Culture Negative Infective Endocarditits: a Changing Paradigm

A Daly1, JM Redmond1, MM Hannan2

1Department of Cardiothoracic Surgery, Mater Misercordiae University Hospital, Eccles St, Dublin 7

2Department of Microbiology, Mater Misercordiae University Hospital, Eccles St, Dublin 7


Traditionally, the modified Duke's criteria, based primarily on positive blood cultures, is used to diagnose Infective Endocarditis (IE). However, reports demonstrate that 31% of cases are diagnosed as Culture Negative Infective Endocarditis (CNIE)1. Consequently, empiric broad-spectrum antibiotics are prescribed to cover unidentified organisms and, as a result, antibiotic therapy may be compromised. Molecular diagnostic techniques aid with identifying causative organisms in cases of CNIE and we question if the increasing use of such technologies will change the local epidemiology of CNIE. We present the first case of Tropheryma whipplei Infective Endocarditis (TWIE) reported in Ireland. 


Approximately 30% of all IE cases are culture negative. Diagnosing causative organisms is dependant on serology and molecular techniques, supported by histological analysis of explanted valves. Sequencing 16s rDNA using PCR provides a diagnostic test for bacterial isolates which is 67% sensitive and 91% specific in the diagnosis of CNIE2. TWIE, a cause of CNIE, is rarely reported, either in the context of classical Whipple's disease or isolated TWIE3. To date, approximately 100 cases of TWIE are reported in the literature, we present the first case of TWIE in Ireland.

Case Report

A 47 year old man was admitted with pleuritic chest pain, three pillow orthopnoea and paroxysmal nocturnal dyspnoea. He also noted a two year history of arthralgia and intermittent abdominal cramps. Examination revealed a new pansystolic murmur in the mitral area. Serial blood cultures were negative. Routine serology for CNIE including Brucella species(sp), Coxiella burnetti, Bartonella sp, Legionella sp and T. whipplei was requested. Echocardiography showed severe aortic incompetence and moderate mitral regurgitation. Urgent aortic valve replacement and mitral valve repair was performed. During surgery, the aortic valve was severely destroyed and noted to be bicuspid, a predisposition for IE. All leaflets had the appearance of IE. The second chordae of the mitral valve was ruptured at A2. A mechanical aortic prosthesis was implanted. Postoperatively, the patient recovered well. The explanted valve cultured no organisms and was sent for analysis by PCR. The patient was anticoagulated with warfarin and treated empirically for CNIE with a two week course of intravenous(IV) gentamycin and six week course of vancomycin. PCR results available two weeks post-surgery tested positive for T. whipplei. Subsequent investigation including; urine, saliva and blood PCR, duodenal biopsy and PET-CT revealed no source of T. whipplei other than IE. The patient, who was penicillin allergic, was prescribed IV ceftriaxone and gentamycin for two weeks. Subsequently, he was discharged well and prescribed oral hydroxychloroquine and doxycycline for 18 months.


IE is a potentially life-threatening condition unless appropriately treated. The causative organisms of culture positive native-valve IE include Streptococcus viridans, Staphylococcus aureus and Enterococci sp in 80% of cases4. Antibiotic therapy should be specific to the sensitivites of cultured organisms. However, Fournier et al noted in a prospective study of 819 patients with suspected IE that nearly one-third of cases of confirmed IE were blood culture negative1. C. burnetti, Bartonella sp, T. whipplei, Chlamydia pneumonia, Mycoplasma pneumonia and fungal causes are sited as the most common causes of CNIE1,5. We believe that with improving molecular diagnostic techniques, reporting of TWIE as a cause of CNIE will increase. The diagnosis of CNIE is difficult and underestimated5. Modified Duke's criteria has been noted to be ineffective for diagnosis before analysis of heart valves in certain series6. As a result, serological, molecular and histopathological analysis is suggested in all cases of CNIE1. At our centre, all valves are delivered internationally for broad-range PCR analysis. Two-step broad-range 16s rDNA PCR analysis increases the sensitivity of valve analysis7. Real-time PCR should be performed and, if positive, followed by traditional end-point PCR to augment sensitivity and aid diagnosis. Full investigations including urine, saliva and blood PCR, OGD, colonoscopy and PET-CT should be performed to investigate for systemic Whipple's disease5.

T. whipplei is not covered by empirical antibiotic therapy for CNIE5. Therefore, accurate diagnosis is crucial to initiating appropriate treatment: doxycycline and hydroxychloroquine for at least 12 months6. This case, the first in Ireland, highlights the importance of sending explanted valves for appropriate analysis. With improving molecular techniques, we postulate the incidence of diagnosed TWIE will increase.  Therefore increased awareness of this disease will allow early diagnosis and effective treatment of patients with CNIE. 


Correspondence: Adam Daly, Department of Cardiothoracic Surgery, Mater Misercordiae University Hospital, Eccles St, Dublin 7

Email: [email protected] 



1 Fournier PE, Thuny F, Richet H, Lepidi H`, Casalte JP, Arzouni JP, Maurin M, Mainardi JL, Caus T,Collart F, Habib G, Raoult D. Comprehensive diagnostic strategy for blood culture-negative endocarditis: a prospective study of 819 new cases. Clin Infect Dis [Internet]. 2010 Jul 15 ;51:131-40.

2 Harris KA, Yam T, Jalili S, Williams OM, Alshafi K, Goulioris T, Munthali P, Niriain U, Hartley JC. Service Evaluation to establish the sensitivty, specificity and additional value of broad-range 16s rDNA PCR for the diagnosis of infective endocarditits from resected endocardial material in patients from eight UK and Ireland hospitals. Eur J Clin Microbiol Infect Dis [Internet]. 2014 Jun 15.

3 Geissdorfer W, Moow V, Moter A, Loddenkemper C, Jansen A, Tandler R, Morguet AJ, Fenollar F, Raolt D, Bogdan C, Schneider T. High frequency of Tropheryma whipplei in culture-negative infective endocarditis. J Clin Microbiol [Internet]. 2012 Feb ;50(2):216-22.

4 Arturo J Marti-Carvajal, Lucieni O Conterno, Ricardo Hidalgo, Joey SW, Kwong PG. Antibiotic therapy for treatment of infective endocarditis (Protocol). CochraneDatabase Syst Rev. Chichester, UK: John Wiley & Sons, Ltd: 2012 Sep 1.

5 Brondex A, Jobic Y. Infective endocarditis as the only manifestation of Whipple's disease: an atypical presentation. Ann Cardiol Angeiol (Paris)[Internet]. 2012 Feb;61:61-3.

6 Fenollar F, Celard M, Lagier JC, Lepidi H, Fournier PE, Raoult D. Tropheryma whipplei endocarditis. Emerg Infect Dis [Internet]. 2013 Nov;19:1721-30.

7 Boussier R, Rogez S, Francois B, Denes E, Ploy MC, Garnier F. Two-step bacterial broad-range polymerase chain reaction analysis of heart valve tissue improves bacteriological diagnosis of infective endocarditis. Diagn Microbiol Infect Dis [Internet]. 2013 Mar;75:240-4.