Actinomyces neuii: a case report of a rare cause of acute infective endocarditis and literature review

Background Infective endocarditis caused by Actinomyces spp. is extremely rare. However, cases by new species of Actinomyces have been increasingly reported due to advances in laboratory techniques, and many of these species do not cause classic presentations of actinomycosis. Actinomyces neuii is reported to have a tendency to cause endovascular infection. The course of infective endocarditis caused by Actinomyces spp. is usually indolent. Case presentation A 61-year-old man with history of infective endocarditis, end stage renal disease, and monoclonal gammopathy was admitted for an abrupt fever, confusion, dysarthria, and facial droop after hemodialysis. Echocardiogram showed vegetations on both the aortic and mitral valves. Two sets of blood culture grew A. neuii. Brain MRI showed multiple bilateral cerebral infarcts consistent with septic emboli. The patient recovered after valvular surgery and prolonged intravenous and oral antibiotic therapy. Conclusions This case illustrates an unusually acute presentation of A. neuii infective endocarditis. As with other Gram-positive bacilli, Actinomyces spp. isolates are often regarded as a result of contamination. One should keep it in mind as a cause of infective endocarditis in vulnerable patient populations.


Background
Actinomyces spp. classically cause human actinomycosis, an indolent granulomatous infectious disease characterized by orocervicofacial, thoracic, abdominopelvic, or central nervous system abscess formation and draining sinuses [1]. Many novel Actinomyces species have been reported in recent decades with the advance in laboratory identification methods, and are associated with a wide range of infection at many body sites [2]. However, infective endocarditis by Actinomyces spp. is still extremely rare. We report a patient who presented with an acute Actinomyces neuii (A. neuii) aortic and mitral valve endocarditis complicated by aortic root abscess and septic cerebral emboli. He was treated successfully with surgery and prolonged antibiotics. We then present a review of published Actinomyces spp. endocarditis cases following a systematic literature search.

Clinical presentation and diagnostic findings
A 61 year-old man was admitted with a 103°F fever, confusion, weakness and slurred speech after hemodialysis. He had a history of viridans streptococcal mitral valve endocarditis, end stage renal disease on hemodialysis, atrial fibrillation not on anticoagulation due to GI bleeding, and monoclonal gammopathy of undetermined significance. He had a productive cough for a week without any identifiable sick contact. Physical examination was notable for an agitated edentulous man with a left central facial palsy, severe dysarthria, and a systolic murmur at the left lower sternal border. His lungs were clear to auscultation and there was no stigmata of endocarditis.
The patient was initially treated empirically for pneumonia and worked up for stroke. However, the treatment plan was quickly modified when a transthoracic echocardiogram on day two of admission revealed two echogenic structures consistent with vegetations: 0.4 × 0.4 cm on the anterior leaflet of the mitral valve, and the other 0.7 × 1.8 cm attached to left coronary cusp of the aortic valve (Fig. 1). There was also thickening of the aortic root suggestive of abscess formation. Two sets of blood culture grew Gram-positive rods after 37.5 h incubating in anaerobic bottles (Fig. 2), and after 86 h in aerobic bottles. The organism was identified as A. neuii by MALDI-TOF MS on day five of admission. Serial brain MRI scans revealed multiple bilateral infarcts on day two with increased number of infarcts and a small focus of hemorrhage on day five. The patient was diagnosed with infective endocarditis by A. neuii complicated by aortic root abscess and presumed cerebral septic emboli.

Treatment and outcome
The patient was initially treated with vancomyin and piperacillin/tazobactam until A. neuii was identified. Subsequently, he was treated with ampicillin and gentamicin for two days, followed by ampicillin for the rest of his hospitalization. The choice of ampicillin was based on a large series that studied susceptibility to antibiotics of Actinomyces species [3], and a previously successfully treated A. neuii endocarditis case [4]. Antibiotic susceptibility was not tested for our patient because he responded to the treatment well, and repeat blood cultures were all negative. A CT angiography of the brain and neck on day six ruled out mycotic aneurysm. It was concluded that the risk of further septic embolization outweighed the risk of intracranial hemorrhage, and the patient underwent aortic valve replacement, debridement of aortic root subannular abscess, mitral valve repair, and repair of a fistula between the aorta and left atrium on hospital day fourteen. A 2.5 × 0.6 cm vegetation on the aortic valve and a vegetation on the mitral chordae tendineae were removed. There was no microscopic evidence of bacterial elements on the aortic valve based on histopathology with Gram stain, and culture did not grow any organisms. The patient's postoperative course was complicated by shock requiring intraaortic balloon pump, and a cardiac arrest from ventricular fibrillation 10 days after surgery. He recovered without further neurological deterioration, and was discharged to a nursing facility two months after heart surgery. He received 12 weeks of IV ampicillin followed by 11 months of oral doxycycline.
One year after the diagnosis of A. neuii endocarditis, while on chronic doxycycline, the patient had a fever and a bacteremia with coagulase negative Staphylococcus and group B Streptococcus. The bacteremia was sterilized after the initiation of antibiotic therapy and there was no growth from subsequent blood cultures. Transthoracic echocardiogram showed a small, mobile echogenic density on the non-coronary cusp of the bioprosthetic aortic valve. The patient refused to undergo transesophageal echocardiogram to further evaluate the prosthetic valve, so he was treated empirically for possible prosthetic valve endocarditis. The patient was cured from infection after two weeks of IV vancomycin and gentamicin, followed by four weeks of IV vancomycin. He had been taking oral doxycycline in addition to his IV antibiotics.
The patient eventually died of a sudden cardiac arrest after hemodialysis. This was 15 months after the diagnosis of A. neuii infective endocarditis, and four weeks after discontinuation of oral doxycycline. The family declined autopsy.

Literature review
Primary infective endocarditis caused by Actinomyces spp. is rare. After PubMed (search term ((actinomyces spp) OR actinomyces) AND ((infective endocarditis) OR endocarditis)) and additional bibliographical search, we found 26 human cases dating back to 1939 (Table 1), after excluding four reports, two with bacteria that have been subsequently reclassified to different genera [29,30], one report with possible direct extension of pulmonary actinomycosis to the endocardium [31], and one with primary IUD-associated actinomyosis and secondary endocarditis [32]. Cases were reported at all ages (6-87 years old). Two thirds of patients were men. The most commonly identified species were A. israelii (19%) and A. viscosus (15%). Twenty-two cases involved leftsided valves (mitral 9; aortic 5; prosthetic aortic 3; both mitral and aortic 4; undetermined 1). Risk factors included valvular disease (41%), poor dental hygiene or dental procedure (36%), and prosthesis (14%). All four right-sided cases were associated with intravenous drug use [17,19,22,25]. Most left-sided endocarditis patients had indolent courses. This did not seem to vary over time. However, the mortality and complications have improved significantly over time. Five of eight patients reported before 1990 died and five had embolic events (brain, spleen, kidneys, small bowel and skin), whereas only two of 14 cases reported after 1990 died, and only one had emboli to skin. Despite temporal courses of a subacute endocarditis, where stigmata of endocarditis are more common, only one report described Roth's spots [27]. It is unclear whether this was related to virulence factors from Actinomyces spp., or simply the rarity of these complications [33]. Right-sided endocarditis cases had more acute and fulminant courses, and were all complicated by septic emboli to the lungs. Two (50%) of them had polymicrobial endocarditis [19,25], which might have contributed to more complicated clinical courses. All four rightsides cases survived and all were reported after the year of 2000. Irrespective of the side of endocarditis, most patients were treated with a prolonged course of penicillin or β-lactam antibiotics. Four cases had surgery (three aortic valves [4,13,18] and one Eustachian valve [22], an embryologic remnant of the valve of the inferior vena cava).
Two cases of infective endocarditis by A. neuii were previously reported [4,24]. Both were in older men with preexisting aortic valvular anomalies (one had a bicuspid valve and the other a prosthetic valve). Both presented with subacute endocarditis, large aortic vegetations (2 cm) and root abscesses. The patient with a native valve underwent surgery [4]. Both patients were cured from the infection. One was initially treated with ampicillin, then ceftriaxone due to interstitial nephritis, and finally doxycycline for 9 months [4]. The other was treated with penicillin, followed by amoxicillin for 12 months [24].

Discussion and conclusion
Infections caused by Actinomyces species, including classic actinomycosis and a range of other infections, usually have indolent courses and favorable outcomes [2]. This pattern was also supported by our review of endocarditis patients. Actinomyces species are also very susceptible to antibiotics, except for metronidazole [3,34]. Such susceptibility to antibiotics, along with advances in diagnosis and management of infective endocarditis, likely contributed to the temporal drop of mortality and systemic complication rates observed from our literature review. Therefore, it was unexpected for our patient to present with an acute course and severe complications. Little is known about the virulence properties of Actinomyces spp. [2], but we hypothesize that the valvular damage from previous endocarditis and relative immune deficiency from his end stage renal disease and monoclonal gammopathy may have weakened our patient's host defense mechanism, and consequently led to a  A. neuii was classified to the genus of Actinomyces in 1994. It is a small, non-filamentous rod that does not produce sulfur granules commonly seen in other Actinomyces species. Unlike most Actinomyces spp. that are anaerobic or at best aerotolerant organisms, A. neuii grows in both anaerobically and aerobically incubated samples [35]. It was the third most common diphtheroid and the most common Actinomyces species isolated from a tertiary center [36]. It has been reported in infected atheromas [37], abscesses [37], infected foreign bodies [2], urine [36] and endophthalmitis [38,39]. There have been only a few case reports of classic actinomycosis caused by A. neuii. Notably they were all related to breast infections [40][41][42][43][44]. The infection caused by it is thought to be endogenous [35]. The affinity of A. neuii to atheromas was only reported in one of the earliest reports, and how infections in atheromas were determined is unclear [37]. However, with such propensity to endovascular infection, it is possible that frequent cannulation for hemodialysis might have contributed to our patient's infection by A. neuii. The outcomes from infections by A. neuii are favorable [45]. Given the paucity of cases, our antibiotic selection was based on a previously successfully treated A. neuii endocarditis case [4]. The evaluation of neurological complications, and the timing of surgery were challenging, but our management was in line with the latest surgical guideline [46]. The patient's subsequent possible prosthetic valve endocarditis and eventual death likely reflected his overall poor prognosis, rather than recurrent A. neuii endocarditis.
Gram-positive rods, "diphtheroid" or "coryneform", are often disregarded as contaminants from skin or mucosal surfaces, but 20% of diphtheroid isolates were found to cause clinically significant infections in a large study [36]. Actinomyces spp. are among these Grampositive rods, and their identification in clinical microbiology laboratories can be challenging [2,47]. As such, delayed diagnoses are common [13,18,23], and it is thought endocarditis by Actinomyces spp. is underestimated and Actinomyces spp. are likely a cause of culture negative endocarditis. Advances in laboratory methods, primarily MALDI-TOF MS, are correctly and increasingly identifying Actinomyces spp. from clinical samples. Clinicians should carefully evaluate the relevance of an Actinomyces spp. isolate before disregarding it, especially in a vulnerable patient like ours, and in a species that is associated with endovascular infection like A. neuii.
To conclude, we reported a successfully treated acute infective endocarditis case with severe complications by A. neuii, a rare but increasingly clinically relevant Actinomyces species associated with endovascular infection. Our review showed Actinomyces spp. infective endocarditis is usually indolent and responds favorably to treatment. Clinicians should carefully evaluate the relevance of Actinomyces spp. in infections to avoid delayed or missed diagnoses.