|Important key words or phrases.|
|Important concepts or main ideas.|
1. Key Concepts for evaluating the patient with an intravascular infection:
- What is the bug?
- How did it get there?
- Where did it come from?
- Where did it go?
- The invasion of the blood stream by pathogenic bacteria.
- Primary bacteremia
- Most often a nosocomial infection that is typically associated with an indwelling intravascular catheter, or it is a result of direct inoculation of the blood stream as, for example, a result of intravenous drug use.
- Secondary bacteremia
- Occurs when microorganisms causing infection at another site (e.g. pneumonia, pyelonephritis, skin or soft tissue) invade the blood stream and disseminate via the circulation
- Infective endocarditis (IE)
- Infection of the endocardial surface of the heart, usually the heart valves. Infection may rarely occur on the chordae tendinae or the atrial or ventricular wall surfaces especially at an area of anatomic abnormality such as septal defects or arteriovenous shunts (such as patent ductus arteriosus). Historically, infective endocarditis has been classified by the timing of the infection.
- Acute bacterial endocarditis (ABE)
- Infection caused by invasive pyogenic bacteria, such as Staphylococcus aureus, and characterized by high fevers and a relatively short toxic course of a few days to weeks. Structurally normal or abnormal valves may be involved.
- Subacute bacterial endocarditis (SBE)
- More indolent infection caused by less virulent bacteria characterized by lower fevers, prolonged constitutional symptoms of anorexia, weight loss, and night sweats lasting for several weeks. This is usually an infection of abnormal valvular surfaces.
At present, a useful classification is by risk category, i.e. native-valve; prosthetic-valve; infective endocarditis in intravenous drug users; and nosocomial (or device) related. This may be expressed by describing the microorganism, type and site of the affected heart valve and any predisposing event such as, “α-hemolytic streptococcal native valve endocarditis” or “Staphylococcal aureus tricuspid valve infective endocarditis in an intravenous drug user”.
3. Entry: Where did it come from?
Bacteria enter the blood stream by translocation from the contained source or by direct inoculation. Transient bacteremias, defined as bacteremia of short duration (15-30 minutes), occur daily, for example as a consequence of defecation or brushing one’s teeth. Any break in the skin barrier or trauma to heavily colonized mucosal surfaces is a potential source of direct inoculation into the blood stream. Intravenous drug use is a substantial risk for bacteremia.
The type of transient bacteremia depends on the colonizing organisms at the site of entry. Table 1 depicts some common organisms documented at sites of entry:
|Table 1. Microorganisms Associated with Spontaneous or Procedure Related Transient Bacteremia|
|Site||Activity or Procedure||Microorganisms|
|Oral Cavity||Brushing Teeth,
|α-hemolytic streptococci (Viridans group), anaerobic streptococci, dipththeroids|
|Skin||Intravenous or arterial catheters; Chronic skin lesions||Staphylococci (S. epidermidis, S. aureus), Streptococci|
|Respiratory||Bronchoscopy||Streptococci, aerobic gram neg rods, S. epidermidis|
|Gastrointestinal||Esophagogastroscopy (EGD) Colonoscopy||Streptococci, diptheroids, Neisseria, S. epidermidis Aerobic gram negative rods, streptococci, Bacteroides species|
|Urinary Tract||Urethral dilatation Cystoscopy Transurethral prostatic resection||Aerobic gram negative rods, diptheroids, Streptococci|
|Adapted from Schaechter, Table 64.2|
The incidence of bacteremias is 300,000-500,000 cases per year. Approximately 200,000 cases are nosocomial bacteremias accounting for 14% of hospital-acquired infections. Nosocomial bacteremia is the most frequent infectious cause of hospital death and excess length of stay. Typical risk factors for nosocomial bacteremias are devices – such as central venous catheters, arterial catheters, cardiac support devices, and ventilators.
The incidence of IE is 1-5 cases per 1000 hospital admissions, or 3.6 per 100,000 (estimated from review of 26 studies). Incidence rises dramatically with age, and more than 50% occur in persons over the age of 50. Varying predisposing conditions exist, but in over 50% of cases, no identified valvular lesion can be found.
|Risk Group||Predisposing condition||Pathophysiologic Consequence||Heart valve most often affected|
|Native Valve||Rheumatic heart disease||Turbulence of blood flow||Mitral|
|Congenital heart defect||"||Bicuspid aortic valve|
|Degenerative heart lesions resulting in calcific disease||"||Aortic, mitral valve annulus|
|Nosocomial||Intravascular device (central venous catheter)||Fibrin deposition, damage to valve||Tricuspid valve|
|Prosthetic Valve||Lack of full endothelialization of valve surface||Early (< 2 mos): perioperative wound contamination Late (> 2 mos): community acquired bacteremia, turbulence of flow across foreign surface||------------|
|Intravenous Drug Use||No known pre-existing valve lesions||Direct inoculation through skin||Tricuspid (>50%)|
5. Diagnosis of bacteremia by aerobic and anaerobic blood cultures (a “set”)
- Before empiric antibiotics given to a febrile patient
- To evaluate the extent of a systemic or localized infection
- peripheral vein preferred;
- one set from central line and one from peripheral vein acceptable
6. Microbiology of Infective Endocarditis: What is the bug?
This is not a complete list, but rather a table of the more common organisms associated with types of endocarditis
|Native Valve||Prosthetic Valve||Intravenous Drug User||Rare Organisms|
|Young Patients||Early (within 1 year)||Fastidious gram negative rods|
|Viridans streptococci||Staphylococci||Streptococci||Haemophilus spp.|
|S. sanguis||S. epidermidis||Staphylococci||Actinobaciilus spp.|
|S. mutans||S. aureus||Enterococci||Cardiobacterium spp.|
|S. mitis||Gram negative rods||Eikenella|
|S. milleri||Late (after 1 year)||Kingella|
|Enterococci||Viridans streptococci||Other gram negative rods|
|Coxiella burnetii (Q fever)||Enterococci|
|Fastidious gram negative rods|
|Culture negative||Culture negative|
|Coxiella burnetii (Q fever)|
Formerly, the most common cause of IE was Viridans Streptococci, but in the past decade Staphylococcus aureus is of increasing prevalence and is associated with a fulminant course and high mortality rate. It is the most common cause of right sided IE (tricuspid valve) due to IVDU.
7. Pathogenesis of Infective Endocarditis: How did it get there?
For in depth review of pathophysiology and molecular basis of fingronectin-mediated adherence see Moreillon P, Que Y-A. Infective Endocarditis. The Lancet 2004;363:139-149 and Schwarz-Linek U, Hook M, Potts JR. The molecular basis of fibronectin-mediated bacterial adherence to host cells. Molec Microbiol 2004;52:631-641
Damage to the endocardial surface (usually the heart valve) and subsequent direct contact with blood triggers coagulation and platelet and fibrinogen-fibrin deposition at the site. This collection is called non-bacterial thrombotic endocarditis (NBTE). Damaged endothelial cells express transmembrane proteins called integrins which can bind fibronectin to the cell surface. Some bacteria, especially Stapholococcus aureus, express fibronectin-binding proteins on their surface and avidly bind to the integrin bound fibronectin on the endothelial cell surface. If heavily colonized mucous membranes are traumatized, as in dental cleaning, for example, transient bacteremia can occur and bacteria adhere to the NBTE lesion(s) mediated by their surface adhesins called MSCRAMMs or Microbial Surface Component Reacting with Adhesive Matrix Molecules. Once adhered, bacterial virulence mechanisms, such as induction of tissue factor production by monocytes or platelet-activating factors enhance adherence. The cardiac vegetation is the hallmark of IE resulting from the collection of fibrin, platelet aggregates and microorganisms. The host responds to the invasion by release of proinflammatory cytokines (IL-6, IL-8) and thromboplastin which increases fibrin deposition and promotes growth of the vegetation. Ultimately circulating immune complexes develop.
8. Consequences of the fibrin/platelet/microorganism filled vegetation explain the complications seen clinically with this infection:
- Persistent bacteremia and risk of seeding distant sites (Where did it go?) resulting in septic arthritis, osteomyelitis, splenic or kidney abscesses, meningeal or brain abscesses, mycotic aneurysms (particularly associated with pyogenic bacteria) that arise from infection of the vasa vasorum of the arterial wall and lead to weakened arterial wall architecture and aneurysm formation.
- Host response and release of proinflammatory cytokines that provoke the “constitutional symptoms” seen in this infection (fevers, fatigue, anorexia, weight loss, night sweats).
- Tissue destruction by the microorganism, as in the case for S. aureus through expression of exoenzymes and exotoxins controlled by global regulators such as agr and sar leading to incompetent valvular function and congestive heart failure or atrioventricular conduction abnormalities.
- Fragmentation of the vegetation into smaller pieces that break off, travel through the circulation until they reach an arteriole or capillary where they lodge (peripheral emboli) and cause vascular insufficiency or necrosis of the surrounding tissue.
antibodies, which when combined with bacterial
antigens form circulating immune complexes that can deposit in kidneys
(glomerulonephritis) or other organs (choroids plexus = Roth spots, spleen,
skin = Osler’s nodes, synovium).
Consequence of Vegetation Complication Host Consequence Persistent bacteremia Seeding of distant sites
Joint, bone, organ disease
Tissue destruction Valvular insufficiency
AV conduction abnormalities
Congestive heart failure
Heart blocks (1°, 2°or 3°)
Fragmentation Peripheral emboli CNS emboli and stroke, myocardial infarction, splenic or kidney infarcts
Arterial insufficiency to limbs
Janeway lesions (emboli to distal extremities)
Release of bacterial antigen Immune complex formation Glomerulonephritis
Roth spots (deposition in choroid plexus)
The diagnosis of IE is suggested by persistently positive blood cultures. In the absence of positive blood cultures, clinical signs and symptoms and a high index of suspicion will often lead to the diagnosis. The advent of echocardiography allowed for the development of diagnostic criteria to aid in determining definite or possible IE. The Duke Diagnostic Criteria utilizes microbiological, clinical, echocardiographic and pathologic factors to predict the likelihood of IE.
Major criteria are:
Positive blood cultures of typical
microorganisms that cause IE or persistently positive blood cultures without
- At least 95% of patients with IE have positive blood cultures
- Cultures should be obtained before antibiotics are given
Evidence of endocardial involvement
- echocardiography: vegetation, abscess or new partial dehiscence of prosthetic valve seen on echocardiography
- clinical: new insufficiency (regurgitation) murmur
Minor criteria are:
- Predisposition: heart condition, valvular abnormality or IVDU
- Clinical symptoms – unexplained fever and other constitutional symptoms
- Vascular and/or embolic phenomena
- Immunologic phenomena (glomerulonephritis, Osler’s nodes, Roth spots)
- Microbiologic evidence not meeting major criteria
- Echocardiographic evidence not meeting major criteria
A definite case of IE has
- Microorganisms by culture or histology from a vegetation or embolus
- Vegetation or intracardiac abscess confirmed by histology
- 2 major criteria
- 1 major and 3 minor criteria
- 5 minor criteria
Do NOT memorize this definition of definite IE, but be aware of the Duke Classification Criteria and the components involved in establishing a diagnosis, i.e., clinical events, microbiology, pathology and echocardiography.
Proper identification of the causative organism and institution of effective antimicrobial therapy is essential for successful treatment of IE. Bacteria within vegetations are not easily killed by host defenses, thus an antimicrobial regimen that is bactericidal is required. To achieve high serum concentrations effective enough to penetrate deep into avascular vegetations, antibiotics are given parenterally. Synergistic combinations of antibiotics may be used initially to clear the bacteria from the blood stream more rapidly or for the duration of treatment for the more resistant bacteria such as Enterococci.
Surgery for valve replacement may be necessary to treat antibiotic resistant organisms or severe valvular dysfunction.
No controlled studies have been completed to determine the efficacy of prophylactic antibiotics, but animal data suggest a role for such a strategy. The patients at highest risk of IE are those with known valvular abnormalities or prosthetic valves who undergo procedures that may lead to transient bacteremias such as dental cleaning or extraction or invasive gastrointestinal or genitourinary tract procedures. The type of antibiotic prophylaxis used depends on the type of procedure being performed and the risk of known pathogens at the site.
12. Summary: Key Concepts
12.1. What is the bug?
- Gives clue to portal of entry for bacteremia or intravascular infection and possible source
- Streptococcus viridans - oral/mucous membrane; dental hygiene
- Staphylococcus aureus – skin flora; IVDU
- Prior colonization
12.2. How did it get there?
- Nosocomial infection - device associated
- Community acquired: primary or secondary bacteremia
- Pathogenesis of IE: NBTE + Bacteremia; VEGETATION
12.3. Where did it come from?
- Gives clues as to what the bug is
- Oral flora: Streptococcus viridans, HACEK group
- Skin flora: Gram positives, mostly Staphylococcus spp. or Streptococci
- GI tract flora: Gram negative rods – enterobacteraciae, Pseudomonas aeruginosa, Enterococci
13. Ancillary Material
- Schaechter M, Engleberg NC, Eisenstein BI, Medoff G. Mechanisms of Microbial Disease. Third Edition; Williams and Wilkins, 1998, Chapter 64, pages 596-603
- McGowan JE, Shulman JA. Blood Stream Invasion. In: Infectious Diseases, 2nd ed, Gorbach SL, Bartlett JG, Blacklow NR (Eds), W B Saunders Co., Philadelphia, 1998.
- Moreillon P, Que Y-A. Infective Endocarditis. The Lancet 2004;363:139-149.
- Hoen B, Alla F, Selton-Suty C et al. Changing profile of infective endocarditis: Results of a 1-year survey in France. JAMA 2002;288:75-81.
- Schwarz-Linek U, Hook M, Potts JR. The molecular basis of fibronectin-mediated bacterial adherence to host cells. Molec Microbiol 2004;52:631-641.
- Bayer AS, Bolger AF, Taubert KA et al. Diagnosis and management of infective endocarditis and its complications. Circulation 1998;98:2936-2948.
- Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of invective endocarditis: utilization of specific echocardiographic findings. Am J Med 1994;96:200-209.
- Sekeres MA, Abrutyn E, Berlin JA et al. An assessment of the usefulness of the Duke criteria for diagnosing active infective endocarditis. Clin Infect Dis 1997;24:1185-1190.
- Li Js, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000;30:633-38.
- Dajani AS, Taubert KA, Wilson W et al. Prevention of bacterial endocarditis: recommendations by the American Heart Association. JAMA 1997;277:1794-1801.