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The article explores infective endocarditis (IE) caused by rare and fastidious bacteria, which frequently lead to culture-negative cases and complicate the diagnostic process. While IE is typically diagnosed through persistent bacteremia with gram-positive cocci and the detection of vegetations via echocardiography, advanced echocardiographic techniques—particularly transesophageal echocardiography—significantly enhance the sensitivity of the Duke criteria. However, echocardiography is more effective in confirming the presence of IE rather than identifying the specific microbial cause, with approximately 24% of proven IE cases being misclassified as “possible” when blood cultures are negative.

**Uncommon Pathogens and Specialized Diagnostics:**

Uncommon pathogens such as **Bartonella spp.**, **Coxiella burnetii**, **Lactobacillus**, and members of the **HACEK** group necessitate specialized diagnostic approaches. For instance, *Bartonella spp.*, including *B. henselae* and *B. quintana*, are small facultative intracellular gram-negative bacteria that cause various clinical syndromes. *B. henselae* is associated with cat scratch disease and endocarditis in patients with prior valve injury and cat exposure, whereas *B. quintana* is linked to trench fever and endocarditis in homeless or alcoholic individuals exposed to body lice. Specialized diagnostics for these pathogens involve serological tests (e.g., immunofluorescence assays), polymerase chain reaction (PCR) amplification of specific genes (such as the 16S rRNA gene), special staining techniques like Warthin-Starry, and optimized culture conditions.

Effective identification strategies include obtaining multiple blood cultures under stringent conditions—typically three sets within 24 to 48 hours with adequate blood volume—to establish culture-positive endocarditis. Prior antibiotic therapy, common in many patients, can significantly reduce blood culture yields. To mitigate this, methods such as diluting blood samples in broth, using antimicrobial agent removal devices, and employing specialized culture media are essential for isolating fastidious organisms.

**Clinical Presentations and Diagnostic Challenges:**

IE caused by these atypical organisms may present with subacute and insidious symptoms, often lacking conventional signs like fever and cardiac murmurs, especially in elderly patients or those who have received prior antibiotics. Patients commonly present with acute cardiac failure, fever exceeding 38°C, cardiac murmurs, dyspnea on exertion, and bibasilar lung rales indicative of global cardiac failure. Aortic valves are more frequently involved, and embolic phenomena occur in approximately 41% of patients, potentially initiating clinical manifestations.

Advanced molecular and histological techniques have substantially improved the identification and management of these challenging IE cases. Techniques such as PCR amplification of the 16S rRNA gene, immunohistologic testing, and specialized histologic stains (e.g., Warthin-Starry, Gimenez) are invaluable. Additionally, thorough patient histories regarding animal contact, occupational exposures, and potential sources of infection are crucial for accurate diagnosis.

**Treatment and Prognosis:**

Treatment of IE caused by rare pathogens like *Bartonella spp.* typically involves a combination of antibiotics tailored to the specific organism's susceptibility profile. For instance, **Bartonella endocarditis** is often treated with aminoglycosides in combination with doxycycline or ceftriaxone for a prolonged course. Surgery, such as valve replacement, is frequently required due to extensive valvular damage. The prognosis can be poor, especially in cases with delayed diagnosis and treatment, as evidenced by higher mortality rates among certain populations like homeless individuals with *B. quintana* endocarditis.

**Other Rare Etiologies:**

Beyond Bartonella, other rare causative agents of IE include:

- **Mycobacterium spp.**: Acid-alcohol-resistant bacteria causing exceptionally rare forms of endocarditis, often associated with prosthetic valves or medical procedures. Diagnosis typically relies on histologic examination and specialized culture techniques, with combination antibiotic therapy recommended.
  
- **Mycoplasma spp.**: Cell wall-deficient bacteria implicated in very few reported cases of IE. Detection is challenging due to their inability to be visualized by Gram stain and growth in routine cultures. Strategies for isolation include specific agar media and PCR techniques.
  
- **Whipple's Disease Bacterium (Tropheryma whippelii)**: A rare systemic disorder that can present with endocarditis among other symptoms. Diagnosis may involve PCR and specialized culture methods, with limited treatment data available.

**Conclusion:**

The integration of enhanced echocardiographic methods with the Duke criteria, combined with advanced microbiological and molecular diagnostics, significantly improves the detection and management of infective endocarditis caused by less common and fastidious bacterial agents. Understanding the epidemiology, clinical presentations, and appropriate diagnostic and therapeutic strategies for these rare pathogens is essential for improving patient outcomes.
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Intern.

Med.

126:920, 1997).

More recently, the relationship between endocarditis and the Whipple's disease bacillus was established in a patient who presented with diarrhea, fever, grand mal seizure, and a history of a 20-kg weight loss over 4 years297.

The diagnosis was based upon the presence of numerous PAS-positive macrophages in the duodenal biopsy specimen.

After successful antibiotic therapy, he developed acute congestive heart failure due to aortic valve endocarditis, requiring urgent prosthetic valve replacement.

Histologic examination revealed PAS-positive macrophages scattered throughout the entire valve (Fig.

3).

DNA prepared from paraffin-embedded valve tissues identified T. whippelii by PCR and sequencing of the PCR product.

Interestingly, PAS-positive granules have been demonstrated in the brains of patients with and without cerebral manifestation of the disease 84, and rheumatoid factor is found in 8% of these patients.

It is likely that Whipple's disease endocarditis is much more frequent than currently reported.

Recently, four cases were reported in patients without fever or evidence of systemic Whipple's disease110.

Before pathologic examination of the resected valves, which established the diagnosis, one patient fulfilled none of the Duke criteria, two patients fulfilled one major Duke criteria, and one patient fulfilled two Duke criteria (one major and one minor).

Without examination of the excised valves, the diagnosis of IE could not have been made, indicating that Duke criteria for endocarditis are not pertinent for Whipple's disease endocarditis 110, 221.

This underlined the fact that occurrence of the disease is probably underestimated and must depend on an active search for the cause by physician.

In a recent, not yet published review on Whipple's disease endocarditis, we found that data for 34 patients had already been published with enough details to include the valvular lesion as a part of the disease and that those patients presented with aortic damage (14 of 34), mitral damage (5 of 34), tricuspid valve damage (2 of 34), mitral and aortic valve damage (5 of 34), mitral and tricuspid valve damage (3 of 34), and damage to three valves (5 of 34).

The diagnosis is currently based on the histologic observation of PAS-positive macrophages in the surgically resected valve tissues and by PCR identification from either the valve or a duodenal biopsy specimen.

Cultures on axenic media, using chocolate or Columbia sheep blood agar incubated at 32 or 37°C under 5% CO2, or in a microaerophilic or anaerobic atmosphere were unsuccessful.

Similarly, cultures on cell culture medium and cell culture medium with lysates of HEL cells incubated at 32 or 37°C under 5% CO2 were not able to recover the bacilli.

However, Whipple's bacilli can be cultured using human fibroblast cells lines (HEL and MRC5) which are grown in minimal essential medium with 10% fetal calf serum and 2 mMl-glutamine without antibiotics; a control strain is available for the scientific community (222).

By observing the flask monolayer under an inverted microscope, a cytopathic effect could be observed after several weeks; small coarse dark inclusions and large coarse round structures were detected within cells.

The cultured bacterium can been identified by PCR and sequencing of the 16S rRNA.

Legionella spp.

Legionella spp.

are small, facultative, gram-negative intracellular bacteria that cause nosocomial pneumonia and, rarely, disease of extrapulmonary sites165.

Endocarditis due to Legionella spp.

has been cited in only three publications.

In 1984, McCabe reported the first case of Legionella pneumophila endocarditis in a patient with porcine aortic and mitral valve prostheses182.

In 1988, Tompkins et al.

reported seven cases of nosocomial prosthetic-valve endocarditis at Stanford University Hospital Center.

L. pneumophila was isolated in two cases,L.

dumofii was isolated in three cases, both species were identified in one case, and an undefined Legionella sp.

was serologically diagnosed in one case 281.

In 1994, Park et al.

reported one case of serologically diagnosed Legionella micdadei prosthetic-valve endocarditis 208.

(i) Epidemiology.

The natural habitat for L. pneumophila appears to be water, and numerous outbreaks of nosocomial legionellosis due to contaminated water distribution systems have been reported.

The most frequently implicated reservoirs forLegionella spp.

are cooling towers and hot-water tanks268.

In the report of Tompkins et al., L. pneumophila was repeatedly isolated from drinking-water sites in the Medical Center, but these investigators were unable to clarify whether these bacteria were inoculated during or after surgery281.

All documented cases reported in the literature were nosocomial in origin.

(ii) Signs and symptoms.

Patients withLegionella endocarditis often have chronic symptoms, including low-grade fever, night sweats, weight loss, malaise, and symptoms of congestive heart failure.

Anemia was reported as a frequent feature, and its severity appeared to be correlated with the duration of the infection.

Leukocyte counts were normal, but thrombocytopenia was observed.

Unlike prosthetic-valve endocarditis caused by fungi,Legionella endocarditis has not been associated with embolic phenomena.

(iii) Echocardiography and pathology.

Similar to the situation reported for Q fever, Legionella endocarditis vegetations are rarely reported on echocardiography, including transesophageal echocardiography.

Only three of the nine patients reported in the literature were diagnosed by echocardiography281.

Small vegetations were observed on excised valves in five of six surgically treated patients 281.

The small size of these vegetations may explain the lack of embolic manifestations and the low echocardiographic sensitivity.

(iv) Diagnosis.

Legionella endocarditis should be suspected in febrile patients with prosthetic valves and negative blood cultures when serologic testing does not support a diagnosis of Q fever.

Since most of reported cases are nosocomial in origin, Legionella endocarditis is likely to occur in small outbreaks.

Diagnostic delays vary from 3 to 19 months after surgery.

Definitive diagnosis may be made by cultivation of the excised valve, a method that was successful in seven of eight cases, and by blood culture, which was successful in three of eight cases 182, 281.

In fact, when endocarditis caused by Legionellaspp.

is suspected, the clinical microbiology laboratory should be contacted.

Legionella spp.

will grow in most commercial automated blood culture systems, but the amount of growth may be inadequate to attain preestablished thresholds for detection.

Consequently, periodic subcultures of incubating blood cultures from those systems to the preferred medium for Legionellaspp.—buffered charcoal yeast extract (BCYE)—is recommended15.

Serum antibody titers are usually high in cases ofLegionella endocarditis, but the role of serologic testing has not yet been evaluated and the positive predictive value is not known.

PCR assays have been used to detect Legionella spp.

in clinical samples 268.

Despite the high specificity of PCR, it is no more sensitive than culture 268.

(v) Prognosis, prevention, and treatment.

None of the nine reported patients with Legionella endocarditis died, but six patients required prosthetic valve replacement.

Erythromycin at 2 g/day intravenously with rifampin at 600 to 1,200 mg/day or ciprofloxacin at 600 mg/day intravenously was used in all patients except for one, who was treated with doxycycline at 200 mg twice a day 208.

The duration of therapy was at least 5 months, and no relapses were observed 281.

Chlamydia psittaci.

Chlamydia spp.

are obligate intracellular organisms that can be grown only in tissue culture.

The intracellular location explains the difficulty in isolation and identification and the difficulty in investigating its role as a causative agent of endocarditis.

Chlamydia spp.

have often been suggested to be causative agents of endocarditis (18, 24, 60, 61, 89, 132, 136, 156, 201, 231, 253, 285, 291, 295; R. Norton, S. Schepetiok, and T. W. Kok, Letter, Lancet 345:1376–1377, 1995.

D. Dumont, D. Mathieu, M. Alemanni, F. Eb, and G. Manigand, Letter, Press Med.19:1054, 1990).

However, in a recent review of 10 patients reported to have chlamydial endocarditis, 8 were finally diagnosed withBartonella endocarditis after their sera were tested by antibody cross-absorption and Western immunobloting 176, 225.

Interestingly, epidemiologic data for three of these eight patients were comparable to those reported for Bartonellaendocarditis patients, including homelessness and alcoholism 172, 176.

Therefore, by using serologic testing only, it is difficult to know how many patients really have chlamydial endocarditis.

Culture-confirmed chlamydial endocarditis has been identified in only one patient 253, in whom Chlamydia psittaci was cultured from throat and blood.

Even in this case, the diagnosis could not be totally accepted since the cultured microorganism was identified by immunologic techniques only, and still might have represented aBartonella sp.

or atherosclerosis-related Chlamydia pneumoniae219.

The recent report of a serologic cross-reaction betweenChlamydia and Bartonella suggest that serologic results should be carefully interpreted 176.

In patients with suspected Chlamydia endocarditis, Bartonellaspp.

should be excluded by careful serologic analysis including cross-absorption assays and attempts at isolation ofBartonella spp.

Direct identification of microorganisms by monoclonal antibody immunohistochemistry in resected valves may help, but the sensitivity and specificity of such techniques have not yet been evaluated 253.

In the only reported case involving isolation of the organism, whole blood was collected in the absence of anticoagulant, the serum was removed, and the clot was liquefied in a vortex in the presence of glass beads before the suspension was centrifuged to remove debris 253.

The suspension was inoculated onto L929 cells in a shell vial, and the organisms were detected with a rabbit polyclonal antibody directed against C. psittaci.

However, it is again important to note that cross-reactions of Chlamydia spp.

with Bartonellaspp.

using rabbit polyclonal antibody may preclude a definitive identification.

Monoclonal antibodies, cross-absorption of sera with Western immunoblots, and/or molecular techniques such as PCR with hybridization, which is now commercially available, should be used to clearly identify Chlamydia spp.

in patients with endocarditis.

Coxiella burnetii (Q fever agent).

Q fever endocarditis is caused by the obligate intracellular pathogen C. burnetii.

This bacterium lives and multiplies in the phagolysosomes of infected cells at pH 4.8.

In culture, it demonstrates phase variation (phase 1 to phase 2) that is equivalent to the lipopolysaccharide smooth-rough phase variation of members of the family Enterobactericeaceae, an extremely valuable property for diagnosis.

Only C. burnetii cells expressing phase 1 lipopolysaccharide are infectious.

Only patients with chronic Q fever present with high-level phase I immunoglobulin G (IgG) and IgA antibodies.

(i) Epidemiology.

Q fever is prevalent in all countries where it has been studied 227.

At the time of this writing, 359 cases of Q fever endocarditis have recorded throughout the world, with 249 being diagnosed in our laboratory228.

Q fever is a zoonosis that is widespread throughout the world and can present as an acute or chronic disease.

Culture-negative endocarditis is the most prevalent chronic form and represents 78% of cases of chronic Q fever.

Q fever endocarditis represents 8.7 to 11% of all reported Q fever cases 170, 207, causing 3 to 5% of all cases of endocarditis in France, Israel, and Great Britain 207.

The incidence of the disease has been determined to be 1 case per million inhabitants per year in France.

The reservoir of C. burnetii is only partially known.

Although farm animals such as cattle, goats, and sheep are considered primary reservoirs, pets including cats and dogs have also been reported to be infected, explaining urban outbreaks171.

When infected, all of these mammals shed the desiccation-resistant organisms in urine, feces, milk, and birth products 12.

The extreme resistance to physical agents allows C. burnetii to survive for a long period in the environment.

Subsequently, efficient transmission and infection may be wind-borne over long distances owing to the ability of this organism to persist in an environment that lacks mammalian hosts 266, 276.

In humans, infection usually results from inhalation of dust contaminated with parturient fluids of infected livestock.

In France, 80.2% of patients with endocarditis had an identified risk exposure; 59.6% of patients reported animal exposures, and half of these reported exposures to sheep 29.

Infection by consuming raw milk occurs in only 9.6% of patients 29.

Interestingly, only 30% of endocarditis patients live in rural areas, indicating that contamination occurs mainly during short exposures such as farm visits or other recreational activities.

Occupational exposure is found in 12.5% of endocarditis patients, of whom most are male farmers 29.

Together, occupational risk, rural life, and raw milk are significantly associated with C. burnetiiendocarditis compared with endocarditis of other etiologies (D. Raoult, unpublished data).

Two-thirds of patients are male (gender ratio, 2.49).

The relative risk of contracting Q fever endocarditis is five times higher in the 60- to 69-year age range, whereas patients younger than 40 years have only a minor risk.

Underlying disease is found in 90% of patients 266.

Most patients (88.5%) have a preexisting valvular injury.

Underlying heart diseases may be congenital, rheumatic, degenerative, or syphilitic.

Aortic and mitral valves are equally involved, but tricuspid valve endocarditis has been reported only once, in a child with a congenital fistula 166.

Valvular prostheses are present in 55.7% of patients.

Immunocompromising conditions such as cancer, leukemia, and chronic renal failure with dialysis are found in 9% of Q fever endocarditis patients.

Immunocompromise is especially frequent in endocarditis patients without preexisting valvular injury, being present in five of seven patients in one study 29, indicating that immunity plays a critical role in the clinical expression of Q fever 223.

(ii) Signs and symptoms.

Q fever is a severe and often fatal disease that is often associated with a long diagnostic delay.

Complaints are related either to the heart (cardiac failure, valve dysfunction) or to a general illness such as low-grade and intermittent fever, fatigue, and weight loss.

Because these symptoms are not specific and vegetations are rarely detected by echocardiography, diagnosis is often made late, with a mean delay of 12 months.

Fever and acute cardiac failure are the most frequent signs of Q fever endocarditis and are observed in 68 and 67% of patients, respectively.

Cardiac failure is usually diagnosed with general manifestations of dyspnea, acute pulmonary edema, angina, and palpitation.

Fever is often low-grade (38 to 38.5°C), remittent, and well tolerated, explaining why few patients directly seek medical intervention for this alone.

The presence of splenomegaly can be very prominent and is correlated with diagnostic delays 259, sometimes leading to a misdiagnosis of hematologic malignancy28.

Hepatomegaly is also correlated with diagnostic delay, and when it is present, the liver is generally hard and considerably enlarged.

Histologic test results for the liver in endocarditis are not specific; granulomas may be observed, but the fibrin ring surrounding the granulomas, with a lipid vacuole in the center giving the typical “doughnut” aspect frequently observed in acute Q fever, have never been found in the livers of patients with endocarditis 57, 283.

Digital clubbing is seen in one-third of patients, a higher rate than is generally observed for other types of endocarditis266.
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