The acronym HACEK refers to a group of fastidious gram-negative coccobacillary organisms. (Haemophilus species; Actinobacillusactinomycetemcomitans [In 2006 the genus was renamed Aggregatibacter actinomycetemcomitans]; Cardiobacterium hominis; Eikenella corrodens; and Kingella kingae).[1] HACEK microorganisms grow slowly in standard blood culture media, and recovery may require prolonged incubation.
Identification can be performed by automated systems but performance may be suboptimal. As with many other organisms, MALDI-TOF is emerging as as potential identification technique for the HACEK group.
HACEK organisms typically are oropharyngeal commensals and have long been recognized as a cause of infective endocarditis (IE).[2, 1] Eikenella and Cardiobacterium species have been recovered from the gastrointestinal tract and female genital tract.[3] In addition to infective endocarditis, these organisms have been 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.
When introduced into healthy tissue, the HACEK group organisms have the potential for invasive disease and abscess formation. The pathogenesis of HACEK endocarditis is thought to be due to colonization of the oropharynx with bacteria that reach the vascular space following either trauma or local infection.
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. H parainfluenzae requires NAD (V factor) but not hemin (X factor), in contrast to H influenzae, which requires both. H parainfluenzae is capable of causing a variety of infections such as IE, otitis media, abscesses, and pneumonia, although it is an uncommon cause of these infections.[4] H influenzae on the other hand very rarely causes IE.
Aggregatibacter actinomycetemcomitans with 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. It can cause periodontal disease as well as IE. 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. Cardiobacterium hominis is very rarely implicated in diseases other than endocarditis. C hominis is found in the oropharynx but rarely the gastrointestinal tract.[4]
Eikenella corrodens, as the name indicates, 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 exudes a chlorine bleach odor. It is a member of the Neisseriaceae family, however can not be recovered on selective media for Neisseria spp such as Thayer-Martin agar. E corrodens can cause IE and is associated with infection following traumatic inoculation from the oral cavity and is found in up to 42% of abscesses from human bite wounds.[4]
Kingella kingae,also is a member of the Neisseriaceae but unlike Eikenella, it usually can be recovered on Thayer-Martin agar. In comparison to others in the HACEK group, K kingae is isolated from endocarditis infrequently. However, it is a significant cause of osteomyelitis/septic arthritis in children aged 6 months-3 years. The organism also may be transmitted person to person by respiratory droplets, and it caused a 2004 outbreak of septic arthritis in children attending daycare.[5]
Infective endocarditis is a rare disease with an annual incidence of 3 to 10 cases per 100,000 people.[6] The most common IE pathogens in children are gram-positive cocci, especially virulence group α-hemolytic streptococci, staphylococci and enterococci. The HACEK group are responsible for 1-3% of all infective endocarditis.[7] HACEK endocarditis mostly affects patients with underlying heart disease or prosthetic valves, and is characterized by an insidious course, with a mean diagnosis delay of 1 month (Haemophilus spp) to 3 months (Aggregatibacter and Cardiobacterium spp).
In Olmsted County, Minnesota, about 0.14 of every 100,000 people develop HACEK endocarditis each year. Twelvcases occurred in patients with prosthetic valve, and 33 cases occurred and in patients with native valve.[8]
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.[9]
Infective endocarditis (IE) caused by the HACEK organisms typically is subacute, with the exception of H parainfluenzae endocarditis, which may present more acutely.[10] At the time of presentation, large valvular vegetations are common. Embolization is common and results in significant morbidity.
Patients hospitalized with definite or possible infective endocarditis by the International Collaboration on Endocarditis Prospective Cohort Study in 64 hospitals from 28 countries were included and characteristics of patients with HACEK endocarditis (HE) were compared with IE due to other pathogens. Of 5591 patients enrolled, 77 (1.4%) had HE. HE was associated with a younger age (47 vs 61 years; p< 0.001), a higher prevalence of immunologic/vascular manifestations (32% vs 20%; p< 0.008) and stroke (25% vs 17% p=0.05) but a lower prevalence of congestive heart failure (15% vs 30%; p=0.004), death in-hospital (4% vs 18%; p=0.001) or after 1 year follow-up (6% vs 20%; p=0.01) than IE due to other pathogens (n=5514). On multivariable analysis, stroke was associated with mitral valve vegetations (OR 3.60; CI 1.34–9.65; p< 0.01) and younger age (OR 0.62; CI 0.49–0.90; p< 0.01). The overall outcome of HE was excellent with the in-hospital mortality (4%) significantly better than for non-HE (18%; p< 0.001). Prosthetic valve endocarditis was more common in HE (35%) than non-HE (24%).[11]
Mortality rates range from 10-40% and may vary by organism. Contemporary case series have suggested a modern mortality risk closer to 10-15%.[8]
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.[12]
No racial differences have been reported in endocarditis caused by the HACEK organisms.
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.[13]
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.[14]
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.[15]
The prognosis is 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.[8]
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.[13] This delay often is due to failure to use special culture techniques.[16] (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, fever was present in only 50% of cases.[13]
Nonspecific symptoms, such as weight loss, anorexia, nausea and vomiting, fatigue, back pain, and night sweats, are common. Symptoms may be insidious 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 (MA). Typically MAs are multiple, distal, and fusiform aneurysms, but the angiographic and clinical presentations can vary widely. The most common presentation of MA is intracranial bleed.[17] Mycotic aneurysm can be intra or extra cranial.
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.[9, 18]
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.
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.[19, 20, 21]
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 [22]
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.[17]
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 septic 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.
Patients may have a history of a preceding dental, urologic, or gastroenterologic procedure.[22]
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.[23]
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.[24]
Rare case reports have linked wound contamination with canine saliva and subsequent invasive infections, particularly of the head and neck, leading to brain abscess.[18, 25]
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 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.
When a HACEK organism is suspected, consider consulting a microbiologist so that special attention can be given to the blood culture specimen. Special procedures performed in the microbiology laboratory may improve the chances of isolating the organisms.[16]
Although prolonged incubation commonly is recommended in this setting, current research suggests it is the special laboratory procedures, rather than the time of incubation, that matter most.[16]
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.[4]
Molecular techniques for the detection and identification of microorganisms have been increasingly used for diagnostics in clinical microbiology. Polymerase chain reaction (PCR) of the 16S rRNA genes and sequencing has increased diagnostic yield, although diagnostic sensitivity is difficult to be determined at this time.[26]
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 and C-reactive protein, although these are nonspecific.
Echocardiography (TTE) plays a key role for the diagnosis of IE and must be performed as soon as IE is suspected. It allows to identify vegetation, abscess, new dehiscence of prosthetic valve, and assesses the number, size, shape, location, echogenicity, and mobility of vegetations so it also useful for prediction embolic risk. Transesophageal echocardiography (TEE) is indicated when TTE is positive or non diagnostic, in case of suspected complications, and when intracardiac device leads are present.[27]
HACEK group organisms typically produce vegetations that are larger than vegetations found in IE due to other organisms, probably because of the longer mean time to diagnosis.
In addition to its diagnostic utility, echocardiography may play a prognostic role. Certain vegetation characteristics are associated with increased risk for embolism and mortality.[28]
The new guidelines propose new diagnostic criteria that consider the potentiality on integrated multimodality imaging so according to this new definitions include: (1) the identification of paravalvular lesions by cardiac computed tomography (CT) as a major criterion; (2) in the setting of the suspected endocarditis on a prosthetic valve, abnormal activity around the site of implantation detected by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT (only if the prosthesis was implanted for >3 months) or radiolabeled leukocyte single-photon emission CT (SPECT)/CT as a major criterion; and (3) the identification of recent embolic events or infectious aneurysms by imaging only (silent events) as a minor criterion.[27, 29]
Computed tomography (CT) scanning can be used for diagnosis of soft-tissue or visceral abscess.
Magnetic resonance imaging (RI) is more sensitive and specific for bone infection.
The most common presentation of HACEK endocarditis is an indolent or subacute endocarditis that is cured with an appropriate course of intravenous antibiotics. In cases of less-common acute clinical presentation with perivalvular abscess and rapid hemodynamic deterioration with heart failure, valve replacement may be necessary.[30]
An arterial embolectomy for large emboli may be needed to salvage a limb or viscera.
Surgical interventions such as incision and drainage or abscess evacuation may be needed if clinically prompted.
The valvular lesions and vegetations of HACEK IE are very similar to those found in other types of subacute endocarditis, except that the larger size of the vegetations resembles those seen in fungal or staphylococcal disease.[31, 32]
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[33] :
Antibiotic therapy may be fine-tuned when susceptibility data for the causative organism are available.[34]
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.
The decision to consider surgical therapy in patients with IE often is challenging and must be made on an individual basis. The following are several accepted indications for surgery in IE[12] :
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.
Surgery consult is prompted for abscess drainage.
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.
The risk for 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.[36]
High-risk conditions include the following:
Relapse may occur during the first 6 months following the end of treatment. Patients should be counseled and observed regarding relapse.
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).
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.[12]
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.
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.
Clinical Context: Drug of choice for treatment of endocarditis due to HACEK organisms. Third-generation cephalosporin with broad-spectrum, gram-negative activity. Arrests bacterial growth by binding to one or more penicillin-binding proteins. Recommended dose 2 gm q24 hrs IV. No adjustment necessary in persons with renal or hepatic impairment. Dose should be administered postdialysis if undergoing hemodialysis.
Clinical Context: 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.
Clinical Context: Alternative to ceftriaxone when treating HACEK in patients who are unable to tolerate beta-lactam treatment. Inhibits bacterial DNA synthesis and, consequently, growth. Recommended dose for HACEK Infective endocarditis is 1000 mg/24 h orally or 800 mg/24 h IV in 2 equally divided doses. Consider dose adjustment based on renal function.
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.