilus), Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella species. These organisms share an enhanced capacity to produce endocardial infections. Based on large reviews, HACEK organisms are responsible for approximately 3% of cases of native valve infective endocarditis (IE).¹ They are also the most common cause of gram-negative endocarditis among persons who do not abuse intravenous drugs.

These organisms are found as part of the normal human oral flora. Because of their fastidious and slow growth, they are often a cause of culture-negative endocarditis, although modern culture and genetic identification techniques are challenging this paradigm.²

In addition to cardiac valve infections, this group is also a cause of other infections, including periodontal infections, bacteremia, abscesses, peritonitis, otitis media, conjunctivitis, pneumonia, septic arthritis, osteomyelitis, urinary tract infections, wound infections, and brain abscess.

Pathophysiology

When introduced into healthy tissue, the HACEK group organisms have the potential for abscess formation and invasive disease. In addition, many examples produce 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 a combination of these two 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 underlying 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 H aphrophilus IE .

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 A actinomycetemcomitans IE, 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 HACEK 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 C hominis 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, with 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 is usually isolated with other organisms, especially strains of streptococci. This organism is a well-recognized cause of cellulitis resulting from human bites and clenched-fist injuries. It has also 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 are often complicated by osteomyelitis of the underlying bones. It may produce various pulmonary infections (eg, empyema, pneumonia, septic emboli) that mimic those caused by strict anaerobes. Most patients with E corrodens endocarditis have underlying valve lesions. Compared to cases of IE caused by the other members of the HACEK group, the valvular infections of E corrodens are usually 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 can also cause pitting of the agar. The Kingella genus includes 3 species: Kingella kingae, Kingella denitrificans, and Kingella indologenes. IE is usually caused by K kingae. Only approximately 20 cases of endocarditis have been described. Unlike with the other HACEK organisms, Kingella IE progresses quite rapidly.

Frequency

United States

In a study performed in 1982, the HACEK organisms were found to be responsible for 57% of endocarditis cases due to gram-negative organisms.³ It is apparent that non-HACEK gram-negative endocarditis is likely increasing in incidence owing to the increased use of endovascular devices.⁴ However, whether the incidence of HACEK group infections is increasing or decreasing is unclear based on the current literature. Reporting of these infections has increased, but this may be due simply to increased awareness of the infections among physicians and laboratory personnel, along with new laboratory techniques. Mayo Clinic data suggest the incidence of the HACEK group endocarditis to be 0.14 per 100,000 patient-years.¹

International

Several reviews of endocarditis in various countries have detailed IE related to the HACEK group of organisms.⁵ However, the incidence in the international community as a whole is unknown.

Mortality/Morbidity

Endocarditis caused by the HACEK organisms is typically subacute, with the exception of H parainfluenzae endocarditis, which may present more acutely.⁶ At the time of presentation, large valvular vegetations are common. Embolization is common and results in significant morbidity.

• Mortality rates range from 10%-40% and may vary by organism. Contemporary case series have suggested a modern mortality risk closer to 10%-15%.¹
• The morbidity of IE caused by the HACEK group is similar to that of other types of endocarditis and includes embolization, local extension into the perivalvular area, congestive heart failure (CHF), and regurgitant valve lesions. Compared with all causes of IE, these organisms may be associated with an increased risk of embolization.⁷

Race

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

Sex

• Older data suggest that HACEK endocarditis has a male predominance. However, there is not enough data available to say that, in the modern era, there is a predilection toward either sex.³

Age

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

Clinical

History

Most cases of infective endocarditis (IE) caused by the HACEK organisms are subacute. Patients present with progressive symptoms developing over weeks. Some cases have been present for as long as 18 months before the correct diagnosis is made.³ This delay is often due to failure to use special culture techniques.² (See Lab studies.) HACEK IE should be considered in the differential diagnoses of fever of unknown origin.

• Fever is common but may be absent in elderly individuals, immunocompromised patients, or patients taking anti-inflammatory drugs. In some series, it was present in only 50% of cases.³
• Nonspecific symptoms, such as weight loss, anorexia, nausea and vomiting, fatigue, back pain, and night sweats, are common and may lead to a delay in diagnosis.
• Patients may have a history of prior valvular disease.
• A history of prior dental, urologic, and other procedures should be elicited.
• A history of intravenous drug abuse should be elicited.
• A sentinel headache may indicate the impending rupture of a mycotic aneurysm.⁸

Physical

The diagnosis of endocarditis is challenging. The physical findings are often subtle and difficult to identify for many clinicians. Special care should be taken to perform a comprehensive physical examination looking for evidence of endocarditis. Some of the areas to focus on are noted below.⁹

• Heart: A new or changing heart murmur is the most consistent physical finding, but it may be absent, especially in right-sided endocarditis.
• Peripheral
  • Because of the increased use of healthcare and diagnostic imaging, the peripheral manifestations of endocarditis are not seen as commonly as they once were.
  • Examine the patient for clubbing (with or without hypertrophic osteoarthropathy), splinter hemorrhages, mucocutaneous petechiae, Osler nodes, Janeway lesions, and Roth spots.
  • Splenomegaly is common.
• Embolic complications¹⁰
  • A vegetation can embolize to virtually any vessel and can result in various sequelae.
  • Observe for compromise of circulation to the limbs due to embolization.
  • Emboli to the CNS often presents as a focal neurological deficit or a stroke. Emboli to the frontal lobe may be more subtle, causing personality changes or loss of inhibition.⁸
  • Emboli to the kidney may cause flank tenderness, hematuria, and/or oliguria.
  • Embolization to heart vessels can have various manifestations, including acute myocardial infarction and arrhythmia.
  • A large mesenteric embolus can cause bowel ischemia and thus manifest as abdominal pain and tenderness.
  • A right-sided vegetation can embolize to the lung and present similarly to a pulmonary embolus or focal pneumonia.

Causes

• Patients may have a history of a preceding dental, urologic, or gastroenterologic procedure.¹⁰
• A history of intravenous drug use also should be considered because many drug users clean their needles or venipuncture sites with saliva. Among the HACEK organisms, E corrodens is the bacterium that has been most frequently associated with intravenous drug abuse.¹¹
• A history of heart valve abnormalities or the presence of a prosthetic heart valve also predisposes to endocarditis.

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