Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Jack McHugh
 -- 1612 2023-08-23 04:18:00 |
2 format correction
Dean Liu
 Meta information modification 1612 2023-08-24 03:16:27 |

Video Upload Options

We provide professional Video Production Services to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Mchugh, J.; Saleh, O.A. Updates in Culture-Negative Endocarditis. Encyclopedia. Available online: https://encyclopedia.pub/entry/48344 (accessed on 21 December 2024).
Mchugh J, Saleh OA. Updates in Culture-Negative Endocarditis. Encyclopedia. Available at: https://encyclopedia.pub/entry/48344. Accessed December 21, 2024.
Mchugh, Jack, Omar Abu Saleh. "Updates in Culture-Negative Endocarditis" Encyclopedia, https://encyclopedia.pub/entry/48344 (accessed December 21, 2024).
Mchugh, J., & Saleh, O.A. (2023, August 23). Updates in Culture-Negative Endocarditis. In Encyclopedia. https://encyclopedia.pub/entry/48344
Mchugh, Jack and Omar Abu Saleh. "Updates in Culture-Negative Endocarditis." Encyclopedia. Web. 23 August, 2023.
Updates in Culture-Negative Endocarditis
Edit
This entry is adapted from the peer-reviewed paper 10.3390/pathogens12081027

Blood culture-negative infective endocarditis (BCNE) is a challenging condition associated with significant morbidity and mortality.

endocarditis culture-negative bacteremia

1. Definition

Blood culture-negative endocarditis is defined as endocarditis where traditional methods for culturing blood do not yield an organism. BCNE may be classified into three groups [1]:
  • Bacterial endocarditis with sterilized blood cultures from previous antibiotic treatment, which accounts for the majority of cases;
  • Endocarditis due to fastidious microorganisms, which have historically included the HACEK (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella) group, nutritionally variant Streptococci, Pasteurella spp., mycobacteria, and fungal organisms;
  • “True” BCNE due to infection with intra-cellular organisms that cannot be cultured in blood using traditional techniques but may be diagnosed with serology (e.g., Bartonella sp., Coxiella burnetii) or polymerase chain reaction (PCR) of valvular tissue (e.g., Tropheryma whipplei).
Non-infectious causes of endocarditis, specifically nonbacterial thrombotic endocarditis (NBTE), should also be included in the differential diagnosis of BCNE in the right clinical context. NBTE is associated with hypercoagulable states, e.g., malignancy or autoimmune disease, which may result in the deposition of sterile thrombi on cardiac valves.

2. Epidemiology of BCNE

A systematic review of 142 studies reporting IE microbiology over five decades from 1960–2010 found a decrease in the incidence of BCNE over that time period from 23.1% to 14.2% [2]. Conversely, Vogkou et al. reviewed 105 studies from 2003 to 2013, with 26.6% of cases classified as BCNE [3]. Accounting for these variations, the incidence of BCNE in modern times is likely in the range of 10–20% [4]. A notable feature of these reviews is the significant variation in the incidence of BCNE in individual studies, with rates ranging from 7.7% to 66% [5][6]. The variation in incidence is attributable to several factors, most notably local variation in the early use of antibiotic therapy prior to obtaining blood cultures but also differences in testing strategies [7] and geographic variation of specific organisms, in particular zoonotic agents [4].

3. Infectious and Non-Infectious Etiologies of BCNE

3.1. BCNE Associated with Previous Antibiotic Treatment

Sepsis is a common clinical presentation of IE, and as a result antibiotics are often administered prior to obtaining blood cultures. In retrospective studies, the prevalence of BCNE attributed to antibiotic administration prior to culture has varied from 35% to 74% [5][8][9]. The microbiological profile in this cohort is similar to that of cases where blood cultures are obtained prior to administration of antibiotics (i.e., streptococci, staphylococci, or enterococci), with the caveat that organisms that are quickly cleared from the bloodstream may be more common.

3.2. BCNE Associated with Fastidious Microorganisms

3.2.1. The HACEK Group and Nutritionally Variant Streptococci

The HACEK group of organisms and nutritionally variant streptococci (Granulicatella spp., Abiotrophia defectiva) have traditionally been cited as common causes of BCNE due to the difficulty associated with culturing in standard media. However, modern automated culture systems can identify these organisms within 5 days of incubation in the vast majority of cases [10][11].

3.2.2. Fungi

Fungi account for approximately 1–2% of cases of IE [4]. Candida albicans is the most common cause, accounting for around 25% of cases, and automated culture systems can readily culture this organism along with other yeasts. Invasive mold infections (e.g., IE associated with Aspergillus spp.) and IE associated with endemic fungi, e.g., Histoplasma capsulatum, do not traditionally grow on routine blood cultures, and close attention to risk factors in the history (Table 1) are important when considering these agents as potential etiologies of BCNE.
Table 1. Blood culture-negative endocarditis: diagnostic clues and treatment.
Organism Risk Factor(s)/Diagnostic Clues Diagnostic Tests Suggested Treatment
Coxiella burnetii
(Q Fever)		 Inhalation of aerosols from infected animals (cattle, dogs, cats),
Ingestion of unpasteurized dairy products, bioterrorism		 Coxiella burnetii antiphase I IgG Ab titer > 1:800
Coxiella specific PCR on blood or valve tissue		 Doxycycline + Hydroxychloroquine
(18 months) [12]
Bartonella henselae Contact with cats Indirect immunofluorescence assays for detection of IgM and IgG
antibodies to Bartonella spp. with IgG titer ≥ 1:800
Bartonella specific PCR on blood or valve tissue		 Gentamicin IV (2 weeks) + Ceftriaxone IV (6 weeks) [13]
Bartonella quintana Presence of body lice, contact with homeless shelters
Tropheryma whipplei Exposure to soil or farm animals Tropheryma whipplei specific PCR on blood or valve tissue Penicillin G or Ceftriaxone IV (2–4 weeks) followed by co-trimoxazole for one year [14]
Brucella sp. Contact with unpasteurized dairy products, undercooked meat, or infected farm animals (sheep, cattle goats). Travel to endemic regions: the Mediterranean basin, the Middle East, Mexico [15] Blood cultures
Brucella total antibody titer ≥ 1:160 by standard tube agglutination test
Brucella-specific PCR on blood or valve tissue		 Gentamicin IV (4 weeks) followed by
Rifampin and doxycycline (12 weeks) [16]
Legionella sp. Exposure to artificial water systems Molecular methods (targeted or shotgun metagenomic sequencing) Macrolide + rifampin/ciprofloxacin (6 weeks)
Mycoplasma hominis History of vaginosis or pelvic inflammatory disease Molecular methods (targeted or shotgun metagenomic sequencing) Doxycycline (4–6 weeks) [17]
Fungi Intravenous drug use, organ transplantation, indwelling catheter, HIV positive Blood cultures (Candida sp.), fungal blood cultures
Shotgun metagenomic sequencing		 Prolonged therapy based on species identified and susceptibility data
Tuberculosis
Mycobacterium chimera		 Tuberculosis exposure
Cardiac surgery [18]		 Mycobacterial cultures, histopathology with Ziehl–Neelsen stain
Shotgun metagenomic sequencing		 Prolonged therapy based on species identified and susceptibility data
Non-infective endocarditis
Behcet’s Disease Young male, aortic insufficiency, recurrent oral and genital ulcers Clinical diagnosis, positive pathergy test Immunosuppression ± anti-coagulation
Lupus endocarditis Female patient, rash, cytopenias, arthralgias, kidney injury, history of autoimmune disease Serologies and clinical correlation Immunosuppression ± anti-coagulation
Marantic endocarditis Known primary malignancy Tumor markers, cancer screening Cancer-directed treatment, anticoagulation
Allergic endocarditis on porcine bioprosthesis Multiple small vegetations, allergy to porcine products Clinical diagnosis Replacement with non-porcine bioprosthesis
IgG Ab: immunoglobulin G antibody; PCR: polymerase chain reaction; IgM Ab: immunoglobulin M antibody.

3.2.3. Mycobacteria

IE due to Mycobacterial species is most frequently caused by non-tuberculous mycobacteria, with rapidly growing mycobacteria most commonly implicated [19][20]. Blood cultures do not routinely identify Mycobacterial species, and alternative diagnostic methodologies such as histopathologic evaluation of the valve and molecular techniques may be required to establish a diagnosis. IE due to M. tuberculosis is rare, with only a handful of cases reported in the literature. Cardiac surgery, the presence of indwelling prosthetic material, and intravenous drug use have been identified as the most common risk factors for mycobacterial endocarditis [20]. Several outbreaks of M. chimaera prosthetic valve endocarditis have been reported in the United States and Europe over the past decade [18]. These outbreaks have been associated with contaminated heater–cooler units during cardiopulmonary bypass, and this organism should be considered in patients presenting with prosthetic valve endocarditis of insidious onset. The significant lag time from the index surgery and subtle cardiac imaging findings contribute to the significant delay in diagnosis. Mycobacterial blood cultures and molecular detection methods should be performed in suspected cases.

3.2.4. Tropheryma whipplei

Tropheryma whipplei is a Gram-positive bacterium that causes Whipple’s disease; a chronic multi-systemic disease that predominantly affects middle-aged men and typically causes diarrhea, weight loss, and arthralgias and that may progress to involve the heart, lungs, and central nervous system [21]. Estimates of the frequency of T. whipplei as a causative organism in BCNE have ranged from 0.3% to 3.5% [22][23][24] in studies examining all patients with BCNE and up to 6.3% in patients in whom cardiac tissue was available for analysis [25].

3.3. BCNE Associated with Intracellular Pathogens

3.3.1. Coxiella burnetii

Coxiella burnetii is an obligate intracellular pathogen found worldwide that is associated with exposure to aerosols from infected animals (Table 1). Infection with this organism causes Q fever, a febrile illness associated with myalgias, headaches, and hepatitis and that may progress to endocarditis in the chronic phase if not diagnosed and treated early in the disease course. In the largest prospective studies evaluating cases of BCNE, C. burnetii was identified as the causative pathogen in 37% [23] and 48% [22] of cases. Positive phase 1 IgG titer is considered a major Duke criterion and is considered diagnostic. Coxiella specific PCR performed on the plasma or heart valves can also be used to confirm the diagnosis.

3.3.2. Bartonella Species

Bartonella spp. are small intracellular Gram-negative bacteria with protean manifestations and have been associated with up to 12.4–28.4% of cases of BCNE [22][23]. Bartonella henselae is associated with cat-scratch disease, and clinicians should be aware of its association with crescentic glomerulonephritis with PR3-ANCA positivity [26]. B. quintana is associated with exposure to the human body louse (Table 1) and has also been associated with BCNE, along with rarer species such as B. elizabethae and B. vinsonii [27][28]. Although most of the literature with respect to B. quintana endocarditis has come out of Europe and Africa, a resurgence in North America has been noted in the past decade [29]. Bartonella serologies are the most commonly used diagnostic tests; Bartonella-specific PCR on peripheral blood specimens or tissue valves could also be used to confirm the diagnosis.

3.3.3. Other Intracellular Pathogens

Rare cases of BCNE associated with Legionella spp., Chlamydia spp., and Mycoplasma spp. have been reported in the literature [17][30][31]. Cases of Legionella endocarditis are typically preceded by pneumonia. Diagnosis may be established with histopathological examination of explanted valves or molecular techniques; the role of serological testing is questionable given the rarity of these pathogens [32]. Brucellosis should also be considered in a patient with specific risk factors or returning from an endemic region (Table 1). Although serological testing for Brucella sp. can be added in these cases [33], detection in routine blood cultures is typically achieved within 5 days [34].

3.4. Non-Infectious Causes of IE

In the largest prospective evaluation of cases of BCNE at a tertiary reference center in France, Fournier et al. found a non-infectious cause of BCNE in 2.5% of cases [22]. Specific diagnoses included systemic lupus erythematosus (SLE), also known as Libman–Sacks endocarditis; rheumatoid arthritis; and IE associated with metastatic malignancy, also known as marantic endocarditis. Endocarditis has also been associated with Behçet’s disease [35]. Clinicians should also be aware of the link between endocarditis on porcine bioprosthetic valves and allergy to pork. A handful of cases of recurrent endocarditis on porcine valves in patients with pork allergies has been reported to date in the literature [36], and replacement of the valve with non-porcine material is necessary in these cases.

References

  1. Tattevin, P.; Watt, G.; Revest, M.; Arvieux, C.; Fournier, P.E. Update on blood culture-negative endocarditis. Médecine Et Mal. Infect. 2015, 45, 1–8.
  2. Slipczuk, L.; Codolosa, J.N.; Davila, C.D.; Romero-Corral, A.; Yun, J.; Pressman, G.S.; Figueredo, V.M. Infective endocarditis epidemiology over five decades: A systematic review. PLoS ONE 2013, 8, e82665.
  3. Vogkou, C.T.; Vlachogiannis, N.I.; Palaiodimos, L.; Kousoulis, A.A. The causative agents in infective endocarditis: A systematic review comprising 33,214 cases. Eur. J. Clin. Microbiol. Infect. Dis. 2016, 35, 1227–1245.
  4. Murdoch, D.R.; Corey, G.R.; Hoen, B.; Miró, J.M.; Fowler, V.G., Jr.; Bayer, A.S.; Karchmer, A.W.; Olaison, L.; Pappas, P.A.; Moreillon, P.; et al. Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: The International Collaboration on Endocarditis-Prospective Cohort Study. Arch. Intern. Med. 2009, 169, 463–473.
  5. Dähler, R.; Brugger, S.D.; Frank, M.; Greutmann, M.; Sromicki, J.; Marques-Maggio, E.; Imkamp, F.; Bauernschmitt, R.; Carrel, T.; Zinkernagel, A.S.; et al. A retrospective analysis of blood culture-negative endocarditis at a tertiary care centre in Switzerland. Swiss Med. Wkly. 2022, 152, 40012.
  6. Math, R.S.; Sharma, G.; Kothari, S.S.; Kalaivani, M.; Saxena, A.; Kumar, A.S.; Bahl, V.K. Prospective study of infective endocarditis from a developing country. Am. Heart J. 2011, 162, 633–638.
  7. Raoult, D.; Casalta, J.P.; Richet, H.; Khan, M.; Bernit, E.; Rovery, C.; Branger, S.; Gouriet, F.; Imbert, G.; Bothello, E.; et al. Contribution of systematic serological testing in diagnosis of infective endocarditis. J. Clin. Microbiol. 2005, 43, 5238–5242.
  8. Lamas, C.C.; Eykyn, S.J. Blood culture negative endocarditis: Analysis of 63 cases presenting over 25 years. Heart 2003, 89, 258–262.
  9. Lamas, C.C.; Fournier, P.E.; Zappa, M.; Brandão, T.J.; Januário-da-Silva, C.A.; Correia, M.G.; Barbosa, G.I.; Golebiovski, W.F.; Weksler, C.; Lepidi, H.; et al. Diagnosis of blood culture-negative endocarditis and clinical comparison between blood culture-negative and blood culture-positive cases. Infection 2016, 44, 459–466.
  10. Baron, E.J.; Scott, J.D.; Tompkins, L.S. Prolonged incubation and extensive subculturing do not increase recovery of clinically significant microorganisms from standard automated blood cultures. Clin. Infect. Dis. 2005, 41, 1677–1680.
  11. Petti, C.A.; Bhally, H.S.; Weinstein, M.P.; Joho, K.; Wakefield, T.; Reller, L.B.; Carroll, K.C. Utility of extended blood culture incubation for isolation of Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella organisms: A retrospective multicenter evaluation. J. Clin. Microbiol. 2006, 44, 257–259.
  12. Van Roeden, S.E.; Bleeker-Rovers, C.P.; de Regt, M.J.A.; Kampschreur, L.M.; Hoepelman, A.I.M.; Wever, P.C.; Oosterheert, J.J. Treatment of Chronic Q Fever: Clinical Efficacy and Toxicity of Antibiotic Regimens. Clin. Infect. Dis. 2017, 66, 719–726.
  13. Baddour, L.M.; Wilson, W.R.; Bayer, A.S.; Fowler, V.G.; Tleyjeh, I.M.; Rybak, M.J.; Barsic, B.; Lockhart, P.B.; Gewitz, M.H.; Levison, M.E.; et al. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications. Circulation 2015, 132, 1435–1486.
  14. McGee, M.; Brienesse, S.; Chong, B.; Levendel, A.; Lai, K. Tropheryma whipplei Endocarditis: Case Presentation and Review of the Literature. Open Forum Infect. Dis. 2019, 6, ofy330.
  15. CDC. Areas at Risk Atlanta, USA: Centers for Disease Control and Prevention 2012. Available online: https://www.cdc.gov/brucellosis/exposure/areas.html (accessed on 2 July 2023).
  16. Cay, S.; Cagirci, G.; Maden, O.; Balbay, Y.; Aydogdu, S. Brucella endocarditis-a registry study. Kardiol. Pol. 2009, 67, 274–280.
  17. Fenollar, F.; Gauduchon, V.; Casalta, J.-P.; Lepidi, H.; Vandenesch, F.; Raoult, D. Mycoplasma Endocarditis: Two Case Reports and a Review. Clin. Infect. Dis. 2004, 38, e21–e24.
  18. Lecorche, E.; Pean de Ponfilly, G.; Mougari, F.; Benmansour, H.; Poisnel, E.; Janvier, F.; Cambau, E. Disseminated Mycobacterium chimaera Following Open-Heart Surgery, the Heater-Cooler Unit Worldwide Outbreak: Case Report and Minireview. Front. Med. 2020, 7, 243.
  19. Bouchiat, C.; Saison, J.; Boisset, S.; Flandrois, J.P.; Issartel, B.; Dauwalder, O.; Benito, Y.; Jarraud, S.; Grando, J.; Boibieux, A.; et al. Nontuberculous Mycobacteria: An Underestimated Cause of Bioprosthetic Valve Infective Endocarditis. Open Forum Infect. Dis. 2015, 2, ofv047.
  20. Yuan, S.M. Mycobacterial endocarditis: A comprehensive review. Rev. Bras. Cir. Cardiovasc. 2015, 30, 93–103.
  21. Schneider, T.; Moos, V.; Loddenkemper, C.; Marth, T.; Fenollar, F.; Raoult, D. Whipple’s disease: New aspects of pathogenesis and treatment. Lancet Infect. Dis. 2008, 8, 179–190.
  22. Fournier, P.E.; Thuny, F.; Richet, H.; Lepidi, H.; Casalta, J.P.; Arzouni, J.P.; Maurin, M.; Célard, M.; Mainardi, J.L.; Caus, T.; et al. Comprehensive diagnostic strategy for blood culture-negative endocarditis: A prospective study of 819 new cases. Clin. Infect. Dis. 2010, 51, 131–140.
  23. Houpikian, P.; Raoult, D. Blood culture-negative endocarditis in a reference center: Etiologic diagnosis of 348 cases. Medicine 2005, 84, 162–173.
  24. García-Álvarez, L.; Sanz, M.M.; Marín, M.; Fariñas, M.C.; Montejo, M.; Goikoetxea, J.; García, R.R.; de Alarcón, A.; Almela, M.; Fernández-Hidalgo, N.; et al. Antimicrobial management of Tropheryma whipplei endocarditis: The Spanish Collaboration on Endocarditis (GAMES) experience. J. Antimicrob. Chemother. 2019, 74, 1768.
  25. Geissdörfer, W.; Moos, V.; Moter, A.; Loddenkemper, C.; Jansen, A.; Tandler, R.; Morguet, A.J.; Fenollar, F.; Raoult, D.; Bogdan, C.; et al. High frequency of Tropheryma whipplei in culture-negative endocarditis. J. Clin. Microbiol. 2012, 50, 216–222.
  26. Ordaya, E.E.; Abu Saleh, O.M.; Mahmood, M. “Let the Cat Out of the Heart”: Clinical Characteristics of Patients Presenting with Blood Culture-negative Endocarditis due to Bartonella species. Open Forum Infect. Dis. 2023, 10, ofad293.
  27. Brouqui, P.; Raoult, D. Endocarditis due to rare and fastidious bacteria. Clin. Microbiol. Rev. 2001, 14, 177–207.
  28. Edouard, S.; Nabet, C.; Lepidi, H.; Fournier, P.E.; Raoult, D. Bartonella, a common cause of endocarditis: A report on 106 cases and review. J. Clin. Microbiol. 2015, 53, 824–829.
  29. Lam, J.C.; Fonseca, K.; Pabbaraju, K.; Meatherall, B.L. Case Report: Bartonella quintana Endocarditis Outside of the Europe-African Gradient: Comprehensive Review of Cases within North America. Am. J. Trop. Med. Hyg. 2019, 100, 1125–1129.
  30. Teira, A.; Sánchez, J.; Santiago, I.; Zarauza, J.; Nan, D.; Teira, R. Legionella endocarditis: A case report and review. Enferm. Infecc. Microbiol. Clin. 2020, 40, 190–194.
  31. Bendjelloul, I.; Lourtet-Hascoët, J.; Galinier, J.L.; Charbonneau, H.; Robinet, N.; Fourcade, C.; Bonnet, E. Chlamydia psittaci endocarditis: A case report and literature review. Infect. Dis. Now 2023, 53, 104687.
  32. Liesman, R.M.; Pritt, B.S.; Maleszewski, J.J.; Patel, R. Laboratory Diagnosis of Infective Endocarditis. J. Clin. Microbiol. 2017, 55, 2599–2608.
  33. Raju, I.T.; Solanki, R.; Patnaik, A.N.; Barik, R.C.; Kumari, N.R.; Gulati, A.S. Brucella endocarditis-a series of five case reports. Indian Heart J. 2013, 65, 72–77.
  34. Sagi, M.; Nesher, L.; Yagupsky, P. The Bactec FX Blood Culture System Detects Brucella melitensis Bacteremia in Adult Patients within the Routine 1-Week Incubation Period. J. Clin. Microbiol. 2017, 55, 942–946.
  35. Demirelli, S.; Degirmenci, H.; Inci, S.; Arisoy, A. Cardiac manifestations in Behcet’s disease. Intractable Rare Dis. Res. 2015, 4, 70–75.
  36. Loyens, M.; Thuny, F.; Grisoli, D.; Fournier, P.-E.; Casalta, J.-P.; Vitte, J.; Habib, G.; Raoult, D. Link between endocarditis on porcine bioprosthetic valves and allergy to pork. Int. J. Cardiol. 2013, 167, 600–602.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Infectious Diseases
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Jack McHugh
,
Omar Abu Saleh
View Times: 264
Revisions: 2 times (View History)
Update Date: 24 Aug 2023
Table of Contents
    1000/1000
    Hot Most Recent
    Video Production Service
    Feedback