**5. Noninfective endocarditis**

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

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].

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 microbio-

**Pathogens Standard therapy Treatment outcome**

Treatment success defined

Treatment success defined as phase I IgG < 1:200 IgM, IgA < 1:50

as IgG < 1:60

Success rate > 90%

Optimal treatment

Long-term treatment, optical duration unknown

unknown

unknown

with an infectious doctor specialist in the Endocarditis Team is recommended.

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

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

+ contrimocazole (960 mg/12 h) + rifampicine (300~600 mg/day for ≥3~6 months orally

Legionella sp. Levofloxacin (500 mg/12 h) iv or orally for ≥6 weeks or

+ gentamicin (3 mg/day) iv for 2 weeks

4 weeks + rifampin (300–1200 mg/24 h)

Doxycycline (200 mg/day) + hydroxychloroquine (200–600 mg/day) orally for ≥18 months

Doxycycline (200 mg/day) + hydroxychloroquine (200–600 mg/day) orally for ≥18 months

clarithromycin (500 mg/12 h) iv for 2 weeks, then orally for

Mycoplasma sp. Levofloxacin (500 mg/12 h) iv or orally for ≥6 weeks Optimal treatment

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

Bartonella sp. Doxycycline (100 mg/12 h) orally for 4 weeks

logical documentation.

66 Advanced Concepts in Endocarditis

Coxiella.burnetii (Q fever)

Treaponema whipplei (Whipple's disease)

Brucella sp. Doxycycline (200 mg/day)

When all microbiological assays are negative, the diagnosis of noninfectious endocarditis should systematically be considered (**Figure 1**).

## **5.1. Nonbacterial thrombotic endocarditis**

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 identify by conventional methods.

#### **5.2. Systemic diseases**

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

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.

#### **5.3. Allergy for porcine valve**

When the patient has a porcine bioprosthesis implanted during last 6 months, anti-pork antibodies should be sought [22, 23] to consider allergy for the valve.
