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:
In the US: 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.
Internationally: 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.

CLINICAL
History: IE produced by any of the HACEK organisms usually is of the subacute type. Rarely, this group may produce acute disease. Patients present with progressive symptoms developing over weeks. The mean time to diagnosis is approximately 3 months. Some cases have been present for as long as 18 months before the correct diagnosis is made. This delay often is due to difficulty in culturing the organisms. HACEK IE should be considered in the differential diagnosis 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.
Nonspecific symptoms, such as weight loss, anorexia, nausea and vomiting, fatigue, back pain, and night sweats, are frequent and may lead to a delay in diagnosis.
Most patients have had previously known valvular disease.
A history of a dental procedure or recent oral pathology should be elicited.
A history of intravenous drug abuse should be elicited.
A sentinel headache may indicate the impending rupture of a mycotic aneurysm.

Physical: Given the difficulty of making the diagnosis early, performing a detailed physical examination is especially important. Special attention should be given to the heart, possible peripheral stigmata of IE (approximately 50% of patients, see Pathophysiology), CHF (up to 50% of patients), and possible embolic complications.
Heart: A new or changing heart murmur is the most consistent physical finding, but it may be absent, especially in right-sided endocarditis.
Peripheral/teguments
Improvements in health care have contributed to earlier diagnosis and a reduction in the percentage of patients presenting with typical peripheral manifestations of subacute endocarditis.
Examine the patient for clubbing (with or without hypertrophic osteoarthropathy), splinter hemorrhages, mucocutaneous petechiae, Osler nodes, Janeway lesions, and Roth spots.
Splenomegaly is frequent.
Embolic complications
A vegetation can embolize to virtually any vessel. H parainfluenzae has the highest rate of embolization (60%).
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.
Emboli to the kidney may cause flank tenderness, hematuria, and/or oliguria.
Listen for a rub after a splenic infarct.
Embolization to heart vessels can present as a myocardial infarct with hypotension and arrhythmias. Most commonly, cardiac physical findings are due to valvular destruction.
A large mesenteric embolus can cause bowel ischemia with secondary abdominal tenderness.
Limbs may be affected by an occlusive thrombus. Watch for signs of hypoperfusion.
A right-sided vegetation can metastasize to the lung and present similar to a pulmonary embolus or focal pneumonia.

Causes:
Patients often have a history of dental manipulation or poor oral hygiene.
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.
Finally, as in other causes of infectious endocarditis, a history of abnormal native valves (eg, mitral valve prolapse) or prosthetic valves is a predisposing factor.

Lab Studies:
Precise information regarding how and where the specimen was collected should be specified to the microbiology laboratory.
Ideally, when a HACEK organism is suspected, consult a microbiologist so that special attention can be given to the specimen. With this information, the microbiology laboratory team incubates specimens to enhance the yield of fastidious organisms.
Inoculate blood cultures demonstrate microbial growth on blood agar and chocolate agar supplemented with vitamins and either hemoglobin or lysed blood. Incubate agar media in a humid atmosphere of 5% carbon dioxide or anaerobically for 24-72 hours.
Many days may pass (range 2-9 d) before growth is detected in blood culture bottles. Keeping the bottles for a minimum of 14 days is recommended, and terminal subculture of the broth may be useful.
Specimens collected from other sterile sites should be inoculated on chocolate and blood agars and incubated in a carbon dioxide–rich atmosphere for 24-72 hours. An enrichment media, such as a thioglycolate broth, should be inoculated and incubated for 14 days. For blood cultures, terminal subculturing is advisable.
Complete cell count may show anemia with or without reactive thrombocytosis. Total white cell count may or may not be increased.
Other inflammatory parameters should include erythrocyte sedimentation rate, rheumatoid factor (ie, "the poor man's immune complex"), and C-reactive protein. If any of these are elevated at diagnosis, they should decrease markedly and usually disappear with successful therapy.
Subacute endocarditis can cause complement to be consumed. C3 and C4 can be decreased. However, these are not used to assess response to treatment.
Urinalysis may reveal microscopic hematuria and casts due to autoimmune glomerulonephritis.

Imaging Studies:
Echocardiography
Echocardiography plays an important role in the diagnosis and management of endocarditis. Characteristic vegetations, abscesses, new prosthetic-valve dehiscence, or new regurgitant murmur are 4 powerful identifiers of IE (in combination with other clinical parameters).
Transthoracic echocardiography (TTE) has the advantages of being fast and easy to perform. Specificity for vegetations is 98%; however, sensitivity is lower than 60%. TTE views may be inadequate in approximately 20% of the adult population because of obesity, chronic obstructive pulmonary disease, or chest-wall deformities. TTE cannot exclude infection of prosthetic valves, periannular abscess, leaflet perforation, and fistulae.
Transesophageal echocardiography has the advantage of having higher sensitivity for vegetations and greater specificity and sensitivity for perivalvular extension than TTE.
HACEK group organisms typically produce vegetations that are larger than vegetations found in IE due to other organisms. This probably is due to the longer mean time to diagnosis.

Procedures:
An arterial embolectomy, necessary to salvage a limb, may yield a specimen, which, by culture or histological examination, indicates the correct diagnosis.
Histologic Findings: The valvular lesions and vegetations of HACEK IE are very similar to those found in other types of subacute endocarditis, except that the size of the vegetations resembles those seen in fungal or staphylococcal disease.

TREATMENT

Medical Care:
Antibiotics are the mainstay of treatment
Diagnosis should be clearly established before starting treatment because administration of antimicrobial agents to patients with IE before blood cultures are obtained reduces the recovery rate of bacteria by 35-40%.
Because of slow growth, antimicrobial sensitivity testing is not always available; therefore, ceftriaxone should be considered the drug of choice. Ampicillin combined with gentamicin is another therapeutic option.
In the case of beta-lactam allergy, clinical experience is much more limited. Ciprofloxacin or a broader quinolone antibiotic could be a reasonable option for empiric therapy based on in vitro data. In the case of beta-lactam allergy, waiting for 48 hours until a preliminary antibiogram is available rather than desensitizing the patient to an allergen may be wise.

Careful selection of the appropriate antibiotic eventually should be based on the sensitivity profile and on an expert's advice.

Again, no official recommendations have been made and experience is limited with drugs other than beta-lactams.
Although embolic complications are frequent with native-valve IE due to HACEK organisms, in general, anticoagulation is believed to be contraindicated because of the risk of intracranial bleeding.
Complications of IE, such as heart failure, also require medical support.

Surgical Care:
Valve replacement has become an important adjunct to medical therapy and may be necessary in as many as 25% of cases.

Surgical removal of large vegetations unresponsive to medical therapy ("vegectomy") without valve replacement has been successful in some pediatric cases of H parainfluenzae IE.
Unlike IE caused by fungi or more resistant organisms, IE caused by HACEK organisms usually responds well to medical treatment alone.
Because an important delay may occur before diagnosis, embolic complications and significant valve destruction may warrant surgical therapy.
In general, the following are recognized indications for surgery in IE:
Refractory CHF
More than one serious embolic episode
Uncontrolled infection
Physiologically significant valve dysfunction as demonstrated by echocardiography: According to the American Heart Association Committee on IE, criteria associated with an increased need for surgical intervention are (1) persistent vegetations after a major systemic embolic episode; (2) anterior mitral valve vegetations larger than 1 cm in diameter; (3) increase in size of vegetations after 1 month of therapy; (4) periannular extension of infection; and (5) valvular dysfunction, perforation, or rupture.
Ineffective antimicrobial therapy (usually not the case with HACEK organisms)
Resection of mycotic aneurysms

Most cases of prosthetic valve endocarditis caused by more resistant organisms (eg, methicillin-resistant S aureus [MRSA], vancomycin-resistant enterococci [VRE], enteric gram-negative bacilli)

Local suppurative complications including perivalvular or myocardial abscess

Consultations: Treatment of HACEK endocarditis requires a multidisciplinary approach.
Consultation with an infectious disease specialist is recommended to ensure adequate antimicrobial coverage and for management advice.
Consultation with a cardiologist may be necessary to ensure that heart function remains optimal and for quick recognition and treatment of heart failure.
Optimal management of large vegetations or mechanical complications may warrant a cardiovascular surgeon's advice.
The advice of a dentist should be sought if periodontal disease is present.
Physiotherapists can help the patient regain mobility after an extended illness or major CNS embolic episodes. Ergotherapy and/or speech therapy and social workers are other resources that may be sought depending on the patients rehabilitation needs.

Activity:
Restrict physical activity to light exercises until the infection is well under control.


Further Inpatient Care:
Careful clinical observation is the most important aspect of monitoring adequacy of therapy.
Persistent or recurrent fever may be a sign of treatment failure, but it also may be due to hypersensitivity reactions, thrombophlebitis, or sterile embolization.
Serum bactericidal titer has not been studied in the context of HACEK infections; however, it may be useful when the response to therapy is suboptimal.
Observe patients closely for signs of complications.
Repeat blood cultures every 48 hours until they become negative.
Fever lasting longer than 10 days after starting appropriate antibiotics should cause concern.
Causes of persistent fever include drug fever, myocardial or septal abscesses, large vegetations that are difficult to sterilize, and metastatic infection (intracerebral mycotic aneurysms).

Further Outpatient Care:
Relapse may occur during the first 6 months following the end of treatment. Patients should be counseled and observed regarding relapse.

In/Out Patient Meds:
The entire course should be with intravenous antibiotics. Once the patient is stable and cultures are negative, completing IV therapy on an outpatient basis can be considered. Placing a percutaneous intravenous central catheter line may ease antibiotic delivery. Close and frequent outpatient monitoring for drug toxicity and cardiovascular or embolic events is essential.

Transfer:
If HACEK infection is diagnosed early, managing the infection in a center that does not offer cardiovascular surgery services may be possible. However, consider transfer to a health center with complete cardiac and neurological care for any patient at high risk for complications.
If the patient is stable, has good social support, and is afebrile after 2 weeks of therapy, the individual may complete the remaining 2-4 weeks of antibiotic therapy at home.

Deterrence/Prevention:
The risk of endocarditis due to HACEK organisms can be reduced by early diagnosis and treatment of periodontitis.
Incidence and magnitude of bacteremias of oral origin are directly proportional to the degree of oral inflammation and infection.
Oral hygiene should be maintained at all times, especially in patients with high-risk cardiac conditions.
Antibiotic prophylaxis should be considered before oral/dental procedures in patients with high-risk and intermediate-risk cardiac conditions.
High-risk conditions include the following:
Prosthetic valves
Previous bacterial endocarditis
Complex cyanotic congenital heart disease
Surgically constructed systemic pulmonary shunts or conduit
Intermediate-risk conditions include the following:

Acquired valve disfunction

Hypertrophic cardiomyopathy

Mitral valve prolapse with regurgitation or thickened leaflets

Complications:
Many complications can occur from IE, regardless of the causative organisms.
CHF is the complication of IE that has the greatest impact on prognosis. It may develop acutely from perforation of a valve leaflet, rupture of an infected chordae, valve obstruction, or because of sudden intracardiac shunts from fistulous tracts. When it appears more insidiously, CHF usually develops during the first month of therapy. Any deterioration in heart function should be taken very seriously because operative mortality increases dramatically when frank ventricular decompensation has occurred.
Neurologic complications, whether from emboli, abscess, hemorrhage, or arteritis, are the most frequent causes of death in patients with IE. Mycotic aneurysms usually are clinically silent until they rupture. Consider performing a magnetic resonance angiogram or cerebral CT scan to look for aneurysm in patients with subacute IE.
Splenic infarctions can occur in more than one third of patients but often are clinically silent.
Septic or bland emboli may reach the lung in right-sided endocarditis. These may cause pulmonary infarction, pneumonia, and empyema.

Prognosis:
Prognosis is quite variable, depending on many factors such as delay in diagnosis, age of the patient, and occurrence of complications. Patients with uncomplicated IE caused by HACEK organisms generally respond well to therapy and have an excellent prognosis.

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