Background

Trueperella pyogenes (T. pyogenes) is a Gram-positive, non-motile, non-spore-forming coccobacillus or short rod that occurs singly, in pairs, or in clusters [1, 2]. Over the years, various taxonomic revisions have been made, changing its classification from Bacillus pyogenes, to Corynebacterium pyogenes, Actinomyces pyogenes, Arcanobacterium pyogenes, and finally Trueperella pyogenes [2, 3]. It is known to colonize the skin and mucosal surfaces of many domestic animals, such as cattle, swine, sheep and goats, causing a variety of infections, including mastitis, wound infections, pneumonia and liver abscess [4, 5]. Infections in humans occur only sporadically and mostly in immunocompromised patients with contact to farm animals [4], leading to sepsis [6], endocarditis [7], pneumonia [8], and skin ulcers [9], among others. We report a case of sepsis and endocarditis caused by T. pyogenes in a Swiss farmer and summarize eight similar cases from the literature.

Case presentation

A 71-year-old man presented to the emergency department of a Swiss university hospital with a three-day history of general weakness, malaise and fever. Symptoms occurred three days after administration of a first dose of cemiplimab for treatment of a recurring locally advanced basal cell carcinoma of the left cheek. Due to a pancreatic neuroendocrine tumor with liver metastasis, the patient was currently under palliative treatment with everolimus and somatostatin receptor-targeted radionuclide therapy. A routine transthoracic echocardiogram (TTE) prior to the start of immunotherapy had shown signs compatible with cardiac amyloidosis and coronary artery disease (CAD). The patient was a retired farmer, still living on a cattle farm in Switzerland.

On presentation ear temperature was 38.6 °C, blood pressure 79/44 mm Hg, heart rate 89 beats per minute, respiratory rate 27 breaths per minute, and oxygen saturation 88% on ambient air. He was somnolent, but no focal neurologic deficits were observed. The heart sounds were regular, with a systolic murmur at the third intercostal space, left lower sternal border. Auscultation of the lungs was unremarkable. The ulcerating basal cell carcinoma, measuring 3 × 5 cm, was visible on the left cheek, without signs of inflammation. Examination of the skin and joints was otherwise unremarkable. Laboratory workup showed a C-reactive protein (CRP) of 96 mg/L (normal < 5 mg/L), with normal leucocytes of 5,5 × 109/L (normal range 3 to 10,5 × 109/L), and thrombocytopenia of 107 × 109/L (normal range 150 to 450 × 109/L). Chest X-ray demonstrated signs of mild pulmonary venous congestion. A computed tomography (CT) of the head showed no evidence of soft tissue abscess in the area surrounding the basal cell carcinoma. After collection of blood cultures, empiric treatment with piperacillin/tazobactam (4.5 g every eight hours) was initiated for suspected sepsis of unknown origin in an immunocompromised patient. The patient initially required hemodynamic stabilization with norepinephrine in the intermediate care unit.

In both pairs of blood cultures growth of T. pyogenes was detected. The species was identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI Biotyper® system, Bruker-Daltonics, Germany). Time to positivity (TTP) was 29 h for the aerobic culture, and 26 h for the anaerobic culture. Blood cultures collected 72 h after initiating antibiotic treatment remained positive. In the wound swab of the basal cell carcinoma growth of Staphylococcus aureus and Candida albicans were noted, but not of T. pyogenes. TTE showed new evidence of mild mitral valve stenosis and tricuspid valve insufficiency. A transesophageal echocardiography (TEE) revealed two vegetations at the posterior leaflet of the mitral valve with a size of 9 × 8 and 15 mm, respectively (Fig. 1). Additionally, mild mitral valve insufficiency and moderate tricuspid valve insufficiency were documented.

Fig. 1
figure 1

Transesophageal echocardiogram with mid-position view, 135° left: mitral valve with a vegetation of the posterior leaflet. Abbreviations: Ao, ascending aorta; AV, aortic valve; LA, left atrium; LV, left ventricle, MV, mitral valve; RV, right ventricle

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The persistently positive blood cultures with isolation of T. pyogenes in consecutive samples, the echocardiographic evidence of mitral valve vegetations, and the presence of fever were consistent with two major and one minor modified Duke Criteria, respectively [10]. Furthermore, somnolence, thrombocytopenia, hypoxemia, and arterial hypotension corresponded to a Sequential Organ Failure Assessment (SOFA) Score of 6 points [11]. A diagnosis of sepsis due to mitral valve endocarditis with T. pyogenes was made.

The antibiotic therapy with piperacillin/tazobactam was deescalated to amoxicillin/clavulanic acid intravenously (2.2 g every four hours) and was switched to targeted treatment with penicillin G (4 million units every four hours) upon receipt of antibiotic sensitivity testing results (minimum inhibitory concentration (MIC) for penicillin G 0,016 mg/L). The case was discussed at the multidisciplinary endocarditis board, and despite the size of > 10 millimeters of one of the vegetations and increased risk of embolism, a decision against surgery was made [12]. This was based on the rapid clinical stabilization, the mild degree of mitral valve insufficiency, and the patient’s comorbidities. Additionally, it took into account the patients’ aversion against surgery and a prolonged hospital stay. Under antibiotic treatment with penicillin G, the patient’s condition gradually improved. Blood cultures drawn ten days after start of the antibiotic treatment remained negative. Clinical signs of septic emboli did not occur at any time.

The patient was discharged after 13 days, receiving an outpatient parenteral antibiotic therapy (OPAT). As he declined treatment with continuous infusion therapy, the antibiotics were switched from penicillin G to ceftriaxone (2 g every 24 h). A follow-up TEE three weeks after diagnosis showed a reduction in size for both vegetations and an unchanged mild insufficiency of the mitral valve. The antibiotic therapy was terminated after a total of six weeks. Blood cultures drawn two weeks after stop of the antibiotic treatment remained negative.

Discussion and conclusions

T. pyogenes is an uncommon cause of infections in humans and the current literature is restricted to case reports. Patients with intraabdominal infection, skin ulcer, sepsis, arthritis, pneumonia, and pyelitis have been described [6, 8, 9, 13,14,15,16,17]. A literature search revealed only eight other reported cases of T. pyogenes endocarditis (Table 1), which occurred in Europe, Asia, and Northern America. To our knowledge, no literature review focusing on endocarditis has been published so far. Patients with T. pyogenes endocarditis were predominantly male (7/9 patients), and their age ranged from 20 to 77 years (median 57 years). The left-sided valves, i.e., aortic and mitral valve were affected in all nine patients.

Table 1 Overview of nine cases of infectious endocarditis with Trueperella pyogenes in humans
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The reservoirs and routes of transmission of T. pyogenes are still poorly understood [4]. It is thought to be a common colonizer of the skin and mucosal membranes of various domestic and wild animals, leading to endogenous infections by mechanical injuries [5]. The animal-to-animal transmission may occur by contaminated utensils [18], by natural environment [19], or by biting flies (Hydrotaea irritans) [18,19,20]. In humans, T. pyogenes is not part of the normal flora and infections are often associated with animal contact [5]. Interestingly, only in 3/9 patients in our literature review, confirmed exposure to farm animals was reported, which raises the question for an alternative route of transmission. Another patient lived close to a cattle farm but had no direct contact to the animals or their products.

Infections caused by T. pyogenes in humans seem to occur primarily in immunocompromised populations [4], and 5/9 of the patients in our literature review had a functionally impaired immune system. In our patient, history of two active malignancies, ongoing chemo- and immunotherapy, and residency on a cattle farm are predisposing factors for developing a T. pyogenes infection. The open facial wound of the basal cell carcinoma could have been a possible entry site. Since the wound swab did not show growth of T. pyogenes, the site of inoculation could not be determined with certainty.

T. pyogenes shows marked beta-hemolysis on blood agar culture plates and is therefore unlikely to be missed during routine diagnostics in the clinical microbiology laboratory: beta-hemolytic bacteria are regularly further characterized, as this feature can indicate pathogens such as Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus agalactiae. In the present case, the diagnosis was not made upon specific suspicion or instruction; the bacteria were identified during routine analysis.

The increase of antimicrobial resistance of T. pyogenes in animals due to the frequent use of antibiotics in agriculture is an emerging problem [4, 21]. Resistance to tetracyclines, aminoglycosides and trimethoprim-sulfamethoxazole are common [21, 22]. According to susceptibility tests in cattle, penicillin and cephalosporin may retain activity [23]. In our literature review of human patients with T. pyogenes endocarditis, resistance to trimethoprim-sulfamethoxazole was reported for 3/4 patients [7, 24]. Susceptibility to penicillin, ceftriaxone, and macrolides was noted in all cases reporting results of antibiotic resistance testing (6/6). Beta-lactam antibiotics were the predominant antibiotic class used for treatment. In one patient additional surgical treatment was performed. The mortality of endocarditis caused by T. pyogenes was high, with 6/9 patients not surviving the disease. Due to little knowledge about this bacterial species, considering the size of valvular vegetation, we decided to treat our patient for 6 weeks instead of the generally recommended 4 weeks of treatment for native valve endocarditis [12]. Historically, the treatment of Arcanobacterium endocarditis has involved a combination of beta-lactam and aminoglycoside antibiotics, but the clinical benefits of this approach remain uncertain. At the time of endocarditis diagnosis, the patient was clinically stable, afebrile, and willing to finish the antibiotic treatment in an outpatient setting. Adding an aminoglycoside to the prescribed beta-lactam regimen at this stage would have complicated treatment logistics, such as the need for additional timed infusions and therapeutic drug monitoring, potentially leading to additional drug toxicity. In view of the scarce data supporting combination treatment in this situation, we decided to refrain from this approach.

In conclusion, T. pyogenes is a rare causative organism of infectious endocarditis in humans and descriptions are mainly restricted to case reports. In our case report and review of the literature, we found that both an impaired immune system and contact with farm animals might be risk factors for the infection. Growth of T. pyogenes in blood cultures is unlikely to be missed during routine analysis, as it shows marked beta-hemolysis on blood agar culture plates, which generally leads to further characterization of the bacteria. Susceptibility to penicillin, ceftriaxone, and macrolides seems to be retained and the reported mortality in the few patients with T. pyogenes endocarditis is high.