HACEK Group Infections


Background

The acronym HACEK refers to a group of fastidious gram-negative coccobacillary organisms. HACEK stands for Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species. The HACEK group accounts for approximately 5%-10% of community-acquired native-valve endocarditis cases in patients who do not use intravenous drugs. [1HACEK microorganisms grow slowly in standard blood culture media, and recovery may require prolonged incubation.

HACEK organisms are typically oropharyngeal commensals and have long been recognized as a cause of infective endocarditis (IE). [2Eikenella and Cardiobacterium species have been recovered from the gastrointestinal tract and female genital tract. [3In addition to infective endocarditis, these organisms have also known to cause wound infections (particularly of bite wounds), soft-tissue abscess, brain abscess, endophthalmitis, parotitis, periodontitis, empyema and bacteremia without endocarditis, and osteomyelitis. In addition, rare cases of endometritis and urinary tract infection have been identified. Invasive infections commonly occur in the setting of trauma, underlying structural heart disease, malignancy, and other immunocompromised states.

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. Haemophilus species are responsible for 0.5%-1% of all cases of IE. Of those, most are due to Haemophilus aphrophilus, followed by Haemophilus parainfluenzae. Haemophilus 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.

Actinobacillus 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.

Epidemiology

Frequency

United States

HACEK organisms are responsible for a small but recognizable percentage (roughly 3%) of endocarditis cases. [4It is apparent that non-HACEK gram-negative endocarditis is likely increasing in incidence owing to the increased use of endovascular devices. [5Reporting 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. [6]

International

In a prospective multinational cohort study from 64 hospitals in 28 countries, HACEK organisms were isolated in approximately 1.4% of infective endocarditis cases. [2]

For the most part, endocarditis is the focus of incidence studies of HACEK infections, but other infections can be caused by these organisms. By the mid-1980s, 132 cases of H aphrophilus infection had been reported: 55% endocarditis, 15% brain abscess, and the remainder sinusitis, meningitis, pneumonitis, bacteremia, and empyema.

Nineteen cases of Eikenella brain infections were reported through 1983. [7]

Mortality/Morbidity

Infective endocarditis (IE) caused by the HACEK organisms is typically subacute, with the exception of H parainfluenzae endocarditis, which may present more acutely. [8At 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%. [6]

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. [9]

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. [10]

Age

The great majority of IE cases caused by HACEK organisms have been reported in older adults. HACEK IE in children with congenital heart disease has been reported.

In children, 70% of Kingella infections involve the skeletal system, predominantly septic arthritis. In a study of K kingae infections in children from southern Israel, Yagupsky and Dagan found that 45% of affected children were aged 13-24 months, with an attack rate of 27 cases per 100,000 children younger than 24 months. Almost 90% of all children with invasive K kingae infections have been younger than 5 years. [11]

Actinobacillus is highly associated with dental disease, being found in 50% of adults with periodontitis and 97% of children with juvenile periodontal disease. In a series of 57 cases of A actinomycetemcomitans endocarditis, poor dentition (46%) and abnormal cardiac valves (60%) were found to be predisposing factors. [12]

Prognosis

The 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.

CLINICAL PRESENTATION


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. [10This delay is often due to failure to use special culture techniques. [13(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. [10]

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. [14]

Brain abscess can manifest as neurologic symptoms, such as focal weakness or numbness, cranial nerve dysfunction, and/or seizure. Primary brain abscess cases have been associated with canine saliva contamination or head and neck wounds. [715]

Human bite or clenched fist injuries can be infected with HACEK organisms and can present as wound and deeper-tissue infections.

Various other presentations, including orbital cellulitis, necrotizing pneumonia, visceral abscess, bacteremia, and thrombophlebitis, have been reported.

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. [161718]

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 can be present.

Embolic complications  [19]

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 central nervous system 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. [14]

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.

Bone and joint foci can present as osteomyelitis and/or septic arthritis, manifesting as bone or joint tenderness, swelling, or nonhealing wound.

Other clinical manifestations

Other clinical manifestations, such as dental infection, skin and soft tissue infection/abscess, pneumonia/empyema, parotitis, eye infection, and sinus infection, require examination of the involved area, a thorough history, and assessment for underlying comorbidities.

Causes

Patients may have a history of a preceding dental, urologic, or gastroenterologic procedure. [19]

Periodontal disease is a known predisposing factor.

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. [20]

A history of heart valve abnormalities or the presence of a prosthetic heart valve or pacemaker device also predisposes to endocarditis.

A review of literature from Mayo Clinic between 1971 and 1976 identified predisposing factors such as trauma with wound infections, malignancies with abscesses, and congenital heart disease with endocarditis. [21]

Rare case reports have linked wound contamination with canine saliva and subsequent invasive infections, particularly of the head and neck, leading to brain abscess. [1522]

Complications

Many complications can result 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 after frank ventricular decompensation.

Neurologic complications, whether from emboli, abscess, hemorrhage, or arteritis, are the most frequent causes of death in patients with IE. Mycotic aneurysms are usually 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 are often clinically silent.

Septic or bland emboli may reach the lung in right-sided endocarditis. These may cause pulmonary infarction, pneumonia, and empyema.

DDx

Differential Diagnoses

TREATMENT & MANAGEMENT

Medical Care

Appropriate antibiotic therapy is key to the management of infective endocarditis (IE) caused by the HACEK organisms (see Medications). The Infectious Disease Society of America (IDSA) recommends the following: [28]

  • Unless in vitro growth is adequate to obtain susceptibility testing results, HACEK microorganisms are considered ampicillin-resistant, and penicillin and ampicillin should not be used for the treatment of IE. Ampicillin sodium may be an option if the growth of the isolate is sufficient to permit in vitro susceptibility results.
  • Ceftriaxone is reasonable for treatment of HACEK IE.
  • Four weeks of therapy for HACEK native-valve endocarditis is reasonable; for HACEK prosthetic valve endocarditis, a therapy duration of 6 weeks is reasonable.
  • Gentamicin is not recommended because of its nephrotoxicity risks.
  • A fluoroquinolone (ciprofloxacin, levofloxacin, or moxifloxacin) may be considered an alternative agent in patients who are unable to tolerate ceftriaxone (or other third- or fourth-generation cephalosporins).
  • Patients with HACEK IE who cannot tolerate ceftriaxone therapy should be treated in consultation with an infectious diseases specialist.

Antibiotic therapy may be fine-tuned when susceptibility data for the causative organism are available. [29]

Complications that arise (eg, heart failure, embolic complications) also require supportive medical therapy.

When treating a clenched fist injury or bite wound infection, HACEK organisms should be kept in consideration. E corrodens is resistant to macrolides, clindamycin, and metronidazole. H aphrophilus is also typically resistant to clindamycin.

Surgical Care

The decision to consider surgical therapy in patients with IE is often challenging and must be made on an individual basis. The following are several accepted indications for surgery in IE: [9]

  • Refractory CHF

  • One or more embolic episode

  • Uncontrolled infection (persistently positive blood cultures after 1 week of therapy)

  • 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 include (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. [30]

  • 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 may be helpful for selecting antibiotics, monitoring therapy, and selecting the duration of therapy.

Consultation with a cardiologist may be helpful, especially if transesophageal echocardiography is needed or if CHF develops.

Management of large vegetations or mechanical complications warrants a cardiovascular surgeon's advice.

Consultation with a dentist is indicated if periodontal disease is present.

Diet

No special diet is necessary in patients with HACEK group infections.

Activity

Although there is no evidence-based recommendation for activity levels in patients with endocarditis, it is prudent to keep activity light in the initial phase of treatment.

Prevention

The risk of endocarditis due to HACEK organisms may be reduced by maintenance of good dental hygiene.

Guidelines for infective endocarditis (IE) prophylaxis prior to dental procedures were updated in 2007. Current recommendations support the use of prophylactic antibiotics for high-risk lesions only.

Antibiotic prophylaxis should be considered before oral/dental procedures in patients with high-risk cardiac conditions. [31]

High-risk conditions include the following:

  • Prosthetic valves

  • Previous bacterial endocarditis

  • Complex cyanotic congenital heart disease

  • Surgically constructed systemic pulmonary shunts or conduits

  • Valvulopathy in cardiac transplantation recipients

Long-Term Monitoring

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

Further Inpatient Care

Careful clinical observation is the most important aspect of monitoring adequacy of therapy in HACEK group infections. Persistent or recurrent fever may be a sign of treatment failure, but it also may be due to hypersensitivity reactions, thrombophlebitis, or sterile embolization. Observe patients closely for signs of complications, such as embolic events or CHF.

Repeat blood cultures every 48 hours until they become negative.

Fever that lasts longer than 10 days after starting appropriate antibiotics should cause concern.

Causes of persistent fever include drug fever, antibiotic resistance, myocardial or septal abscesses, large vegetations that are difficult to sterilize, and metastatic infection (intracerebral mycotic aneurysms).

Inpatient & Outpatient Medications

In general, the entire course should be with intravenous antibiotics. Once the patient is stable and cultures are negative, completing intravenous therapy on an outpatient basis is reasonable. However, even in the outpatient setting, frequent evaluations are necessary to assess for response to therapy and for drug toxicity.

Although little evidence exists to support its use in this setting, ciprofloxacin could be used in oral form in certain circumstances. However, given the lack of evidence, this be reserved for special circumstances and in consultation with an infectious disease specialist. [9]

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 with negative blood cultures, outpatient therapy can then be offered for the remainder of the treatment course.

MEDICATION

Medication Summary

Empiric therapy with ceftriaxone or ampicillin-sulbactam is the recommended approach. Fluoroquinolones can be used in the case of allergy or intolerance to the recommended regimen. Treatment duration is 4 weeks for native valve disease and 6 weeks for prosthetic valve disease.

Antibiotics

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Ceftriaxone (Rocephin)

Drug of choice for treatment of endocarditis due to HACEK organisms. Third-generation cephalosporin with broad-spectrum, gram-negative activity. Lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin-binding proteins. No adjustment necessary in persons with renal or hepatic impairment. Dose should be administered postdialysis if undergoing hemodialysis.

Ampicillin and sulbactam (Unasyn)

Drug combination of beta-lactamase inhibitor with ampicillin. Interferes with bacterial cell wall synthesis during active replication, causing bactericidal activity against susceptible organisms. Alternative to amoxicillin when unable to take medication orally.

Covers skin, enteric flora, and anaerobes. Not ideal for nosocomial pathogens.

Ciprofloxacin (Cipro)

Alternative to ceftriaxone when treating HACEK in patients who are unable to tolerate beta-lactam treatment. Inhibits bacterial DNA synthesis and, consequently, growth.