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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**, **Legionella spp.**, **Chlamydia psittaci**, 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.

Additionally, **Whipple's Disease** caused by *Tropheryma whippelii* presents unique diagnostic challenges. Diagnosed through the presence of PAS-positive macrophages in duodenal or valvular biopsy specimens and confirmed by PCR and sequencing, Whipple's disease endocarditis is likely underreported due to its subtle presentation and reliance on invasive diagnostic methods. **Legionella spp.** endocarditis, though exceedingly rare, is associated primarily with nosocomial infections and prosthetic valves, requiring specialized culture techniques such as buffered charcoal yeast extract (BCYE) media and PCR for accurate identification. **Chlamydia psittaci** endocarditis is often misdiagnosed due to cross-reactivity with Bartonella spp. in serological tests, necessitating advanced molecular techniques for definitive identification. **Coxiella burnetii** (Q fever) endocarditis is another significant etiology, particularly prevalent in individuals with occupational exposure to farm animals, diagnosed through high-phase I IgG and IgA antibodies, PCR, and histologic observation of infected tissues.

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.

Specifically, **Whipple's Disease Endocarditis** may present with a history of systemic symptoms such as diarrhea, weight loss, and neurological manifestations, alongside acute congestive heart failure. **Legionella Endocarditis** often involves chronic symptoms like low-grade fever, night sweats, weight loss, and signs of congestive heart failure without embolic events. **Coxiella burnetii Endocarditis** typically affects individuals with preexisting valvular injuries and presents with prolonged fever, cardiac dysfunction, and may include splenomegaly and hepatomegaly.

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. **Whipple's Disease Endocarditis** requires prolonged antibiotic therapy, often with combinations targeting *T. whippelii*, and frequently necessitates surgical intervention such as valve replacement due to extensive valvular damage. **Legionella Endocarditis** is treated with macrolides or fluoroquinolones, and **Coxiella burnetii Endocarditis** typically requires doxycycline combined with hydroxychloroquine for an extended duration. Surgery, such as valve replacement, is frequently required across these atypical infections due to the extensive damage they cause. 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 and the newly detailed pathogens, 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. Active investigation for atypical organisms, especially in culture-negative cases, and a high index of suspicion based on patient history and clinical features are crucial for timely and accurate diagnosis and effective treatment.
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Digital clubbing is seen in one-third of patients, a higher rate than is generally observed for other types of endocarditis266.

A purpuric rash is found in one-fifth of patients and generally occurs on the extremities and the mucosa 266.

When a skin biopsy is performed, histologic examination of the specimen shows immune complex vasculitis.

Renal involvement can occur, and proliferative glomerulonephritis has been reported 212, 280, 284, increasing the risk of renal insufficiency.

Embolic manifestations occur in about 20% of patients and can involve cerebral and upper- or lower-extremity vessels.

Embolectomy or amputation may be required.

One typical manifestation of arterial embolism is stroke.

Pulmonary and pleural manifestations can be observed as a complication of endocarditis 169.

Clues to the diagnosis of Q fever endocarditis include valvular heart disease, such as valvular dysfunction, in association with an unexplained infectious or inflammatory syndrome 227.

This could be a purpuric rash, renal failure, stroke, or, more frequently, progressive heart failure.

Some patients require several valve replacement surgeries before the diagnosis is established.

Laboratory findings during Q fever endocarditis 29, 266 include circulating immune complexes (in 89% of patients), rheumatoid factor (in 83%), anaemia (<10 mg/100 ml) (in 60%), thrombocytopenia (<150,000/mm3) (in 50%), and microscopic hematuria (in 38%).

Serum hepatic transaminase concentrations, particularly aspartate aminotransferase and alkaline phosphatase, are elevated in most patients 29.

Lactate dehydrogenase and creatinine phosphokinase levels are also frequently increased, as are cryoglobulin levels 266.

Hyperglobulinemia is observed in 94% of patients.

This is reported to be helpful when the globulin fraction represents more than 50% of the total protein concentration.

In this case, a polyclonal increase in the IgG and IgA levels is noted.

The longer the diagnostic delay, the higher the globulin concentration becomes.

Anti-smooth muscle antibodies, circulating anticoagulant antibodies, antimitochondrial antibodies, a positive Coombs test, and low titers of antinuclear antibodies may be observed (158; L. Elovaer-Blanc, C. Andre, E. S. Zafrani, M. F. Saint-Marc Girardin, M. Govault-Helmann, and D. Dhumeaux, Letter, Gastroenterol.

Clin.

Biol.

8:980, 1984).

(iii) Pathophysiology and echocardiography.

Patients suffering from Q fever endocarditis have profound lymphocyte unresponsiveness to C. burnetii that results in a lack of macrophage activation 244.

Peripheral blood mononuclear cells from patient with Q fever endocarditis produce large amounts of interleukin-10 and transforming growth factor β that may play a role in the survival of C. burnetii in macrophages37.

A very high level of specific antibodies is found in the humoral immune response in Q fever endocarditis.

These antibodies are not protective and, in association with C. burnetiiantigen, result in immune complexes that are responsible for many aspects of the disease 49.

The general pathologic changes of valves in patients with Q fever endocarditis differs from those seen in patients with other causes of endocarditis in that Q fever vegetations often have a nodular appearance and a smooth surface.

In some cases, the valves even appear normal on gross examination.

By histologic testing, the valves demonstrate a mixture of acute and chronic inflammation with fibrin deposits, necrosis, and fibrosis; no well-formed granulomas are observed.

C. burnetii can be detected in valves by immunohistochemistry, which shows that bacteria occur nearly exclusively in macrophages at sites of inflammation and valvular injury and only in the vegetations (Fig.

5) 25.

Transthoracic echocardiography detects vegetations in only 12.5% of patients 29.

In fact, Turck et al.

reported that of 10 valves from patients with Q fever endocarditis examined either at autopsy or after surgery, small vegetations with insignificant valve damage were observed in 5 283.

The use of transesophageal echocardiography appears to be promising 137.

(iv) Diagnosis.

Q fever should be considered in all patients with culture-negative endocarditis.

A specific diagnosis is easily made by serologic testing.

Antibody to phase 1 and phase 2 antigens may be determined using a variety of tests.

The reference technique is IFA, which should distinguish between titers of IgM, IgG, and IgA antibodies.

Q fever endocarditis is characterized by a very high titer of antibody to both phase 1 and phase 2 antigens of C. burnetii.

An anti-phase 1 IgG antibody titer of ≥800 plus IgA antibody ≥100 is highly predictive and sensitive 279.

IgM titers may vary.

In these situations, a single serum sample is sufficient for the diagnosis of Q fever endocarditis.

C. burnetii may be isolated from the blood in 53% of untreated patient 193 and from the valves even in treated patients192.

Isolation of C. burnetii in cell culture should be restricted to laboratories equipped for isolation of dangerous pathogens.

In our laboratory, culture of C. burnetii is obtained by inoculation of human fibroblasts grown in shell vials 229.

After 6 days, infected tissue culture cells are revealed by IFA with rabbit polyclonal antibodies or mouse monoclonal antibodies.

The diagnosis of Q fever endocarditis may also be established by demonstrating C. burnetii in heart valves by immunohistochemistry.

In a recent immunohistologic study, C. burnetii was visualized in the valves of 10 of 14 culture-confirmed Q fever endocarditis patients 25.

Detection of C. burnetii DNA by PCR is another diagnostic method 264 that can be used on blood or for paraffin-embedded infected heart valves 265.

(v) Prognosis and treatment.

In untreated patients, the prognosis of Q fever endocarditis is poor.

In older studies, death was reported in 60% of patients, most probably related to diagnosis delay 29.

Due to better treatment, prognosis has considerably improved, but Q fever endocarditis is still a severe disease with numerous relapses unless properly treated.

In vitro,C.

burnetii is susceptible to doxycycline, rifampin, co-trimoxazole, and clarithromycin 178.

Quinolones, chloramphenicol, ceftriaxone, and fucidic acid have variable efficacy220.

Until recently, a tetracycline in combination with a quinolone was recommended as first-line therapy for Q fever endocarditis.

Although this approach was more effective than other combinations, relapses and positive valve cultures still occurred even after several years of therapy 157.

Subsequently, prolonged treatment for at least 3 years was proposed 157.

The ineffectiveness of this therapy was related to the fact that these antibiotics were only bacteriostatic in vitro.

The lack of bactericidal activity was speculated to be due to antibiotic inactivation in the acidic phagolysosome in which C. burnetii lives and multiplies 224.

The bactericidal activity of doxycycline was restored when a lysosomotropic alkalinizing agent was added174.

More recently, the combination of doxycycline with hydroxychloroquine, a lysosomotropic alkalinizing agent used for malaria, has proved more effective than therapy with doxycycline and a quinolone in human clinical trials 226; this treatment was prescribed for at least 18 months.

No relapses were observed among 21 patients treated with hydroxychloroquine compared to relapses in 7 of the 14 patients treated with the doxycycline-quinolone regimen.

Moreover, this treatment shortened the duration of therapy.

Conditions for discontinuation of therapy were met after a mean of 31 months in the doxycycline-hydroxychloroquine group versus 55 months in the doxycycline-quinolone group 226.

We conclude that the treatment for Q fever endocarditis should involve a combination of 200 mg of doxycycline per day plus 200 mg of hydroxychloroquine three times a day 226.

The dosage of hydroxychloroquine should be determined by monitoring its levels in plasma to maintain a concentration between 0.8 and 1.2 μg/ml for at least 18 months226.

Surveillance of antibodies to phase 1 lipopolysaccharide by IFA is recommended six times a year, and treatment may be stopped when phase 1 IgG antibodies drop below a titer of 800 and phase 1 IgM and IgA antibodies drop below a titer of 50226.

Surgery for Q fever endocarditis has occasionally been reported as an effective therapy 19.

In our opinion, surgery should be reserved for patients with hemodynamic instability only, since no studies have yet proved a beneficial effect.

Although prevention of Q fever endocarditis has not yet been studied, patients with known underlying valve injury who acquire acute Q fever should probably be treated for longer than patients without valve damage since one-third will progress to Q fever endocarditis.

Vaccination should be recommended for such patients who are specifically exposed, but currently an effective vaccine is available only in Australia.

Gram-Negative Bacilli
The gram-negative bacilli that cause endocarditis are listed in Table 4 and discussed below.

Table 4.

HACEK group bacteria.

Fastidious, small gram-negative bacilli (primarily members of the oropharyngeal flora) have been long recognized as a cause of infective endocarditis.

Collectively, these organisms are referred to as the HACEK group and includeHaemophilus parainfluenzae, H. influenzae,H.

aphrophilus, H. paraphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis,Eikenella corrodens, and Kingella spp.

Common features of the HACEK group of microorganisms are that they frequently colonize the oropharynx, they are slow growing, and their growth is enhanced by the presence of carbon dioxide 54.

These organisms are not monophyletic based on their 16S rRNA sequence and do not represent a bacterial classification (Fig.

7).

Fig.

7.

HACEK microorganisms are reported to cause 3% of all endocarditis cases, with 399 cases having been reported in the literature, a number comparable to that of C. burnetii endocarditis cases (Table2).

Despite the common epidemiologic characteristics, which include previous dental procedures, infections in young and middle-aged adults, previous underlying heart disease, and a preference for mitral valves, every infectious agent demonstrates some unique characteristics that require description.

(i) Epidemiology.

Only 21 cases of H. paraphrophilus endocarditis have been reported 46, 52, 99.

Fever, cardiac murmur, acute congestive heart failure, and embolic manifestations are common clinical characteristics.

H. paraphrophilus endocarditis usually occurs on previously abnormal valves, but it is interesting that mitral valve prolapse is a frequently reported predisposing condition, having been observed in 10 of 16 reported cases and potentially representing a clue to the etiological diagnosis 46.

In one case, oral manipulation was reported as a possible source of infection.

In other cases, there was no clear evidence of a primary focus.

As in other HACEK group endocarditis cases, valve replacement has been performed in 24% of patients.

H. aphrophilus is frequently found in dental plaque and gingival scrapings.

It is the most prevalent of theHaemophilus spp.

involved in endocarditis 52.

A total of 78 cases have been published 52, 73, 99.

Dental manipulation as a source of infection is well documented, but upper respiratory tract infection is another site from which infection may be initiated 73.

Previous valve injury is a common finding, and prosthetic valves are noted in 20% of patients 73.

Echocardiography demonstrates vegetations in 70% of patients.

Death following emboli or congestive heart failure in older reports was close to 50% 73.

A shortened diagnostic delay has improved the prognosis, and no deaths were documented in the last study reported52.

H. parainfluenzae has been reported in 66 cases of endocarditis 53, 99, 109, 113, 167.

H. parainfluenzae endocarditis has an insidious onset, with the first symptoms developing more than 1 month following routine dental procedures 109.

Endocarditis usually occurs in patients with previous heart disease, and prosthetic valves are involved in 10% of patients.

The mitral valve is most often involved.

When detected by echocardiography, emboli from large vegetations led to major occlusive disease in 85% of patients.

H. parainfluenzae endocarditis is polymicrobial in 10% of patients, leading to potential misdiagnoses.

The case fatality rate is reported to be between 10 to 35% 167.

H. influenzae endocarditis has been reported in 13 patients52, 99, 167.

The clinical presentation is unremarkable but is often associated with evidence of focal infection such as sinusitis or encephalitis; valve infection may occur following bacteremia.

Underlying heart disease is rarely documented.

The reservoir forH.

influenzae is the oropharynx.

With 93 reported cases, Actinobacillus actinomycetemcomitansis the most frequent agent of endocarditis in the HACEK group 11, 20, 41, 100, 106, 107, 139, 206, 249.

This bacterium was frequently found associated with Actinomyces infections, as suggested by its name, and is commonly found in human periodontal cultures 139.

It may be transmissible among individuals since approximately 50% of family members of patients with localized juvenile periodontal disease harbor the organisms compared with less than 25% of the general population 41.

Prior dental disease was found in 46% of patients with A. actinomycetemcomitans endocarditis, which occurs in young middle-aged patients.

Underlying heart disease was noted in 70% of infected patients including those with previous cardiac valve damage (33%) and prosthetic valves (28%) 11, 106.

The case fatality rate is between 9 and 15%, depending on the series.

Valve replacement was required for 28% of patients after acute cardiac failure, persistent infection, or systemic emboli.

Cardiobacterium hominis endocarditis has been recorded in 76 patients 97, 135, 155, 218, 248, 273, 302.

C. hominis is a member of the normal oral flora, and earlier dental procedures or oral infections were found in 44% of patients with endocarditis 302.

Prior cardiac disease was reported in 75% of patients, including 13% with prosthetic valves that were infected as a late complication of cardiac surgery.

In contrast to other HACEK organisms, C. hominis infects the aortic valve more frequently than it infects the other valves.

Death occurs in 13% of patients, and valve replacement is required in 30% of patients.

Eikenella corrodens endocarditis has only been reported in 19 patients in the literature 56, 98, 115, 148, 203.E.

corrodens has been found in dental and gingival scrapings and can be isolated from 16% of blood cultures taken 1 minute after tooth extraction 148.

E. corrodens has been found with a particularly high frequency in intravenous drug users, perhaps due to contamination of syringe needles with saliva before injection.

The infection is usually polymicrobial (50%) and is associated with Streptococcus spp.

E. corrodensfrequently infects the tricuspid valve.

Other recognized predisposing conditions for endocarditis are previous valve damage, prosthetic heart valves, and immunocompromised states such as leukemia.

E. corrodens endocarditis is an insidious disease that does not result in rapid clinical deterioration and is rarely fatal.

The fatality rate in all studies since 1972 is 15%, and only 1 valve replacement was reported in these 19 patients.

Endocarditis due to Kingella spp.

has been reported in 33 patients, 28 of whom were infected with Kingella kingae(79, 105, 183, 190, 202, 303; D. B. Jenny, P. W. Letendre, and G. Iverson, Letter, Rev.

Infect.

Dis.10:1065–1066, 1988 [Erratum, 10:1065]) and 5 of whom were infected with Kingella denitrificans116.

K. kingae endocarditis occurred more frequently in very young children, and 40% of patients were younger than 20 years.

Half of these patients had normal cardiac valves, while the others had congenital heart conditions such as tetralogy of Fallot or mitral valve prolapse.

In older patients, the most prevalent underlying heart disease factor was prosthetic valve replacement, which was observed in one-third of patients.
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