Septic Emboli

Etiology

Infective endocarditis has long been established as a major cause of septic emboli, with reports dating back to 1883.[4] Septic embolization occurs when fragments of infected valvular vegetations dislodge, travel through the bloodstream, and occlude vessels, with clinical manifestations determined by the size and location of the embolus. Historically, septic embolism was almost exclusively a complication of septic pelvic thrombophlebitis, typically associated with septic abortion and postpartum uterine infection. Currently, risk factors for septic emboli include intravenous drug use, indwelling vascular catheters, and patients with prosthetic cardiovascular devices.

Septic emboli originate from the anatomical site of the infection and the associated venous or arterial drainage. The microorganisms most commonly associated with septic emboli include Staphylococcus aureus, coagulase-negative staphylococci, the streptococcal and enterococcus groups, and polymicrobial infections. Less frequently, gram-negative organisms are implicated. In addition, fungal pathogens, most notably Candida and Aspergillus species, have also been reported.[5]

A multinational study on infective endocarditis reported that pathogens were identified in 91.7% of cases. The leading organisms were S aureus (33.6%), Streptococcus viridans (18.7%), enterococci (16.1%), and coagulase-negative staphylococci (11.6%), many demonstrating significant antimicrobial resistance. Notably, 44.4% of patients experienced major embolic events, most frequently involving the brain (26.3%).[6] A systematic review and meta-analysis identified septic pulmonary emboli in 70 patients (6%) among 1,158 cases of Klebsiella pneumoniae liver abscess.[7]

Clinical examples include orbital cellulitis caused by Streptococcus constellatus, which has been reported to progress to cavernous sinus thrombosis with subsequent pulmonary embolism.[8] Septic thrombosis of the superior vena cava has been reported in association with infection at a peripherally inserted central catheter line in a neutropenic patient with methicillin-resistant S aureus (MRSA) bacteremia.[9] Paradoxical septic emboli to the brain may occur in right-sided pacemaker endocarditis, when embolic material traverses a patent foramen ovale, creating a right-to-left shunt.[10] Also, there are reports of septic pulmonary emboli from the right atrial thrombus related to tunneled hemodialysis catheters.[11]

Cardiac implantable electronic devices infections occur in approximately 0.5% of de novo implants and up to 2% of device replacements.[12] Diagnosis is typically established by detecting lead vegetations on echocardiography, which may be complicated by septic embolism. One case study described septic thrombophlebitis involving the internal jugular vein due to S aureus following insertion of an implantable cardioverter-defibrillator.[13]

Epidemiology

The reported incidence of septic emboli in infective endocarditis varies considerably across studies. In a cohort of 437 patients undergoing surgery for endocarditis, septic emboli were identified in 10.52% of cases.[14] Systemic embolization complicates about 20% to 50% of left-sided infective endocarditis.[15] Another series of 493 patients reported a markedly higher prevalence, with 57% developing septic embolism.[16] A systematic review and meta-analysis estimated a pooled prevalence of 25% among infective endocarditis cases.[17] Furthermore, septic embolization occurs in at least 30% of patients with infective endocarditis referred for cardiac valve replacement. [18]

In a 25-year review of infective endocarditis, intracardiac device-associated endocarditis increased substantially in the last decade compared with native valve disease. Rates rose from 5.4% to 23% (P < 0.0001) for pacemaker-related cases and from 8.5% to 19.2% to 47.5% (P < 0.0001) for prosthetic valve endocarditis.[19] In a recent study of infective endocarditis by Erdem et al, 44.4% of patients experienced major embolic events. The distribution included cerebral (26.3%), splenic (6.8%), pulmonary (6.1%), renal (2.9%), peripheral (2.2%), as well as less frequently coronary (n= 4) and mesenteric (n= 3).[6]

Pathophysiology

Septic emboli originate from an infectious source complicated by bloodstream infection. A large bacterial inoculum forms on a vulnerable vascular territory, such as cardiac valve or pacemaker vegetations or a thrombus in an indwelling vascular catheter or graft. Portions of the vegetation can dislodge, fragment, and embolize to distant sites. The resulting occlusion produces a dual insult: an ischemic event due to vascular obstruction and an infectious or inflammatory process at the new deposition site. 

Right-sided endocarditis typically results in septic pulmonary emboli due to embolization of vegetations to the pulmonary circulation. A patent foramen ovale, a congenital cardiac anomaly associated with cryptogenic stroke, may provide a conduit for paradoxical embolization. In contrast, left-sided endocarditis more commonly produces cerebral emboli, leading to ischemic stroke from occlusion of cerebral arteries by dislodged vegetations. Septic embolic stroke has been associated with brain abscess formation, increased mortality, and upregulation of Orm1 and Cxcl2 gene expression compared to noninfective embolic stroke.[20]

In an experimental canine model, Molinari, MD, demonstrated that septic embolism can produce both ischemic injury and infection within the brain. Septic cerebral emboli may result in a mycotic aneurysm or brain abscess, with the pathology and clinical course influenced by the organism's virulence. Highly virulent pathogens such as S aureus and Escherichia coli cause rapid arterial wall infection, often leading to aneurysm formation and hemorrhage. In contrast, streptococcal species typically produce more indolent, progressive lesions originating in prior infarction or ischemia.[21]

In a review of 39 patients with human parainfluenza endocarditis, a fastidious organism, 28 developed septic emboli involving the central nervous system, pulmonary, renal, and splenic circulation. Notably, the mortality rate was lower than that typically observed with more virulent organisms.[22] In another case report, septic embolism manifested as unilateral Janeway lesions and Osler nodes in a patient with ipsilateral endovascular infection from an arteriovenous fistula.[23]

Histopathology

Histopathological analysis demonstrates fibrinoid necrosis of vessel walls with neutrophilic infiltration both within and around the affected vessels. Dense, paucicellular fibrinoid material interspersed with clusters of bacterial cocci is characteristic of septic emboli. This distinctive clot morphology was identified in thrombi retrieved during endovascular thrombectomy from 4 patients with infective endocarditis presenting with acute ischemic stroke.[24]

History and Physical

Septic emboli encompass a broad clinical spectrum, ranging from asymptomatic presentations to fulminant disease associated with significant morbidity and mortality. Because of this variability, a high index of suspicion is essential. Clinicians should particularly consider the diagnosis in patients with endovascular devices or recent vascular cannulation who develop recurrent or persistent bacteremia, as these populations are at elevated risk of endovascular infection and embolic complications. 

The clinical manifestations of septic emboli depend primarily on the location of the primary infection and the vascular territory involved. In right-sided infective endocarditis, embolization to the pulmonary circulation may cause septic pulmonary emboli, typically presenting with fever, dyspnea, pleuritic chest pain, cough, and, occasionally, hemoptysis. In contrast, left-sided endocarditis more often results in systemic embolization, producing organ-specific syndromes such as cerebral ischemia, splenic infarction, renal emboli, or peripheral vascular occlusion.  

Cerebral Emboli

Septic cerebral emboli present with neurological deficits that vary according to the location of the stroke, the extent of infarction and inflammation, and the number of affected territories. Importantly, cerebral embolization in patients with infective endocarditis may be clinically silent. In a prospective study of 56 patients with left-sided endocarditis, cerebral emboli were identified on MRI in 80% of cases, 48% remaining subclinical.[25] 

Coronary Artery Embolization

Septic coronary artery embolization has been reported following aortic valve endocarditis and was successfully managed with aspiration thrombectomy.[26] Such cases highlight the importance of early recognition, as coronary embolization may mimic acute coronary syndrome and require prompt intervention to prevent fatal outcomes.

Mesenteric Emboli

Septic mesenteric emboli have also been described, including occlusion of the superior mesenteric artery secondary to mitral valve endocarditis, which requires resection of the affected bowel and mitral valve replacement for definitive management.[27] Additionally, a case of infective endocarditis due to Streptococcus bovis was complicated by systemic septic emboli and a superior mesenteric artery mycotic aneurysm in a patient with diverticulitis. Treatment involved surgical resection of the aneurysm, removal of mycotic thrombi, and mitral valve replacement.[28]

Liver and Spleen

The spleen is the most common abdominal site affected by systemic septic emboli, often complicating infective endocarditis. Septic splenic embolization may lead to splenic infarction, hemorrhage, or abscess formation.[29] Pylephlebitis, or septic portal vein thrombosis, arises from intrabdominal infections such as ascending cholangitis or diverticulitis. This condition typically presents with nonspecific symptoms of fever and abdominal pain, is diagnosed with contrast-enhanced computed tomography (CT) or abdominal ultrasound, and is often polymicrobial in etiology. Pyogenic liver abscesses may be complicated by metastatic infections, including the development of septic emboli, which can disseminate to distant organs and worsen clinical outcomes.[30]

Extremities and Skin 

Septic emboli of the extremities usually present as acute limb ischemia complicating infective endocarditis. The severity ranges from transient ischemia, which is managed with antibiotics and anticoagulation, to severe ischemia requiring amputation. Cases of acute lower limb ischemia have also been reported after MRSA pneumonia.[31] Septic emboli of the skin most often manifest as Janeway lesions, which represent microembolic phenomena in bacterial endocarditis. Histopathology has confirmed the presence of septic microemboli within these lesions, underscoring their diagnostic value.[32]

Oropharyngeal

Lemierre syndrome is an acute oropharyngeal infection caused by Fusobacterium necrophorum, characterized by secondary septic thrombophlebitis of the internal jugular vein. First described in 1936, this condition typically progresses from a peritonsillar suppurative infection to local thrombophlebitis with subsequent hematogenous spread and distant septic emboli.[33] Septic emboli frequently involve the liver and lungs, often producing multiple abscesses.[33] One report also described extensive epidural abscess formation with neurological deficits, which was successfully treated using a combination of intravenous antibiotics and extensive hemilaminectomies for decompression, resulting in complete recovery without long-term sequelae.[34] Septic emboli have also been reported from infected radial artery catheters, manifesting as Janeway lesions and splinter hemorrhages.[35] Similarly, recurrent septic retinal emboli have been documented following dental procedures.[36]

Renal

Renal septic emboli can result in renal infarction or hemorrhage, potentially progressing to renal failure when a substantial portion of the parenchyma is involved. For example, a case of MRSA bacteremia in a patient with HIV was complicated by septic pulmonary embolism, right renal abscess, and ipsilateral renal vein thrombosis.[37]

Evaluation

The evaluation of septic emboli requires a comprehensive approach that integrates clinical suspicion with targeted diagnostic studies. Assessment typically involves a combination of blood cultures, advanced imaging modalities, and echocardiography, guided by the suspected source of infection and the vascular territories involved.

Laboratory Evaluation

Laboratory evaluation of septic emboli begins with blood cultures, essential for identifying the causative pathogen and guiding antimicrobial therapy. Additional studies, including complete blood count, inflammatory markers (C-reactive protein, erythrocyte sedimentation rate, procalcitonin), and renal and hepatic function tests, help assess systemic involvement and monitor disease severity. Persistently positive blood cultures despite appropriate therapy raise concern for ongoing endovascular infection and embolic complications.

Imaging Studies

Vascular imaging, such as arterial and venous duplex studies, is essential for evaluating arterial emboli and venous thrombophlebitis. In one report, femoral occlusive septic emboli were successfully identified by point-of-care ultrasound following mitral valve replacement.[38] Echocardiography remains central to evaluating septic emboli, with transesophageal echocardiography (TEE) providing greater sensitivity than transthoracic echocardiography (TTE) for detecting valvular vegetations. TEE is particularly valuable for identifying small vegetations, abscesses, and prosthetic valve involvement, making it the preferred modality in suspected endocarditis.

Chest radiography often reveals nonspecific abnormalities in cases of septic pulmonary emboli. A contrast-enhanced CT chest is the diagnostic modality of choice, demonstrating characteristic findings of multiple peripheral nodular infiltrates, with or without cavitation. If intravenous contrast cannot be administered, a ventilation/perfusion scan may aid in diagnosis. Ultrasound can detect hypoechoic lesions in the spleen and kidneys, while abdominal CT is recommended for all patients, given the high frequency of splenic septic emboli in endocarditis.[39]

MRI with and without gadolinium is preferred for diagnosing septic cerebral emboli. Advanced imaging techniques such as 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT have demonstrated high diagnostic value for detecting peripheral emboli in patients with infective endocarditis and cardiac device infections, significantly impacting treatment strategies. However, PET/CT has limited sensitivity for intracranial lesions, where CT angiography or MRI remains mandatory.[40] Furthermore, using white blood cell single photon emission CT and 18F-FDG PET/CT allows for the early detection of septic emboli across various sites.[41]

Treatment / Management

Source control and prolonged antibiotic therapy remain the cornerstones of managing septic emboli. The causative pathogen, embolization site, and drug pharmacokinetic and pharmacodynamic properties should guide the selection of antibiotics. Management strategies also vary according to the location of the embolus and the extent of the associated infarction or inflammatory process. 

Guidelines for the treatment of infective endocarditis and associated septic emboli recommend 4 to 6 weeks of intravenous antimicrobial therapy. The choice of appropriate agents should be guided by established references, including the American Heart Association Scientific Statement on Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications.[42] Additional recommendations can be found in the JCS 2017 Guidelines on the Prevention and Treatment of Infective Endocarditis.[43](B3)

Anticoagulation Role

Anticoagulation remains a controversial aspect of managing infective endocarditis and septic emboli. Current evidence supports the continuation of anticoagulation in patients with established preexisting indications, particularly in cases of left-sided endocarditis, provided no contraindications are present.[44]

Interventions

Patients with infective endocarditis who present with acute symptoms are at increased risk for septic complications and in-hospital mortality. Early surgical intervention, performed within the first 2 days of diagnosis, has been shown to play a pivotal role in improving outcomes. Endovascular management of acute ischemic stroke secondary to septic emboli from bacterial endocarditis remains case-specific and is not addressed within established guidelines. Scharf et al described managing 3 such cases across 2 different centers, highlighting the variability in therapeutic approaches.[45] While endovascular therapy may be effective for select patients with acute septic emboli or mycotic aneurysms, current evidence remains limited and derived mainly from case reports and small series.[46] (B3)

Management of embolic splenic abscesses usually involves surgical splenectomy or image-guided drainage; however, the natural history of untreated splenic abscesses remains unclear. Notably, Alnasser et al reported the successful conservative management of a large, complex splenic abscess with antibiotic therapy alone in a patient with aortic valve infective endocarditis.[29] Cardiac implantable electronic device  infections are managed primarily with transvenous lead extraction. This intervention carries an associated stroke risk of approximately 1.9%.[47] Mycotic aneurysms of the superior mesenteric artery have been successfully managed with surgical resection of the aneurysm, removal of associated mycotic thrombi, and concurrent infected valve replacement.[28](B3)

Differential Diagnosis

The differential diagnosis of septic emboli is broad, as its clinical manifestations often mimic other vascular, infectious, and inflammatory conditions. Careful evaluation is required to distinguish septic emboli from noninfective embolic and thrombotic events, as management strategies differ significantly. The differential diagnosis includes the following:

• Marantic endocarditis (nonbacterial thrombotic endocarditis) and Libman-Sacks endocarditis are noninfectious conditions, typically associated with malignancy and collagen vascular diseases. These entities should be considered in patients with culture-negative endocarditis and elevated inflammatory markers. 
• Metastatic disease and tumor embolism require a high index of suspicion and a careful evaluation of the patient's history of underlying malignancy.
• Disseminated fungal and mycobacterial infections can produce multiorgan involvement that mimics septic emboli. Examples include disseminated histoplasmosis and blastomycosis in endemic regions, diagnosed through microbiologic modalities such as tissue biopsy, cultures, antigen detection, and polymerase chain reaction testing. Additionally, disseminated nontuberculous mycobacterial infections and miliary tuberculosis should be considered in immunosuppressed patients, such as patients with HIV infections or receiving immunosuppressive or immunomodulator therapy. 
• Noninfectious thromboembolic events, particularly in patients with atrial fibrillation not receiving anticoagulation or with other arrhythmias, are an important consideration.
• Fat embolism also merits consideration following orthopedic trauma or surgical procedures.

Prognosis

The prognosis of septic emboli varies significantly, from asymptomatic cases to severe disease, depending on the organs involved and the combined effects of ischemic and infectious insults. In a large prospective observational study on infective endocarditis, Habib et al reported in-hospital mortality of 17.1% (532 patients), with higher rates observed in prosthetic valve infectious endocarditis. Independent predictors of mortality include the Charlson comorbidity index, serum creatinine greater than 2 mg/dL, congestive heart failure, vegetation length over 10 mm, cerebral complications, abscess formation, and failure to undertake surgery when indicated.[48]

Complications

Septic emboli may affect multiple organs throughout the body. The complications are primarily determined by the size of the embolus and the organ system involved. In the central nervous system, septic cerebral emboli may lead to ischemic strokes through vascular occlusion, or to brain abscess formation, producing variable neurological deficits depending on the site and extent of injury. They are also recognized as a risk factor for hemorrhagic transformation following thrombolysis.[49] In addition, intracranial mycotic aneurysms, though relatively rare, account for fewer than 10% of neurologic complications associated with infective endocarditis.

Mycotic aneurysms (infected arterial aneurysms) are misnamed, as fungi rarely cause them and are most often of bacterial origin. They represent focal dilation of an infected arterial wall and commonly arise when septic emboli invade the vasa vasorum.[50] The observation that veins, despite having a denser vasa vasorum, do not develop mycotic aneurysms further supports the role of septic emboli in their pathogenesis. Potentially infected emboli are often filtered by the capillary beds of large organs such as the lungs, liver, and spleen.[51] Infected (mycotic) aneurysms result from hematogenous dissemination of septic emboli and occur more frequently in patients with cardiac valvular abnormalities or prosthetic valves and intravenous drug abuse. Their natural history is variable, as they may undergo spontaneous thrombosis, size reduction, rapid enlargement, or rupture.[52]

Complications of septic splenic emboli include splenic abscess and splenic infarction, which may present as severe abdominal pain or hemorrhage and can necessitate urgent surgical intervention. Septic renal emboli can cause renal infarction. In severe cases, they may progress to renal abscess formation or renal failure, particularly when a large portion of the parenchyma is compromised. Complications of septic pulmonary emboli vary with the severity and extent of pulmonary parenchyma involvement, ranging from asymptomatic nodular lesions on imaging to severe dyspnea and hypoxemic respiratory failure. Long-term sequelae may include persistent cavitary lung lesions. Additionally, pneumothorax has been reported as a complication, such as in a case of MRSA bacteremia, occurring 10 days after initiation of treatment.[53]