Infective endocarditis (IE) is a rare but serious infection affecting the endocardium, inevitably fatal without treatment. Its estimated incidence is 3–7.5 per 100,000 person-years, but in-hospital mortality rates reach 15–30% [1],[2],[3],[4]

Despite diagnostic and therapeutic refinements, reflected in the latest European and American guidelines, its management is still challenging and often individualized. Timely identification of high-risk patients is of paramount importance for it can change the course of disease, improving prognosis. These patients should be carefully assisted in experienced centers and opportunely considered for surgery [5],[6].

Factors to be considered on risk evaluation include patients’ characteristics (age, comorbidities, immune status), cardiac and extracardiac complications, echocardiographic findings, and the culprit infectious organism [5]. We report a case of G. adiacens endocarditis, a rare (eventually underestimated) cause of endocarditis, associated with a particularly unfavorable course and high mortality [7],[8].

Granulicatella spp. and Abiotrophia spp. are facultative anaerobic gram-positive cocci, members of oral, intestinal and urogenital flora. Since their identification as nutritionally variant Streptococci (NVS) they’ve experienced some taxonomical alterations until their current classification. Both genera cause circa 1–5% of all IE cases, but this percentage might be higher considering their difficult isolation: they are fastidious organisms requiring specific nutrients (L-cystein, pyridoxal) and supplemented culture media to grow. Despite being commensal bacteria, they are notoriously virulent agents both in immunocompromised and immunocompetent patients, with high rates of complications and surgical interventions (~50% [5]), mortality rates approaching 17% [8],[9],[10],[11].

Considering Granulicatella is a rare, yet poorly studied and difficult to diagnose organism, associated with poor outcomes, it should be actively remembered as a possible causal agent of IE. We report a case of Granulicatella IE, which emphasizes its role as a serious and possible underestimated cause of endocarditis.

A 55-year-old man was admitted with fever of undetermined origin (FUO). Previous medical history included depressive syndrome and an asymptomatic mild mitral regurgitation, with no other relevant echocardiographic findings. He denied any previous medications, other than antidepressants (sertraline). He had no drug allergies.

Epidemiological relevant data comprised living in a rural area, close contact to dogs and farm animals, and regular trekking activities.

He was asymptomatic until 12 weeks before attending our infectious diseases (ID) outpatient clinic. In this period, he reported asthenia, anorexia, and weight loss (6.5% of total body weight) and he went to a general practitioner, who admitted depressive syndrome reactive to a recent divorce and prescribed sertraline. Three weeks before going to the ID clinic he referred recurrent chills, and fever (once daily, maximum axillary temperature of 39°C). He was seen in a private hospital, where he did laboratory blood testing, a thoracic radiograph and an abdominal ultrasound: there were no abnormal imaging findings and blood tests revealed hemoglobin (Hb) 12 g/dL, C-reactive protein (CRP) 6.4 mg/dL, and sedimentation rate (SR) 30 mm/h (leukogram, platelets, ionogram, renal and hepatic panels were normal). He also did SARS-CoV-2 polymerase chain reaction (PCR), human immunodeficiency virus (HIV) serology, and a treponemal-specific test, all negative. For persistent fever, he was referred to our outpatient clinic and electively admitted for investigation.

On admission he referred mild dyspnoea on exertion during intense physical activities. He denied other new symptoms, previous antibiotic therapy, dental or surgical interventions.

On physical examination his tympanic temperature was 38.5°C, blood pressure 120/79 mmHg, pulse 120 bpm, oxygen saturation 99% (ambient air). There were no signs of peripheral oedema or hypoperfusion. His oral cavity and oropharynx had no identifiable lesions. A holosystolic murmur (3/6) was noted, best heard at the apex, with axillary radiation; discrete bilateral basal crackles were present. He had a non-tender palpable hepatosplenomegaly, with the remainder of the physical examination, including optic fundi, unremarkable. Laboratory tests revealed normocytic anemia Hb 11.7 g/dL, 293,000 platelets/μL, 13,400 leukocytes/μL (93% neutrophils), CRP 9.6 mg/dL, positive rheumatoid factor; albumin, troponin, ionogram, renal, hepatic, and coagulation tests were within normal limits. Urinalysis revealed microscopic hematuria, without signs of infection, urine culture was negative. Blood cultures were taken. Electrocardiogram (EKG) showed sinus tachycardia with a 1st degree atrioventricular (AV) block (already documented previously). Thoracic and abdominopelvic computed tomography (CT) scan confirmed hepatosplenomegaly and disclosed a small splenic infarction. Transthoracic echocardiogram (TTE) identified a posterior mitral leaflet vegetation; severe mitral regurgitation and flail of the posterior leaflet, with left atrium enlargement and an estimated pulmonary artery systolic pressure of 64 mmHg. Left ventricle and ejection fraction were unremarkable.

Infective endocarditis diagnosis complicated by valvular heart disease and embolic phenomena was assumed. Empiric antibiotic therapy with ceftriaxone 2g qd and gentamicin 3 mg/kg/d was initiated after 3 separate sets of blood cultures had been collected. A transoesophageal echocardiogram (TOE) was requested and the case discussed with cardiology and cardiothoracic surgery.

Two days after antibiotics initiation the patient remained hemodynamically stable and became afebrile, with significant improvement of inflammatory markers (CRP 2 mg/dL). All three paired blood samples came back positive within 48 hours, and direct gram smear revealed gram positive cocci in chains. Subcultures were performed on human blood and chocolate agar and bacterial colonies obtained. The isolate was identified as being G. adiacens using Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Complementary etiological investigation studies (Brucella spp., Rickettsia spp., Coxiella burnetii, Borrelia burgdorferi, Bartonella spp., Legionella spp.) were negative. Blood cultures collected 72 hours after antibiotic initiation were negative. Transoesophageal echocardiogram was done on D5 and confirmed the presence of an irregular and mobile 18 mm vegetation in the mitral posterior leaflet, associated with ruptured chordae. These findings were rediscussed within the multidisciplinary team and urgent surgical intervention was considered necessary. Preoperative coronary angiography had no alterations and a triangular resection mitral valve repair was successfully performed on D7 of antibiotic therapy. The excised valve fragment was sent to microbiology, and direct and culture exams were negative. Postoperative period was complicated by an episode of paroxysmal rapid atrial fibrillation with hemodynamic instability, resolved with electric cardioversion. Anticoagulation was started. The remaining in-hospital period was uneventful. The patient completed a six-week course of ceftriaxone and two weeks of gentamicin. Antimicrobial susceptibility testing was not performed due to loss of bacterial viability. Four weeks after discharge he was asymptomatic and had resumed his normal daily activity.

We report a case of subacute endocarditis in a previously healthy and immunocompetent patient, whose only risk factor was a known mild mitral regurgitation. He presented with a FUO, which rapidly unveiled a definite endocarditis: he had fever and a murmur (the latter previously known), anemia, elevated inflammatory markers, positive rheumatoid factor, microscopic hematuria, echocardiographic vegetation, positive blood cultures and splenic infarction, totalizing 2 major and 4 minor Duke modified criteria [5]. He had both cardiac (severe mitral regurgitation, ruptured chordae, pulmonary hypertension) and extracardiac (splenic infarction) complications. Granulicatella adiacens, an oral commensal, was isolated in all three sets of blood cultures, with no previous trigger event identified (he denied oral infections, dental manipulation, or intestinal derangements). This NVS has a notorious virulence, which might be related, not exclusively, to its ability to bind to extracellular matrix proteins and adhere to a damaged endocardium [8]. Our patient presented with a protracted (12 weeks) course of disease (asthenia, anorexia, weight loss, later with fever and dyspnoea), a subacute pattern described in Granulicatella spp. endocarditis [1],[8],[9].

Identification of this organism is exceedingly difficult: it is a fastidious and pleomorphic bacterium with specific nutritional requirements that can compromise culture isolation: in our case loss of viability prevented obtaining antimicrobial susceptibility tests, and the diagnosis was possible using MALDI-TOF MS.

Antibiotic therapy with ceftriaxone and gentamicin was empirically initiated (admitting the possibility of oral Streptococci from the gram), with good clinical and analytical response: on D2 the patient was afebrile, inflammatory markers had significantly diminished and blood cultures collected on D3 and valve cultures, were negative. After isolation we maintained treatment according to European guidelines [5] that recommend a course of either penicillin, ceftriaxone, or vancomycin for six weeks, combined with an aminoglycoside for two weeks. The patient had a favorable clinical and analytical evolution. Nevertheless, some studies report increasing rates of ceftriaxone resistance among G. adiacens isolates[8],[12],[13]and ceftriaxone is not included in American Heart Association guidelines recommendations [6].

Surgical intervention, reported in approximately 50% of cases of Granulicatella adiacens endocarditis [5], was early considered. Despite significant risk associated to surgery in the active phase of the disease, it must be considered in heart failure, uncontrolled infection, and prevention of embolic events. In this case, structural cardiac damage with ruptured chordae, aggravation of mitral regurgitation with pulmonary hypertension, and clinical signs of cardiac failure (exertional dyspnoea, crackles) associated to silent embolic phenomena were noted. Additionally, an 18 mm mobile vegetation was identified, and vegetations >10–15 mm are considered for urgent surgery in endocarditis guidelines [5],[6]. Moreover, our patient was young and had no co-morbid conditions which could worsen postoperative prognosis, further supporting a surgical approach. In fact, early surgical intervention has been associated with improved in-hospital and long-term survival and successful mitral valve repair can be achieved by experienced teams in circa 80% of cases [5],[14],[15].

Infective endocarditis is an uncommon but life-threatening infectious disease. Granulicatella adiacens is being increasingly recognized as a particularly virulent agent of endocarditis, associated to severe complications and an exceptionally challenging diagnosis and treatment. It is a commensal of our oral flora with recognized ability to adhere to damaged valves. Although rare, its reporting might be underestimated and it should be early considered in endocarditis.