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**Final Refined Summary:**

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. In older patients, the most prevalent underlying heart disease factor is prosthetic valve replacement, observed in one-third of such cases. Additionally, poor dental hygiene or recent oral surgery has been associated with an increased risk of infection.

**Uncommon Pathogens and Specialized Diagnostics:**

Uncommon pathogens such as **Bartonella spp.**, **Coxiella burnetii**, **Lactobacillus**, **Legionella spp.**, **Chlamydia psittaci**, members of the **HACEK** group, **Klebsiella spp.**, **Serratia marcescens**, **Neisseria spp.**, **Listeria monocytogenes**, **Nocardia spp.**, **Erysipelothrix rhusiopathiae**, **Clostridium spp.**, **Corynebacterium diphtheriae**, **Abiotrophia spp.**, and **Gemella spp.** necessitate specialized diagnostic approaches.

For instance:

- **Bartonella spp.**, including *B. henselae* and *B. quintana*, require serological tests, PCR amplification of specific genes (such as the 16S rRNA gene), special staining techniques like Warthin-Starry, and optimized culture conditions.
  
- **Whipple's Disease** caused by *Tropheryma whippelii* is diagnosed through the presence of PAS-positive macrophages in biopsy specimens and confirmed by PCR and sequencing.
  
- **Legionella spp.** endocarditis necessitates buffered charcoal yeast extract (BCYE) media and PCR for accurate identification.
  
- **Chlamydia psittaci** endocarditis often requires advanced molecular techniques due to serological cross-reactivity with Bartonella spp.
  
- **Coxiella burnetii** (Q fever) diagnosis involves high-phase I IgG and IgA antibodies, PCR, and histologic observation of infected tissues.
  
- **HACEK Group Bacteria** require prolonged incubation times and specific culture conditions, including subculture on 5 to 8% sheep blood and chocolate agar in a CO₂-enriched environment.
  
- **Klebsiella spp.**, particularly *K. pneumoniae* and *K. oxytoca*, are associated with high virulence, often originating from urinary tract infections, and require continuous bacteremia detection through positive blood cultures.
  
- **Serratia marcescens** endocarditis is predominantly seen in intravenous drug users, with a high mortality rate if diagnosis is delayed.
  
- **Neisseria spp.**, including *N. gonorrhoeae* and other species like *N. elongata* and *N. sicca*, present with acute febrile endocarditis and often require valve replacement alongside antibiotic therapy.
  
- **Listeria monocytogenes** endocarditis occurs mostly in immunocompromised individuals and is treated with ampicillin and aminoglycosides.
  
- **Nocardia spp.** endocarditis, though exceedingly rare, is associated with prosthetic valves and requires aggressive antibiotic therapy combined with surgical intervention.
  
- **Erysipelothrix rhusiopathiae** endocarditis is linked to occupational exposure and animal contact, diagnosed via positive blood cultures, and treated with penicillin G.
  
- **Clostridium spp.** endocarditis presents with clostridial sepsis symptoms and requires prompt antibiotic therapy, though prognosis remains poor.
  
- **Corynebacterium diphtheriae** endocarditis, often linked to respiratory or skin sources, is treated with penicillin and aminoglycosides.
  
- **Abiotrophia spp.** (formerly nutritionally variant streptococci) and **Gemella spp.** require molecular identification techniques and are treated with high-dose penicillin and aminoglycosides.

  - **Abiotrophia spp.** cause approximately 5 to 6% of all streptococcal endocarditis cases. These fastidious organisms are often misdiagnosed as culture-negative IE, potentially underestimating their prevalence. Preexisting heart disease is found in 90% of patients, with prosthetic heart valves involved in only 10% of cases. Clinical presentations are typically slow and indolent, with complications such as septic arthritis observed as the disease progresses. Diagnosis has improved with enhanced culture media, including cysteine supplementation, and molecular techniques like 16S rRNA gene sequencing. Treatment is challenging due to high rates of bacteriological failure (41%) despite antibiotic therapy, necessitating combination treatments such as penicillin with gentamicin or vancomycin alone in certain cases. Morbidity and mortality exceed those of other streptococcal forms, with significant proportions of patients requiring valve replacement or succumbing to uncontrolled heart failure or embolic events.

  - **Gemella spp.**, including *Gemella morbillorum* and *Gemella haemolysans*, are easily decolorized during Gram staining and often misidentified as gram-negative cocci. They account for a notable percentage of misclassified viridans group streptococci. Endocarditis due to Gemella spp. is associated with poor dental hygiene and previous valvular damage, presenting with low-grade intermittent fever and new or modified cardiac murmurs in two-thirds of cases. Embolic manifestations are common, and diagnosis relies on accurate Gram staining interpretation and molecular identification methods like 16S rRNA gene sequencing. Treatment typically involves penicillin and gentamicin, with reported outcomes being favorable, including low fatality rates and minimal requirement for surgical interventions.

**HACEK Group Bacteria:**

The HACEK group comprises fastidious, small gram-negative bacilli primarily from the oropharyngeal flora, responsible for approximately 3% of all endocarditis cases. This group includes *Haemophilus parainfluenzae*, *H. influenzae*, *H. aphrophilus*, *H. paraphrophilus*, *Actinobacillus actinomycetemcomitans*, *Cardiobacterium hominis*, *Eikenella corrodens*, and *Kingella spp.* These organisms are slow-growing, with growth enhanced by carbon dioxide, and require specific culture conditions. Each HACEK organism demonstrates unique epidemiological and clinical characteristics:

- **Haemophilus paraphrophilus**: Rare, often associated with mitral valve prolapse and previous valve abnormalities. Clinical features include fever, cardiac murmurs, and embolic events. Valve replacement is required in 24% of cases.
  
- **Haemophilus aphrophilus**: Commonly linked to dental procedures and upper respiratory infections. Echocardiography detects vegetations in 70% of patients. Improved diagnostic delay has led to better prognoses in recent reports.
  
- **Haemophilus parainfluenzae**: Presents insidiously, often following dental procedures. Embolic complications are frequent, with a case fatality rate between 10-35%.
  
- **Actinobacillus actinomycetemcomitans**: Associated with periodontal disease and prior dental infections. Affects young to middle-aged patients, with a case fatality rate of 9-15% and valve replacement required in 28% of cases.
  
- **Cardiobacterium hominis**: Linked to dental infections and underlying heart disease, predominantly affecting the aortic valve. Mortality is around 13%, with 30% requiring valve replacement.
  
- **Eikenella corrodens**: Often found in intravenous drug users due to syringe contamination. Generally causes a mild course with a 15% fatality rate and rare need for valve replacement.
  
- **Kingella spp.**: *Kingella kingae* primarily affects young children, while *Kingella denitrificans* is less common. In older patients, prosthetic valves are a significant risk factor. Kingella spp. predominantly colonize the upper respiratory tract, particularly the tonsils, and are not primary pathogens but exploit mucosal impairments resulting from viral infections. Concomitant stomatitis, pharyngitis, or varicella virus-induced buccal ulcers have been reported in children with *Kingella* bacteremia. A fatality rate of 16% has been reported in *K. kingae* endocarditis, with central nervous system emboli detected in 25% of cases.

**Effective Identification Strategies:**

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. Due to the slow growth of HACEK bacteria and other fastidious organisms, prolonged incubation times (3 to 5 days, potentially up to 30 days for organisms like *A. actinomycetemcomitans*) are essential. Specialized culture methods, such as subculture on 5 to 8% sheep blood and chocolate agar at 35 to 37°C in 5 to 10% CO₂, are required. Molecular techniques using 16S rRNA gene analysis may be necessary for difficult identifications. 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. No significant difference in bacterial growth was found between the Septicheck bottle and the Isolator tube.

**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. Additional clinical manifestations include:

- **Digital Clubbing**: Observed in one-third of patients, a higher rate than typically seen in other forms of endocarditis.
  
- **Purpuric Rash**: Found in one-fifth of patients, usually occurring on the extremities and mucosa. Skin biopsies reveal immune complex vasculitis.
  
- **Renal Involvement**: Proliferative glomerulonephritis has been reported, increasing the risk of renal insufficiency. Laboratory findings may include microscopic hematuria, elevated serum hepatic transaminases, lactate dehydrogenase, creatine phosphokinase, cryoglobulins, and hyperglobulinemia.
  
- **Embolic Manifestations**: Occur in about 20-41% of patients, involving cerebral and extremity vessels. Arterial embolism may present as stroke, potentially requiring embolectomy or amputation.
  
- **Pulmonary and Pleural Manifestations**: Can be complications of endocarditis.

**Specific Presentations in Rare IE Types:**

- **Whipple's Disease Endocarditis**: May include systemic symptoms like diarrhea, weight loss, neurological manifestations, and acute congestive heart failure.
  
- **Legionella Endocarditis**: Associated with chronic symptoms such as low-grade fever, night sweats, weight loss, and signs of congestive heart failure without embolic events.
  
- **Coxiella burnetii Endocarditis (Q Fever)**: Typically affects individuals with preexisting valvular injuries, presenting with prolonged fever, cardiac dysfunction, splenomegaly, and hepatomegaly. Laboratory findings often include high-phase IgG and IgA antibodies, circulating immune complexes, rheumatoid factor, anemia, thrombocytopenia, hyperglobulinemia, and various autoantibodies.
  
- **Klebsiella Endocarditis**: Characterized by antecedent urinary tract infections, high virulence with native and prosthetic valve involvement, continuous bacteremia, and a high mortality rate (49%) if diagnosis is delayed. Echocardiography usually demonstrates large vegetations, and blood cultures are always positive. Cardiac murmurs may be absent or missed, especially in right-sided endocarditis. Myocardial abscesses may lead to culture-negative diagnoses, eventually identified post-surgery.
  
- **Neisseria gonorrhoeae Endocarditis**: Presents in younger patients (mean age 27) with a prolonged symptom duration (~45 days), fever in 60%, and acute congestive heart failure in one-third. Associated with sexually transmitted diseases and often requires valve replacement (50% of cases) with a high mortality rate (25%) despite antibiotic therapy.
  
- **Listeria monocytogenes Endocarditis**: Occurs mainly in immunocompromised individuals, presenting as a subacute disease with fever, weakness, dyspnea, and cardiac murmurs. Acute congestive heart failure is common (50%), and treatment involves ampicillin and aminoglycosides.
  
- **Lactobacillus Endocarditis**: Associated with dental manipulations in 75% of cases and a high frequency of systemic emboli (42%). Underlying heart disease is present in 83% of patients, and relapse occurs in 39% of inadequately treated cases.
  
- **Nocardia spp. Endocarditis**: Extremely rare, mostly in patients with prosthetic valves, with a high mortality rate (67%) despite treatment involving intravenous antibiotics and valve replacement.
  
- **Erysipelothrix rhusiopathiae Endocarditis**: Linked to occupational exposure (89%), particularly in butchers and fishermen, with characteristic skin lesions (erysipeloid) in 40% of patients. Treatment with penicillin G is effective, though mortality remains high (38%).
  
- **Clostridium spp. Endocarditis**: Presents with clostridial sepsis symptoms such as shock, jaundice, and intravascular hemolysis. Associated with high mortality (47%) despite antibiotic treatment, often linked to intravenous drug use or underlying malignancies.
  
- **Corynebacterium diphtheriae Endocarditis**: Often occurs in the context of pharyngitis or intravenous drug use, with underlying heart diseases like valve damage. Treated with penicillin and aminoglycosides.
  
- **Abiotrophia spp. Endocarditis**: Characterized by a slow and indolent course, often in patients with preexisting heart disease (90%). Classical peripheral manifestations like digital clubbing, petechiae, and Osler nodes are infrequent, but embolization occurs in one-third of patients. Diagnosis has improved with specialized culture media and molecular techniques. Treatment is challenging due to high rates of bacteriological failure and resistance to penicillin in over 30% of strains. Combination therapies, such as penicillin with gentamicin or vancomycin alone, have shown effectiveness in certain models and patient populations. Prognosis remains poor with significant mortality and a high need for valve replacement.
  
- **Gemella spp. Endocarditis**: Associated with poor dental hygiene and previous valvular damage, presenting with low-grade intermittent fever and new or modified cardiac murmurs in two-thirds of cases. Embolic events are common, and diagnosis relies on accurate Gram stain interpretation and molecular identification. Treatment typically involves penicillin and gentamicin, with favorable outcomes reported, including low fatality rates and minimal surgical interventions.

**Treatment and Prognosis:**

Treatment of IE caused by rare pathogens typically involves a combination of antibiotics tailored to the specific organism's susceptibility profile:

- **Bartonella Endocarditis**: Often treated with aminoglycosides in combination with doxycycline or ceftriaxone for a prolonged course.
  
- **Whipple's Disease Endocarditis**: Requires prolonged antibiotic therapy targeting *T. whippelii*, often necessitating surgical intervention such as valve replacement due to extensive valvular damage.
  
- **Legionella Endocarditis**: Treated with macrolides or fluoroquinolones.
  
- **Coxiella burnetii Endocarditis (Q Fever)**: Typically requires doxycycline combined with hydroxychloroquine for at least 18 months, along with serum antibody surveillance and plasma level monitoring of hydroxychloroquine.
  
- **HACEK Group Bacteria**: Treated with β-lactamase-stable cephalosporins for 4 weeks (native valves) or 6 weeks (prosthetic valves). Prophylaxis for dental procedures includes amoxicillin, with alternatives like clindamycin or pristinamycin for allergic patients.
  
- **Klebsiella Endocarditis**: Managed with broad-spectrum cephalosporins or fluoroquinolones, though high mortality necessitates prompt diagnosis and aggressive treatment.
  
- **Neisseria Endocarditis**: Requires appropriate antibiotic therapy and often valve replacement, with improved outcomes in recent years.
  
- **Listeria and Lactobacillus Endocarditis**: Treated with combinations such as ampicillin and aminoglycosides, with considerations for high relapse and mortality rates in inadequately treated cases.
  
- **Nocardia, Erysipelothrix, Clostridium, Corynebacterium, Abiotrophia, and Gemella Endocarditis**: Require specific antibiotic regimens, often combined with surgical interventions, to improve prognosis. Mortality rates vary, with some infections like *Clostridium spp.* having particularly poor outcomes despite treatment.
  
- **Gemella spp.** specifically respond well to penicillin and gentamicin, with reported favorable outcomes and low fatality rates.

The prognosis of IE caused by rare pathogens can be poor, especially in cases with delayed diagnosis and treatment. High mortality rates are noted in infections like *Klebsiella* and *Clostridium* endocarditis. However, advancements in diagnostic and therapeutic strategies, including the use of molecular techniques and tailored antibiotic therapies, have improved outcomes for many patients. Early identification and appropriate management are crucial for reducing mortality and the need for surgical interventions.

**Other Rare Etiologies:**

Beyond the 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 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.
  
- **Pasteurella spp.**: Small, gram-negative, nonmotile coccobacilli commonly associated with close contact with cats or dogs (44% of cases). Endocarditis caused by Pasteurella spp. has been reported in 21 cases, with a mortality rate of 31%, often related to diagnostic delays rather than antibiotic resistance.
  
- **Brucella spp.**: Small, facultative, gram-negative, intracellular bacteria causing zoonotic infections primarily through ingestion of contaminated milk or close contact with infected animals. Brucella endocarditis occurs in 0.3-0.6% of brucellosis cases, with a high fatality rate. Diagnosis relies on prolonged blood culture incubation and serological tests, while treatment typically involves a combination of doxycycline and rifampin or streptomycin for several months, often accompanied by surgical intervention.
  
- **Bordetella spp.**: Only one reported case of *Bordetella holmesii* endocarditis, diagnosed via molecular techniques after isolation from blood culture in a patient with a bicuspid aortic valve.
  
- **Francisella tularensis**: A single reported case of endocarditis, identified through extended blood culture incubation using radiometric systems.
  
- **Aeromonas hydrophila**: Two reported cases of endocarditis in cirrhotic patients, associated with waterborne exposure.
  
- **Yersinia enterocolitica**: Twelve reported cases of endocarditis, often in patients with underlying conditions such as iron-overloading states or immunosuppression. Treatment typically involves broad-spectrum cephalosporins and gentamicin, with a 25% mortality rate in untreated cases.
  
- **Salmonella spp.**: Thirty-three reported cases of endocarditis, primarily *Salmonella enterica* serovar Enteritidis. Occurs mostly during or after concomitant Salmonella infections like gastroenteritis, especially in immunocompromised individuals or those with prosthetic valves. Echocardiography usually demonstrates large vegetations with positive blood cultures.

**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.

**Acknowledgment**

We thank J. S. Dumler (Johns Hopkins Medical Institution, Baltimore, Md.) for a review of English usage.