**4. Treatment**

**Pathogen Diagnostic procedures**

still recommended in the 2015 ESC guidelines [4].

**3.5. Evaluation of valve tissue**

64 Advanced Concepts in Endocarditis

ture-negative endocarditis:

(*T. whipplei*) [11].

materials

Tropheryma whippplei hystology and PCR of surgical materials

Brucella sp. blood cultures, serology, immunohistology, PCR of surgical materials

Summary of diagnostic procedure of rare pathogens of BCNIE is shown in **Table 3**.

Mycoplasma sp. serology, culture, immunohistology, PCR of surgical materials

Coxiella burnetii serology (IgG phaseI >1:800, tissue culture, immunohistology, PCR of surgical

including 266 cases of *C. burnetii* (n = 167) or Bartonella sp. (n = 99) [5]. The same team reported a second series of 745 patients presenting with suspected BCNIE having received a panel of serological tests between 2001 and 2009. They documented the predominance of Q fever and Bartonellosis. A total of 354 of the 356 cases documented by serological tests were positive for *C. burnetii* (n = 274) or Bartonella sp. (n = 80) [6]. In other words, if only Bartonella sp. and *C. burnetii* serological tests had been used, only 4 out of 624 diagnoses obtained by serological tests would have been missed. A review of endocarditis caused by fastidious pathogens shows that Mycoplasma sp. endocarditis is very rare (<10 reliable observations published to date, mostly due to M. hominis), as well as Legionella sp. endocarditis [7]. Moreover, most cases of endocarditis supposedly due to Chlamydophila sp. are probably cross-reactions with a Bartonella sp. In 2015, the only routinely recommended serological tests in case of negative blood cultures are tests for Q fever and Bartonellosis [4]. Brucellosis serological tests can be added in case of risk factors (living in endemic areas, occupational exposure, consumption of nonpasteurized dairy products). Serological tests for Mycoplasma sp. and Legionella sp. are

The more frequent use of valve replacement in the acute phase of infective endocarditis and the advent of molecular biology techniques have revolutionized the diagnosis of blood cul-

PCR systems based on universal bacterial 16S ribosomal RNA have demonstrated excellent sensitivity and specificity [8, 9], as well as PCR targeting bacteria specifically responsible for endocarditis with negative blood culture: Bartonella sp., *C. burnetii* [10] and *Tropheryma whipplei*

Moreover, the microscopic examination of valves after Gram staining, and cultures on appropriate media provide important information not only for the identification of the pathogen involved when the data were not available preoperatively [12], but also information on its viability at the time of valve replacement, which will impact the duration of post-replacement treatment [11, 13]. The histological analysis of valves is not contributive to diagnose except some rare diagnoses such as porcine bioprosthesis endocarditis mediated by allergy to porcine proteins [22, 23].

Bartonella sp. blood cultures, serology, culture, immunohistology, PCR of surgical materials

Legionella sp. blood cultures, serology, culture, immunohistology, PCR of surgical materials Fungi blood cultures, serology, immunohistology, PCR of surgical materials

**Table 3.** Summary of diagnostic procedure of rare pathogens of blood culture-negative infective endocarditis.

#### **4.1. Empirical therapy**

Selection of medical therapy for patients with BCNIE is difficult. Some of the laboratorybased diagnostic techniques to define fastidious or rare pathogens are not available in most clinical laboratories. It consumed considerable time for completion of testing if specimens are sent to a referral laboratory. Patients with BCNIE are often treated empirically for the more common bacterial causes of IE during the waiting time. There is a need to provide empirical antimicrobials for all likely pathogens, though certain therapeutic agents, including aminoglycosides, have potentially toxic effects. Consultation with an ID specialist to define the most appropriate choice of therapy is recommended. Once additional clinical and laboratory data were brought, initial empirical therapy should be changed to more specific treatment. For patients with acute (days) clinical presentations of native valve infection, coverage for S aureus*,* β-hemolytic streptococci, and aerobic Gram-negative bacilli is reasonable. Empirical coverage could include vancomycin and cefepime as an initial regimen [1, 4, 14]. For patients with a subacute (weeks) presentation of native valve IE, empirical coverage of *S. aureus*, Viridance group streptococci (VGS), HACEK, and enterococci is reasonable. One treatment option could include vancomycin and ampicillin-sulbactam to provide some coverage for these organisms [1, 4, 14]. For patients with culture-negative prosthetic valve IE, coverage for staphylococci, enterococci, and aerobic Gram-negative bacilli is reasonable if the onset of symptoms is within 1 year of prosthetic valve placement. A regimen could include vancomycin, rifampin, gentamicin [1, 4, 14]. If symptom onset is >1 year after valve placement, then IE is more likely to be caused by staphylococci, VGS, and enterococci, and antibiotic therapy for these potential pathogens is reasonable [1, 4, 14]. One initial treatment option could include vancomycin and ceftriaxone. If subsequent blood culture results or other laboratory methodologies define a pathogen, then empirical therapy should be changed to focused therapy that is recommended for the specific pathogen identified.

#### **4.2. Antibiotic treatment for fastidious microorganisms**

HACEK Gram-negative bacilli are fastidious organisms, and the laboratory should be made aware that infection with these agents needs consultation to specialist. Because of slow growth, standard MIC tests may be difficult to interpret. Some HACEK-group bacilli produce betalactamases, and ampicillin is therefore no longer the first-line option. They are susceptible to ceftriaxone, other third-generation cephalosporins and quinolones; the standard treatment is ceftriaxone 2 g/day for 4 weeks in native valve endocarditis and for 6 weeks in prosthetic valve endocarditis. If they do not produce beta-lactamase, ampicillin (12 g/day i.v. in four or six doses) plus gentamicin (3 mg/kg/day) divided into two or three doses for 4–6 weeks is an option [1, 4, 13]. Ciprofloxacin (400 mg/8–12 h i.v. or 750 mg/12 h orally) is a less wellvalidated alternative. Clinical outcome of HACEK endocarditis is favorable.

In cases with fungi, mortality is very high, and treatment necessitates combined antifungal administration and surgical valve replacement. Antifungal therapy for Candida sp. includes liposomal amphotericin B with or without flucytosine or an echinocandin at high doses; and for Aspergillus spp., voriconazole is the drug of choice and some experts recommend the addition of an echinocandin or amphotericin B. Suppressive long-term treatment with oral azoles (fluconazole for Candida and voriconazole for Aspergillus) is recommended [1, 4, 14]. Consultation with an infectious doctor specialist in the Endocarditis Team is recommended.

**5. Noninfective endocarditis**

identify by conventional methods.

**5.2. Systemic diseases**

**5.3. Allergy for porcine valve**

should systematically be considered (**Figure 1**).

**5.1. Nonbacterial thrombotic endocarditis**

When all microbiological assays are negative, the diagnosis of noninfectious endocarditis

Blood Culture-Negative Endocarditis http://dx.doi.org/10.5772/intechopen.76767 67

Nonbacterial thrombotic endocarditis (marantic endocarditis, Trousseau syndrome) is observed in 1.2% of patients with active cancer at autopsy [16]. Usually, the single or multiple small vegetation-like lesions are observed predominantly on the mitral and aortic valves with no underlying valve diseases. These are associated with an underlying hypercoagulable state that justifies routine anticoagulation. Control of pathologically altered coagulation mechanism is essential for the treatment and the prognosis is poor without resolving the problem. The differential diagnosis with an infectious cause of BCNIE is often difficult, and the prognosis is poor [17]. The initial lesion is usually breast, lung, prostate, ovarian or colon cancer. However, it should not be forgotten that undiagnosed infective endocarditis is also common in cancer patients with sterile blood cultures and/or fastidious organisms that are difficult to

Inflammatory diseases can cause endocarditis and produce a syndrome similar to culturenegative IE. Perhaps the one most often encounter is antiphospholipid antibody (APA) syndrome [18], which has been described as both a primary and a secondary syndrome of systemic lupus erythematosus(SLE) and malignancies. Sterile valvular vegetations form and often embolize, clinically mimicking in many respects with IE. The mitral valve is most often affected, and valvular regurgitation is the frequent functional abnormality. To complicate

In patients with SLE, valve abnormalities are common (15–75% of autopsy series, depending on the severity of the disease), but rarely progress to a clinical stage of Libman-Sacks endocarditis [20]. The patients are usually young individuals with a very severe lupus poorly controlled by treatments. Immunological manifestations (Osler nodes) and embolism (stroke, often in combination with an antiphospholipid syndrome) may be observed. Valve lesions are mainly found in the left heart. Endocardium involvement may occur in Behҫet's disease [21]. It is a disease of young ± male patients with a predominantly aortic involvement. Endocardium involvement in Behҫet's disease is a poor prognostic factor. The treatment is of course should be targeted on the systemic disease (immune-suppressants, immune-modulators) with lifelong curative anticoagulation. Checkup for antinuclear antibodies as well as antiphospholipid antibody {anticardiolipin antibodies [immunoglobulin (Ig) G and anti-b2-glycoprotein 1 antibodies [IgG and IgM]} should be performed for the patients who are suspected to have noninfective endocarditis.

When the patient has a porcine bioprosthesis implanted during last 6 months, anti-pork anti-

matters, the APA syndrome may also develop secondary to IE [19].

bodies should be sought [22, 23] to consider allergy for the valve.

#### **4.3. Specific therapy for true culture-negative microorganisms**

The recommended therapy for true culture-negative microorganisms in the European guidelines 2015 is shown in **Table 4** [4, 12]. Consultation with ID specialist is highly recommended for the treatment of these special organisms. This is an area with a very limited level of evidence. The treatment of *T. whipplei* endocarditis has not been standardized. Doxycycline + hydroxychloroquine for 12–18 months, with monitoring of plasma levels of these two agents (objective: achieving plasma concentrations of 0.8–1.2 mg/L for hydroxychloroquine, and < 5 mg/L for doxycycline), and of negativation of samples initially positive for *T. whipplei* was proposed. The treatment of Bartonella sp. endocarditis is a beta-lactam antibiotic (amoxicillin or ceftriaxone) or doxycycline for 4 weeks in combination with gentamicin for the first 2 weeks [1, 4, 14] the treatment of *C. burnetii* endocarditis, is doxycycline + hydroxychloroquine until a phase1 antibody rate <800 is reached for IgG, and <50 for IgM and IgA [1, 4, 14].

#### **4.4. Surgical treatment of blood culture-negative IE**

There is no specific recommendation for surgical treatment of BCNIE: cardiac surgery indications rely on the same criteria that apply for any type of endocarditis (heart failure, uncontrolled infection, risk of embolism [1, 4, 15]). However, an additional argument for the surgical treatment of BCNIE is the ability to harvest valve tissue, which often finally allows microbiological documentation.


**Table 4.** Recommended therapy for true culture-negative microorganisms in the European guidelines 2015.
