Abstract
Background
Prosthetic valve endocarditis (PVE) remains challenging to diagnose and is associated with poor long-term outcomes, particularly when blood cultures are negative.
Case Summary
We describe recurrent culture-negative PVE diagnosed using multimodality imaging and tissue molecular diagnostics. A 50-year-old man with prior bioprosthetic aortic and mitral valve replacement, transcatheter mitral valve-in-valve implantation, and an atrial septal occluder presented with acute limb ischemia due to embolization. Blood cultures were negative, and transesophageal echocardiography and cardiac computed tomography favored thrombus over vegetation. Fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) demonstrated abnormal tracer uptake involving both prosthetic valves and septal occluder, consistent with infection. The patient underwent redo mechanical aortic and mitral valve replacement with device explantation. Pathology confirmed endocarditis, and tissue polymerase chain reaction identified Streptococcus sanguinis.
Discussion
This case highlights the diagnostic value of FDG PET-CT in recurrent culture-negative PVE.
Take-Home Messages
FDG PET-CT and molecular diagnostics aid in the diagnosis of culture-negative prosthetic and device-related endocarditis. Longitudinal surveillance is important in patients with multiple intracardiac prostheses.
Key words: device-related infection, FDG PET-CT, multivalve endocarditis, prosthetic valve endocarditis, transcatheter valve interventions
Visual Summary
Visual Summary.
Chronology and Diagnostic Pathway of Recurrent Culture-Negative Multivalve and Device-Related Prosthetic Valve Endocarditis
Timeline illustrating the longitudinal course, diagnostic evaluation, and management of recurrent culture-negative prosthetic and device-related infective endocarditis. At 40 years of age, the patient underwent surgical bioprosthetic aortic and mitral valve replacement (MVR) for infective endocarditis. At 48 years of age, progressive prosthetic mitral stenosis was treated with transcatheter mitral valve-in-valve replacement, complicated by an iatrogenic atrial septal defect (ASD) requiring closure with an atrial septal occluder device. At 50 years of age, the patient presented with systemic embolization, including renal infarction and acute bilateral limb ischemia, raising suspicion for recurrent prosthetic valve endocarditis in the setting of persistently negative blood cultures and indeterminate echocardiography. Fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) demonstrated abnormal uptake involving multiple prosthetic valves and intracardiac devices, establishing the diagnosis of culture-negative multivalve and device-related infective endocarditis (IE) and directly prompting definitive surgical management. The patient underwent redo sternotomy with mechanical aortic and MVR and explantation of the atrial septal occluder, achieving durable source control. Created in BioRender, Dreher L, 2026, https://BioRender.com/gsn72c9. AVR = aortic valve replacement; TMVR = transcatheter mitral valve replacement.
History of presentation
A 50-year-old man with prior aortic and mitral prosthetic valves and paroxysmal atrial fibrillation presented with sudden-onset bilateral leg pain and paresthesias. He had been in his usual state of health until several days prior, when he developed progressive lower-extremity discomfort and fatigue. He was afebrile (temperature 36.8 °C) with a heart rate of 92 beats/min, a blood pressure of 118/64 mm Hg, and an oxygen saturation of 97% on room air. Physical examination revealed cool, pale lower extremities with absent distal pulses bilaterally. Cardiac auscultation revealed regular rate and rhythm, a soft systolic murmur without new diastolic murmur, and there were no peripheral stigmata of endocarditis. The presentation of acute bilateral limb ischemia with a history of paroxysmal atrial fibrillation and prosthetic valves raised immediate concern for the potential cardioembolic process.
Past medical history
He had a history of infective endocarditis approximately 10 years prior (at age 40 years), treated with bioprosthetic aortic and mitral valve replacement. In the same year, he sustained a traumatic subdural hematoma from a fall requiring craniotomy. Approximately 8 years later (at age 48 years), he developed severe prosthetic mitral stenosis and underwent valve-in-valve transcatheter mitral replacement, complicated by an iatrogenic atrial septal defect closed with an Amplatzer occluder. He had recurrent atrial fibrillation/flutter requiring cardioversion and amiodarone therapy and was on long-term fluconazole for coccidioidomycosis pneumonia.
Approximately 10 years after the first episode of infective endocarditis, he presented with severe left lower abdominal pain with a new left renal infarct identified by computed tomography (CT) abdomen. These findings were consistent with systemic embolization, raising concern for recurrent prosthetic valve endocarditis (PVE). Blood cultures grew Streptococcus sanguinis and transesophageal echocardiogram (TEE) revealed multiple independently mobile echodensities attached to the prosthetic mitral valve leaflets consistent with valvular vegetations. The patient was treated for PVE with intravenous ceftriaxone for 6 weeks. TEE after antibiotic treatment showed resolution of vegetations, and repeat blood cultures remained negative.
Differential diagnosis
At presentation, differential included a thromboembolic event related to paroxysmal atrial fibrillation, a hypercoagulable condition, prosthetic valve thrombosis, sterile thrombus formation on the atrial septal occluder device, recurrent PVE, or culture-negative prosthetic endocarditis.
Investigations
Laboratory evaluation showed normal white blood cell count, subtherapeutic international normalized ratio (INR) 1.1 (goal INR 2-3 with paroxysmal atrial fibrillation and bioprosthetic aortic and mitral valves), and mildly elevated creatinine. Electrocardiography demonstrated atrial fibrillation with rapid ventricular response.
A CT angiogram of the lower extremities demonstrated occlusions of the right common femoral, superficial femoral, and profunda arteries and of the left external iliac and common femoral arteries. Doppler ankle-brachial indices were severely reduced (right 0.23, left 0.30), confirming critical ischemia.
TEE revealed diffuse thickening and immobility of the posterolateral mitral prosthetic leaflet with a mean transmitral gradient of 4 mm Hg (heart rate: 63 beats/min) and trivial regurgitation (Figure 1). Multiple echodensities were seen on the aortic and ventricular sides of the aortic prosthesis, particularly at the left coronary cusp, concerning for thrombus or vegetation (Figure 2). The prosthetic aortic valve leaflets were thickened with restricted motion and a significant increase in the mean transaortic gradient (41 mm Hg compared with 20 mm Hg on prior TEE), suggestive of new prosthetic obstruction. The atrial septal occluder showed focal thickening on the inferior left atrial aspect consistent with a small mass-like echodensity, suspicious for thrombus or vegetation (Figure 3).
Figure 1.
TEE Demonstrating Thickened Posterolateral Leaflet of the Mitral Prosthesis
TEE showing diffuse thickening of the posterolateral leaflet of the prosthetic mitral valve (red arrows). These findings were concerning for prosthetic leaflet pathology in the setting of recurrent culture-negative prosthetic valve endocarditis. Color Doppler (bottom right) demonstrates no evidence of significant regurgitation. See Video 1. TEE = transesophageal echocardiography.
Figure 2.
TEE Showing Thickened Leaflets and Mass-Like Echodensity on the Prosthetic Aortic Valve
TEE demonstrating marked thickening of the prosthetic aortic valve leaflets with restricted systolic excursion (red arrows). A focal mass-like echodensity is visualized along the left coronary cusp, raising concern for thrombus vs vegetation. Color Doppler imaging provided at the bottom right. See Video 2. TEE = transesophageal echocardiography.
Figure 3.
TEE Demonstrating Focal Thickening of the Amplatzer Atrial Septal Occluder Consistent With Thrombus or Vegetation
TEE image showing focal thickening and a small mass-like echodensity on the atrial septal occluder (red arrow). Findings were suspicious for device-related thrombus or vegetation in the setting of recurrent prosthetic and device-associated infection. Corresponding color Doppler demonstrates normal shunt closure without residual flow. See Video 3. TEE = transesophageal echocardiography.
Bacterial, fungal, and mycobacterium blood cultures were negative. The work-up for culture-negative endocarditis etiologies was negative, including Brucella IgG and IgM, Coxiella burnetii polymerase chain reaction (PCR), Q Fever Ab, and Tropheryma whipplei PCR. The work-up for antiphospholipid syndrome was negative, including β2-glycoprotein IgG and IgM, phospholipid (cardiolipin) antibodies IgG and IgM, and lupus anticoagulant.
Given indeterminate echocardiographic findings and persistently negative blood cultures, whole-body fluorodeoxyglucose (FDG) positron emission tomography-CT (PET-CT) was performed and demonstrated hypermetabolic foci surrounding the prosthetic aortic valve (maximum standardized uptake value [SUVmax] 6.0), mitral prosthesis (SUVmax 3.1), and left atrial appendage clip (SUVmax 7.3), confirming prosthetic/device-related infection. Mediastinal lymphadenopathy (SUVmax 6.8-7.3) was presumed reactive, and a left upper-lobe pulmonary nodule showed mild uptake (SUVmax 3.6), possibly infectious (Figure 4). The PET-CT findings fulfilled a major imaging criterion under the modified Duke criteria and aligned with Class I, Level of Evidence: B recommendations in the 2023 European Society of Cardiology (ESC) guidelines for the diagnosis of PVE and directly informed the multidisciplinary decision to proceed with definitive surgical management.
Figure 4.
FDG PET-CT Demonstrating Multivalve and Device-Related Prosthetic Infection
FDG PET-CT showing abnormal radiotracer uptake involving multiple intracardiac prostheses, exceeding mediastinal and hepatic reference activity. These findings fulfill a major imaging criterion for prosthetic valve endocarditis according to the 2023 European Society of Cardiology guidelines. Left column: attenuation-corrected CT, middle column: fused PET-CT, and right column: non–attenuation-corrected PET images. (A) Intense FDG uptake surrounding the prosthetic aortic valve (SUVmax 6.0) and lesser uptake around the mitral prosthesis (SUVmax 3.1). (B) Focal FDG uptake surrounding the mitral prosthetic valve (SUVmax 3.1). (C) Marked FDG uptake along the length of the left atrial appendage clip (SUVmax 7.3). FDG = fluorodeoxyglucose; PET-CT = positron emission tomography-computed tomography; SUVmax = maximum standardized uptake value.
Management
He was treated empirically with intravenous ceftriaxone, vancomycin, and doxycycline while continuing therapeutic warfarin. On hospital day 5, he underwent bilateral iliofemoral thromboembolectomy with vein patch angioplasty for critical limb ischemia.
Given recurrent peripheral embolization and PET-CT imaging evidence of prosthetic valve and device infection, the multidisciplinary team recommended cardiac surgery intervention. Patient subsequently underwent high-risk redo sternotomy. Operative findings included vegetations on the Amplatzer device and the mitral annulus. There were dense adhesions and inflamed tissue requiring lysis, which contributed to the complexity of procedure and prolonged cardiopulmonary bypass times. Mechanical aortic and mitral valve replacement was performed, along with removal of the atrial septal occluder and patch closure of the atrial septal defect.
Pathologic examination of all explanted prostheses revealed acute inflammation, fibrin deposition, and granulation tissue consistent with active and healing endocarditis (Figure 5). Intraoperative cultures were negative, but broad-range bacterial PCR and sequencing identified S sanguinis, confirming the microbiologic diagnosis.
Figure 5.
Histopathology of Explanted Prosthetic Valve Tissue Demonstrating Acute Inflammation and Healing Endocarditis
Histopathology (H&E stain) of explanted prosthetic valve tissue showing fibrin deposition, granulation tissue, and dense mixed inflammatory infiltrate consistent with active and healing infective endocarditis. High-power magnification (lower inset) highlights neutrophilic inflammation and tissue destruction. Special stain (upper inset) demonstrates organisms embedded within extracellular matrix material, correlating with broad-range polymerase chain reaction identification of Streptococcus sanguinis despite negative cultures.
Outcome and follow-up
The patient recovered uneventfully. Dobutamine was weaned by postoperative day 3. Recurrent atrial fibrillation/flutter with rapid ventricular response was managed with intravenous followed by oral amiodarone. Anticoagulation was transitioned from heparin to warfarin (goal INR 2.5-3.5). He completed a 6-week course of intravenous ceftriaxone and daptomycin via a peripherally inserted central catheter.
At follow-up, TEE demonstrated well-seated mechanical aortic and mitral prostheses with mean gradients of 4 mm Hg and no periprosthetic regurgitation. The left ventricular ejection fraction was 50% to 55% with mild right ventricular dysfunction. He underwent successful electrical cardioversion for atrial flutter and remained asymptomatic and functionally active without recurrence of infection. At 6-month follow-up, he remained in sinus rhythm with therapeutic anticoagulation and no evidence of reinfection or recurrent embolization.
Discussion
PVE accounts for approximately 20% of all infective endocarditis and is associated with disproportionately high morbidity and mortality compared with native valve disease.1 Diagnosis is often challenging because of intermittently negative blood cultures, acoustic shadowing from prosthetic material, and nonspecific findings on echocardiography or CT.2,3
In this patient, FDG PET-CT was pivotal in confirming prosthetic and device-related infection. The scan demonstrated increased FDG uptake around the aortic and mitral prostheses, as well as along the left atrial appendage clip and Amplatzer occluder, with SUV values exceeding both mediastinal and hepatic reference activity. Mild FDG uptake within a pulmonary nodule further supported septic embolization. According to the 2023 ESC endocarditis guidelines, PET-CT carries a Class I, Level of Evidence: B recommendation for suspected PVE when echocardiographic findings are inconclusive.1
Given the persistent embolic events and imaging evidence of infection, the decision to proceed with high-risk redo multivalve surgery was consistent with both ESC and American Heart Association/American College of Cardiology guidelines, which recommend surgical intervention for recurrent embolization with vegetation >10 mm despite appropriate antimicrobial therapy (Class I).1,4 Intraoperative findings confirmed vegetations and extensive adhesions requiring prolonged cardiopulmonary bypass and cross-clamp times. Pathology revealed active and healing endocarditis, and broad-range PCR confirmed S sanguinis despite negative intraoperative cultures.
Observations from large registry series demonstrate that redo surgery for multivalve PVE carries operative mortality rates of 15% to 20% or higher.5 Nonetheless, surgical treatment remains the only definitive therapy for source control and was crucial for this patient's recovery. The favorable outcome underscores the importance of multidisciplinary coordination among cardiology, cardiothoracic surgery, infectious diseases, and vascular teams in managing such complex cases.
This case also illustrates that recurrent PVE may present without fever, with negative cultures, and with subtle imaging findings, emphasizing the need for ongoing vigilance in patients with prosthetic material. The chronic risk of infection is thought to be driven by biofilm formation, wherein bacteria adopt dormant phenotypes within an extracellular matrix that shields them from antimicrobial therapy and host immune responses.6 This mechanism likely contributed to persistent infection despite prolonged antibiotic exposure.
Finally, this case raises broader implications for transcatheter valve and intracardiac device infections. Although registry data suggest that early postimplant mortality for transcatheter valve endocarditis is relatively low (around 10% at 1 year), long-term reinfection and late complication rates remain uncertain.7, 8, 9 Device-associated infections are uncommon but can be devastating, often requiring surgical explantation for durable cure. As transcatheter and device-based structural interventions become increasingly prevalent, clinicians should maintain longitudinal surveillance for infection, even in patients with negative cultures, especially when multiple prosthetic materials coexist.7, 8, 9
Conclusions
In summary, this case highlights the diagnostic complexity and clinical consequences of recurrent culture-negative PVE in the setting of multiple intracardiac prostheses. Consistent with current guideline recommendations, FDG PET-CT proved decisive when conventional imaging and blood cultures were inconclusive, enabling timely recognition of prosthetic and device-related infection and informing definitive management. The accumulation of prosthetic material after surgical and transcatheter interventions may predispose to delayed, atypical presentations of endocarditis driven by biofilm-associated infection. In such cases, multidisciplinary evaluation and complete surgical source control remain essential for durable cure. As transcatheter valve and device-based therapies continue to expand, heightened vigilance and longitudinal surveillance are increasingly important to mitigate the risk of late infectious complications.
Funding Support and Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Take-Home Messages
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Multimodality imaging, particularly fluorodeoxyglucose positron emission tomography-computed tomography, combined with molecular diagnostics such as tissue polymerase chain reaction, is essential for diagnosing culture-negative prosthetic and device-related endocarditis.
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Patients with multiple intracardiac prostheses after transcatheter valve and device interventions require longitudinal surveillance and thoughtful risk stratification to detect late infectious complications.
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Complete surgical removal of infected prosthetic material remains the cornerstone of durable cure in recurrent prosthetic valve endocarditis with embolic manifestations.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
Appendix
For supplemental videos, please see the online version of this paper.
Appendix
Live TEE of the Prosthetic Mitral Valve
Real-time TEE clip demonstrating thickening and restricted motion of the posterolateral leaflet of the prosthetic mitral valve. TEE = transesophageal echocardiography.
Live TEE of the Prosthetic Aortic Valve
Real-time TEE clip showing thickened prosthetic aortic valve leaflets with restricted systolic excursion and a focal mass-like echodensity. TEE = transesophageal echocardiography.
Live TEE of the Amplatzer Atrial Septal Occluder
Real-time TEE clip demonstrating focal thickening and a small mass-like echodensity on the atrial septal occluder. TEE = transesophageal echocardiography.
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Associated Data
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Supplementary Materials
Live TEE of the Prosthetic Mitral Valve
Real-time TEE clip demonstrating thickening and restricted motion of the posterolateral leaflet of the prosthetic mitral valve. TEE = transesophageal echocardiography.
Live TEE of the Prosthetic Aortic Valve
Real-time TEE clip showing thickened prosthetic aortic valve leaflets with restricted systolic excursion and a focal mass-like echodensity. TEE = transesophageal echocardiography.
Live TEE of the Amplatzer Atrial Septal Occluder
Real-time TEE clip demonstrating focal thickening and a small mass-like echodensity on the atrial septal occluder. TEE = transesophageal echocardiography.