Chapter 49. Endocarditis and Other Intravascular Infections

• The possibility of intravascular infection should be considered in all critically ill patients with bacteremia or fungemia of uncertain origin, particularly when there are known intravascular or endocardial abnormalities or intravascular devices; fever or hemodynamic instability of unclear origin; or signs of inflammation related to an indwelling intravascular device.
• Blood cultures are the most important diagnostic test for this group of infections because most intravascular infections will result in persistent bacteremia or fungemia.
• Successful therapy often requires prolonged administration of microbicidal agents plus removal of devices.
• Certain microbes, including staphylococci, enterococci, aerobic gram-negative bacilli, and yeasts, are especially likely to cause intravascular infectious disease.

Patients hospitalized in ICUs may have an intravascular infectious disorder as their primary problem, as a complication of their main disorder, or as a nosocomial infection occurring during their stay. Specific populations common to the ICU, including hemodialysis patients, injection drug users, HIV-infected patients, and those with congenital heart disease, are at increased risk of intravascular infection. Furthermore, violation of anatomic barriers by indwelling intravascular devices and by surgery, as well as impairment of cellular or humoral immune function related to critical illness, contributes to invasion by a variety of microbial pathogens. Infections of intravascular foreign bodies or native vascular structures themselves are likely to be associated not only with symptoms and signs of local inflammation but also with evidence of disseminated disease due to metastatic spread of infectious agents. This chapter provides the clinician caring for patients in an ICU with an approach to the patient with suspected or proved intravascular infectious disorders. We will emphasize the underlying clinical situations that predispose to intravascular infection, the pathogenesis of the disorders, the symptoms and signs of disease, and the appropriate diagnostic procedures, particularly those that provide assistance in the choice of antimicrobial therapy and selection of ancillary medical and surgical procedures. Table 49-1 lists the intravascular infections of native vessels and those associated with intravascular devices, respectively.

Infective Endocarditis on a Native Valve

Pathogenesis

The pathogenesis of infective endocarditis (IE) usually involves transient bloodstream invasion by microorganisms, followed by adherence of the organism to the endocardial surface and multiplication of the microorganism within a layer of platelets and fibrin that is relatively inaccessible to host phagocytic defenses. The likelihood that a patient with or without underlying valvular heart disease may develop IE depends on the species and concentration of microorganisms in the blood, the duration of the bloodstream invasion, the presence or absence of antimicrobial agents in serum at the time of bacteremia/fungemia, and the characteristics of the endocardium. Clearly, some microorganisms are much more likely to adhere to endocardium than others. Staphylococcus aureus, enterococci, and other streptococci are most adherent. Enteric gram-negative bacilli and anaerobic microorganisms are less so. Since S. aureus is adherent and invasive, is found commonly on the skin, and causes skin infection that can result in transient bacteremia, this organism is associated with acute bacterial endocarditis, even in patients without significant underlying valvular heart disease. Viridans-type streptococci, which are normal flora of the upper airway, may gain access to the bloodstream from trauma to the teeth or gingiva (as in dental work) and cause IE nearly always in a patient with a significant predisposing valvular abnormality. Many distinctions between acute and subacute endocarditis are blurred. Enteric gram-negative organisms, because they are much less adherent to endocardium, cause fewer cases of endocarditis relative to the frequency of bacteremia caused by these organisms. However, gram-negative organisms that have a greater propensity to adhere to surfaces, such as Pseudomonas aeruginosa, and that can gain access to the circulation via contaminated intravenous injections (as in drug abusers) or infection at other body sites produce a significant proportion of cases. The most common nosocomial pathogenesis of IE in critically ill patients is from central venous catheters, with peripheral IVs and urologic instrumentation also identified as sources.1–4

Clinical and Laboratory Features

Table 49-2 lists the most common signs and symptoms encountered in patients with native-valve IE. Table 49-3 lists the most commonly encountered laboratory abnormalities. Because most reports stress community-acquired disease, patients developing IE while hospitalized in an ICU may not manifest identical findings. Fernandez-Guerrero and colleagues1 reported fever in 100% of patients with hospital-acquired IE. A murmur was present in only 20% of patients with vascular catheter–associated IE but was present in 75% of patients with IE following a urologic procedure. Still, fever and a heart murmur are the most common findings in IE; both are found in at least 80% of patients with community-acquired left-sided IE. The incidence is less in patients with right-sided disease only.5

A number of peripheral manifestations may be present in patients with IE. A number of skin lesions occur, petechiae being most common. These are 1- to 2-mm red, nonblanching macules that become darker and fade within 2 to 3 days. 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.6 Vascular hemorrhages in the optic fundus are referred to as Roth spots. Splinter hemorrhages are vascular hemorrhages occurring under the nails, and often they are difficult to distinguish from traumatic lesions. Splinter hemorrhages due to trauma are more common and are more typically an isolated finding. Osler nodes are erythematous, tender subcutaneous papules that occur on the finger pads (Fig. 49-1). They are 2 to 5 mm in diameter and may be multiple. Janeway lesions are painless, erythematous macules, larger than Osler nodes, that occur on the palms and soles (Fig. 49-2). It is unclear whether Osler nodes and Janeway lesions are due to septic emboli directly or to immunologic phenomena.

Systemic emboli occur in approximately 40% of patients with left-sided valvular infection. In the central nervous system (CNS), embolic occlusion of peripheral arteries results in the stroke syndrome. Emboli to the spleen and kidney often cause abdominal pain. Emboli to mesenteric arteries may cause ischemic bowel disease or frank infarction of bowel. Emboli to muscles are common but usually clinically unapparent. Embolic disease can occur after the institution of antibiotics; patients at increased risk for this complication include those with embolic disease prior to the institution of antibiotics, those with larger vegetations, those with mitral valve involvement, and those infected with staphylococci.7 Drug abusers with right-sided IE frequently have evidence of septic pulmonary emboli on chest x-ray.5

Patients with IE also may present with heart failure due to valve malfunction, embolic myocardial infarction, myocarditis, or systemic toxicity owing to sepsis syndrome. Renal insufficiency is also a prominent sequela of untreated IE, whether occurring on a native or prosthetic valve.

Disorders of the CNS are prominent in patients with IE. Between 10% and 50% of patients with IE will develop some neurologic abnormality. Mental status changes such as confusion, delirium, and psychosis are most common. Focal neurologic symptoms and signs may be caused by an embolic stroke, a bleeding mycotic aneurysm, meningitis, or cerebral artery vasculitis. Overall, approximately 30% of patients with IE will have evidence of a focal neurologic event during their illness.

Anemia is common in patients with IE. Leukocytosis occurs in about 40% of patients. Changes in the renal sediment, particularly proteinuria and microscopic hematuria, usually are present in patients with IE. In long-standing disease, rheumatoid factor is present in about one-half of patients.

Diagnosis

Blood cultures are the most important laboratory tests in the diagnosis of IE. The vast majority of blood cultures obtained when a patient is not receiving antimicrobial therapy will be positive. In approximately 5% to 10% of patients with presumed IE, no etiologic organism is isolated initially. The causes of culture-negative endocarditis are prior antibiotics and endocarditis due to fastidious organisms, including anaerobes, nutritionally deficient streptococci, Coxiella burnetii, Legionella pneumophila, Chlamydia psittaci, C. pneumoniae, members of the HACEK group, and various fungi. 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.8 Longer incubation of cultures, special culture techniques to aid in isolation of fastidious microorganisms, and use of serologic studies for Coxiella, Bartonella, and Chlamydia may aid in diagnosis. Other potentially useful laboratory techniques currently under study for intravascular infections and endocarditis include the urinary histoplasmosis antigen, polymerase chain reaction (PCR) using universal bacterial (16S) and fungal (18S, 28S, and 5.8S) RNA primers,9 and serology for lipid S, a component of the gram-positive cell wall.10

Echocardiography is useful in identifying vegetations or local complications of IE. Transthoracic echocardiography has around 60% sensitivity in detecting vegetations in IE. Transesophageal echocardiography (TEE) has emerged as a major tool in the diagnosis and management of native-valve endocarditis (NVE). The sensitivity of TEE in the diagnosis of NVE is 90% to 99%, with a specificity of 90%. Therefore, when NVE is likely clinically but blood cultures are sterile, a TEE may be obtained to assist in diagnosis.11–13 A TEE also should be obtained in patients with an equivocal transthoracic echocardiogram (TTE) or those with a complicated course. One study has suggested that if the pretest probability of IE is between 4% and 60%, it is cost-effective to proceed to TEE without TTE.15 Durack and colleagues12 have proposed criteria for diagnosis of infective endocarditis, and they have been proved useful by other investigators.13 Finally, intracardiac echocardiography is an emerging diagnostic tool that has been used to identify pacemaker lead vegetations even in patients whose TEE is unremarkable.16

Management

Patients encountered in the ICU with fever, cardiac murmurs, or other findings suggesting the possibility of IE always should be evaluated for the possibility of valve infection; this evaluation should include multiple blood cultures and echocardiography. While this evaluation proceeds, two central questions arise: Which clinical situations warrant empirical antimicrobial therapy, and what empirical therapy should be selected? In general, physicians managing patients with possible IE should initiate therapy when one of the following situations is present: (1) the patient is critically ill, (2) antimicrobial therapy appears be necessary for some other infectious disorder, (3) early valve replacement is contemplated because of valve malfunction, and (4) IE is suspected clinically and one or more blood cultures are positive for an etiologic microorganism.

In patients with undiagnosed fever or other findings suggesting IE as a diagnostic consideration but without any of these indications for immediate therapy, withholding antimicrobials is reasonable until blood cultures and the results of other investigations provide support for the diagnosis.

In centers with lower rates of methicillin-resistant S. aureus (MRSA), it is still reasonable to initiate therapy with IV nafcillin at 2 g every 4 hours plus IV ampicillin at 2 g every 4 hours and gentamicin. Gentamicin doses should be at lower levels (1 mg/kg q8h) because synergistic killing with β-lactam agents does not require conventional gentamicin dosage. In the many hospitals and communities where increasing rates of infection with MRSA have been identified, empirical therapy with vancomycin rather than nafcillin should be considered. However, this regimen may not be adequate for IE secondary to vancomycin-resistant enterococci (VRE), which are being reported from many centers. Newer agents, such as linezolid and quinupristin-dalfopristin (faeceium isolates only), may be useful alternatives if VRE are identified and other agents, especially ampicillin, are also unavailable because of resistance profiles.14

In a febrile patient without the usual risk factors for coronary artery disease admitted with acute myocardial infarction, careful consideration of a diagnosis of IE should be undertaken prior to the administration of thrombolytics because catastrophic CNS bleeds from ruptured mycotic aneurysms have been reported.17

In patients with an established diagnosis of IE, management entails a careful choice of antimicrobial therapy based on identification of the etiologic microorganism and ongoing consideration of surgical measures that may be necessary. Table 49-4 lists the most common etiologic microorganisms causing community-acquired NVE and the valves involved. Staphylococci, enterococci, and Candida are the most common microorganisms responsible for nosocomial IE.1 Table 49-5 describes the recommended antimicrobial regimens for treatment of IE. Certain principles are followed when treating patients with IE. Parenteral antibiotics are preferred over oral agents because of more sustained antibacterial activity associated with IV antibiotics and erratic absorption associated with many oral drugs. Bactericidal agents are superior to bacteriostatic drugs. Long-term antimicrobial therapy almost always is required for cure. However, 2 weeks of antibiotics may be adequate in selected patients with uncomplicated viridans streptococcal IE or staphylococcal IE of the tricuspid valve.18,19 Determination of minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) of antimicrobial agents necessary to inhibit or kill the microorganism, respectively, are useful in choosing treatment regimens in patients with streptococcal or enterococcal infections. The serum bactericidal test (Schlicter test) is a measurement of antibacterial activity of the patient's serum, at peak and trough antimicrobial concentrations, against the patient's microorganisms. This test remains somewhat controversial. However, some investigators believe that a peak serum inhibitory concentration (SIC) of 1:8 or greater is more likely to be associated with successful treatment of IE.

Valve replacement may be life-saving in patients with IE. Indications for urgent valve replacement include severe heart failure, valvular obstruction, fungal endocarditis, ineffective antimicrobial therapy, and the presence of an unstable prosthetic device.20 A point system to aid in evaluation of the need for surgical intervention in IE has been described.21 The various complications that develop during IE are assigned a weighted point value according to their importance as indicators for valve replacement. A total of five or more points indicates the need for urgent surgery. Table 49-6 lists the conditions associated with need for valve replacement and their relative point ratings. Severe heart failure is considered heart failure that does not respond to maximal medical therapy (see Chaps. 22 and 23). Moderate heart failure is failure that is still present after routine but not maximal medical therapy.

Prognosis

The outcome of treatment for IE is heavily influenced by the relative pathogenicity of the infecting organism, the location of the infected valve, and the presence of complications of the infection. S. aureus typically produces a severe and destructive endocarditis that is fatal in more than a third of patients when the infection occurs on the aortic or mitral valve. In patients with tricuspid valve endocarditis, as typically occurs in intravenous drug users, the prognosis is substantially better.5 Recent data indicate that patients with large (>1 cm) vegetations have an increased morbidity and mortality.22 Other factors associated with worse prognosis include mitral valve involvement, severe cardiac failure, shock, major arterial emboli, myocardial abscess formation, and associated major organ system failure. As noted earlier, several of these would constitute indications for surgical intervention.

Antimicrobial Prophylaxis

Prevention of IE in susceptible individuals has been emphasized for many years because of the significant morbidity and mortality associated with the disease. Prophylactic antimicrobial therapy is based on evidence suggesting that bacteremia commonly occurs during certain procedures and that certain cardiac abnormalities place patients at an increased risk for the development of IE following bacteremia. Procedures most frequently associated with bacteremia and for which prophylaxis is recommended include dental extractions, periodontal surgery, lower gastrointestinal procedures, and genitourinary procedures. Bronchoscopy, endoscopy, and barium enemas are also associated with bacteremia but much less commonly, and none of these procedures routinely justifies antimicrobial prophylaxis. Most of the common procedures carried out in ICUs, including endotracheal intubation, urethral catheterization, and insertion of central vascular catheters percutaneously, pose little risk of bacteremia and do not require prophylaxis (except for urethral catheterization in the presence of a urinary tract infection).

Cardiac abnormalities that appear to especially predispose patients to IE following bacteremia include significant aortic and mitral valve deformity/disease, unrepaired ventricular septal defects, patent ductus arteriosus, coarctation of the aorta, prosthetic heart valves, and previously infected native valves. Patients with atrial septal defects, cardiac pacemakers, and atherosclerotic lesions are at much less risk. Mitral valve prolapse with a systolic murmur and/or redundancy of the valve seen on echocardiogram may be an indication for prophylaxis.

The specific antimicrobial agents chosen for prophylaxis depend on the specific procedure to be performed, the cardiac abnormality present, and the presence or absence of penicillin allergy (Table 49-7). In critically ill patients with underlying cardiac abnormalities who are undergoing procedures with a risk of bacteremia, a parenteral regimen usually is appropriate.

Mycotic Aneurysm

Pathogenesis and Microbial Etiology

Mycotic aneurysms are aneurysmal dilations of arteries caused by infection of the vessel wall with consequent weakening of the vessel's structure. These aneurysms occur most commonly in patients with IE and in that instance usually involve vessels of smaller caliber. The pathogenesis probably involves embolic localization of a valvular vegetation with extension of suppuration from the lumen circumferentially into the vessel wall. Another proposed mechanism is embolization of the vasa vasorum by infected material from the valve. In the absence of underlying IE, mycotic aneurysm may occur following transient bacteremia with seeding of a previously damaged site in a large artery, most commonly an ulcerated atherosclerotic plaque in the abdominal aorta. Mycotic aneurysms also may occur in intravenous drug abusers who both damage and contaminate the wall of a large artery by direct intra-arterial injections of drugs; mycotic aneurysms of the lower extremity, particularly the femoral artery, are most common in this population.

Endocarditis-associated mycotic aneurysms are caused by the same microorganisms causing the IE—streptococci, staphylococci, and occasionally, gram-negative enteric bacilli, the latter being more common among drug abusers. S. aureus and Salmonella spp. are the most frequent causes of mycotic aneurysms of the abdominal aorta and usually are not associated with IE.

Clinical Features

Intracranial mycotic aneurysms are encountered most commonly in patients who already carry a diagnosis of IE. These aneurysms usually are asymptomatic unless they rupture. In that circumstance, symptoms and signs are consistent with subarachnoid or intracerebral hemorrhage, with sudden onset of severe headache, decrease in the level of consciousness, and focal neurologic signs. Mycotic aneurysms of visceral arteries have a variable presentation based on the organ involved. In the case of the small bowel, there may be colicky abdominal pain and symptoms of small-bowel obstruction. In the case of hepatic arterial aneurysms, an important differential diagnostic consideration is ascending cholangitis because of fever, right upper quadrant pain, and jaundice. Mycotic aneurysms of the external iliac artery may present with pain in the lower anterior abdomen, quadriceps wasting, diminished deep tendon reflexes, and arterial insufficiency of the ipsilateral lower extremity.23

Patients with mycotic aneurysms of the abdominal aorta present with pain and fever, often of weeks' or months' duration. In as many as one-third of patients with abdominal aortic aneurysms, there is extension into the lumbar or thoracic vertebrae with resulting osteomyelitis. Aortoenteric fistula may occur if an aneurysm erodes into bowel lumen. On physical examination, in addition to fever, there may be a palpable mass in the abdomen.

Diagnosis

In patients with IE, clinical suspicion of a mycotic aneurysm usually arises after an episode of new neurologic symptoms in the case of intracranial aneurysms or local findings suggestive of aneurysms, as noted earlier. Clinical suspicion of a leaking intracerebral aneurysm should prompt contrast- and non–contrasted-enhanced computed tomographic (CT) examinations initially; however, an angiogram generally is necessary to exclude or confirm the diagnosis. The diagnosis of mycotic aneurysm of the abdominal aorta is also made on the basis of clinical suspicion, demonstration of bacteremia, and radiologic examination. CT scan of the abdomen may indicate a perivascular collection of fluid or actual blood in an aneurysm or pseudoaneurysm. Arteriography also may be helpful in demonstrating an aortic mycotic aneurysm, and bone films may show erosion of adjacent vertebral bodies.

Management

The management of mycotic aneurysm depends on the organ involved. In the case of intracranial mycotic aneurysms, there is debate regarding the most appropriate therapy. For peripheral intracranial aneurysms, clipping probably is indicated. For deep lesions, for which a surgical approach is felt to be hazardous, antimicrobial therapy alone is advisable because many aneurysms will resolve spontaneously with medical treatment. A history of bleeding, large aneurysm size, and persistence of the aneurysm following antimicrobial therapy are all factors that increase the advisability of surgery for accessible lesions. In the case of abdominal aortic aneurysms, surgical resection of the involved aorta is almost always necessary. Antimicrobial therapy for mycotic aneurysms and other intravascular infections without foreign bodies is outlined in Tables 49-5 and 49-8.

Cavernous Sinus Thrombosis

Cavernous sinus thrombosis usually results from direct spread of bacteria from a contiguous focus of infection. Extension of bacteria may occur by several routes, including septic thrombophlebitis of the angular and ophthalmic veins from facial cellulitis, along the lateral sinus and petrosal sinuses from middle ear infections, via the pterygoid venous plexus from a peritonsillar abscess, following a dental infection from osteomyelitis of the maxilla or from a cervical abscess, and along the venous plexus surrounding the internal carotid artery from the middle ear or jugular bulb.

S. aureus is the cause of cavernous sinus thrombosis in about 60% to 70% of patients. Streptococci, anaerobes, and other aerobes account for most of the rest.24 Patients with cavernous sinus thrombosis generally present with the early onset of external ophthalmoplegia with decreased sensation around the eye. The physical examination reveals periorbital edema and chemosis, and as the illness develops, meningismus, altered mental status, and cranial nerve palsies, especially of cranial nerves III, IV, V, and VI, become evident. Examination of the fundus often reveals striking venous congestion. The differential diagnosis of cavernous sinus thrombosis includes orbital cellulitis and rhinocerebral phycomycosis (mucormycosis). The distinction between cavernous sinus thrombosis and orbital cellulitis is sometimes difficult. Bilateral involvement and fifth nerve palsy, a fixed, dilated pupil, and signs of meningitis are all more likely in cavernous sinus thrombosis than in orbital cellulitis.

Although the diagnosis may be evident on clinical grounds alone, several imaging modalities can be useful. Ultrasound examination of the orbit can be useful in defining a periorbital abscess that may require surgical intervention. CT examination with contrast or MRI also can aid in this, will be useful in demonstrating sinusitis or underlying osteomyelitis, and may establish the diagnosis of cavernous sinus thrombosis as well. Carotid angiography and orbital venography also have been used to establish the diagnosis but are not recommended because they are unlikely to influence management. Following CT scan, a lumbar puncture is warranted, but it is usually sterile (80%)24 with a parameningeal inflammatory pattern: pleocytosis and elevated protein without significant hypoglycorrhachia. Blood cultures are mandatory and often are positive (70%)24; if sinus or abscess drainage is performed, fluid should be cultured for both aerobic and anaerobic bacteria. When rhinocerebral mucormycosis is a consideration, usually in a diabetic patient with blackish nasal discharge in addition to the rest of the syndrome, surgical exploration with biopsy and histologic examination for fungi is needed to establish the diagnosis.

Successful management of cavernous sinus thrombosis depends on early, effective antimicrobial therapy. Even with the best medical and surgical therapy, the outcome is often unsatisfactory. For this reason, adjunctive therapies such as corticosteroids and anticoagulation have been tried without success, and they cannot be recommended. The regimens shown in Tables 49-5 and 49-8 can be used when a bacterial etiology has been established. Prior to bacteriologic confirmation, empirical therapy depends on the underlying infection suspected.

Postanginal Sepsis

In 1936, in an article entitled, “On Certain Septicemias Due to Anaerobic Organisms,” Lemierre25 described a group of patients with pharyngitis complicated by bacteremia due to anaerobic microorganisms. Subsequently, this disorder, usually referred to as postanginal sepsis, has been described frequently.26 The pathogenesis is thought to involve bacterial invasion of the mucosa of the posterior pharynx with extension of suppurative thrombophlebitis (ST) into the internal jugular veins. Bacteremic spread of the infection is common, with lung, liver, and joints the most common sites of metastatic disease. Clinically, patients present with sore throat, chills, fever, and occasionally jaundice. On physical examination, in addition to the toxicity and fever, there may be palpable tender thrombosis of the jugular vein as well as evidence of septic arthritis, pleuropulmonary disease, or jaundice. An enhanced CT scan usually will demonstrate internal jugular vein thrombophlebitis and is useful to localize purulent collections requiring drainage. Chest radiograph may show scattered infiltrates owing to septic pulmonary emboli. Fusobacterium necrophorum has been isolated most commonly from blood, although Bacteroides fragilis and other mouth anaerobes have been reported as well.

Management includes early recognition and treatment of the disorder with effective antimicrobial therapy. Antibiotics should be directed against anaerobic bacteria, with drugs such as metronidazole, chloramphenicol, imipenem-cilastatin, or ticarcillin-clavulanic acid. Prompt surgical intervention to drain any purulent material present locally or distantly is required in addition to antibiotics.

Septic Pelvic Vein Thrombophlebitis

Pelvic vein thrombophlebitis develops most often 1 to 2 weeks after delivery or gynecologic surgical intervention or in the setting of pelvic suppuration, such as following septic abortion or post–Cesarean section endometritis. Symptoms include fever, chills, anorexia, nausea, vomiting, and abdominal pain.27 On physical examination, there may be tenderness in the lower quadrants, and tender venous structures may be palpated in one-third of patients.28 Eighty percent of pelvic vein thromboses complicating pregnancy and delivery occur on the right side, perhaps because of compression of the right ovarian vein at the pelvic brim by the enlarged uterus. In 5% of episodes, thrombosis is apparent only on the left, and in 14%, it is bilateral. Spread distally to femoral veins is unusual.

The most serious complication of suppurative pelvic vein thrombosis is pulmonary embolization. When this occurs, the patient presents with respiratory distress associated with pulmonary opacities that often are pleural-based. Even though the process is associated with thrombosis and bacterial suppuration in the venous lumen, bacteremia is unusual, with an overall prevalence of only 30%. Microorganisms isolated from the blood, or from the veins if surgery is carried out, include those that are normally present in the pelvis, particularly Peptostreptococcus spp., Peptococcus spp., B. fragilis, aerobic gram-negative bacilli such as Escherichia coli, Klebsiella, and Enterobacter, group A and group B β-hemolytic streptococci, and rarely, staphylococci.

The diagnosis can be difficult because the findings are similar to a wider range of other pelvic and lower abdominal inflammatory conditions. Probably the best imaging modality to support the diagnosis is contrast-enhanced CT scan; ultrasound examination also may be useful if the intravascular thrombus can be demonstrated.

Successful treatment frequently requires both antimicrobial therapy and heparinization; indeed, in the appropriate clinical context, fever that is failing to respond to apparently appropriate antimicrobials and that responds to the addition of intravenous heparin can be regarded as support for the diagnosis.29 Complications are mainly those related to suppurative pulmonary emboli.

Pylephlebitis

Pylephlebitis is septic thrombosis of the portal vein and its branches. It is a rarely seen complication of intra-abdominal suppuration and was first described in patients with appendicitis or diverticulitis. The illness evolves in three phases. In the first phase, symptoms and signs of the original intra-abdominal disorder such as acute appendicitis or perforated diverticulum predominate. The second phase involves portal bacteremia, with resulting invasion and thrombosis of portal veins. In the third phase, abscesses form in the liver owing to proximal spread of the suppurative material. Late signs and symptoms include fever, abdominal pain, jaundice, and right upper quadrant tenderness. The liver is enlarged in one-half of patients. Laboratory studies reveal an elevated white blood cell count with increased numbers of immature granulocytes and abnormal liver function tests, particularly elevations of the alkaline phosphatase and aspartate aminotransferase (AST) levels. Bacteremia is not a consistent finding. CT scan is especially useful in demonstrating this disorder, showing clot in the portal veins and occasionally gas in portal vein radicals in the liver. The microorganisms responsible reflect large bowel flora and include aerobic gram-negative bacilli such as E. coli, Klebsiella, and Enterobacter; anaerobic microorganisms such as Peptococcus, Peptostreptococcus, B. fragilis, and Fusobacterium; and gram-positive aerobic species such as staphylococci and enterococci.

Successful therapy requires surgical correction of the primary problem, as well as high-dose antibacterial therapy directed against the offending pathogens. Pyogenic liver abscesses resulting from this disorder usually are best treated with prolonged medical therapy alone, unless they are few and relatively large, in which case percutaneous drainage may be useful. Surgical drainage of multiple small abscesses is very difficult, often requires a transperitoneal approach, and is not recommended. The effectiveness of antibacterial therapy may be judged by physical examination, resolution of fever and leukocytosis, and improvement of abnormalities demonstrated by ultrasound or CT scan.

Prosthetic Valve Endocarditis

Pathogenesis and Microbiology

Prosthetic heart valves may become infected early following implantation or later during the life of the device. Overall, about 2% of patients with prosthetic heart valves become infected, one-third in the first few months after valve implantation and two-thirds later. In early prosthetic valve endocarditis (PVE), the presumed pathogenesis involves inoculation of the operative site at the time of surgery or the localization of microorganisms on the new device following transient bacteremia associated with indwelling lines used in the perioperative period. Factors associated with an increased risk of PVE include IE of the native valve prior to valve resection and replacement, use of a mechanical valvular device in contrast to a tissue heterograft or homograft, a history of intravenous drug abuse, male gender (possibly because of the greater likelihood of superficial cellulitis as a result of shaving prior to surgery), and longer cardiopulmonary bypass time.30

In late PVE, i.e., disease appearing more than 12 months after replacement, the pathogenesis more closely resembles that of native-valve disease.31 Extension of local tissue disease via lymphatics to the bloodstream or direct inoculation of microorganisms via capillary beds, as occurs during dental work, results in transient bacteremia with localization on the prosthetic device. Nosocomial PVE is acquired most commonly via intravascular devices but may be initiated by cutaneous and other infections as well.32

Microorganisms most commonly responsible for PVE are listed in Table 49-9. Staphylococcus epidermidis is the most common cause of early PVE. S. aureus and gram-negative bacilli are also prominent etiologic microorganisms during this period. Other less commonly encountered microorganisms are enterococci, other streptococci, and yeast. Microorganisms found in patients with late PVE tend to be similar to those seen in native-valve disease. Viridans streptococci are common, as is S. aureus; S. epidermidis and gram-negative bacilli are less common. Nosocomial PVE is most commonly due to staphylococci, epidermidis followed by aureus; enterococci, gram-negative bacilli, Candida, and viridans streptococci are less common pathogens.32

Clinical Features

The signs, symptoms, and clinical laboratory abnormalities seen in PVE generally are similar to those encountered in patients with NVE, except that patients with PVE have a higher prevalence of cardiac complications. Clinical evidence of these cardiac complications may include new and changing regurgitant murmurs caused by paravalvular leak from dehiscence of the valve ring, intraventricular and atrioventricular conduction defects resulting from extension of a paravalvular abscess into the interventricular septum, and muffling of prosthetic heart sounds or new stenotic murmurs related to malfunction of the valve caused by a vegetation. Fang and colleagues31 reported on patients with nosocomial PVE having peripheral stigmata in 20%, splenomegaly in 5%, stroke in 3%, and a new or changing murmur in 31%.

Diagnosis

Diagnostic difficulty arises in the immediate postoperative period when bacteremia occurs in a patient with a new prosthetic valve. In this setting, blood cultures yielding staphylococci, “diphtheroids,” and yeasts are more likely to represent true prosthetic valve infection than is gram-negative bacilli bacteremia, which more likely results from indwelling venous catheter infection.

In patients with late PVE caused by staphylococci or streptococci, bacteria usually are recovered consistently from blood cultures, provided that the patient has not received prior antimicrobial therapy. Generally, three sets of blood cultures obtained over a brief period from different venipuncture sites are sufficient to identify the etiology of prosthetic valve infection. Echocardiography helps identify vegetations and local suppurative complications, as well as determine ventricular function and valvular integrity, although the metallic devices tend to result in distorted echo signals, confusing the interpretation. TEE is superior to TTE in visualizing the mitral valve; visualization of aortic valve prostheses with TEE is less clear. The reported sensitivity and specificity of TEE for detection of morphologic abnormalities are 86% and 88%, respectively.11 Patients with neurologic symptoms associated with PVE also should undergo a contrast-enhanced CT scan of the head to detect embolic hemorrhagic infarcts and abscesses. Since a CT scan does not reliably exclude mycotic aneurysm, cerebral angiography also may be indicated when CT findings do not explain the neurologic symptoms adequately.

Management

The same principles described for the treatment of NVE apply for the treatment of PVE.33 The antimicrobial agents used in the treatment of PVE are outlined in Table 49-5. In general, initial antimicrobial therapy is chosen on the basis of identification and susceptibility tests of the infecting microorganism. When the infecting microorganism has not been identified, initial therapy should include vancomycin and gentamicin to cover the likely possibilities of S. epidermidis, S. aureus, and streptococci. This combination would cover most nosocomial pathogens as well; however, the choice of antibiotics also should be determined by the usual organisms encountered at the specific hospital environ. In addition, previous or current antibiotic use should be considered when choosing an empirical regimen, especially for nosocomial PVE. Ill, bacteremic patients who may have IE should be treated without delay. In addition, if heart surgery is scheduled because of valve deterioration or antimicrobial therapy is required for some other indication in a patient with suspected endocarditis, therapy should be initiated without waiting for the results of blood cultures. Relative indications for valve replacement in PVE include early PVE, nonstreptococcal late PVE, and periprosthetic leak. Patients with PVE should be treated for 6 to 8 weeks in most instances whether or not the valve is removed. If microorganisms can be cultured at the time of valve replacement, we recommend 6 to 8 additional weeks of therapy beginning at that time.

Cardiac Pacemaker Infections

Four major varieties of pacemakers are presently in use: transvenous and epicardial temporary pacemakers with external generators and transvenous and epicardial pacemakers of the permanent variety with implanted generator boxes. The pathogenesis and management of infections of temporary transvenous pacemakers are essentially identical to those for other percutaneous central vascular catheters and are not discussed further here (see Chap. 50). The most common complication affecting permanently implanted pacemakers is mechanical failure (failure to pace or sense correctly), but infection is the next most common. Approximately 4% of pacemakers become infected at some point after placement. Generator box infections, infection of the electrode along its subcutaneous course, and bacteremic infection of the intravascular portion of the electrode, with or without associated endocarditis, each contribute approximately one-third to the overall infection problem. Diabetes mellitus, cancer, and corticosteroid therapy all have been noted to predispose to infection of the device. Skin erosion adjacent to a generator pouch also predisposes to direct invasion of the apparatus. As with PVE, pacemaker infections can be classified as early or late; early infections occur in the first 3 to 6 months. Early infections generally can be attributed to wound contamination by skin organisms at the time of implantation, whereas late infection, particularly of the intravascular electrode, often results from transient bacteremia with adherence of organisms to the surface of the device. Particularly in the case of staphylococcal infections, adherence to the foreign material is facilitated by an exopolysaccharide glycocalyx produced by the organism. This material also forms a protective layer over the biofilm on the foreign body, contributing to impairment of the local antibacterial activity of polymorphonuclear leukocytes and reducing the effectiveness of antimicrobial therapy.

S. epidermidis and S. aureus are the most common microorganisms isolated from patients with generator pocket or electrode infections. In one large study of pacemaker infections, S. epidermidis accounted for 44% of episodes and S. aureus, 29%.34 They are also the most common organisms isolated from the blood of patients with pacemaker infections in the absence of obvious generator pocket or electrode disease. Other etiologic microorganisms that have been reported include Corynebacterium spp., gram-negative aerobic bacilli, and occasionally, fungi.

Chills, fever, and other constitutional symptoms without another evident source constitute the usual presentation of pacemaker infection. The diagnosis is made by inspecting the generator pocket and the subcutaneous electrodes and obtaining blood cultures. Generator pocket and subcutaneous electrode infections usually evidence local inflammation without bacteremia or with transient bacteremia. Persistent bacteremia in a patient with an intravascular pacemaker suggests intravascular electrode infection or IE. Since most pacemakers are implanted in the right ventricle, the associated endocarditis is usually not accompanied by systemic embolic phenomena but may produce septic pulmonary emboli or multifocal pneumonia, as in right-sided endocarditis of other causes. TEE is more sensitive than TTE with regard to detecting pacemaker-related vegetations. As mentioned previously, intracardiac echocardiography is an emerging technology that also may prove useful in identifying pacemaker lead vegetations.16

There are three main considerations in developing a therapeutic plan for the management of pacemaker infection. One is the identity of the suspected or proved infecting microorganisms, second is the particular component of the apparatus that is involved, and the third is the presence or absence of bacterial infection at sites other than the pacemaker itself. Infected pacemakers must be removed when the generator box is infected, when there is persistent bacteremia, and when there is evidence of IE. A few authors have suggested that patients with permanent transvenous pacemakers that have been present for a long duration and who have bacteremia without evidence of generator box infection or IE can be tried on antibacterial therapy in the hope that the infection on the device may be cured without replacement. If treatment of pacemaker infection is attempted without removal of the device, 4 to 6 weeks of intravenous antimicrobial therapy probably is necessary as an initial trial. In the case of fungal agents or mycobacteria, a longer duration of therapy is necessary and is more likely to be unsuccessful. If the decision is made to remove the pacemaker, then the new transvenous generator should be located in a deeper pocket. Antimicrobial therapy is chosen on the basis of the microorganism isolated from the skin and subcutaneous tissue or bloodstream and is described in Tables 49-5 and 49-10. Two weeks of antimicrobial therapy after removal of the device probably is sufficient in the case of most generator pocket infections resulting from pyogenic microorganisms unless there is metastatic disease or secondary NVE, in which case the usual duration of treatment for NVE is used after the device is removed. Transvenous lead infections also require device removal and parenteral antimicrobial therapy. It is sometimes difficult to extricate the transvenous electrode tip from the right side of the heart. Tricuspid valve or ventricular wall tears have occurred. If percutaneous electrode removal is impossible, thoracotomy is required.

Ventricular Assist Device Infections

Ventricular assist devices (VADs) are becoming more common in ICU patients. VADs often serve as bridges to cardiac transplantation. Because they are an intravascular device, VADs may become colonized and serve as a site for recurrent bacteremias or fungemias. It has been estimated that 25% to 50% of VAD placements are complicated by infection.35 VAD-associated infections often involve the pump driveline, the pocket, or both. Commonly reported etiologic organisms include S. aureus,35,36 S. epidermidis,35,36 P. aeruginosa,35 and Candida species.35,36 If this complication should develop, replacement is one consideration; however, others would argue that this approach will fail more often than not owing to reinfection of the subsequent device and that these patients should receive priority for transplantation. However, lack of donor organs often leaves the former as the only available option.

Arterial Graft Infections

Arterial grafts have an infection rate that has varied between 2% and 6% in different studies,37–39 with a mortality rate as high as 50%. The pathogenesis of graft infection is analogous to that of prosthetic valve disease, with some patients presumably developing infectious disorders of the graft owing to inoculation of microorganisms at the time of surgery and others developing infection later owing to adherence of microorganisms that have gained access to the circulation. Grafts remain susceptible to infection for a rather long period because of the slow process of pseudointima formation in the graft lumen. Overall, graft infections present a mean of 8 months after implantation, but late disease may occur as long as 7 to 10 years after graft placement.40 Autogenous vein grafts are the least susceptible to infection. Knitted Dacron grafts appear to be more susceptible, and woven Dacron grafts have a risk of infection somewhere in between. Grafts that cross the femoral area seem to be at greatest risk for infection, possibly due to contamination by bowel flora at the time of implantation.

The microbial etiology of vascular graft infection is shown in Table 49-11. Gram-positive microorganisms, particularly S. aureus, are the most common cause of graft infections, particularly in the groin or popliteal area. Gram-negative enteric microorganisms such as E. coli,Proteus, or Pseudomonas are more often the cause of abdominal graft suppuration.

Graft infections generally present with variable systemic constitutional symptoms, nonspecific laboratory evidence of an inflammatory process (leukocytosis, elevated erythrocyte sedimentation rate [ESR]), and findings at the graft site that vary depending on the location of the graft. Early infections (occurring less than 4 months after graft placement) more often present as sepsis or wound infection, whereas late infections present with graft malfunction or cutaneous sinus formation. Intraluminal infection may present as fever and nonspecific constitutional complaints resulting from bacteremia. Patients with a vascular graft who have persistent bacteremia with no other known source must be approached as if they have a graft infection. Extraluminal infection may present with evidence of local graft infection with erythema, tenderness, and swelling over the graft site; with systemic inflammatory symptoms without definite localizing findings; or with graft occlusion. Rapid swelling suggests disruption of the suture line with bleeding and false aneurysm formation and frequently implies graft infection. The most common presentation of groin or leg graft site infection is a localized abscess or draining sinus. Graft thrombosis should be suspected when signs and symptoms of peripheral arterial insufficiency develop. Exteriorization of the graft secondary to breakdown of tissue overlying the graft is rare but, when present, is pathognomonic of infection.

With infection of abdominal aortic grafts, swelling of tissues surrounding the graft may produce a mass effect, sometimes with evidence of ureteral obstruction or hydronephrosis. In addition, symptoms and signs of lower extremity ischemia may occur. The development of an aortoduodenal fistula between an infected aortic graft and the duodenum is a catastrophic complication. Patients in this group present with hematemesis or circulatory collapse.

Not infrequently, a diagnosis of graft infection must be based predominantly on the clinical features noted earlier because blood cultures are negative. The most useful imaging procedure is scanning with indium- or technetium-labeled white blood cells, which can demonstrate the inflammatory process along the course of the vascular graft.41 CT scan or MRI is perhaps preferable if soft-tissue edema resulting from infection surrounding the graft or false aneurysm formation can be demonstrated. Vascular imaging may be combined with percutaneous fine-needle aspiration of perigraft fluid that can be Gram-stained and cultured. When the graft is removed for presumed infection, the graft itself and swabs from the graft bed should be cultured for both aerobes and anaerobes and examined for fungi.

Management of an infected intravascular graft almost always requires specific antimicrobial therapy chosen on the basis of the presumed or demonstrated infecting microorganism, as well as graft removal. When antimicrobial therapy alone is attempted, graft infection usually persists. If a graft provides the only blood supply to a distal organ or extremity, then some variety of revascularization must be carried out at the time of graft removal. An example is the use of an axillofemoral graft to bypass an infected aortic bifurcation prosthesis.

Specific antimicrobial regimens and suggested duration of therapy are indicated in Tables 49-5 and 49-10.

Intravascular infection is usually suspected in a critically ill patient when fever or other clinical or laboratory features of sepsis are present without a satisfactory alternative explanation. Blood cultures are mandatory in all such patients as an initial step, and all permanent or temporary intravascular devices should be inspected carefully for local evidence of infection.

Patients with otherwise unexplained positive blood cultures in the presence of an intravascular device must be presumed to have an infection of the device. When the device is a temporary one, such as a peripheral intravenous line, central venous catheter, or temporary pacemaker, it should be removed. In most cases, IV antimicrobial agents appropriate for the organism should be given for 1 to 2 weeks. If pus can be expressed from the puncture site or there is persistent bacteremia, surgical exploration of the peripheral veins is indicated. Tunneled central venous catheters call for a more selective approach (see Chap. 50). When positive blood cultures are attributed to an infected permanent intravascular device, the initial clinical decision is whether the device should be removed. Indications for permanent intravascular device removal depend on the variety of the device and have been discussed previously.

Positive blood cultures in the absence of an intravascular device and without an evident infection such as cellulitis, pneumonia, urinary tract infection, cholangitis, or intra-abdominal abscess predisposing to bacteremia most commonly result from an occult abscess or an intravascular suppuration. When sufficient clinical suspicion suggests the possibility of an intravascular infection such as a mycotic aneurysm, NVE, postanginal sepsis, pelvic vein thrombophlebitis, or pylephlebitis, appropriate special diagnostic studies outlined earlier should be performed promptly, and appropriate antimicrobial therapy for the bacteremia should be initiated. In addition, when the diagnosis has been established, appropriate surgical intervention frequently is required, as noted earlier.

Another group of critically ill patients in whom intravascular infection must be considered consists of those with fever and persistently sterile blood cultures, either while receiving antimicrobial therapy or not. When antimicrobial agents are being administered for some other reason, making a diagnosis of the precise etiology of intravascular infection may be especially difficult. Even if antimicrobial therapy can be discontinued, blood cultures may still take as long as 2 weeks to become positive again. In the patient with a prosthetic heart valve, blood-culture–negative IE is a consideration. In those with permanent pacemakers or vascular grafts, infection with a fastidious organism that is difficult to detect by usual methods is also a possibility, as is infection of a part of the device that is extravascular. The approach to these infections involves blood cultures designed to detect more fastidious organisms (see above), serologic studies for infections not detected by culture, and imaging studies aimed at acquiring nonmicrobiologic support for the diagnosis of infection. An echocardiogram demonstrating a vegetation on a valve, an arteriogram showing a mycotic aneurysm, or a scan with labeled white blood cells demonstrating increased uptake around a vascular graft may be sufficient to raise the index of suspicion high enough to proceed to more definitive therapy.

Patients with fever, negative blood cultures, and temporary devices in place should be examined carefully for evidence of local inflammation at the site of the device, and if present, the device should be removed and cultured semiquantitatively: A colony count of less than 15 when the intracutaneous portion of a vascular catheter is rolled on an agar plate virtually excludes sepsis due to infection of that line, whereas higher bacterial counts provide some support for the diagnosis.42

A common practice in some centers involves changing the central venous line over a guidewire in the febrile patient whose central vascular catheter exit site does not look infected and who is not bacteremic; if the line tip culture is positive, then the central venous line is replaced in a sterile site. Data to support or refute this practice are not compelling; therefore, one must weigh the risk of the catheter being the source of sepsis against the risk associated with placement of a new catheter or doing without it. A more complete discussion of the problem of suspected temporary intravascular device infection is given in Chap. 50.

Finally, even in the patient with fever of unknown source, negative blood cultures, and no intravascular device in place, an intravascular infection remains an important diagnostic consideration. Mycotic aneurysms, culture-negative NVE, pelvic vein septic thrombophlebitis, and pylephlebitis are all examples. The key points in the diagnostic approach are a careful history and physical examination and consideration of the clinical context. Examples include a woman with fever without bacteremia following delivery, in whom a pelvic vein thrombophlebitis, a new or previously demonstrated pathologic heart murmur (raising the possibility of culture-negative IE), or known intravenous drug abuse suggesting the possibility of mycotic aneurysm must be considered.