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Research Article
1 January 2001
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Endocarditis Due to Rare and Fastidious Bacteria
Authors: P. Brouqui, D. RaoultAuthors Info & Affiliations
DOI: https://doi.org/10.1128/cmr.14.1.177-207.2001
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SUMMARY
The etiologic diagnosis of infective endocarditis is easily made in the presence of continuous bacteremia with gram-positive cocci.

However, the blood culture may contain a bacterium rarely associated with endocarditis, such as Lactobacillus spp., Klebsiella spp., or nontoxigenic Corynebacterium, Salmonella, Gemella, Campylobacter, Aeromonas, Yersinia, Nocardia, Pasteurella, Listeria, or Erysipelothrix spp., that requires further investigation to establish the relationship with endocarditis, or the blood culture may be uninformative despite a supportive clinical evaluation.

In the latter case, the etiologic agents are either fastidious extracellular or intracellular bacteria.

Fastidious extracellular bacteria such as Abiotrophia, HACEK group bacteria, Clostridium, Brucella, Legionella, Mycobacterium, and Bartonella spp.

need supplemented media, prolonged incubation time, and special culture conditions.

Intracellular bacteria such as Coxiella burnetii cannot be isolated routinely.

The two most prevalent etiologic agents of culture-negative endocarditis are C. burnetti and Bartonella spp.

Their diagnosis is usually carried out serologically.

A systemic pathologic examination of excised heart valves including periodic acid-Schiff (PAS) staining and molecular methods has allowed the identification of Whipple's bacillus endocarditis.

Pathologic examination of the valve using special staining, such as Warthin-Starry, Gimenez, and PAS, and broad-spectrum PCR should be performed systematically when no etiologic diagnosis is evident through routine laboratory evaluation.

Infective endocarditis (IE) is usually suspected in a patient with fever and a new or changing cardiac murmur and is diagnosed based on the presence of a vegetation on echocardiography and positive blood cultures.

Diagnosis of endocarditis is usually easy in febrile patients with a continuous bacteremia and the presence of vegetation on echocardiography or on gross examination or histologic testing of the removed valve.

However, although numerous clinical situations lead to a high degree of suspicion of endocarditis, culture or histologic examination does not confirm the diagnosis.

Although fever is the single most common finding in endocarditis, it may be absent in the elderly or in patients given previous antibiotic therapy before presentation or it may be intermittent or low-grade as for Q fever endocarditis 29.

Cardiac murmur is the second most frequent finding in endocarditis.

However, it is not usually present at the initial stage of right-sided endocarditis, and new or changing murmurs are detected in only 40% of patients with endocarditis 261; this rate is even lower in the elderly.

Despite the fact that transesophageal echocardiography is more sensitive than transthoracic echocardiography, a vegetation is rarely detected in Q fever or Whipple's disease 29, 221.

Sterile blood cultures have been noted for 2.5 to 31% of patients with endocarditis 286.

Blood cultures are frequently sterile when antibiotic therapy was administered before sampling and in patients with subacute right-sided endocarditis, mural endocarditis, and endocarditis caused by slow-growing or fastidious organisms such as anaerobes, the HACEK group, Abiotrophia spp.,Brucella spp., Bartonella spp.,Legionella spp., and Mycoplasma spp.

or when obligate intracellular organisms such as Coxiella burnetiiare involved 3, 124.

These bacteria require specific media and conditions such as l-cysteine-enriched medium forAbiotrophia spp., buffered charcoal yeast extract (BCYE) agar for Legionella spp., or special culture conditions favorable for anaerobes or intracellular bacteria.

Moreover, in some cases, slow-growing bacteria require incubation times as long as 6 weeks 179.

In such situations, infective endocarditis remains a diagnostic challenge.

To both assist physicians in establishing the final diagnosis of endocarditis and allow comparisons of published cases, diagnostic criteria have been defined 70, 122, 123, 290.

For many years, the Beth Israel criteria 290 were the only recognized diagnostic criteria.

In 1994, Durack et al.

from the Duke Endocarditis Service 70 added echocardiographic findings and other clinical and laboratory data to the well-established clinical and microbiological criteria.

More recently, additional criteria have been proposed to improve the list 147, such as includingC.

burnetii serology or culture as additional major criteria86.

According to the Duke Endocarditis Service, the diagnosis of IE is definite (i) when a microorganism is demonstrated by culture or histologic testing in a vegetation, an embolism, or an intracardiac abscess; (ii) when active endocarditis is confirmed by histologic examination of the vegetation or intracardiac abscess; or (iii) in the presence of two major clinical criteria, one major and three minor criteria, or five minor criteria (the major and minor Duke criteria are listed in Table 1).

The diagnosis of IE is rejected when a firm alternate diagnosis explains the manifestations of endocarditis, when the fever resolves with antibiotic therapy for 4 days or less, or when no pathologic evidence of infective endocarditis is found at surgery or autopsy after antibiotic therapy for 4 days or less 70.

Table 1.

Consequently, suspected cases of endocarditis should be investigated until all clinical, epidemiologic, echocardiographic, and laboratory data are compiled in order to be able to establish the diagnostic score.

New etiologic agents of endocarditis such as Bartonella spp.

and the Whipple's disease bacillus 233 have been identified by PCR amplification and sequence analysis of the amplified DNA.

These molecular tools have considerably improved the detection and the identification of noncultivable causative agents of endocarditis88.

This technique is particularly useful for microbial identification in excised infected valves, even after antibiotic therapy.

PCR amplification and subsequent sequence analysis of amplified genes has also been used to better identify fastidious organisms such as Gemella spp.

152.

New cultivation techniques, especially tissue cell culture, have also been successfully used for isolation of fastidious organism such asBartonella65 or strict intracellular pathogens such as C. burnetii and Chlamydia spp.

229, 253.

Tissue cell culture has been greatly improved by using the shell vial technique 229.

Culture of the removed valve has been shown to be much more efficient than blood culture in recovering the organisms in patients with culture-negative endocarditis 192, 193.

The use of enriched media for specific microorganisms such as nutritionally deficient Streptococcus spp.,Legionella spp., or Mycobacteria spp.

has also been helpful in the etiologic diagnosis of endocarditis.

The availability of these improved and new diagnostic tools has considerably enlarged the spectrum of bacteria involved in the etiologic diagnosis of endocarditis.

Herein, we review the epidemiology, clinical presentation, and diagnosis of endocarditis caused by rare and fastidious organisms and then focus on the strategies used for the recovery and identification of the etiologic agents of IE.

This review has been based on a MEDLINE search from 1966 to 1999 using Internet Grateful Med search V2.6.2 from the National Library of Medicine with the following key words: negative blood culture or culture-negative plus endocarditis or endocarditis plus (name of the bacteria and/or the disease).

When a bacterium had different names, such as Abiotrophia spp., all known synonyms were used.

The research was carried out without restriction, except that endocarditis or the name of the bacteria should be included in the title.

Only papers written in English or French were selected.

This research yielded 1,056 references, from which 304 have been selected.

APPROACH TO ETIOLOGIC DIAGNOSIS OF INFECTIVE ENDOCARDITIS
Once the diagnosis of IE is suggested or confirmed, the causative agent can be specifically investigated by evaluation of the medical history, clinical examination, and echographic findings (Fig.1).

Fig.

1.

Medical History
The patient's medical history is an important clue for the etiological diagnosis of IE.

Contact with animals is an important feature; for example, contact with a cat (including scratches or bites) suggests Bartonella henselae or Pasteurella spp., while contact with cattle should suggest a role for C. burnetii or Brucella spp.

Parrots, pheasants, and pigeons have been reported to play a role in Chlamydia psittaci IE 253.

Contact with domestic animals such as swine, fish, and poultry is frequently reported in the history of patients with Erysipelothrix endocarditis.

Consequently, occupational exposure is an important finding.

For example, farmers and veterinarians are exposed to both C. burnettii andErysipelothrix.

The latter is a causative agent of endocarditis in butchers, fishermen, and even in homemakers by contact with organic matter in which the organism is commonly found230.

Contact with arthropods such as lice and fleas should also be considered.

The human body louse is involved in the transmission of Bartonella quintana27, whereas cat fleas are involved in the epidemiology of B. henselaeinfections 143.

Some pathogens are mostly nosocomial in origin.

For example, IE following open heart surgery should suggestLegionella spp., Mycobacterium spp.,Nocardia spp., or fastidious fungi, especially if routine blood cultures are negative 160, 281.

Most reported cases of nosocomial endocarditis occur as small outbreaks, and all available epidemiologic information should be obtained for a diagnosis of postoperative IE.

Since a large number of pathogens involved in IE are of oral origin, a history of a dental procedure is an important feature.

HACEK group bacteria are often found to be pathogens in young adults after dental procedures, but Lactobacillus spp.

andGemella spp.

have also been reported in such situations152, 270.

All information on underlying conditions should be obtained from the patient or from the patient's medical history.

Patients with prosthetic valves are at particular risk for IE.

Of note, patients with prosthetic valves for whom blood cultures are negative are likely to be infected by C. burnetii or B. henselae as etiologic agents, since more than 55% of C. burnetii endocarditis occurs in patients with prosthetic valves266.

Underlying immunocompromising conditions, including AIDS, cancer, and lymphoma, have been reported in 9% of C. burnetii endocarditis patients, especially in the absence of underlying valvular disease.

A medical history of cancer, especially adenocarcinoma associated with disseminated intravascular coagulation, should also suggest the possibility of marantic or nonthrombotic endocarditis, a diagnosis of exclusion when all other investigations are nonrevealing 161.

In a similar manner, IE can be suspected in patients with collagen vascular diseases such as systemic lupus erythematosus, particularly if associated with the presence of antiphopholipid antibodies such as in Libman-Sack endocarditis238.

Even if noninfective endocarditis is suspected, it is important to remember that the valvular lesions induced by inflammatory disease may facilitate the infection of the inflamed valve or graft and cause secondary IE.

Patients should be questioned about their life habits, especially their sexual practices.

A few decades ago,Neisseria gonorrhoeae IE was reported very frequently in sexually active patients; active surveillance and prompt treatment has now significantly reduced this rate.

In a similar way, behaviors such as intravenous drug use and alcohol abuse should be evaluated.

Intravenous drug users are at risk for Neisseria sicca, Clostridium spp., and Eikenella corrodens IE related to injection 8, 56, 118.

E. corrodens has been reported in patients who clean needles with their saliva.

For chronic alcoholics, the involved pathogens are more likely to be related to the underlying immunocompromising condition rather than to specific practices.

B. quintana, Erysipelothrix rhusiopathiae, Campylobacter fetus, Aeromonas hydrophila, Pasteurella spp., and Listeria monocytogenes are most commonly found 38, 65, 77, 104.

Portal hypertension and splenic shunt, which occurs with cirrhosis in these patients, may allow prolonged bacteremia and subsequent valvular infection.

Social conditions may impart specific risks.

For example, homeless persons are often chronic alcoholics and may harbor lice, allowing the transmission of B. quintanainfection, the major fastidious etiologic agent of IE in the homeless27.

Finally, the relative frequency of the microorganism as a cause of IE should be considered in the laboratory investigation.

For example, it is noteworthy that C. burnetii is as frequently recognized as an etiologic agent of IE as are all the HACEK group bacteria together (Table 2).

Table 2.

Clinical Approach
Some clinical presentations are characteristic and should indicate possible IE.

Febrile congestive heart failure is a frequent mode of presentation for patients with endocarditis caused by fastidious organisms, especially C. burnetii and Bartonellaspp., but may also be present with Whipple's disease or HACEK group endocarditis.

In fact, it is likely that this mode of presentation is related to a diagnostic delay.

Emboli are reported in more than 50% of patients infected with microorganisms such as withCorynebacterium diphtheriae, N. sicca, and Haemophilus paraphrophilus46, 278; R. Lopez-Velez, J. Fortun, C. de Pablo, and J. Martinez Beltran, Letter, Clin.

Infect.

Dis.18:660–661, 1994).

When these emboli involve the brain, they may mimic an acute cerebrovascular accident or stroke syndrome, but fever should suggest the diagnosis of endocarditis.

Pulmonary manifestations such as repetitive bronchopneumonia are common in right-sided endocarditis.

Such findings in intravenous drug users or in patients with intravenous catheters should suggest a diagnosis of right-sided endocarditis.

Staphyloccocus spp.,Candida spp., Eikenella corrodens, andSalmonella enterica serovar enteritidis in patients with AIDS and N. sicca and Clostridium spp.

in other patients are potential etiologic agents.

It is important to note that the absence of cardiac murmur does not rule out the diagnosis of IE and can suggest ride-side endocarditis.

Genital organs should be examined, since most cases of gonoccocal endocarditis are associated with active sexually transmitted diseases.

Concomitant gastroenteritis, sinusitis, or pneumonitis should suggest Salmonella spp., H. influenzae, or Chlamydia psittaci as etiologic agents, respectively, while upper respiratory tract infection and pharyngitis is frequently observed in patients with H. aphrophilusendocarditis and in intravenous drug users with C. diphtheriae endocarditis.

In patients with Klebsiella pneumoniae endocarditis, urinary tract infection is common9, and during pregnancy, Listeria monocytogenesis a possible etiologic agent.

Finally, culture-negative endocarditis associated with chronic diarrhea should suggest Whipple's disease.

Echocardiography
Over the past 15 years, a number of investigations have confirmed the important role of transthoracic echocardiography in the diagnosis and management of IE.

Echocardiography must be performed in all patients suspected of having IE.

If transthoracic echocardiography is noncontributory but there is still a high suspicion of IE, transesophageal echocardiography should be performed.

Compared to transthoracic echocardiography, transesophageal echocardiography has improved the sensitivity in defining both vegetative lesions and perivalvular infections, particularly in mural abscesses in patients with IE (sensitivity, 80 to 90%) 237, 247."


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