KEY POINTS
Intravascular infection should be considered in any critically ill patient who has an indwelling intravascular device.
Positive blood cultures should always raise the specter of intravascular infection.
Intravascular infection should be considered even in a patient with negative blood cultures where there is an unexplained febrile or septic illness.
Intravascular infection should especially be considered when there is S aureus bacteremia.
PATHOGENESIS OF INTRAVASCULAR INFECTIONS
The pathogenesis of intravascular infections depends on the location of the infection, the organism involved, and the integrity of the underlying vasculature. Native valve endocarditis (NVE) generally results from a cascade of events that begins when mechanical lesions promote microbial adherence to the injured endothelium during transient bacteremia by certain organisms. This initiates a cycle of monocyte activation along with cytokine and tissue factor production that causes enlargement of an infected vegetation, which consists primarily of bacteria, platelets, and fibrin. Local extension, as well as distant metastasis, may result as the primary infection expands.
NVE is most often due to streptococci of dental origin. Nosocomial NVE in critically ill patients is most often the result of urinary tract infection related to urologic catheterization or bacteremia related to central venous line infection.1
Intravascular infection involving veins generally results from extension of local microbes or infection into local vasculature by certain pathogens prone to intravascular infection. Intravascular infection involving arteries usually results from bacteremic seeding of arteries at bifurcation sites in the brain or periphery as well as seeding of preexisting aneurysms.2
Infection involving foreign devices is the result of local spread of bacteria or bacteremic seeding of a vegetation, which has previously formed on the device.
INFECTIVE ENDOCARDITIS
Viridans streptococci remain the most common cause of NVE, accounting for 50% of infections. The other causes of NVE are
Staphylococcus aureus in 25%
Enterococci in 7%
Coagulase-negative staphylococci in 6%
Gram-negative bacilli in 6%
Fungi in 1%
Culture negative in 7%
S aureus accounts for 40% to 50% of infections in patients admitted to the intensive care unit (ICU).3
Recently there has been a trend toward an increase in the percentage of infections caused by both methicillin-sensitive and methicillin-resistant S aureus (MRSA). This is at least partially related to the increased usage of central venous catheters among both hospitalized and nonhospitalized patients.4 Enterococci and coagulase-negative staphylococci are both twice as common a cause of nosocomial NVE compared to community acquired NVE.5
The number of infections caused by Streptococcus bovis has also increased and has been attributed to the aging population and related colonic disease.6
The etiology of prosthetic valve endocarditis (PVE) depends on the onset of infection in relation to the time of valve replacement (Table 67-1).7
Etiology of Prosthetic Valve Endocarditis
| Microorganism | Early Onset (%) | Late Onset (%) |
|---|---|---|
| Coagulase-negative staphylococci | 38 | 25 |
| Staphylococcus aureus | 21 | 11 |
| Methicillin-sensitive S aureus | 13 | 8 |
| Methicillin-resistant S aureus | 8 | 3 |
| Viridans streptococci | 4 | 15 |
| Enterococcus | 4 | 7 |
| Diphtheroids | 4 | 0 |
| Gram-negative bacilli | 0 | 4 |
| Candida | 0 | 4 |
| Peptococcus species | 0 | 1 |
| Miscellaneous | 17 | 11 |
| Culture negative | 13 | 19 |
Infective endocarditis (IE) is often suspected in a critically ill patient only after blood culture results reveal a pathogen typically associated with endocarditis. Fever is present in 85% to 95% of patients at presentation. Prior to finding bacteremia the working diagnosis is typically urinary tract infection given that 50% of patients have an abnormal urinalysis on presentation. Others may be diagnosed with pneumonia, especially those with right-sided endocarditis and resultant septic pulmonary emboli.8 Drug abusers with right-sided NVE frequently have evidence of septic pulmonary emboli on chest x-ray.9 Encephalitis and diskitis are also in the differential diagnosis as half of the time patients will have altered mental status and a quarter will present with back pain. Rarely do patients present with overt systemic embolic stigmata. These are seen in less than 50% of patients but, when present, are seen most often on the conjunctiva, soft palate, and distal portions of the extremities.10 Most patients with left-sided disease will have a murmur but this is a nonspecific finding in a critically ill septic patient. Gouello et al found that 41% of patients with nosocomial endocarditis had a new murmur.11 Benito et al found that 55% of patients with nosocomial NVE had a new or changed murmur.4 Patients with right-sided endocarditis often do not exhibit a heart murmur.
Patients with PVE are at an increased risk of cardiac complications caused by valve dehiscence and paravalvular abscess formation. Abscesses are primarily manifest by persistent fever and conduction abnormalities. Patients with nosocomial PVE have a new or changing murmur in 31% of cases and peripheral stigmata in 20%.12 The risk of embolic phenomena is highest the first week and is more likely in patients with large vegetations, those with mitral valve involvement, and in those infected with S aureus.
Patients with IE may also present with signs and symptoms due to congestive heart failure or renal insufficiency. IE may present with focal neurologic signs and symptoms due to a stroke caused by septic emboli, rupture of a mycotic aneurysm, or rarely from cerebral artery vasculitis. Overall, approximately 30% of patients with IE will have evidence of a focal neurologic event during their illness. Mourvillier et al reported that 6% and 14% of patients with IE admitted to the ICU presented with cerebral hemorrhage or emboli, respectively.3 The other complications seen in ICU patients with IE include
Congestive heart failure in 28%
Septic shock in 26%
Peripheral of pulmonary emboli in 15%
Renal failure in 14%
Death in 45%
Routine laboratory findings are neither specific nor sensitive, therefore they are of little help in making or excluding a diagnosis of IE. Urinalysis reveals proteinuria or hematuria in roughly 50% of patients. Anemia and thrombocytopenia are present in 80% and 20%, respectively. A leukocytosis is present in only 30% and rheumatoid factor may be positive in patients with a subacute presentation.
A definitive clinical diagnosis is made when two major, one major and three minor, or five minor criteria are met as defined by the modified Duke Criteria.13 The first major criterion is two positive blood cultures for organisms, which typically cause IE. The second major criterion is echocardiogram findings typical of IE; these findings include an oscillating intracardiac mass on the valve or supporting structures in the path of regurgitant jets, an abscess, or new valvular regurgitation. Minor criteria include
Predisposing valvular disease
Intravenous drug use
Fever
Vascular phenomena
Immunologic phenomena
Culture or serologic evidence of infection that does not meet major criteria
A pathologic diagnosis is made when pathologic lesions are identified and microorganisms are demonstrated on histologic examination of a cardiac vegetation, a vegetation that has embolized or from an intracardiac abscess.
A diagnosis of possible, but not definite, endocarditis is made when there is one major and one minor criterion or three minor criteria.
Blood cultures are the most important laboratory tests in making a diagnosis of IE. Blood cultures are positive in 90% to 95% of patients who have not received prior antimicrobial therapy. In 5% to 10% of patients, no etiologic organism is isolated using routine blood culture methods. Bacterial causes of culture-negative endocarditis in patients who have not received prior antibiotics include infection with
Anaerobes
Nutritionally deficient streptococci
Coxiella burnetii
Legionella pneumophila
Chlamydia psittaci
C pneumoniae
Members of the HACEK group
HACEK is an acronym for a group of small, fastidious, gram-negative bacilli that includes Haemophilus spp, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae.14 It is important to ask the microbiology laboratory to keep blood cultures for 3 weeks rather than the standard 1 week when attempting to identify these organisms.
Many patients in the ICU undergo a transthoracic echocardiogram (TTE) to assess left ventricular function in order to evaluate unexplained hypotension or pulmonary edema as well as to evaluate a patient with a new diagnosis of congestive heart failure. Also, a TTE is often done when a patient in the ICU has a positive blood culture. However, this should only be done in a patient with low suspicion of IE or one who is at low risk for complications.13 All other patients with suspected IE should undergo a transesophageal echocardiogram (TEE). Echocardiography should be done as soon as the diagnosis of IE is suspected, preferably within 12 hours of the initial evaluation. Colreavy et al demonstrated that TEE performed by intensive care physicians is useful not only in making a diagnosis of IE, but also in managing critically ill patients with unexplained hypotension, pulmonary emboli, pulmonary edema, and left ventricular dysfunction.15 Therefore, when IE is likely clinically, a TEE should be obtained to assist in diagnosis and management.16,17 Heidenreich et al suggested that if the pretest probability of IE is between 4% and 60%, it is cost effective to proceed to TEE without TTE.18
Critically ill ICU patients should have empiric antibiotics begun immediately after blood cultures have been obtained. It is important to use bacteriocidal agents dosed at appropriate intervals to maintain therapeutic levels at all times. An empiric agent with activity against MRSA is necessary given the prevalence of community-acquired MRSA infection. Vancomycin remains the gold standard, but newer agents include daptomycin, linezolid, tigecycline, and ceftaroline; daptomycin is currently the only new agent FDA approved to treat bacteremia and right-sided endocarditis.19
Empiric regimens also need to be active against enterococci and gram-negative bacilli. Standard therapy is to add an aminoglycoside to vancomycin. This regimen is adjusted when the blood culture results are known (Table 67-2). If Pseudomonas is cultured, then treatment is usually adjusted to an antipseudomonal penicillin or cephalosporin plus an aminoglycoside, though some data suggest that two agents may not be necessary.20
Antimicrobial Therapy for Infective Endocarditis and Other Intravascular Infectionsa
| Organism | Recommended Therapy | Penicillin-Allergicb |
|---|---|---|
| 1. Penicillin-sensitive streptococci (MIC <0.1) | Penicillin G 10-20 million units IV qd plus aminoglycosidec | Cefazolin 2 g IV q8h plus aminoglycoside |
| OR | ||
| Ceftriaxone 2 g IV qd | ||
| 2. Relatively “resistant” streptococci (Penicillin MIC-0.2-0.5) | Penicillin G 20 million units/d plus aminoglycosided | Cefazolin 2 g IV q8h plus aminoglycoside |
| 3. Resistant streptococci and enterococci (MIC >0.5)e | Penicillin G 20-30 million units IV qd (ampicillin 12 g IV qd is alternative) plus aminoglycosided | Vancomycin 30 mg/kg qd |
| 4. Staphylococci (methicillin-sensitive)—in absence of prosthetic valve | Nafcillin 2.0 g IV q4h | Cefazolin 2 g IV q8h |
| 5. Methicillin-resistant staphylococci—in absence of prosthetic valve | Vancomycin 30 mg/kg IV per day ± rifampin 300 mg PO q8h | Daptomycin 600 mg qdf |
| 6. Staphylococci (methicillin-sensitive)—in presence of prosthetic valve | Nafcillin 2.0 g IV q4h plus rifamping 300 mg PO q8h plus aminoglycoside | Cefazolin 2 g IVb q8h plus rifamping plus aminoglycoside |
| 7. Methicillin-resistant staphylococci —in presence of prosthetic valve | Vancomycin 30 mg/kg 24h IV plus rifampin 300 mg q8h plus aminoglycoside | Same |
| 8. Corynebacterium | Penicillin G 20-30 million units IV qd plus aminoglycoside | Vancomycin 30 mg/kg qd IV |
| 9. Gram-negative bacilli Enterobacteriaceae | Therapy should be directed by in vitro susceptibilities | Same |
| Pseudomonas | Therapy should be directed by in vitro susceptibilities, though usual regimen includes aminoglycoside plus extended-spectrum penicillin | Fourth-generation cephalosporin plus aminoglycoside |
| HACEK group | Ampicillin 2.0 g IV q4h is commonly used, though therapy should be directed by in vitro susceptibilities (aminoglycoside frequently used in combination) | Third-generation cephalosporins (eg, ceftriaxone 2 g IV qd) |
| 10. Rickettsia Coxiella burnetii | Tetracycline 500 mg PO q6h for at least 1 year plus trimethoprim 480 mg plus sulfamethoxazole 2400 mg qd until there is no evidence clinically of disease or phase I antibody titer is <.1:128 | Same |
| 11. Fungal | Amphotericin B | Liposomal ampho B echinocandins |
The most critical management decision to make early in the course of a patient with IE other than antibiotic therapy is whether or not surgical intervention is indicated. Early valve replacement is generally indicated when a patient has refractory congestive heart failure despite medical management.21 In this setting, early surgery is associated with an improved survival. Other indications for valve replacement include
Persistent fever or bacteremia despite appropriate therapy
Highly resistant microorganisms, that is, Candida, Pseudomonas, Coxiella
Development of an abscess or fistula
Large (>1cm), oscillating vegetation
Prosthetic valve dehiscence
Kim et al have shown that early surgery is also associated with a lower morbidity and mortality due to fewer embolic events.22,23
Treatment consists of intravenous antibiotics given for 4 to 8 weeks depending on the organism and whether or not the patient has native valve versus prosthetic valve infection. However, a 2-week course of treatment may be given in patients with uncomplicated NVE due to highly penicillin-sensitive viridans streptococcal or in patients with uncomplicated right-sided infection due to S aureus.24,25
Standardization of care regarding antimicrobial therapy and surgical indications has been shown to be associated with a lower 1-year mortality.26
The prognosis of IE is determined by the specific infecting organism, the valve that is involved, and the presence of certain complications. S aureus typically produces significant tissue destruction so is fatal in more than a third of patients when there is mitral or aortic valve involvement. MRSA has been associated with an even higher mortality as compared to methicillin-sensitive S aureus infections.27 Patients admitted to the ICU have a mortality of 45% to 56%.3 The prognosis is better in patients who acquire right-sided IE through intravenous drug use.28 Data show that left-sided vegetations greater than 1 cm in diameter are associated with a higher rate of adverse complications.29 Also associated with a higher mortality are
Mitral valve involvement
Refractory heart failure
Shock
Major embolic events
Intracardiac abscesses
Major organ system failure
