Your job is to produce a final summary.
We have provided an existing summary up to a certain point: **Refined Summary:**

The article delves into infective endocarditis (IE) caused by rare and fastidious bacteria, which often result in culture-negative cases and complicate the diagnostic process. While IE is generally diagnosed through persistent bacteremia with gram-positive cocci and the detection of vegetations via echocardiography, echocardiographic techniques—especially transesophageal echocardiography—play a pivotal role in enhancing the sensitivity of the Duke criteria. Nonetheless, echocardiography is more effective in confirming the presence of IE rather than determining the specific microbial cause, with approximately 24% of proven IE cases being misclassified as “possible” when blood cultures are negative.

Uncommon pathogens such as Bartonella, Coxiella burnetii, Lactobacillus, and members of the HACEK group require specialized diagnostic approaches. These include serological tests, polymerase chain reaction (PCR), special staining techniques, and optimized culture conditions. Effective identification strategies involve obtaining multiple blood cultures under stringent conditions—typically three sets within 24 to 48 hours with sufficient blood volume—to establish culture-positive endocarditis. Prior antibiotic therapy, which is common in many patients, can significantly reduce the yield of blood cultures. To address 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 of IE caused by these atypical organisms may lack conventional symptoms like fever and cardiac murmurs, particularly in elderly patients or those who have received prior antibiotics. Advanced molecular and histological techniques, including PCR amplification of the 16S rRNA gene, immunohistologic testing, and specialized histologic stains (e.g., Warthin-Starry, Gimenez), have substantially improved the identification and management of these challenging IE cases. Additionally, thorough patient histories regarding animal contact, occupational exposures, and potential sources of infection are crucial for accurate diagnosis.

Overall, 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.
We have the opportunity to refine the existing summary (only if needed) with some more context below.
------------
Table 3.

Bartonella spp.

Bartonella spp.

are small facultative intracellular bacteria that stain gram negative and belong to the α2 division of the proteobacteria (Fig.6).

These organisms cause various clinical syndromes in immunocompetent and immunocompromised hosts.

B. henselae causes cat scratch disease, meningoencephalitis, and prolonged fever in immunocompetent patients and bacillary angiomatosis and hepatic peliosis in human immunodeficiency virus HIV-infected patients 179.

B. quintana causes trench fever, lymphadenopathy with fever, and bacillary angiomatosis.

Endocarditis is caused by both B. henselae and B. quintana, and it has been found to be caused by B. elizabethae51 and B. vinsonii239 in only one reported case each.

Fig.

6.

(i) Epidemiology.

The epidemiology and clinical manifestations of Bartonella infections have been recently reviewed 175, 179.

Bartonella infections were first reported from the United States and France, but many recent reports showed that Bartonella spp.

are distributed worldwide.

B. henselae is transmitted to humans by a cat scratch or bite or by cat fleas.

B. quintana is transmitted by the human body louse.

The reservoir of B. henselae is the cat, which is chronically bacteremic, and humans are likely to be the reservoir of B. quintana.

Review of the literature and personal unpublished observations found a total of 54 cases ofBartonella endocarditis, 8 of which were caused by B. henselae10, 63, 112, 126, 225, 20 were caused byB.

quintana30, 65, 131, 168, 225, 257, 258, 1 was caused by B. elizabethae51, one was caused by B. vinsonii239, and 20 were not characterized at the species level since they were diagnosed by serologic testing alone 75, 172, 225; unpublished data).

Bartonella infection was diagnosed in 3 of 86 patients with endocarditis in Marseilles (3.5%), 3 of 123 patients with endocarditis in Halifax (2.4%), and 4 of 90 patients in Lyons (4.4%) 225.

Bartonella endocarditis accounted for 10 of 299 cases of endocarditis (3%), being as frequent asC.

burnetii (Q fever) endocarditis (unpublished data).

Meta-analyses of these reported cases showed that B. henselae endocarditis occurs in 87% of patients with previous valve injury whereas only 30% of patients with B. quintanaendocarditis have this underlying condition.

Predisposing factors forB.

quintana endocarditis are homelessness and alcoholism, a condition found in 70% of patients and associated with exposure to body lice 26.

Consequently, epidemiology helps to distinguish between the two infections, one caused by B. quintana mainly in alcoholic homeless persons exposed to body lice and without previous valve injury and the other caused by B. henselae in patients with underlying valve injury who have had contact with a cat.

B. quintana endocarditis has been reported in only one HIV-infected patient 257.

The mean age of patients with Bartonella endocarditis is 48 years.

These patients are significantly younger than control patients with IE caused by other microorganims (P. E. Fournier and D. Raoult, submitted for publication).

The gender proportion is 85% male.

(ii) Signs and symptoms.

BecauseBartonella spp.

cause a subacute insidious endocarditis, the diagnosis is usually considerably delayed, which may explain why most patients present with acute cardiac failure 75, 225.

Fever higher than 38°C is found in most patients.

Patients usually present with cardiac murmur, dyspnea on exertion, and bibasilar lung rales, suggesting global cardiac failure.

Aortic valves are more often involved, and prosthetic valve endocarditis has been reported in only 3 of 32 patients.

Embolic phenomena have been reported in 41% of patients and may initiate the clinical manifestations.

Nonblanching purpura and petechiae are frequently observed on the lower extremities, palms, and conjunctiva.

Laboratory data are not specific and a include normal white blood cell WBC count, thrombocytopenia (platelet count, <150 × 109/liter), and elevated blood creatinine levels in some patients with severe cardiac insufficiency.

(iii) Diagnosis.

Pathologic diagnosis after valve surgery was performed in 86% of patients, and the remaining patients all had one major criterion (echocardiographic vegetations) and at least three minor criteria.

In fact, the diagnosis of endocarditis is quite obvious in such patients, but blood cultures are usually negative.

In such situations, especially in alcoholic homeless persons with body lice or in patients with previous valve injury who own cats, a diagnosis of Bartonella endocarditis is likely.

Etiologic diagnosis is usually established by serologic testing, inoculation of the blood or resected valve into tissue culture and blood agar, PCR detection of the citrate synthase gene with identification of DNA by sequence analysis, or Warthin-Starry silver staining with immunohistochemical demonstration of the bacteria in valves.

Serologic testing is carried out by an immunofluorescence assay (IFA).

Low-level cross-reactions with C. burnetii may occur 151, and significant cross-reactions may be seen with Chlamydia pneumoniae176.

In one case, B. quintanaendocarditis was diagnosed by detecting bacteria by PCR in the removed valve despite the fact that the patient did not demonstrate any antibodies to Bartonella spp.

225.

For this reason, attempts to isolate the bacteria are necessary.

The most reliable diagnostic tool, aside from serologic testing, is PCR of freshly removed valves.

In our experience, a PCR amplicon was obtained in 72% of specimens even though 42% of valves were sampled during antibiotic therapy (P. E. Fournier, unpublished data).

In fact, the lack of sensitivity of blood culture is probably related to the previous antibiotic therapy 153.

(iv) Echocardiography and pathology.

The frequency of emboli is related to the large size of the vegetations inBartonella endocarditis.

this explains the efficiency of echocardiography, which identifies vegetations in 100% of B. henselae and 96% of B. quintana endocarditis patients225; P. E. Fournier et al., unpublished data).

Examination of removed valves showed that Bartonella spp.

cause significant valvular tissue destruction.

No well-formed or suppurative granulomas are observed.

Typical lobular vascular proliferations, as found in cutaneous bacillary angiomatosis, are not observed.

Gram staining, PAS staining, and Grocott-Gomori staining of the valve are not useful in detecting the bacteria, whereas Giemsa and, especially, Wharthin-Starry stains reveal many characteristic granular organisms in the valve vegetation or the valve (Fig.

4).

Masses of bacteria occupy an extracellular location, mainly in the fibrin deposits.

No organisms are found within areas of inflammation.

Immunohistologic staining has been successfully used to demonstrateB.

quintana or B. henselae in human cardiac valve tissues (H. Lepidi et al., unpublished data).

(v) Treatment and prognosis.

In vitro antibiotic susceptibility of nine isolates of B. quintana, three isolates of B. henselae, one isolate of B. elizabethae, and one isolate of B. bacilliformis showed that all were highly susceptible to β-lactam agents, aminoglycosides, macrolides, tetracyclines, and rifampin.

They were less susceptible to penicillin, narrow-spectrum cephalosporins, and clindamycin177.

Considerable variation was noted in their susceptibility to fluoroquinolones compounds.

Cocultivation ofBartonella spp.

with eukaryotic cells did not change the bacteriostatic activity of the antibiotics 194.

However, it is interesting that only aminoglycosides (gentamicin, amikacin, and tobramycin) were bactericidal on either axenic medium or in cell cultures.

Clinical data on effective treatment ofBartonella-induced endocarditis are scarce.

Of 42 patients reviewed recently, 76% were treated with aminoglycosides, 74% were treated with a β-lactam compound, 35% were treated with a tetracycline, 20% were treated with vancomycin, 16% were treated with a fluoroquinolone, and 14% were treated with rifampin (Fournier and Raoult, submitted).

Although a standard regimen for the antibiotic treatment of Bartonella endocarditis has not been established, based on the relevant clinical data and the in vitro activity of antimicrobial compounds, we suggest an aminoglycoside in combination with either doxycycline or ceftriaxone for a prolonged course 175.

In addition to antibiotic treatment, surgery is often required owing to the extensive valve damage.

In our series, valve replacement was performed in 80% of cases.

It is likely that severe damage and delay in diagnosis contributed to the poor prognosis of Bartonella endocarditis.

Of the 53 patients for whom the outcome was known, 42 (80%) survived and 11 died.

The mortality rate observed among patients with B. quintana endocarditis was almost three times higher than that observed among the controls (Fournier and Raoult, submitted).

Half of the patients who died and only one-third of survivors were homeless, suggesting that the lack of medical care for homeless people leads to delay in diagnosis and treatment and subsequently a poor outcome for Bartonellaendocarditis.

Mycobacterium spp.

Mycobacteria are acid-alcohol-resistant bacteria that are visualized by the Ziehl-Nelsen stain.

Tuberculous valvular endocarditis is exceptionally rare; only 16 cases have been reported in the literature 47.

It usually presents in the context of miliary tuberculosis, and in all but one case the diagnoses were made at autopsy.

The rare cases reported involved congenital defects of the aortic valves, prosthetic valves, and ventriculoatrial shunts.

However, because of its rarity, there is still uncertainty whether true tuberculous endocarditis exists as a clinical entity 47.

Nonturberculous mycobacterial endocarditis involves mostly porcine or prosthetic valves.

To our knowledge, only two cases involving damaged native valves have been reported 96, 254.

In the literature, we found seven cases of prosthetic-valve endocarditis due to Mycobacterium chelonei92, 160, 241, 288, six cases of prosthetic-valve endocarditis due to Mycobacterium fortuitum6, 43, 146, 254, one case of prosthetic-valve endocarditis due to Mycobacterium gordonae159, and one case of Mycobacterium avium-intracellulare-induced native-valve endocarditis (149; J. Butany, Letter, Con.

J. Cardiol.9:214, 252, 1993).

Reported infections primarily involve atypical, rapidly growing strains that probably were inoculated at valve replacement 293.

The ability of mycobacterial organisms to cause protracted disease is well known.

Prosthetic-valve endocarditis due to mycobacteria is a rare, highly fatal infection that occur as small nosocomial outbreaks in which seasonal environmental conditions, contaminated bone wax, water baths, or surgical personnel are clearly epidemiologic factors.

The disease occurs within 6 months of valve replacement and can be traced to valve contamination at surgery.

In some cases, Mycobacterium spp.

were found to contaminate porcine valves after inadequate sterilization during manufacturing and storage 241.

Other cases have been associated with sternal wound infections following surgery146.

These patients presented with symptoms typical of endocarditis, such as fever, chills, night sweats, anorexia, and headaches 43, 146.

The role of M. avium complex in causing endocarditis is still debated (117, 149; Butany, Letter), and misdiagnoses could result from laboratory contamination by water 117.

(i) Diagnosis.

Mycobacterial endocarditis may be diagnosed by blood culture 92, 254, 288, 293; Middlebrook solid culture medium and the nonradiometric Bactec 9000 MB system have been shown to be equally effective in isolation of nontuberculousMycobacterium spp.

from blood 130.

However, the diagnosis is frequently achieved by histologic examination of the resected valve or at autopsy by Ziehl-Neelsen staining of acid-fast bacilli.

Mycobacterium spp.

have been isolated from valve vegetations, bone marrow, urine, sputum 92, 159, and lung biopsy specimens 92.

(ii) Treatment.

Combination therapy for infections due to Mycobacterium spp.

seems advisable, since single-agent therapy has been shown to select for the emergence of resistant mutants 274.

However, there are no controlled studies regarding therapy.

Courses longer than 6 months may be needed for endocarditis.

Consideration should be given to resection of the focus of infection and to removing foreign material in patients who are surgical candidates 288, 294.

Mycoplasma spp.

Despite the fact that endocarditis due to cell wall-deficient bacteria has been suggested since 1978 215, endocarditis due to Mycoplasmaspp.

has been reported in the literature only twice 45, 217.

The first report described a patient with postrheumatic heart disease; the diagnosis was based on serologic test results alone, and no culture was reported.

He was treated with 12 × 106 U of benzylpenicillin and 280 mg of gentamicin daily for 6 weeks and then given a 4-week course of oxytetracycline217.

The other case was reported in 1989 45and involved a 25-year-old woman with a history of SLE, treated with corticosteroids, in whom Streptoccocus sanguis aortic and mitral valve endocarditis developed.

Aortic and mitral prosthetic valve replacements were performed for acute cardiac failure.

During penicillin treatment, she developed a sternal wound infection and fever.

Swabs of the sternal wound and blood cultures were sterile.

The prosthetic valves were replaced owing to significant valve dysfunction and renewed cardiac failure.

At surgery there was no evidence of sternal or mediastinal infection, but extensive dehiscence of the aortic valve suture line was noted with multiple small abscesses and fistulous tracts extending from the aortic annulus.

The mitral valves appeared grossly infected.

Mycoplasma hominis was isolated from a portion of the mitral annulus.

The presence of sodium polyanetholsulfonate in the blood culture media might be responsible for the lack of M. hominis growth 55.

This patient was cured with clindamycin and rifampin administered for 6 weeks followed by a 4-week course of oral doxycycline 45.

The role of Mycoplasma spp.

in culture-negative endocarditis is unknown and very probably underestimated.

This small organism cannot be detected by Gram stain, and growth is not detected in routine blood culture systems.

Likewise, Mycoplasma spp.

can be difficult to detect in paraffin-embedded valve tissues when using nonspecific staining techniques.

Strategies for isolation of this pathogen in patients with culture-negative endocarditis should include systematic subculture of blood and excised valves.

Inoculation should be made onto specific Mycoplasma agar media such as SP 4 glucose (pH 7.5), which can be used for both M. pneumoniae and M. hominis, provided that arginine is added for the latter organism.Mycoplasma serologic testing should be evaluated.

PCR techniques will be probably very helpful in detectingMycoplasma spp.

in blood or in infected valves.

Whipple's disease bacterium.

Whipple's disease is a rare systemic disorder presenting with arthralgia, diarrhea, abdominal pain, generalized lymphadenopathy, progressive weight loss, and central nervous system involvement.

This disease is caused by a gram-positive bacterium that has been identified by sequence analysis of the 16S rRNA gene 234.

The name Tropheryma whippelii has been suggested for cases when the bacteria have not successfully been established in culture 234.

Recently, the Whipple's disease bacterium was propagated in an interleukin-4-treated macrophage cell culture but showed only limited propagation 251.

In 2000, we reported the successful isolation and establishment of a strain of Whipple's disease bacterium obtained from the valve of a patient with blood culture-negative endocarditis 222.

Up to one-third of patients with Whipple's disease present with concomitant cardiac symptoms, mostly attributed to endocarditis, myocarditis, pericarditis, or coronary lesions (125, 181, 188; M. Jeserich, C. Ihling, and C. Holubarsch, Letter, Ann.

Intern.

Med.

126:920, 1997).
------------
Given the new context, refine the original summary.
If the context isn't useful, return the original summary.