Culture-negative endocarditis (CNE) is a challenging clinical entity, both diagnostically and therapeutically. In this chapter, the changed epidemiology and microbiology of CNE are reviewed with cases highlighting typical pathogens in patients pre-treated with antibiotics, less common fastidious pathogens such as bacteria of the HACEK group, nutritionally deficient bacteria, Legionella spp. and Mycobacteria, “quintessential” CNE pathogens such as Bartonella spp., Coxiella burnetti and Tropheryma whipplei, as well as fungal CNE. Contemporary diagnostic methods are reviewed including polymerase chain reaction-based pathogen 16s RNA amplification coupled with electrospray ionization mass spectrometry (PCR/ESI-MS). Finally, treatment options per the recently updated 2015 American Heart Association and European Society for Cardiology guideline are presented.
- culture-negative endocarditis
- Bartonella spp.
- Coxiella burnetti and Tropheryma whipplei
Culture-negative endocarditis (CNE) is one of the most challenging infectious diseases clinical syndromes both diagnostically and therapeutically. The prevalence of CNE varies widely in various modern series: it is estimated that on average, in 20% (range 5–71%) of echocardiographically evident endocarditis, both native and prosthetic valve, blood cultures do not yield a specific pathogen [1–7]. The morbidity but not necessarily mortality associated with CNE is higher than in instances where a specific pathogen is found, primarily due to the increased burden of diagnostic testing, delays in administration of antibiotics and the extended use of broad spectrum anti-microbial agents . This chapter will review the epidemiology and likely microbiology of CNE, as well as enhanced diagnostic methods and treatment recommendations.
A useful definition of CNE has been put forth by Tattevin et al.  wherein one can think of this entity as (1) true bacterial endocarditis with blood cultures sterilized by previous receipt of antimicrobials; (2) CNE caused by fastidious or unusual organisms such as the bacteria known as the “HACEK” group, nutritionally deficient
2. Epidemiology of CNE
The epidemiology of infective endocarditis, and hence CNE, has changed over the last five decades [5, 10]. Patients are generally older and male, with greater numbers of hospital associated cases, and with indwelling devices such as catheters, pacemakers and prosthetic valves. Accordingly the numbers of cases of infective endocarditis with
3. Microbiology of CNE
The microbiology of CNE is varied and depends on host and environmental factors that predispose to one type of pathogen versus another . As per the classification of Tattevin et al. , the microbiologic discussion will follow this paradigm.
3.1. CNE due to pre-treatment of typical bacterial endocarditis
According to one of the largest surveys of infective endocarditis recently performed, in the last decade, 29.7% of IE were due to
3.2. CNE due to fastidious micro-organisms
3.2.1. HACEK group
Much of the early literature regarding CNE focused on infections with so-called “fastidious” organisms that were traditionally difficult to grow in blood culture, due to specific nutritional requirements of these organisms. These included a number of oral Gram-negative bacteria (
HACEK organisms are rarely the cause of infective endocarditis, and because of the improved ability to isolate these organisms from standard blood culture specimens, even more rarely the cause of CNE. In a recent series, four out of 77 patients with HACEK IE had negative blood cultures . Of these, three had previously received antibiotics. Diagnosis was made by culture of devices, and in one patient, by PCR of valvular tissue.
Pediatric populations, especially young children between the ages of 6 months and four years, appear to be particularly vulnerable to infections with
3.2.2. Non HACEK group organisms
Other fastidious bacteria causing CNE include
3.3. CNE due to
Bartonella spp., C. burnetti and T. whipplei
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 endocarditis .
3.4. CNE due to fungal pathogens
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 culture-negative prosthetic valve endocarditis  but can cause late prosethetic valve, pacemaker associated as well as native valve endocarditis. Among cases in the recent literature, infections with
4. Diagnostic methods
Our understanding of the etiology of CNE and our ability to offer more targeted treatment to patients with CNE have been dramatically affected by the large number of novel diagnostic tests now available to add to our investigative armamentarium. The following discussion will focus on methods that allow diagnosis without removal of infected valves or cardiac devices (prosthetic valves, endovascular grafts, pacemaker and defibrillator leads, ventricular assist devices, etc.) versus methods that require removal of tissue or a device for diagnostic and therapeutic reasons.
4.1. Non-invasive methods
Imaging using positron emission tomography (PET) scanning has been utilized to diagnose a case of
4.2. Invasive methods
Methodologies to increase numbers of planktonic organisms that can be cultured from devices have been devised, using sonication of the devices [66, 67]. Metagenomic analysis of the results of next generation sequencing has been used to diagnose
5. Treatment of CNE
There are some distinct differences in the management of infective endocarditis according to the United States  versus European guidelines  updated in 2015. These are reviewed in Tattevin et al. . However, in regard to treatment of the following etiologic agents of CNE, there is good agreement in general.
5.1. Empiric therapy for CNE
For patients with acute clinical presentations of native valve endocarditis, according to the US guidelines, empiric coverage for
A. defectiva, Granulicatella spp.
As summarized in the European guidelines, these nutritionally deficient bacteria produce endocarditis with a protracted course which is associated with large vegetations (≥10 mm), higher rates of complications and valve replacement (around 50%), possibly due to delayed diagnosis and treatment. Antibiotic recommendations include penicillin G, ceftriaxone or vancomycin for 6 weeks, combined with an aminoglycoside for at least the first 2 weeks.
Per the US and European guidelines, microbiologic susceptibility testing might be difficult to perform on HACEK microorganisms, and they should be considered ampicillin resistant secondary to β-lactamase production. Penicillin and ampicillin should not be used for the treatment of patients with endocarditis. Ceftriaxone should be used unless the patient has a severe β-lactam allergy. The duration of therapy for HACEK native valve endocarditis is 4 weeks; for prosthetic valve infections, duration of therapy is 6 weeks or longer. Gentamicin is not recommended in the US guidelines because of its nephrotoxicity risks but is an option in the European guidelines. A fluoroquinolone (ciprofloxacin, levofloxacin, ormoxifloxacin) can be used in patients with a β-lactam allergy. Ampicillin-sulbactam is also a treatment option.
|Doxycycline 100 mg/12 h orally for 4 weeks
plus gentamicin (3 mg/24 h) i.v. for 2 weeks
|Doxycycline (200 mg/24 h)
plus cotrimoxazole (960 mg/12 h)
plus rifampin (300–600/24 h)
for ≥3–6 months orally
|Doxycycline (200 mg/24 h)
plus hydroxychloroquine (200–600 mg/24 h) orally
(>18 months of treatment)
|Levofloxacin (500 mg/12 h) i.v. or orally for ≥6 weeks
or clarithromycin (500 mg/12 h) i.v. for 2 weeks, then
orally for 4 weeks
plus rifampin (300–1200 mg/24 h)
|Doxycycline (200 mg/24 h)
plus hydroxychloroquine (200–600 mg/24 h)c orally for
Treatment of the following unusual pathogens in CNE is best summarized in the European guidelines and in Broqui et al. .
7. Fungal CNE
Per the European guidelines, for
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