Background

Cardiobacterium spp. are fastidious, pleomorphic Gram-negative bacilli that belong to the HACEK (Haemophilus spp., Aggregatibacter spp., Cardiobacterium spp., Eikenella corrodens, and Kingella spp.) group of microorganisms, a group of bacteria that share similar microbiological and clinical characteristics. Species within this group have been reported to be responsible for 0.8–6.0% of all infective endocarditis cases [1]. Although an uncommon cause of endocarditis overall, Cardiobacterium spp. are the third most common HACEK microorganism implicated in HACEK endocarditis [1]. Few reports of extra-cardiac Cardiobacterium spp. infection have been described [2, 3], and there are no known reports of the C. valvarum species being implicated in osteomyelitis.

Herein, we report a case of C. valvarum aortic endograft infection, which was further complicated by vertebral discitis, epidural phlegmon, septic cerebral emboli, and the first known case of C. valvarum osteomyelitis. A review of the English-language literature follows the case presentation.

Case presentation

In June 2020, a 57-year-old man was directly admitted to the hospital for radiologic evidence of vertebral osteomyelitis, discitis, and epidural phlegmon. He had a history of hypertension, hyperlipidemia, prediabetes, chronic kidney disease, and an acute Stanford Type A and Type B aortic dissection. His Type A aortic dissection (defined as involvement of the ascending aorta) had led to an emergent resection and replacement of the ascending aorta and proximal arch with a Dacron endograft nine years prior to his current presentation. Subsequent progression of an associated aortic arch aneurysm required surgical revision with a Dacron endograft exchange five years after initial surgical repair. His Type B dissection (defined as being limited to the aorta distal to the left subclavian artery without involvement of the ascending aorta) extended from the proximal aortic arch to the aortic bifurcation and remained untreated, though partially thrombosed. He had no other recent surgical instrumentation and his last dental procedure was ~ 24 months prior to his current presentation. Medications included amlodipine, aspirin, atorvastatin, carvedilol, ezetimibe, and lisinopril. He used alcohol socially and had never used tobacco or illicit drugs.

The patient had been well until ~ 6 weeks prior when isolated lower back pain developed. At that time, an outpatient non-contrast-enhanced magnetic resonance imaging (MRI) of the lumbar spine demonstrated significant edema within the vertebral bodies adjacent to the L4–L5 intervertebral disc space. Given his absence of systemic symptoms, short-term follow-up was advised. Two weeks later, a repeat contrast-enhanced MRI of the lumbar spine demonstrated progressive T2 hyperintensity at the L4–L5 intervertebral disc space and adjacent endplates with near complete involvement of the L3 and L4 vertebral bodies, highly suggestive of vertebral osteomyelitis and discitis (Fig. 1a). In addition, there was a 6 mm thick anterior epidural thickening and enhancement suggestive of epidural phlegmon that extended to L3 superiorly, S1 inferiorly, and the posterior wall of the known abdominal aortic aneurysm anteriorly (Fig. 1b). He was admitted for further workup and management.

Fig. 1
figure 1

Magnetic resonance imaging (MRI) of the lumbar spine demonstrating discitis and vertebral osteomyelitis. T1 post-contrast sagittal MRI demonstrating enhancement at the L3–4 intervertebral disc space with erosions in the adjacent endplates (arrow)

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On admission, a temperature of 37.2 °C, heart rate of 74 beats per min, blood pressure of 129/67 mm Hg, and body-mass index of 32.7 were observed. On examination, there were multiple dental amalgam fillings and a 3/6 systolic murmur best appreciated in the aortic region, which was stable from prior. The remainder of the examination, including a focused neurologic, musculoskeletal, and dermatologic assessment, was normal. Basic laboratory tests were remarkable for anemia of inflammation, a C-reactive protein of 1.6 mg/dL (reference range, 0.0–0.5 mg/dL), an erythrocyte sedimentation rate of 53 mm/h (reference range, 3–10 mm/h), and the absence of leukocytosis. Aerobic and anaerobic peripheral blood cultures were obtained, and empiric vancomycin 1 g intravenously every 12 h and cefepime 2 g intravenously every 12 h were administered due to the proximity of the epidural phlegmon to the posterior wall of the known abdominal aortic aneurysm.

A series of diagnostic tests were subsequently performed. Computed tomography (CT) angiography of the thoracic aorta showed a soft tissue density located on the ascending aortic endograft, favored to be infectious in etiology. Transesophageal echocardiogram showed previously noted strand-like mobile echodensities on the right coronary cusp of the aortic valve, favored to represent Lambl’s excrescences (defined as thin, fibrinous structures at the lines of valve closure and postulated to be related to shear forces to the endothelium) [4]. There were no other valvular abnormalities or signs of valvular insufficiency. Contrast-enhanced CT of the face showed no evidence of dental disease. Fluoroscopy-guided bone biopsy of the L4 vertebral body obtained on day 3 of admission showed changes suggestive of resolving osteomyelitis. On day 4 of admission, 2 of 2 bottles on both sets of initial peripheral blood cultures signaled positive at 96 h of incubation. Macroscopically, colonies were described as irregular, small, round, and opaque in color. Nevertheless, due to poor growth secondary to the fastidious nature of the organism, susceptibilities were unable to be performed. Bipolar-staining pleomorphic Gram-negative rod-shaped bacilli were seen on microscopy (Fig. 2). 16S ribosomal RNA sequencing analysis subsequently identified C. valvarum (see Appendix 1 for further information regarding methods). Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry for further identification was not performed. Aerobic and anaerobic vertebral biopsy cultures remained negative and 16S ribosomal RNA sequencing was unfortunately not performed on these specimens. Though not definitively documented in the bone, C. valvarum identified in the blood was presumed to be the cause of the focal lesion as well.

Fig. 2
figure 2

Gram staining. Microscopic morphology in gram staining of blood culture after 96 h of aerobic incubation at 37 °C demonstrating bipolar-staining gram-negative bacilli. 16S ribosomal RNA (rRNA) sequencing subsequently identified the organism as Cardiobacterium valvarum

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Antimicrobial therapy was changed to ceftriaxone 2 g intravenously daily and prescribed for a 6-week course. Given radiologic evidence of a possible aortic endograft nidus, a vascular surgery evaluation was obtained. Surgical intervention was ultimately deferred due to the high likelihood of extensive endograft involvement and the technical difficulty posed by the patient’s complex surgical history. The patient was discharged home on day 9 of admission with multidisciplinary follow-up and outpatient antimicrobial therapy.

Twenty days later, the patient was readmitted for acute headache and blurry vision in the left eye. MRI of the brain at that time showed a moderate-sized acute and subacute right posterior cerebral artery (PCA) territory infarct of the right occipital and posterior temporal lobes with a small focus of associated hemorrhagic transformation. Magnetic resonance angiography of the brain subsequently showed poor flow-related signal of the right PCA P3/P4 segment with a paucity of vessels in the right occipital lobe suspicious for occlusion. Monitoring of the bilateral PCAs with a 2-MHz transcranial doppler ultrasound showed nine microembolic signals within the right PCA, suspicious for septic emboli. No neurosurgical intervention was pursued, initial antithrombotic therapy was held, and repeat peripheral blood cultures were negative. Positron emission tomography–computed tomography (PET/CT) was then obtained to better characterize the aortic endograft, which showed hypermetabolic soft tissue along the right lateral and anterior aspect of the ascending aortic graft, once again suspicious for endograft infection (Fig. 3). Surgical intervention was again deferred, and the patient was discharged home on hospital day 7. He was continued on ceftriaxone 2 g intravenously daily with the addition of clopidogrel 75 mg daily and levetiracetam 1 g twice daily. He remains well in multidisciplinary outpatient follow-up with marked improvement in his back pain and no further complication. He will remain on lifelong suppressive antimicrobial therapy following his initial treatment course.

Fig. 3
figure 3

Positron emission tomography–computed tomography (PET/CT) of the chest. Hypermetabolic soft tissue (arrows) along the right lateral and anterior aspect of the ascending aortic endograft with a maximum standardized uptake value of 9.4, suspicious for aortic endograft infection

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Discussion

The Cardiobacterium genus was first described in 1964 when its major and prior sole species, C. hominis, was recognized as a distinct microorganism by Slotnick and Dougherty [5]. C. hominis itself is a low-virulence, commensal and facultative Gram-negative bacillus that typically manifests in patients with subacute endocarditis. Historically, its microbiologic detection has been challenging due to its fastidious nature and slow-growth on traditional media.

In 2004, a novel Cardiobacterium species designated C. valvarum was isolated from the blood of a 37-year-old man with subacute endocarditis of a congenital bicuspid aortic valve and sudden rupture of a cerebral aneurysm [6]. In comparison to the major C. hominis species, C. valvarum grows more slowly, is non-hemolytic on sheep blood agar, and does not utilize sucrose, maltose, or mannitol on traditional media [6]. Since its initial recognition, there have been 15 total cases of C. valvarum infection reported in the English-language literature, all of which have utilized 16S ribosomal RNA sequencing as a means of detection [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23]. Table 1 provides an overview of these cases. In the overwhelming majority, clinical presentations are insidious and without apparent signs of a systemic inflammatory response, such as pyrexia or chills [6, 7, 12,13,14,15,16]. Factors that appear to predispose patients to infection with C. valvarum include recent dental instrumentation [6, 10, 15, 16], poor dentition [9, 15, 18], and congenital cardiac disease [6, 8,9,10, 12, 13, 15,16,17, 19]. Importantly, the presence of a congenital bicuspid aortic valve appears to be strongly associated with C. valvarum pathogenicity [6, 8, 9, 13, 16, 19]. Common imaging findings in infected hosts typically include large (> 1 cm) valvular vegetations on echocardiography [6,7,8,9, 12, 16, 18, 20], and, in settings where acute neurologic dysfunction is evident, septic cerebral emboli resulting in cerebrovascular accident [6,7,8, 12,13,14, 18].

Table 1 Existing case reports documenting infection by Cardiobacterium valvarum
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In the present case, C. valvarum bacteremia was suspected to have caused an endograft infection, later spreading to the bone. The presumed source of C. valvarum was the oral cavity given that the patient had undergone at least one dental procedure in the interim between his aortic arch surgical revision and the onset of lower back pain. While it is unclear if the patient was ever prescribed prophylactic antibiotic therapy prior to any known dental procedure, one possibility is that transient bacteremia resulting from one of these procedures seeded the aortic Dacron endograft. Transient bacteremia may also have resulted from manipulation associated with toothbrushing. The endograft may have then served as a nidus for recurrent episodes of transient bacteremia, leading to lumbar spine infection with subsequent development of osteomyelitis and contiguous spread into the epidural and intervertebral disc spaces. It should be noted that a single report of C. valvarum aortic endograft infection confirmed by 16S ribosomal RNA sequence analysis has been previously described in a 53-year-old man with total aortic arch replacement and severe aortic regurgitation in Japan [14]. Likewise, a Cardiobacterium spp (C. hominis) causing vertebral osteomyelitis, discitis, and epidural abscess has also been described [21]. To our knowledge, the present case describes the first known case of C. valvarum both affecting an aortic endograft and resulting in osteomyelitis. It should be noted that, in our case, vertebral bone biopsy cultures did not grow any organisms, although the C. valvarum identified in the blood was presumed to be the cause of the osteomyelitis as well.

In any patient with confirmed Cardiobacterium spp. infection, careful evaluation for the presence of infective endocarditis is mandatory given the high likelihood of cardiac involvement. In contrast to the majority of cases shown in Table 1 that met modified Duke criteria for “Definite” infective endocarditis, the present case was designated as “Possible” infective endocarditis by only meeting one major clinical criterion (blood cultures with a typical infective endocarditis microorganism) and two minor clinical criteria (predisposing cardiac condition and vascular phenomena) [22]. Notably, there was no echocardiographic evidence of endocardial or valvular involvement on both transthoracic and transesophageal studies. While mobile strand-like echodensities were noted on aortic valve imaging, these were favored to represent Lambl’s excrescences [4] and had been noted on previous echocardiographic examinations that predated his aortic dissection. Therefore, though rare, it appears that C. valvarum has the potential for pathogenicity in the absence of cardiac involvement.

Antimicrobial therapy is the cornerstone of management for all C. valvarum infections, and surgical consultation is warranted in cases with an obvious radiologic and/or echocardiographic nidus. The standard antimicrobial therapy for HACEK group microorganisms in existing guidelines is ceftriaxone 2 g intravenously daily for 4 weeks [23], and most reports have successfully utilized this regimen [10, 13, 15,16,17, 19]. The empiric choice of antimicrobial therapy has varied in published cases (Table 1), which is likely explained by local patterns of resistance, country-specific practices, and the presence or absence of embolic disease. Given the rarity of extra-cardiac manifestations, no guidelines dictate treatment of C. valvarum infection in this setting. Overall, C. valvarum appears to be susceptible to most antibiotics, with low minimum inhibitory concentrations to penicillins, cephalosporins, fluoroquinolones, and aminoglycosides [6,7,8, 10, 12].

Conclusions

We report a case of C. valvarum-associated aortic endograft infection, which was further complicated by vertebral discitis, epidural phlegmon, septic cerebral emboli, and the first known case of C. valvarum osteomyelitis. C. valvarum is a rare and emerging HACEK group microorganism that warrants consideration in high-risk patients with evidence of subacute infection and disseminated disease. Most cases have successfully been treated with a third-generation cephalosporin. Source control may not be feasible in cases with complex anatomy and disseminated spread.