Infective endocarditis

Infective endocarditis (IE) is an infection of the endocardium that typically affects one or more heart valves. The condition is usually a result of bacteremia, which is most commonly caused by dental procedures, surgery, distant primary infections, and nonsterile injections. IE may be acute (developing over hours or days) or subacute (progressive over weeks to months). Acute bacterial endocarditis is usually caused by Staphylococcus aureus and causes rapid destruction of endocardial tissue, while subacute bacterial endocarditis is most commonly caused by viridans streptococci and generally affects individuals with preexisting damage to the heart valves, structural heart defects, or prosthetic valves. Clinical features include constitutional symptoms (fatigue, fever/chills, malaise), signs of pathological cardiac changes (e.g., new or changed heart murmur, heart failure signs), and, in some cases, manifestations of subsequent damage to other organs (e.g., glomerulonephritis, septic embolic stroke). Management is complex and infectious disease specialists should be involved early. Diagnosis is made based on the Duke criteria, the main features of which are positive blood cultures and evidence of endocardial involvement on echocardiography. Initial treatment of IE consists of empiric IV antibiotics, which are then adapted to blood culture results and continued for several weeks. Categorization into native valve endocarditis or prosthetic valve endocarditis helps to further tailor regimens. Surgery may be necessary for complex cases (e.g., valve perforation). Prophylaxis against IE is administered in certain circumstances, e.g., in patients with preexisting heart conditions, such as congenital heart disease, undergoing dental or surgical procedures. IE is typically fatal if left untreated.

Pathogens

Risk factors for infective endocarditis ^[1][4][10]

• Demographics
  • Male sex
  • Age > 60 years
• Cardiac conditions
  • Acquired valvular disease (e.g., rheumatic heart disease, aortic stenosis, degenerative valvular disease)
  • Prosthetic heart valves
  • Congenital heart defects (e.g., VSD, bicuspid aortic valve)
  • Previous IE
• Noncardiac risk factors
  • Poor dental status
  • Dental procedures
  • Nonsterile venous injections (e.g., in IV drug use)
  • Intravascular devices
  • Surgery
  • Chronic hemodialysis
  • Immunocompromise (e.g., HIV infection, diabetes)
  • Other bacterial infections (e.g., UTIs, spondylodiscitis, periodontal infection)

• Pathogenesis ^[1]
  1. Damaged valvular endothelium → exposure of the subendothelial layer → adherence of platelets and fibrin → sterile vegetation (microthrombus)
  2. Localized infection or contamination → bacteremia → bacterial colonization of vegetation → formation of fibrin clots encasing the vegetation → valve destruction with loss of function ^[11]
• Valve involvement ^[10]
  • Frequency of valve involvement: mitral valve > aortic valve > tricuspid valve > pulmonary valve
  • The tricuspid valve is the most commonly affected valve in IV drug users (associated with Pseudomonas, S. aureus, and Candida).
• Clinical consequences ^[1][11]
  • Bacterial vegetation → bacterial thromboemboli → vessel occlusion → infarctions
  • Emboli can lead to metastatic infections of other organs.
  • Formation of immune complexes and antibodies against tissue antigens → glomerulonephritis, Osler nodes

“Don't tri drugs for the sake of your tricuspid valves.”

Constitutional symptoms ^[1][12]

• Fever and chills, tachycardia
• General malaise, weakness, weight loss, night sweats
• Dyspnea; , cough, pleuritic chest pain
• Arthralgias, myalgias

Cardiac manifestations ^[1][12]

• Development of a new heart murmur or change in a preexisting murmur
  • Tricuspid valve regurgitation
    • Holosystolic murmur that is loudest at the left sternal border
    • Seen in IV drug users, immunocompromised individuals, patients with congenital heart disease, and patients with instrumentation in the right heart (e.g., central venous catheters) ^[2]
  • Aortic valve regurgitation: early diastolic murmur that is loudest at the left sternal border
  • Mitral valve regurgitation: holosystolic murmur that is loudest at the heart's apex and radiates to the left axilla
• Heart failure (e.g., dyspnea, lower limb edema) due to valve insufficiency
• Arrhythmias: Suspect a perivalvular abscess in patients with IE who develop a new conduction abnormality (e.g., heart block). ^[13]

Extracardiac manifestations ^[1][12]

Extracardiac symptoms are more common in left-sided IE, with the exception of pulmonary embolic manifestations, which are more common in right-sided IE. These extracardiac manifestations are mainly caused by bacterial microemboli and/or the precipitation of immune complexes.

• Petechiae, especially splinter hemorrhages (hemorrhages underneath fingernails)
• Janeway lesions
  • Small, nontender, erythematous macules on palms and soles
  • Microabscesses with neutrophilic capillary infiltration and areas of hemorrhage caused by septic microemboli from valve vegetations
• Osler nodes: painful nodules on pads of the fingers and toes caused by immune complex deposition
• Roth spots: round retinal hemorrhages with pale centers
• Acute renal injury
  • Including hematuria and anuria
  • Due to renal artery occlusion or glomerulonephritis
• Splenomegaly and possible LUQ pain
  • Due to splenic artery occlusion or splenic abscess
  • May lead to splenic rupture ^[14]
• Neurological manifestations; (e.g., seizures, paresis): due to septic embolic stroke, hemorrhages, meningitis, encephalitis, and/or abscess
• Signs of pulmonary embolism (e.g., dyspnea); : typically caused by septic emboli resulting from tricuspid valve involvement
• Arthritis

Infective endocarditis should always be considered as a cause of fever of unknown origin (FUO), especially in the presence of a new heart murmur.

“FROM JANE:” Features of infective endocarditis include Fever, Roth spots, Osler nodes, Murmur, Janeway lesions, Anemia, Nail bed hemorrhage, and Emboli.

• IE can be classified by:
  • Type of affected valve (native vs. prosthetic)
  • Acuity of the infection
  • Location of the infection (left- vs. right-sided).
• Although this is not a definitive classification system, it can help in the approach to management and selection of empiric antibiotic regimens.

Classification by valve type and duration of infection

Classification by location

Approach ^[15][17]

• Suspect IE based on clinical findings (e.g., fever without focus combined with a new murmur) and predisposing conditions.
• The modified Duke criteria help categorize the diagnostic likelihood of IE: definite vs. possible vs. rejected. ^[6]
  • Used as a diagnostic guide; not a substitute for clinical judgment
  • Incorporate clinical, microbiological, pathological, and imaging criteria.
• All patients should receive multiple blood cultures and echocardiography.
• Additional diagnostics (e.g., serology, additional imaging) help assess blood culture-negative endocarditis and complications.
• Consult infectious disease (ID) if the diagnosis is uncertain.

Laboratory studies ^[15]

Routine studies

• CBC: leukocytosis with left shift
• Inflammatory markers: ↑ CRP, ↑ ESR ^[17]
• BMP: assessment of renal function for antibiotic dosing

Blood cultures ^[20]

• Sampling protocol
  • Prior to treatment: 3 sets from different venipuncture sites ^[15][20]
  • Monitoring: 2 sets every 24–48 hours until clearance
• Interpretation
  • Positive bacterial cultures: Assess according to the modified Duke criteria.
  • Negative bacterial cultures do not rule out endocarditis. False negatives can be due to: ^[6][20][21]
    • Antibiotic therapy prior to blood culture sampling
    • Fastidious bacteria (most commonly Coxiella burnetii and Bartonella spp.)
    • Fungal infection
    • Noninfective endocarditis

Echocardiography ^[15]

Transthoracic echocardiography (TTE) is the initial test of choice for all patients with suspected IE. It should ideally be performed within 12 hours of presentation and repeated after completing treatment. Transesophageal echocardiography (TEE) is more invasive and is added in select cases. ^[15]

• Indications for TEE include:
  • Presence of high-risk features
  • TTE findings inconclusive or suggestive of IE
  • Preoperative planning
  • Concern for intracardiac complications (e.g., abscess)
• Echocardiographic findings fulfilling Duke criteria for IE: similar in TTE and TEE ^[6][22][23]
  • Valvular vegetations: Hyperechoic mobile masses located on the valve, mural endocardium, or prosthetic material ^[24]
  • Abscess (e.g., perivalvular abscess)
  • New valvular regurgitation (especially with valve prolapse, perforation, or destruction)
  • Prosthetic valve dehiscence
• Other high-risk findings include:
  • Valve aneurysm
  • Fistula or pseudoaneurysm
  • Heart failure

TEE is more sensitive (∼ 90%) than TTE (∼ 75%) and is more reliable in ruling out IE in patients with moderate-to-high pretest probability.

• Acute disease (leading to valve insufficiency, septic embolic infarcts, tendinous cord rupture) ^[27]
  • Erosion → fibrin deposits on valves
  • Ulceration
  • Perforation
• Chronic disease (leading to valve insufficiency and valve stenosis) ^[27]
  • Erosion → reorganization of fibrin layer
  • Granulation tissue → valve scarring/fibrosis
  • Calcification → thickened and/or shortened tendinous cords

Noninfective endocarditis (nonbacterial thrombotic endocarditis) ^[28][29]

• Description
  • Rare, noninfective form of endocarditis due to sterile platelet thrombus formation on the heart valves (usually mitral and aortic valves)
  • Libman-Sacks endocarditis: a type of noninfective endocarditis with verrucous vegetations in individuals with systemic lupus erythematosus or antiphospholipid syndrome ^[28]
• Etiology
  • Malignancy
  • Hypercoagulable states
  • Underlying trauma (e.g., from indwelling vascular catheters)
  • Previous rheumatic fever
  • Autoimmune conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid syndrome) ^[30]
  • Chronic infections (e.g., TB, pneumonia, osteomyelitis)
• Clinical features
  • Valves and cardiac function are rarely impaired.
  • Compared to IE, vegetations are easily dislodged and embolization is common, leading to hemorrhages under the nails, skin, and retina
  • Most affected individuals are asymptomatic until embolization occurs.
• Diagnostics
  • Negative blood cultures
  • Echocardiography: valve vegetations
  • Biopsy (definitive diagnosis)
    • Sterile vegetations on either surface of the valve composed of immune complexes, mononuclear cells, and thrombi interwoven with fibrin strands
    • Not always feasible, therefore diagnosis is mostly made based on clinical findings, negative blood cultures, echocardiography findings, and no response to antibiotic treatment
• Treatment
  • Anticoagulation with heparin
  • Treatment of the underlying condition

Prosthetic valve thrombosis ^[31]

• Overview
  • Usually affects mechanic valves
  • Rare if anticoagulation is adequate
• Etiology: insufficient anticoagulatory therapy after valve replacement
• Clinical features
  • Signs of acute heart failure
    • Left heart failure: dyspnea and cough
    • Right heart failure: edema and jugular venous distention
  • Deterioration of general condition, cardiac arrhythmias, cerebral emboli (stroke)
• Diagnostics: transesophageal echocardiography
• Treatment
  • Anticoagulation and fibrinolysis
  • Surgical valve replacement

The differential diagnoses listed here are not exhaustive.

General principles ^{[6][15][32][33]}

If infective endocarditis is suspected, first obtain blood cultures, then consult ID to plan empiric antibiotic therapy. When culture results are available, adapt the therapy accordingly.

Surgery ^[15][32]

• Indications for surgical consultation include:
  • Prosthetic valve endocarditis
  • Valve dysfunction
  • Signs/symptoms of heart failure
  • New heart block
  • Annular or aortic abscess or destructive penetrating lesions
  • Fungal endocarditis
  • Complications secondary to perivalvular extension: e.g., abscess, pseudoaneurysm, fistula
• Options: valve replacement or valve repair (See “Treatment” in “Valvular heart diseases”.)
• Complications
  • Acute surgical complications: e.g., rebleeding from surgical sites, coagulopathy, acute renal failure, pneumonia
  • Cardiac complications: e.g., CHF, myocarditis, pericarditis, new AV block
  • Systemic emboli: e.g., stroke

Endocarditis prophylaxis ^[32][34]

• Common indications ^[35][36]
  • Prior to the implantation of cardiac implantable electronic devices (e.g., AICD) ^[37]
  • Some dental procedures in patients with high-risk cardiac features, such as:
    • Prosthetic heart valves or prosthetic material used for valve repair
    • History of endocarditis
    • Types of congenital heart disease (CHD): e.g.., unrepaired cyanotic CHD, Repaired CHD with shunt or regurgitation at or near the site of prosthetic material
    • Cardiac transplant with valve regurgitation
• Common regimens (usually administered 30–60 minutes prior to the procedure)
  • Prior to cardiac device implantation: cefazolin
  • Prior to dental procedures
    • No penicillin allergy: amoxicillin OR ampicillin
    • Penicillin allergy: a macrolide (e.g., azithromycin ) OR clindamycin

1. Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC Guidelines for the management of infective endocarditis. Eur Heart J. 2015; 36 (44): p.3075-3128. doi: 10.1093/eurheartj/ehv319 . | Open in Read by QxMD
2. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2017; 135 (25). doi: 10.1161/cir.0000000000000503 . | Open in Read by QxMD
3. Wilson W, Taubert KA, Gewitz M, et al. Prevention of Infective Endocarditis Guidelines From the American Heart Association. Circulation. 2007 . doi: 10.1161/CIRCULATIONAHA.106.183095 . | Open in Read by QxMD
4. Thornhill MH, Dayer MJ, Forde JM, et al. Impact of the NICE guideline recommending cessation of antibiotic prophylaxis for prevention of infective endocarditis: before and after study. BMJ. 2011; 342 (may03 1): p.d2392-d2392. doi: 10.1136/bmj.d2392 . | Open in Read by QxMD
5. Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical Practice Guidelines for Antimicrobial Prophylaxis in Surgery. Surg Infect (Larchmt). 2013; 14 (1): p.73-156. doi: 10.1089/sur.2013.9999 . | Open in Read by QxMD
6. Baddour LM, Wilson WR, Bayer AS, et al. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association. Circulation. 2015; 132 (15): p.1435-1486. doi: 10.1161/CIR.0000000000000296 . | Open in Read by QxMD
7. Shmueli H, Thomas F, Flint N, Setia G, Janjic A, Siegel RJ. Right‐Sided Infective Endocarditis 2020: Challenges and Updates in Diagnosis and Treatment. J Am Heart Assoc. 2020; 9 (15). doi: 10.1161/jaha.120.017293 . | Open in Read by QxMD
8. Chambers HF, Bayer AS. Native-Valve Infective Endocarditis.. N Engl J Med. 2020; 383 (6): p.567-576. doi: 10.1056/NEJMcp2000400 . | Open in Read by QxMD
9. Moss R, Munt B. Injection drug use and right sided endocarditis. Heart. 2003; 89 (5): p.577–581. doi: 10.1136/heart.89.5.577 . | Open in Read by QxMD
10. Murdoch DR. Clinical Presentation, Etiology, and Outcome of Infective Endocarditis in the 21st Century. Arch Intern Med. 2009; 169 (5): p.463. doi: 10.1001/archinternmed.2008.603 . | Open in Read by QxMD
11. Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2). McGraw-Hill Education / Medical ; 2018
12. Abdulamir AS, Hafidh RR, Abu bakar F. The association of Streptococcus bovis/gallolyticus with colorectal tumors: the nature and the underlying mechanisms of its etiological role. J Exp Clin Cancer Res. 2011; 30 (1): p.11. doi: 10.1186/1756-9966-30-11 . | Open in Read by QxMD
13. Cahill TJ, Prendergast BD. Infective endocarditis. Lancet. 2016; 387 (10021): p.882-893. doi: 10.1016/s0140-6736(15)00067-7 . | Open in Read by QxMD
14. Arnold CJ, Johnson M, Bayer AS, et al. Candida infective endocarditis: an observational cohort study with a focus on therapy. Antimicrob Agents Chemother. 2015; 59 (4): p.2365-2373. doi: 10.1128/AAC.04867-14 . | Open in Read by QxMD
15. Tacke D, Koehler P, Cornely OA. Fungal endocarditis. Curr Opin Infect Dis.. 2013; 26 (6): p.501-507. doi: 10.1097/QCO.0000000000000009 . | Open in Read by QxMD
16. Kojic EM, Darouiche RO. Candida infections of medical devices.. Clin Microbiol Rev. 2004; 17 (2): p.255-67. doi: 10.1128/cmr.17.2.255-267.2004 . | Open in Read by QxMD
17. McDonald JR. Acute infective endocarditis.. Infect Dis Clin North Am. 2009; 23 (3): p.643-64. doi: 10.1016/j.idc.2009.04.013 . | Open in Read by QxMD
18. Kasper DL, Fauci AS, Hauser SL, Longo DL, Lameson JL, Loscalzo J. Harrison's Principles of Internal Medicine. McGraw-Hill Education ; 2015
19. Dhawan VK. Infective Endocarditis in Elderly Patients. Clin Infect Dis. 2002; 34 (6): p.806-812. doi: 10.1086/339045 . | Open in Read by QxMD
20. Kang N, Wan S, Ng CS, Underwood MJ. Periannular extension of infective endocarditis. Ann Thorac Cardiovasc Surg. 2009; 15 (2): p.74-81.
21. Winearls JR, McGloughlin S, Fraser JF. Splenic rupture as a presenting feature of endocarditis. European Journal of Cardio-Thoracic Surgery. 2009; 35 (4): p.737-739. doi: 10.1016/j.ejcts.2008.12.045 . | Open in Read by QxMD
22. Pierce D, Calkins BC, Thornton K. Infectious endocarditis: diagnosis and treatment.. Am Fam Physician. 2012; 85 (10): p.981-6.
23. Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000; 30 (4): p.633-638. doi: 10.1086/313753 . | Open in Read by QxMD
24. Büchi AE, Hoffmann M, Zbinden S, Sendi P. Infective Endocarditis: How Do We Currently Interpret the Duke Minor Criterion "Predisposing Heart Condition" in Native Valves?. Cardiol Ther. 2017; 6 (1): p.121-128. doi: 10.1007/s40119-016-0074-2 . | Open in Read by QxMD
25. Liesman RM, Pritt BS, Maleszewski JJ, Patel R. Laboratory Diagnosis of Infective Endocarditis. J Clin Microbiol. 2017; 55 (9): p.2599-2608. doi: 10.1128/jcm.00635-17 . | Open in Read by QxMD
26. Tattevin P, Watt G, Revest M, Arvieux C, Fournier P-E. Update on blood culture-negative endocarditis. Med Mal Infect. 2015; 45 (1-2): p.1-8. doi: 10.1016/j.medmal.2014.11.003 . | Open in Read by QxMD
27. Habib G, Badano L, Tribouilloy C, et al. Recommendations for the practice of echocardiography in infective endocarditis. European Journal of Echocardiography. 2010; 11 (2): p.202-219. doi: 10.1093/ejechocard/jeq004 . | Open in Read by QxMD
28. Bruun NE, Habib G, Thuny F, Sogaard P. Cardiac imaging in infectious endocarditis. Eur Heart J. 2013; 35 (10): p.624-632. doi: 10.1093/eurheartj/eht274 . | Open in Read by QxMD
29. Evangelista A, Gonzalez-Alujas MT. Echocardiography in infective endocarditis.. Heart. 2004; 90 (6): p.614-7. doi: 10.1136/hrt.2003.029868 . | Open in Read by QxMD
30. Subedi S, Jennings Z, Chen SC-A. Laboratory Approach to the Diagnosis of Culture-Negative Infective Endocarditis. Heart Lung Circ. 2017; 26 (8): p.763-771. doi: 10.1016/j.hlc.2017.02.009 . | Open in Read by QxMD
31. Meine TJ, Nettles RE, Anderson DJ, et al. Cardiac conduction abnormalities in endocarditis defined by the Duke criteria. Am Heart J. 2001; 142 (2): p.280-285. doi: 10.1067/mhj.2001.116964 . | Open in Read by QxMD
32. Berk WA. Electrocardiographic findings in infective endocarditis. J Emerg Med. 1988; 6 (2): p.129-132. doi: 10.1016/0736-4679(88)90153-9 . | Open in Read by QxMD
33. Murillo H, Restrepo CS, Marmol-Velez JA, et al. Infectious Diseases of the Heart: Pathophysiology, Clinical and Imaging Overview. Radiographics. 2016; 36 (4): p.963-983. doi: 10.1148/rg.2016150225 . | Open in Read by QxMD
34. Dursun M, Yilmaz S, Yilmaz E, et al. The utility of cardiac MRI in diagnosis of infective endocarditis: preliminary results. Diagn Interv Radiol. 2015; 21 (1): p.28-33. doi: 10.5152/dir.2014.14239 . | Open in Read by QxMD
35. Thiene G, Basso C. Pathology and pathogenesis of infective endocarditis in native heart valves.. Cardiovasc Pathol. 2006; 15 (5): p.256-263. doi: 10.1016/j.carpath.2006.05.009 . | Open in Read by QxMD
36. Murtaza G, Iskandar J, Humphrey T, Adhikari S, Kuruvilla A. Lupus-Negative Libman-Sacks Endocarditis Complicated by Catastrophic Antiphospholipid Syndrome.. Cardiol res. 2017; 8 (2): p.57-62. doi: 10.14740/cr534e . | Open in Read by QxMD
37. el-Shami K, Griffiths E, Streiff M. Nonbacterial thrombotic endocarditis in cancer patients: pathogenesis, diagnosis, and treatment.. Oncologist. 2007; 12 (5): p.518-23. doi: 10.1634/theoncologist.12-5-518 . | Open in Read by QxMD
38. Asopa S, Patel A, Khan OA, Sharma R, Ohri SK. Non-bacterial thrombotic endocarditis. European Journal of Cardio-Thoracic Surgery. 2007; 32 (5): p.696-701. doi: 10.1016/j.ejcts.2007.07.029 . | Open in Read by QxMD
39. Dürrleman N, Pellerin M, Bouchard D, et al. Prosthetic valve thrombosis: twenty-year experience at the Montreal Heart Institute.. J Thorac Cardiovasc Surg. 2004; 127 (5): p.1388-92. doi: 10.1016/j.jtcvs.2003.12.013 . | Open in Read by QxMD
40. Gould FK, Denning DW, Elliott TSJ, et al. Guidelines for the diagnosis and antibiotic treatment of endocarditis in adults: a report of the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother. 2011; 67 (2): p.269-289. doi: 10.1093/jac/dkr450 . | Open in Read by QxMD
41. Herold G. Internal Medicine. Herold G ; 2014
42. Heart Valves and Infective Endocarditis. http://www.heart.org/HEARTORG/Conditions/More/HeartValveProblemsandDisease/Heart-Valves-and-Infective-Endocarditis_UCM_450448_Article.jsp#.WKGuAtIrLIW. Updated: May 1, 2016. Accessed: February 13, 2017.
43. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014; 63 (22): p.e57-185. doi: 10.1016/j.jacc.2014.02.536 . | Open in Read by QxMD
44. Fournier PE, Casalta JP, Habib G, Messana T, Raoult D. Modification of the diagnostic criteria proposed by the duke endocarditis service to permit improved diagnosis of q fever endocarditis. Am J Med. 1996; 100 (6): p.629-633. doi: 10.1016/s0002-9343(96)00040-x . | Open in Read by QxMD
45. Habib G, Hoen B, Tornos P, et al. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009): the Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the International Society of Chemotherapy (ISC) for Infection and Cancer.. Eur Heart J. 2009; 30 (19): p.2369-413. doi: 10.1093/eurheartj/ehp285 . | Open in Read by QxMD
46. Lee A, Mirrett S, Reller LB, Weinstein MP. Detection of Bloodstream Infections in Adults: How Many Blood Cultures Are Needed?. J Clin Microbiol. 2007; 45 (11): p.3546-3548. doi: 10.1128/jcm.01555-07 . | Open in Read by QxMD
47. Werner M, Andersson R, Olaison L, Hogevik H. A clinical study of culture-negative endocarditis.. Medicine. 2003; 82 (4): p.263-73. doi: 10.1097/01.md.0000085056.63483.d2 . | Open in Read by QxMD