Epidemiology, microbiology, and diagnosis of culture-negative endocarditis
- Didier Raoult, MD, PhD
Didier Raoult, MD, PhD
- Faculté de Médecine
- Aix Marseille Université
- Daniel J Sexton, MD
Daniel J Sexton, MD
- Editor-in-Chief — Infectious Diseases
- Section Editor — Bacterial Infections
- Professor of Medicine
- Duke University Medical Center
Infective endocarditis (IE) remains a diagnostic challenge in some patients. Identification of the etiologic agent is critical to selecting an appropriate treatment, as the fatality rate remains high . The proportion of IE that is without an etiologic diagnosis varies from country to country and among different centers in the same country. These variations reflect the local epidemiology of IE, diagnostic criteria used, initiation of antibiotics in patients prior to obtaining blood cultures, and the diagnostic protocol used to establish an etiology .
The epidemiology and microbiology of culture-negative endocarditis will be reviewed here. Criteria for the diagnosis of IE and treatment are discussed separately. (See "Clinical manifestations and evaluation of adults with suspected native valve endocarditis" and "Antimicrobial therapy of native valve endocarditis" and "Antimicrobial therapy of prosthetic valve endocarditis".)
The epidemiology of blood culture-negative infective endocarditis (IE) varies by country and host, as exposure to infection with highly fastidious bacteria (many zoonotic) or fungi depends on whether the organism is endemic to the area and whether the host is particularly susceptible to infection with the organism.
Definition — Blood culture-negative IE is defined as endocarditis without etiology following inoculation of at least three independent blood samples in a standard blood-culture system with negative cultures after five days of incubation and subculturing .
Incidence — Cultures remain negative in 2 to 7 percent of patients with IE even when the utmost care is taken in obtaining the proper number and volume of blood cultures and patients with prior antibiotic treatment are excluded; the frequency is higher in patients who have already been treated with antibiotics [3-7].
- Brouqui P, Raoult D. Endocarditis due to rare and fastidious bacteria. Clin Microbiol Rev 2001; 14:177.
- Raoult D, Casalta JP, Richet H, et al. Contribution of systematic serological testing in diagnosis of infective endocarditis. J Clin Microbiol 2005; 43:5238.
- Molavi A. Endocarditis: recognition, management, and prophylaxis. Cardiovasc Clin 1993; 23:139.
- Hoen B, Selton-Suty C, Lacassin F, et al. Infective endocarditis in patients with negative blood cultures: analysis of 88 cases from a one-year nationwide survey in France. Clin Infect Dis 1995; 20:501.
- Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med 2001; 345:1318.
- Werner M, Andersson R, Olaison L, Hogevik H. A clinical study of culture-negative endocarditis. Medicine (Baltimore) 2003; 82:263.
- Zamorano J, Sanz J, Almería C, et al. Differences between endocarditis with true negative blood cultures and those with previous antibiotic treatment. J Heart Valve Dis 2003; 12:256.
- Benslimani A, Fenollar F, Lepidi H, Raoult D. Bacterial zoonoses and infective endocarditis, Algeria. Emerg Infect Dis 2005; 11:216.
- Koegelenberg CF, Doubell AF, Orth H, Reuter H. Infective endocarditis in the Western Cape Province of South Africa: a three-year prospective study. QJM 2003; 96:217.
- Tariq M, Alam M, Munir G, et al. Infective endocarditis: a five-year experience at a tertiary care hospital in Pakistan. Int J Infect Dis 2004; 8:163.
- Krcmery V, Gogová M, Ondrusová A, et al. Etiology and risk factors of 339 cases of infective endocarditis: report from a 10-year national prospective survey in the Slovak Republic. J Chemother 2003; 15:579.
- Cecchi E, Forno D, Imazio M, et al. New trends in the epidemiological and clinical features of infective endocarditis: results of a multicenter prospective study. Ital Heart J 2004; 5:249.
- Lamas CC, Eykyn SJ. Blood culture negative endocarditis: analysis of 63 cases presenting over 25 years. Heart 2003; 89:258.
- Nakatani S, Mitsutake K, Hozumi T, et al. Current characteristics of infective endocarditis in Japan: an analysis of 848 cases in 2000 and 2001. Circ J 2003; 67:901.
- Houpikian P, Raoult D. Blood culture-negative endocarditis in a reference center: etiologic diagnosis of 348 cases. Medicine (Baltimore) 2005; 84:162.
- Roger PM, Boissy C, Gari-Toussaint M, et al. Medical treatment of a pacemaker endocarditis due to Candida albicans and to Candida glabrata. J Infect 2000; 41:176.
- Acquati F, Semeraro F, Respighi E, et al. Aspergillus flavus-infection of a pacemaker wire: continuing evidence for active management of infected pacemakers. G Ital Cardiol 1987; 17:467.
- Barbone A, Pini D, Grossi P, et al. Aspergillus left ventricular assist device endocarditis. Ital Heart J 2004; 5:876.
- Katsouli A, Massad MG. Current issues in the diagnosis and management of blood culture-negative infective and non-infective endocarditis. Ann Thorac Surg 2013; 95:1467.
- Baron EJ, Scott JD, Tompkins LS. Prolonged incubation and extensive subculturing do not increase recovery of clinically significant microorganisms from standard automated blood cultures. Clin Infect Dis 2005; 41:1677.
- Petti CA, Bhally HS, Weinstein MP, et al. 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.
- Fournier PE, La MV, Casalta JP, et al. Finegoldia magna, an early post-operative cause of infectious endocarditis: report of two cases and review of the literature. Anaerobe 2008; 14:310.
- Fournier PE, Thuny F, Richet H, et al. Comprehensive diagnostic strategy for blood culture-negative endocarditis: a prospective study of 819 new cases. Clin Infect Dis 2010; 51:131.
- Houpikian P, Raoult D. Diagnostic methods. Current best practices and guidelines for identification of difficult-to-culture pathogens in infective endocarditis. Cardiol Clin 2003; 21:207.
- Maurin M, Raoult D. Q fever. Clin Microbiol Rev 1999; 12:518.
- Raoult D. Chronic Q fever: expert opinion versus literature analysis and consensus. J Infect 2012; 65:102.
- Znazen A, Rolain JM, Hammami N, et al. High prevalence of Bartonella quintana endocarditis in Sfax, Tunisia. Am J Trop Med Hyg 2005; 72:503.
- Geissdörfer W, Moos V, Moter A, et al. High frequency of Tropheryma whipplei in culture-negative endocarditis. J Clin Microbiol 2012; 50:216.
- Fenollar F, Célard M, Lagier JC, et al. Tropheryma whipplei endocarditis. Emerg Infect Dis 2013; 19:1721.
- Thuny F, Fournier PE, Casalta JP, et al. Investigation of blood culture-negative early prosthetic valve endocarditis reveals high prevalence of fungi. Heart 2010; 96:743.
- Lepidi H, Fournier PE, Raoult D. Quantitative analysis of valvular lesions during Bartonella endocarditis. Am J Clin Pathol 2000; 114:880.
- Lepidi H, Houpikian P, Liang Z, Raoult D. Cardiac valves in patients with Q fever endocarditis: microbiological, molecular, and histologic studies. J Infect Dis 2003; 187:1097.
- Lepidi H, Fenollar F, Dumler JS, et al. Cardiac valves in patients with Whipple endocarditis: microbiological, molecular, quantitative histologic, and immunohistochemical studies of 5 patients. J Infect Dis 2004; 190:935.
- Dumler JS, Baisden BL, Yardley JH, Raoult D. Immunodetection of Tropheryma whipplei in intestinal tissues from Dr. Whipple's 1907 patient. N Engl J Med 2003; 348:1411.
- Lepidi H, Coulibaly B, Casalta JP, Raoult D. Autoimmunohistochemistry: a new method for the histologic diagnosis of infective endocarditis. J Infect Dis 2006; 193:1711.
- Breitkopf C, Hammel D, Scheld HH, et al. Impact of a molecular approach to improve the microbiological diagnosis of infective heart valve endocarditis. Circulation 2005; 111:1415.
- Greub G, Lepidi H, Rovery C, et al. Diagnosis of infectious endocarditis in patients undergoing valve surgery. Am J Med 2005; 118:230.
- Bosshard PP, Kronenberg A, Zbinden R, et al. Etiologic diagnosis of infective endocarditis by broad-range polymerase chain reaction: a 3-year experience. Clin Infect Dis 2003; 37:167.
- Grijalva M, Horváth R, Dendis M, et al. Molecular diagnosis of culture negative infective endocarditis: clinical validation in a group of surgically treated patients. Heart 2003; 89:263.
- Gauduchon V, Chalabreysse L, Etienne J, et al. Molecular diagnosis of infective endocarditis by PCR amplification and direct sequencing of DNA from valve tissue. J Clin Microbiol 2003; 41:763.
- Podglajen I, Bellery F, Poyart C, et al. Comparative molecular and microbiologic diagnosis of bacterial endocarditis. Emerg Infect Dis 2003; 9:1543.
- Millar B, Moore J, Mallon P, et al. Molecular diagnosis of infective endocarditis--a new Duke's criterion. Scand J Infect Dis 2001; 33:673.
- Goldenberger D, Künzli A, Vogt P, et al. Molecular diagnosis of bacterial endocarditis by broad-range PCR amplification and direct sequencing. J Clin Microbiol 1997; 35:2733.
- Vondracek M, Sartipy U, Aufwerber E, et al. 16S rDNA sequencing of valve tissue improves microbiological diagnosis in surgically treated patients with infective endocarditis. J Infect 2011; 62:472.
- Rampini SK, Bloemberg GV, Keller PM, et al. Broad-range 16S rRNA gene polymerase chain reaction for diagnosis of culture-negative bacterial infections. Clin Infect Dis 2011; 53:1245.
- Morel AS, Dubourg G, Prudent E, et al. Complementarity between targeted real-time specific PCR and conventional broad-range 16S rDNA PCR in the syndrome-driven diagnosis of infectious diseases. Eur J Clin Microbiol Infect Dis 2015; 34:561.
- Rice PA, Madico GE. Polymerase chain reaction to diagnose infective endocarditis: will it replace blood cultures? Circulation 2005; 111:1352.
- Rovery C, Greub G, Lepidi H, et al. PCR detection of bacteria on cardiac valves of patients with treated bacterial endocarditis. J Clin Microbiol 2005; 43:163.
- Million M, Walter G, Bardin N, et al. Immunoglobulin G anticardiolipin antibodies and progression to Q fever endocarditis. Clin Infect Dis 2013; 57:57.
- Mantur BG, Mangalgi SS. Evaluation of conventional castaneda and lysis centrifugation blood culture techniques for diagnosis of human brucellosis. J Clin Microbiol 2004; 42:4327.
- Archibald LK, McDonald LC, Addison RM, et al. Comparison of BACTEC MYCO/F LYTIC and WAMPOLE ISOLATOR 10 (lysis-centrifugation) systems for detection of bacteremia, mycobacteremia, and fungemia in a developing country. J Clin Microbiol 2000; 38:2994.
- Gouriet F, Fenollar F, Patrice JY, et al. Use of shell-vial cell culture assay for isolation of bacteria from clinical specimens: 13 years of experience. J Clin Microbiol 2005; 43:4993.
- Fournier PE, Thuny F, Grisoli D, et al. A deadly aversion to pork. Lancet 2011; 377:1542.
- Risk factors
- Clinical clues to the diagnosis
- Possible etiologies
- Molecular techniques
- - Polymerase chain reaction
- - Serologic assays
- Special culture techniques
- - Lysis centrifugation
- - Shell vial cell culture
- DIFFERENTIAL DIAGNOSIS