|Classification and external resources|
A mitral valve vegetation caused by bacterial endocarditis.
Infective endocarditis is a form of endocarditis, or inflammation, of the inner tissue of the heart (such as its valves) caused by infectious agents. The agents are usually bacterial, but other organisms can also be responsible.
The valves of the heart do not receive any dedicated blood supply. As a result, defensive immune mechanisms (such as white blood cells) cannot directly reach the valves via the bloodstream. If an organism (such as bacteria) attaches to a valve surface and forms a vegetation, the host immune response is blunted. The lack of blood supply to the valves also has implications for treatment, since drugs also have difficulty reaching the infected valve.
- 1 Classification
- 2 Signs and symptoms
- 3 Cause
- 4 Pathogenesis
- 5 Diagnosis
- 6 Prevention
- 7 Treatment
- 8 References
Historically, infective endocarditis has been clinically divided into acute and subacute1 presentations (because untreated patients tended to live longer with the subacute as opposed to the acute form). This classifies both the rate of progression and severity of disease.
- Subacute bacterial endocarditis (SBE) is often due to streptococci of low virulence and mild to moderate illness which progresses slowly over weeks and months and has low propensity to hematogenously seed extracardiac sites.
- Acute bacterial endocarditis (ABE) is a fulminant illness over days to weeks, and is more likely due to Staphylococcus aureus which has much greater virulence, or disease-producing capacity and frequently causes metastatic infection.1
This classification is now discouraged, because the ascribed associations (in terms of organism and prognosis) were not strong enough to be relied upon clinically. The terms short incubation (meaning less than about six weeks), and long incubation (greater than about six weeks) are preferred.2
Infective endocarditis may also be classified as culture-positive or culture-negative. By far the most common cause of a "culture-negative" endocarditis is prior administration of antibiotics.
Sometimes micro-organisms can take a longer period of time to grow in the culture media, such organisms are said to be fastidious because they have demanding growth requirements. Some examples include pathogens like Aspergillus species, Brucella species, Coxiella burnetii, Chlamydia species, and HACEK bacteria. Due to delay in growth and identification in these cases, patients may be erroneously classified as "culture-negative" endocarditis.
Endocarditis can also be classified by the side of the heart affected:
- Patients who inject narcotics or other drugs intravenously may introduce infection which will travel to the right side of the heart classically affecting the tricuspid valve, and most often caused by S. aureus.1
- In other patients without a history of intravenous exposure, endocarditis is more frequently left-sided.1
Another form of endocarditis is healthcare associated endocarditis when the infecting organism is believed to be transmitted in a health care setting like hospital, dialysis unit or a residential nursing home. Nosocomial endocarditis is a form of healthcare associated endocarditis in which the infective organism is acquired during stay in a hospital and it is usually secondary to presence of intravenous catheters, Total parenteral nutrition lines, pacemakers, etc.3
Finally, the distinction between native-valve endocarditis and prosthetic-valve endocarditis is clinically important. Prosthetic valve endocarditis can be early (< 60 days of valvular surgery), intermediate (60 days to 1 year) or late (> 1 year following valvular surgery).
- Early prosthetic valve endocarditis is usually due to intraoperative contamination or a postoperative bacterial contamination which is usually nosocomial in nature.
- Late prosthetic valve endocarditis is usually due to community acquired microorganisms.3
- Fever occurs in 97% of people; malaise and endurance fatigue in 90% of people.4
- A new or changing heart murmur, weight loss, and coughing occurs in 35% of people.4
- Vascular phenomena: septic embolism (causing thromboembolic problems such as stroke in the parietal lobe of the brain or gangrene of fingers), Janeway lesions (painless hemorrhagic cutaneous lesions on the palms and soles), intracranial hemorrhage, conjunctival hemorrhage, splinter hemorrhages, renal infarcts, and splenic infarcts.
- Immunologic phenomena: Glomerulonephritis which allows for blood and albumin to enter the urine,1 Osler's nodes (painful subcutaneous lesions in the distal fingers), Roth's spots on the retina, positive serum rheumatoid factor
- Other signs may include; night sweats, rigors, anemia, splenomegaly
A common mnemonic for the signs and symptoms of endocarditis is FROM JANE:
- Roth's spots
- Osler's nodes
- Janeway lesions
- Nail hemorrhage (splinter hemorrhages)
- microscopic haematuria
- finger clubbing
Many microorganisms can cause infective endocarditis. These are generally isolated by blood culture, where the patient's blood is removed, and any growth is noted and identified. The term bacterial endocarditis (BE) commonly is used, reflecting the fact that most cases of IE are due to bacteria; however, Infective Endocarditis (IE) has become the preferred terms.
Staphylococcus aureus followed by Streptococci of the viridans group and Coagulase negative Staphylococci are the three most common organisms responsible for infective endocarditis. OtherStreptococci and Enterococci are also a frequent cause of infective endocarditis. HACEK group of micro-organisms and Fungi are seen less frequently.5
Viridans Alpha-hemolytic streptococci, that are present in the mouth are the most frequently isolated micro-organisms when the infection is acquired in a community setting. In contrast, Staphylococcus blood stream infections are frequently acquired in a health care setting where they can enter the blood stream through procedures that cause break in the integrity of skin like surgery, catheterisation or during access of long term indwelling catheters or secondary to intravenous injection of recreational drugs.
Enterococcus can enter the bloodstream as a consequence of abnormalities in the gastrointestinal or genitourinary tracts.
Some organisms, when isolated, give valuable clues to the cause, as they tend to be specific.
- Pseudomonas species, which are very resilient organisms that thrive in water, may contaminate street drugs that have been contaminated with drinking water. P. aeruginosa can infect a child through foot punctures, and can cause both endocarditis and septic arthritis.6
- S. bovis and Clostridium septicum, which are part of the natural flora of the bowel, are associated with colonic malignancies. When they present as the causative agent in endocarditis, it usually call for a concomitant colonoscopy due to concerns regarding hematogenous spread of bacteria from the colon due to the neoplasm breaking down the barrier between the gut lumen and the blood vessels which drain the bowel.78
- HACEK organisms are a group of bacteria that live on the dental gums, and can be seen with IV drug users who contaminate their needles with saliva. Patients may also have a history of poor dental hygiene, or pre-existing valvular disease.9
- Less commonly reported etiological bacteria are responsible for so called "culture negative endocarditis". Such bacteria can be identified by serology, culture of the excised valve tissue, sputum, pleural fluid, and emboli; and by polymerase chain reaction or and sequencing of bacterial 16S ribosomal RNA. Such bacteria include Bartonella, Chlamydia psittaci, and Coxiella.10
Multiple case reports of infective endocarditis caused by unusual organisms have been published in literature. Few examples include: Propionibacterium sp., which are normal skin flora, have been responsible for infective endocarditis sometimes leading to deaths due to the indolent course of this abscess producing infection.11Tropheryma whipplei has caused endocarditis without gastrointestinal involvement.12 Citrobacter koseri was found in an immunocompetent adult.13 Neisseria bacilliformis was found in a patient with a bicuspid aortic valve.14
Candida albicans, a yeast, is associated with endocarditis in IV drug users and immunocompromised patients. Other fungi demonstrated to cause endocarditis are Histoplasma capsulatum and Aspergillus.10 Endocarditis with Tricosporon asahii has also been reported in a case report.15
In a healthy individual, a bacteremia (where bacteria get into the blood stream through a minor cut or wound) would normally be cleared quickly with no adverse consequences. If a heart valve is damaged and covered with a piece of blood clot, the valve provides a place for the bacteria to attach themselves and an infection can be established.
In the past, bacteremia caused by dental procedures (in most cases due to streptococci viridans, which reside in oral cavity), such as a cleaning or extraction of a tooth was thought to be more clinically significant than it actually was. However, it is important that a dentist or a dental hygienist be told of any heart problems before commencing treatment. Antibiotics are administered to patients with certain heart conditions as a precaution, although this practice has changed in the US, with new American Heart Association guidelines released in 2007,16 and in the UK as of March 2008 due to new NICE guidelines. Everyday tooth brushing and flossing will similarly cause bacteremia. Although there is little evidence to support antibiotic prophylaxis for dental treatment, the current American Heart Association guidelines are highly accepted by clinicians17 and patients.18
Other conditions that result in high number of bacteria entering into the bloodstream include colorectal cancer (mostly Streptococcus bovis),7 serious urinary tract infections (mostly enterococci), and drug injection (Staphylococcus aureus). With a large number of bacteria, even a normal heart valve may become infected.
A more virulent organism (such as Staphylococcus aureus) can cause infective endocarditis by infecting even a normal heart valve.
Intravenous drug users tend to get their right-sided heart valves infected because the veins that are injected drain into the right side of the heart. In rheumatic heart disease, infection occurs on the aortic and the mitral valves on the left side of the heart.
As previously mentioned, altered blood flow around the valves contributes to development of endocarditis. The valves may be damaged congenitally, from surgery, by auto-immune mechanisms, or simply as a consequence of old age. The damaged part of a heart valve leads to formation of a local blood clot, a condition known as non-bacterial thrombotic endocarditis (NBTE). Altered blood flow, and thus infective endocarditis, are more likely in high pressure areas. Consequently, ventricular septal defects create more susceptibility than atrial septal defects. Damaged vascular endothelium will also promote platelet and fibrin deposition, upon which bacteria can take hold. Valvular lesions are a major cause of such damage, as are jet lesions resulting from ventricular septal defects or patent ductus arteriosus.
In general, the Duke criteria should be fulfilled in order to establish the diagnosis of endocarditis.19 The blood tests C reactive protein (CRP) and procalcitonin have not been found to be particularly useful in helping make or rule out the diagnosis.20
As the Duke criteria rely heavily on the results of echocardiography, research has addressed when to order an echocardiogram by using signs and symptoms to predict occult endocarditis among patients with intravenous drug abuse212223 and among non drug-abusing patients.2425 Unfortunately, this research is over 20 years old and it is possible that changes in the epidemiology of endocarditis and bacteria such as staphylococci make the following estimates incorrect.
Established in 1994 by the Duke Endocarditis Service and revised in 2000, the Duke criteria are a collection of major and minor criteria used to establish a diagnosis of endocarditis.1928 A definite diagnosis of infective endocarditis can be established if the following conditions are fulfilled: two major criteria, one major and three minor criteria, or five minor criteria. Diagnosis of infective endocarditis can only be said to be "possible" if only 1 major and 1 minor criteria are fulfilled or if only 3 minor criteria are fulfilled.
Major criteria include:
- Positive blood culture with typical IE microorganism, defined as one of the following:
- Typical microorganism consistent with IE from 2 separate blood cultures, as noted below:
- Microorganisms consistent with IE from persistently positive blood cultures defined as:
- Two positive cultures of blood samples drawn >12 hours apart, or
- All of 3 or a majority of 4 separate cultures of blood (with first and last sample drawn 1 hour apart)
- Coxiella burnetii detected by at least one positive blood culture or antiphase I IgG antibody titer >1:800
- Evidence of endocardial involvement with positive echocardiogram defined as
- Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation, or
- Abscess, or
- New partial dehiscence of prosthetic valve or new valvular regurgitation (worsening or changing of preexisting murmur not sufficient)
Minor criteria include:
- Predisposing factor: known cardiac lesion, recreational drug injection
- Fever >38°C
- Evidence of embolism: arterial emboli, pulmonary infarcts, Janeway lesions, conjunctival hemorrhage
- Immunological problems: glomerulonephritis, Osler's nodes
- Positive blood culture (that doesn't meet a major criterion) or serologic evidence of infection with organism consistent with IE but not satisfying major criterion
Positive echocardiogram (that doesn't meet a major criterion)(this criterion has been removed from the modified Duke criteria)
Among people who do not use intravenous drugs and have a fever in the emergency room, there is a less than 5% chance of occult endocarditis. Mellors in 1987 found no cases of endocarditis nor of staphylococcal bacteremia among 135 febrile patients in the emergency room.25 The upper confidence interval for 0% of 135 is 5%, so for statistical reasons alone, there is up to a 5% chance of endocarditis among these patients. In contrast, Leibovici found that among 113 non-selected adults admitted to the hospital because of fever there were two cases (1.8% with 95%CI: 0% to 7%) of endocarditis.24
Among people who do use intravenous drugs and have a fever in the emergency room, there is about a 10% to 15% prevalence of endocarditis. This estimate is not substantially changed by whether the doctor believes the patient has a trivial explanation for their fever.23 Weisse found that 13% of 121 patients had endocarditis.21 Marantz also found a prevalence of endocarditis of 13% among such patients in the emergency room with fever.23 Samet found a 6% incidence among 283 such patients, but after excluding patients with initially apparent major illness to explain the fever (including 11 cases of manifest endocarditis), there was a 7% prevalence of endocarditis.22
Among people with staphylococcal bacteremia (SAB), one study found a 29% prevalence of endocarditis in community-acquired SAB versus 5% in nosocomial SAB.29 However, only 2% of strains were resistant to methicillin and so these numbers may be low in areas of higher resistance.
Not all people with heart disease require antibiotics to prevent infective endocarditis. Heart diseases have been classified into high, medium and low risk of developing IE. Those falling into high risk category require IE prophylaxis before endoscopies and urinary tract procedures. Diseases listed under high risk include
- Prior Endocarditis
- Unrepaired cyanotic congenital heart diseases
- Completely repaired congenital heart disease in their first 6 months
- Prosthetic heart valves
- Incompletely repaired congenital heart diseases
- Cardiac transplant valvulopathy
Following are the antibiotic regimens recommended by the American Heart Association for antibiotic prophylaxis:16
- Oral Amoxicillin 1 hour before the procedure
- Intravenous or intramuscular ampicillin 1 hour before the procedure
- In patients allergic to penicillins
- Azithromycin or clarithromycin orally 1 hour before the procedure
- Cephalexin orally 1 hour before the procedure
- Clindamycin orally 1 hour before the procedure
In the UK, NICE clinical guidelines no longer advise prophylaxis because there is no clinical evidence that it reduces the incidence of IE and there are negative effects (e.g. allergy and increased bacterial resistance) of taking antibiotics that may outweigh the benefits.30
Antibiotics were historically commonly recommended to prevent IE in those with heart problems undergoing dental procedures (known as dental antibiotic prophylaxis). They are less commonly recommended for this procedure.
High dose antibiotics are administered by the intravenous route to maximize diffusion of antibiotic molecules into vegetation(s) from the blood filling the chambers of the heart. This is necessary because neither the heart valves nor the vegetations adherent to them are supplied by blood vessels. Antibiotics are continued for a long time, typically two to six weeks depending on the characteristics of the infection and the causative micro-organisms.
In acute endocarditis, due to the fulminant inflammation empirical antibiotic therapy is started immediately after the blood has been drawn for culture. This usually includes vancomycin and ceftriaxone IV infusions until the microbial identification and susceptibility report with the minimum inhibitory concentration becomes available allowing for modification of the antimicrobial therapy to target the specific microorganism. It should be noted that the routine use of gentamicin to treat endocarditis has fallen out of favor due to the lack of evidence to support its use (except in infections caused by Enterococcus and nutritionally variant streptococci) and the high rate of complications.31
The most common organism responsible for infective endocarditis is Staphylococcus aureus,5 which is resistant to penicillin in most cases. High rates of resistant to oxacillin are also seen, in which cases treatment with vancomycin is required.
Relatively resistant strains of viridans group streptococci and Streptococcus bovis are treated with penicillin or ceftriaxone along with a shorter 2 week course of an aminoglycoside during the initial phase of treatment.32
Highly penicillin resistant strains of viridans group streptococci, nutritionally variant streptococci like Granulicatella sp., Gemella sp. and Abiotrophia defectiva, and Enterococci are usually treated with a combination therapy consisting of penicillin and an aminoglycoside for the entire duration of 4–6 weeks.32
Selected patients may be treated with a relatively shorter course of treatment32 (2 weeks) with benzyl penicillin IV if infection is caused by viridans group streptococci or Streptococcus bovis as long as the following conditions are met:
- Endocarditis of a native valve, not of a prosthetic valve
- An MIC ≤ 0.12 mg/l
- Complication such as heart failure, arrhythmia, and pulmonary embolism occur
- No evidence of extracardiac complication like septic thromboembolism
- No vegetations > 5mm in diameter conduction defects
- Rapid clinical response and clearance of blood stream infection
Additionally oxacillin susceptible Staphylococcus aureus native valve endocarditis of the right side can also be treated with a short 2 week course of beta lactam antibiotic like nafcillin with or without aminoglycosides
‣ Patients with significant valve stenosis or regurgitation causing heart failure ‣ Evidence of hemodynamic compromise in the form of elevated end diastolic left ventricular or left atrial pressure or moderate to severe pulmonary hypertension ‣ Presence of intracardiac complications like paravalvular abscess, conduction defects or destructive penetrating lesions ‣ Recurrent septic emboli despite appropriate antibiotic treatment ‣ Large vegetations (> 10 mm) ‣ Persistent positive blood cultures despite appropriate antibiotic treatment ‣ Prosthetic valve dehiscence ‣ Relapsing infection in the presence of a prosthetic valve ‣ Abscess formation ‣ Early closure of mitral valve ‣ Infection caused by Fungi or resistant Gram negative bacteria
Infective endocarditis is associated with 18% in-hospital mortality.5
- Mitchell RS, Kumar V, Robbins SL, Abbas AK, Fausto N (2007). Robbins Basic Pathology (8th ed.). Saunders/Elsevier. pp. 406–8. ISBN 1-4160-2973-7.
- Morris AM (January 2006). "How best to deal with endocarditis". Curr Infect Dis Rep 8 (1): 14–22. doi:10.1007/s11908-006-0030-8. PMID 16448596.
- Kasper DL, Brunwald E, Fauci AS, Hauser S, Longo DL, Jameson JL (May 2005). Harrison's Principles of Internal Medicine. McGraw-Hill. pp. 731–40. ISBN 0-07-139140-1. OCLC 54501403 56437106 56801936 56967424.
- Amal Mattu; Deepi Goyal; Barrett, Jeffrey W.; Joshua Broder; DeAngelis, Michael; Peter Deblieux; Gus M. Garmel; Richard Harrigan; David Karras; Anita L'Italien; David Manthey (2007). Emergency medicine: avoiding the pitfalls and improving the outcomes. Malden, Mass: Blackwell Pub./BMJ Books. p. 63. ISBN 1-4051-4166-2.
- Murdoch, DR; et al. (9 March 2009). "Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study". Archives of Internal Medicine 169 (5): 463–73. doi:10.1001/archinternmed.2008.603. PMC 3625651. PMID 19273776.
- Topics in Infectious Diseases Newsletter, August 2001, Pseudomonas aeruginosa.
- Gold, JS; Bayar, S, Salem, RR (July 2004). "Association of Streptococcus bovis bacteremia with colonic neoplasia and extracolonic malignancy". Archives of surgery (Chicago, Ill. : 1960) 139 (7): 760–5. doi:10.1001/archsurg.139.7.760. PMID 15249410.
- Chew SSB, Lubowski DZ (2001). "Clostridium septicum and malignancy". ANZ Journal of Surgery 71 (11): 647–649. doi:10.1046/j.1445-1433.2001.02231.x. PMID 11736823.
- Mirabelle Kelly, MD (June 7, 2005). "HACEK Group Infections".
- Lamas, CC; Eykyn, SJ (March 2003). "Blood culture negative endocarditis: analysis of 63 cases presenting over 25 years". Heart 89 (3): 258–262. doi:10.1136/heart.89.3.258. PMC 1767579. PMID 12591823.
- Clayton, JJ; et al. (August 2006). "Endocarditis caused by Propionibacterium species: a report of three cases and a review of clinical features and diagnostic difficulties". Journal of Medical Microbiology 55 (8): 981–987. doi:10.1099/jmm.0.46613-0. PMID 16849716.
- Dreier, J; et al. (2004). "Tropheryma whipplei Infection of an acellular porcine heart valve bioprosthesis in a patient who did not have intestinal Whipple's disease". Journal of Clinical Microbiology 42 (10): 4487–4493. doi:10.1128/JCM.42.10.4487-4493.2004. PMC 522317. PMID 15472298.
- Dzeing-Ella, A; Szwebel, T. A.; Loubinoux, J.; Coignard, S.; Bouvet, A.; Le Jeunne, C.; Aslangul, E. (December 2009). "Infective endocarditis due to Citrobacter koseri in an immunocompetent adult". Journal of Clinical Microbiology 47 (12): 4185–4186. doi:10.1128/JCM.00957-09. PMC 2786675. PMID 19812281.
- Masliah-Planchon, J; et al. (June 2009). "Endocarditis due to Neisseria bacilliformis in a patient with a bicuspid aortic valve". Journal of Clinical Microbiology 47 (6): 1973–1975. doi:10.1128/JCM.00026-09. PMC 2691068. PMID 19386832.
- Izumi, K; et al. (October 2009). "A rare case of infective endocarditis complicated by Trichosporon asahii fungemia treated by surgery". Annals of Thoracic and Cardiovascular Surgery 15 (5): 350–353. PMID 19901894.
- Wilson W, Taubert KA, Gewitz M, et al. (October 2007). "Prevention of infective endocarditis: guidelines from the American Heart Association". Circulation 116 (15): 1736–54. doi:10.1161/CIRCULATIONAHA.106.183095. PMID 17446442.
- Zadik Y, Findler M, Livne S, et al. (December 2008). "Dentists' knowledge and implementation of the 2007 American Heart Association guidelines for prevention of infective endocarditis". Oral Surg Oral Med Oral Pathol Oral Radiol Endod 106 (6): e16–9. doi:10.1016/j.tripleo.2008.08.009. PMID 19000604.
- Elad S, Binenfeld-Alon E, Zadik Y, Aharoni M, Findler M. (March 2011). of acceptance of the 2007 American Heart Association Guidelines for the prevention of infective endocarditis: A pilot study "Survey of acceptance of the 2007 American Heart Association guidelines for the prevention of infective endocarditis: a pilot study". Quintessence Int 42 (3): 243–51. PMID 21465012.
- Durack D, Lukes A, Bright D (1994). "New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service". Am J Med 96 (3): 200–9. doi:10.1016/0002-9343(94)90143-0. PMID 8154507.
- Yu, CW; Juan, LI; Hsu, SC; Chen, CK; Wu, CW; Lee, CC; Wu, JY (June 2013). "Role of procalcitonin in the diagnosis of infective endocarditis: a meta-analysis.". The American journal of emergency medicine 31 (6): 935–41. PMID 23601504.
- Weisse A, Heller D, Schimenti R, Montgomery R, Kapila R (1993). "The febrile parenteral drug user: a prospective study in 121 patients". Am J Med 94 (3): 274–80. doi:10.1016/0002-9343(93)90059-X. PMID 8452151.
- Samet J, Shevitz A, Fowle J, Singer D (1990). "Hospitalization decision in febrile intravenous drug users". Am J Med 89 (1): 53–7. doi:10.1016/0002-9343(90)90098-X. PMID 2368794.
- Marantz P, Linzer M, Feiner C, Feinstein S, Kozin A, Friedland G (1987). "Inability to predict diagnosis in febrile intravenous drug abusers". Annals of Internal Medicine 106 (6): 823–8. doi:10.7326/0003-4819-106-6-823. PMID 3579068.
- Leibovici L, Cohen O, Wysenbeek A (1990). "Occult bacterial infection in adults with unexplained fever. Validation of a diagnostic index". Arch Intern Med 150 (6): 1270–2. doi:10.1001/archinte.150.6.1270. PMID 2353860.
- Mellors J, Horwitz R, Harvey M, Horwitz S (1987). "A simple index to identify occult bacterial infection in adults with acute unexplained fever". Arch Intern Med 147 (4): 666–71. doi:10.1001/archinte.147.4.666. PMID 3827454.
- Shively B, Gurule F, Roldan C, Leggett J, Schiller N (1991). "Diagnostic value of transesophageal compared with transthoracic echocardiography in infective endocarditis". J Am Coll Cardiol 18 (2): 391–7. doi:10.1016/0735-1097(91)90591-V. PMID 1856406.
- Erbel R, Rohmann S, Drexler M, et al. (1988). "Improved diagnostic value of echocardiography in patients with infective endocarditis by transoesophageal approach. A prospective study". Eur Heart J 9 (1): 43–53. PMID 3345769.
- Li, J. S.; Sexton, D. J.; Mick, N.; Nettles, R.; Fowler, V. G.; Ryan, T.; Bashore, T.; Corey, G. R. (2000). "Proposed Modifications to the Duke Criteria for the Diagnosis of Infective Endocarditis". Clinical Infectious Diseases 30 (4): 633. doi:10.1086/313753. PMID 10770721.
- Kaech C, Elzi L, Sendi P, et al. (2006). "Course and outcome of Staphylococcus aureus bacteraemia: a retrospective analysis of 308 episodes in a Swiss tertiary-care centre". Clin Microbiol Infect 12 (4): 345–52. doi:10.1111/j.1469-0691.2005.01359.x. PMID 16524411.
- "Prophylaxis against infective endocarditis: Antimicrobial prophylaxis against infective endocarditis in adults and children undergoing interventional procedures". NICE Clinical Guidelines. National Institute for Health Care and Excellence (UK). March 2008. Retrieved 2013-04-30.
- Cosgrove SE, Vigliani GA, Campion M, et al. (2009). "Initial low‐dose gentamicin for Staphylococcus aureus bacteremia and endocarditis is nephrotoxic". Clin Infect Dis 48 (6): 713–21. doi:10.1086/597031. PMID 19207079.
- Baddour, LM; et al. (14 June 2005). "Infective Endocarditis Diagnosis, Antimicrobial Therapy, and Management of Complications: A Statement for Healthcare Professionals From the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: Endorsed by the Infectious Diseases Society of America". Circulation 111 (23): e394–e434. doi:10.1161/CIRCULATIONAHA.105.165564. PMID 15956145.
- Bonow, RO; et al. (23 September 2008). "2008 focused update incorporated into the ACC/AHA 2006 guidelines 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 (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons". Journal of American College of Cardiology 52 (13): e1–142. doi:10.1016/j.jacc.2008.05.007. PMID 18848134.