**3.4. CNE due to fungal pathogens**

*3.2.2. Non HACEK group organisms*

106 Contemporary Challenges in Endocarditis

Other fastidious bacteria causing CNE include *Pasturella multocida* and other *Pasturella* spp. which constitute part of the normal oral flora of dogs and cats in particular [21]. While bite wounds are obviously a portal of entry for *Pasturella* spp., in immunocompromised patients, more superficial contact especially with cat fur, minor cat scratches and cat saliva can lead to bacteremia and subsequent endocarditis [22]. Culture-negative endocarditis caused by *Abiotrophia defectiva* and *Granulicatella* spp.—so-called nutritionally deficient *Streptococci* [23] —can also be associated with infected intracranial aneurysms and may be difficult to isolate in routine blood cultures [24]. Special consideration for length of therapy must be given and is covered below. *Clostridia* and other anaerobic organisms [25] may be difficult to recover in routine blood cultures if specimens are not handled appropriately. These organisms are likely a rare cause of CNE, but true prevalence is unknown. *Gemella* spp. have been described rarely as a cause of CNE [9, 21] including *Gemella burgeri* tricuspid valve endocarditis [26] and *Gemella hemolysans* prosthetic valve endocarditits identified by PCR of prosthetic valve material and requiring implantation of a total artificial heart as a bridge to transplantation [27]. *Brucella mellitensis* is another unusual pathogen associated with culture-negative endocarditis [2], especially in regions of the world where consumption of unpasteurized milk (cow, goat and sheep) occurs. In one series of six patients subsequently found to have *Brucella* endocarditis, only two patients had blood cultures that revealed the diagnosis [28]. Several different *Legionella* spp. have been reported as causes of culture-negative endocarditis, both in native valves and prosthetic valves. These include cases of *Legionella pneumophila* in an immunocompromised patient with pneumonitis, a positive BAL fluid *Legionella* antigen, and subsequent BAL fluid and blood isolation of the organism when subcultured onto buffered charcoal yeast extract agar (BCYE agar) [29]. Another CNE case with *L. pneumophila* was identified when the patient presented with septic arthritis and the organism was identified from synovial fluid by 16s rDNA PCR and was subsequently found to have a new murmur and a mitral vegetation [30]. Mycobacteria are another rare cause of CNE, especially in association with porcine bioprosthetic valves [31]. This study from a reference laboratory conducted between 2010 and 2013 found PCR evidence of Mycobacterial infection in six out of 370 valve samples submitted from patients with suspected CN [31] with five cases of *Mycobacterium chelonae* and one case of *M. lentiflavum\*\*\**. While typically associated with immunodeficiency states, mycobacterial infections have also been reported in immunocompetent hosts as in the case of a patient with disseminated *M. chelonae* infection and resulting pacemaker CNE [32]. Special stains and cultures for acid fast bacilli should be considered in patients with device-related CNE [33]. Finally there are also rare reports with unusual causes of endovascular infections such as CNE in an immunocompromised patient on high dose corticosteroids [34] and infected aortic

aneurysm in an immunocompetent patient [35] with *Helicobacter cinaedi*.

This section deals with CNE attributable to organisms that are not typically identified with blood cultures but are responsible for a significant portion of cases of culture-negative infective

**3.3. CNE due to** *Bartonella* **spp.,** *C. burnetti* **and** *T. whipplei*

endocarditis [36].

Invasive mold infections are another cause of CNE, due to the difficulty in isolating these organisms from routine blood cultures. They are an important cause especially of early culturenegative prosthetic valve endocarditis [52] but can cause late prosethetic valve, pacemaker associated as well as native valve endocarditis. Among cases in the recent literature, infections with *Aspergillus* spp. [53–55], *Histoplasma capsulatum* [56–58] and *Trichosporin* spp. [59, 60] are the most widely reported. Commercial tests that detect fungal wall antigens such as galactomannan [2, 61, 62] and β-1,3-D-glucan [62] can show good sensitivity and specificity in diagnosis of fungal CNE. Jinno et al. [56] reported negative urine *Histoplasma* antigen results in their patient with *H. capsulatum* CNE, with diagnosis based on valvular pathology and tissue culture.
