Abstract

Background. The diagnosis of infective endocarditis is difficult, especially when it involves atypical organisms. Therefore, our study identified risk factors of infective endocarditis caused by rare pathogen, Gemella spp. Methods. A systematic review was conducted to investigate characteristics of endocarditis patients infected with Gemella spp. using the search term “Gemella” and “endocarditis.” Case reports were gathered by searching Medline/Pubmed, Google Scholar, CINAHL, Cochrane CENTRAL, and Web of Science databases. 83 articles were selected for review. Results. 5 species of Gemella were identified. Typical patient affected were male between 31 and 45 years of age. On admission, patients had fever, tachycardia, and normal blood pressure. Common clinical manifestation other than fever included fatigue and weakness, chills and sweating, and nausea, vomiting, diarrhea, and weight changes. 1 in 4 reported a history of congenital heart disease, and a recent oral infection. 1 in 2 patients underwent surgical procedure. Laboratory tests revealed anemia, leukocytosis, and elevated erythrocyte sedimentation in all age groups, as well as elevated C-reactive protein in adult and geriatric populations only. Mitral and aortic valves were most commonly infected by Gemella spp.. The most common Gemella spp.-susceptible antibiotics were penicillin, vancomycin, cephalosporin, macrolide, and aminoglycosides. However, antibiotic resistance was observed against penicillin, aminoglycoside, and fluoroquinolone. Antibiotic therapy of at least 6 weeks resulted in superior clinical improvements than durations under 6 weeks. Finally, 1 in 2 patients underwent valve replacement or repair, with common complications affecting the cardiovascular, neurological, and renal systems. Finally, death occurred in 1 in 8 patients, half of which occurred post-surgical procedure, and the majority occurring equal to or greater than 1 week from admission. Conclusion. Our systematic review highlights the importance of considering rare pathogens, particularly in the presence of predisposing risk factors.

1. Introduction

Infective endocarditis is a rare disease with an incidence of approximately 3-10 per 100,000 people per year in industrialized countries. ^{1, 2, 3, 4} Recognizing infective endocarditis is difficult due to the non-specific symptoms, such as sepsis of unknown origin or fevers without recognizing the risk factors. ⁵ Currently, the accepted criteria for diagnosis are the modified Duke criteria. Furthermore, it is important that for the initiation of targeted antibiotic therapy for infective endocarditis, the organism is isolated from blood cultures, requiring two to three sets of blood cultures obtained from separate venipuncture sites. Any delay in treatment will have negative effects on clinical outcomes in acute bacterial infectious diseases ⁶ and raises the risk of developing complications including infectious recurrences, cardiac surgery because of the valvular sequelae of the disease, and death ⁷.

A number of factors predispose to the development of infective endocarditis, such as age, sex, injection drug use, and dental infection, as well as the presence of co-morbid conditions such as structural heart disease, valvular disease, or intravascular device. Presently, there is ample information available regarding the common causes of infective endocarditis: staphylococci, streptococci, and enterococci. ^{8, 9, 10} However, there is limited knowledge for lesser known pathogens. One prominent microorganism is Gemella spp.

Gemella spp. are facultatively anaerobic non-motile and non-spore forming Gram-positive cocci. Due to its misidentification as viridans group group streptococci, ¹¹ it is very likely that the genus is a more important cause of clinical disease than is presently recognized. These are organisms of the mouth, gastrointestinal tract, and genitourinary tract of humans and other warm-blood animals, although serious systemic infections such as endocarditis are the most prevalent clinical presentation. ¹² Although Gemella spp. are associated with previous valvular injury or prosthetic valves, dental surgery, and colorectal surgery, ¹³ the true mode of infection leading to infective endocarditis still remains unclear.

It is important that to understand the pathogenicity of the microorganism in order to identify risk factors that predisposes an individual to an infection of a rare bacterium. Therefore, a systematic review was conducted to investigate characteristics of endocarditis patients infected with Gemella spp. based on existing case reports and case series.

2. Methods

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was adhered to for this systematic review. The protocol was not registered.

Only articles that reported the association of the genus of the gram-positive bacteria Gamella spp. and endocarditis were included.

Studies were excluded if: (1) they were not case reports or case series, (2) they were not peer-reviewed, and (3) they were not in English.

A comprehensive literature search using Medline/Pubmed, Google Scholar, CINAHL, Cochrane CENTRAL, and Web of Science databases up to and including 1 January 2020 using the terms “Gemella” and “endocarditis.”

Initial triage of articles was based on whether titles or abstracts met the inclusion criteria. Full-text articles were then read, and those that did not satisfy the inclusion/exclusion criteria were excluded. A summary of study characteristics is given in Table 1.

Data extracted from articles included name of first author, year of publication, country, and study design. Variables for which data were sought included viral strain, patient age and sex, presenting complaints on admission, past medical and surgical histories, laboratory tests, diagnostic studies, management of endocarditis, and outcome of the patient.

Data were tabulated, evaluated, and summarized.

Potential bias across studies were analyzed within study characteristics. Two independent reviewers evaluated the methodological quality of the eligible studies. A third reviewer evaluated papers where there were no agreement. The Joanna Briggs Institute critical appraisal tool for case reports was selected for use in this systematic review. Bias was evaluated using a checklist of 8 questions. Each question is specified in Supplementary Table 1 concerning risk of bias whereby an overall appraisal was made of each article: risk of bias is low (included), high (excluded), or uncertain (more information is required). For the purpose of this study, an answer of “yes” equal to or greater than 50% of the questions was considered to be low risk of bias. Similarly, an answer of “no” equal to or greater than 50% of questions was determined to be high risk of bias, whereas “unclear” answers were equal to or greater than 50% response.

3. Results

From 5 databases, 118 articles were selected with relevance to Gemella spp. and endocarditis. 83 case reports were selected once assessed for eligibility. ^{14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92} A PRISMA flow diagram detailing the process of identification, inclusion, and exclusion of studies is shown in Figure 1.

All studies were published between 1989 and 2019. The majority of studies were conducted in Europe and the UK ^{22, 23, 24, 25, 26, 27, 28, 30, 32, 34, 35, 36, 37, 38, 40, 46, 47, 49, 52, 56, 57, 58, 60, 61, 66, 68, 72, 73, 75, 84, 92} followed by North America ^{15, 17, 19, 21, 29, 31, 33, 39, 43, 45, 48, 54, 55, 64, 67, 69, 71, 76, 77, 78, 79, 83, 86, 88, 89, 90} and Asia. ^{14, 16, 18, 20, 41, 44, 50, 51, 53, 62, 63, 65, 74, 80, 81, 82, 87, 91} USA ^{15, 17, 21, 29, 39, 43, 45, 48, 54, 55, 64, 69, 76, 77, 78, 79, 83, 86, 88, 89, 90} reported the most number of cases in the world, followed by the UK. ^{23, 25, 26, 58, 68, 73} Japan ^{16, 41, 63, 74, 81, 82} reported the most cases among Asia, Oceania, and South America.

Results are found in Supplementary Table 1. All articles were rated as low risk of bias, although 3 studies recorded 50.0% “yes” response to the questions. ^{14, 52, 65} 2 articles were missing either sex ¹⁴ or age ⁵² with regards to demographic characteristics. 15 case reports did not have satisfy the patient’s history and timeline criteria, ^{18, 25, 32, 34, 40, 44, 45, 49, 51, 56, 58, 59, 62, 65, 92} while 5 articles omitted details of intervention. ^{14, 52, 65, 77, 86} 71.4% of studies did not include post-intervention clinical condition and/or adverse or unanticipated events. ^{14, 15, 16, 18, 19, 22, 23, 24, 25, 26, 28, 29, 30, 31, 32, 34, 36, 37, 38, 39, 40, 41, 42, 43, 46, 47, 48, 49, 50, 52, 53, 57, 58, 59, 60, 61, 62, 63, 65, 66, 67, 68, 71, 72, 73, 76, 77, 78, 80, 81, 84, 85, 87, 89, 90, 92}.

A summary of findings is given in Table 1.

55 articles involved the discovery of the gram-positive bacteria Gemella spp. in adult patients with infective endocarditis. ^{14, 15, 16, 17, 18, 19, 20, 24, 25, 29, 30, 32, 33, 34, 36, 38, 39, 41, 42, 43, 46, 48, 49, 52, 53, 57, 58, 59, 60, 64, 65, 66, 68, 69, 72, 73, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 87, 88, 89, 90} While the majority of these studies reported the presence of the bacteria in predominantly native-valves, ^{14, 15, 16, 18, 20, 24, 25, 29, 30, 32, 33, 34, 36, 38, 41, 43, 46, 48, 49, 52, 53, 57, 58, 59, 64, 65, 68, 72, 77, 78, 79, 80, 81, 83, 84, 85, 87, 88, 89} 12 of those studies highlighted the association of prosthetic valve endocarditis by Gemella spp. ^{17, 19, 39, 42, 60, 66, 69, 73, 75, 76, 82, 90}.

The remaining 20 studies investigated the possible implication of a second disease in relation to endocarditis as caused by Gemella spp. 3 articles investigated the association of endocarditis and cancer, particular colonic carcinoma ^{40, 56} and multiple myeloma, ⁵⁴ while 4 studies reported the association aneurysms and strokes. ^{21, 27, 44, 63} The effects on the kidneys were discussed in 4 studies, ^{71, 74, 91, 92} while 4 articles reported concurrent implications of the heart, such as cardiogenic shock, STEMI, and hypertrophic cardiomyopathy. ^{47, 50, 70, 86} Finally, 3 articles investigated the contribution of other infections within the body, such as septic arthritis, respiratory tract infection, and presence of anti-streptolysin-O antibodies. ^{26, 31, 45} Hemochromatosis ⁶¹ was the subject of 1 article, while systemic lupus erythematous was the topic the other. ²²

In terms of population studies, 6 studies observed Gemella spp. in the pediatric population, ^{35, 37, 51, 55, 62, 67} while 2 articles found the bacteria in the intravenous drug users or body piercing populations. ^{23, 28}

5 different species of Gemella spp. were identified as shown in Table 1. The most common species was Gemella morbillorum (44.6%) ^{14, 16, 17, 18, 19, 23, 24, 27, 28, 30, 31, 35, 37, 38, 42, 43, 47, 49, 50, 51, 52, 53, 56, 58, 63, 64, 70, 74, 75, 76, 80, 81, 84, 90, 91} followed by Gemella haemolysans (26.5%). ^{15, 21, 22, 25, 26, 32, 36, 40, 46, 48, 52, 54, 59, 60, 61, 68, 69, 72, 73, 88, 92} The predominant strains in studies published in Europe and North America were Gemella morbillorum ^{17, 19, 23, 24, 27, 28, 30, 31, 35, 37, 38, 43, 47, 49, 52, 56, 58, 64, 75, 76, 84, 90} and Gemella haemolysans, ^{15, 21, 22, 25, 26, 32, 36, 40, 46, 48, 52, 54, 60, 61, 68, 69, 72, 73, 88, 91} whereas articles from Asia involved mainly Gemella morbillorum. ^{14, 16, 18, 50, 51, 63, 72, 80, 81, 91}

The distribution of age, shown in Supplementary Figure 1, was stratified in groups of 15 years of age, as well as according to gender. Nearly three-quarter of studies involved male patients. ^{14, 15, 16, 17, 19, 20, 21, 23, 24, 25, 26, 27, 29, 31, 33, 36, 38, 40, 43, 44, 45, 48, 49, 52, 53, 55, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 68, 70, 71, 73, 74, 75, 76, 77, 78, 79, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92}

The average temperature recorded at admission was 38.2 +/- 0.8°C ranging from 36.0°C to 40.4°C, ^{16, 17, 18, 19, 21, 24, 25, 28, 29, 30, 32, 33, 34, 35, 36, 37, 39, 41, 45, 46, 47, 48, 49, 51, 52, 55, 58, 63, 65, 68, 70, 76, 79, 80, 81, 82, 83, 84, 85, 87, 90, 91, 92} while the average heart rate and blood pressure was 103.0 +/- 21.5 bpm ^{15, 16, 17, 21, 28, 30, 32, 33, 34, 36, 39, 41, 43, 44, 45, 47, 48, 49, 51, 52, 53, 55, 57, 59, 62, 65, 67, 68, 76, 79, 80, 81, 82, 83, 84, 86, 87, 90, 92} and 120.6/67.9 +/- 25.3/17.0 mmHg ^{16, 17, 18, 24, 28, 30, 32, 34, 36, 39, 41, 44, 45, 47, 48, 49, 51, 53, 59, 65, 68, 70, 74, 79, 80, 81, 82, 83, 84, 86, 87, 90, 92} respectively.

Distribution of presenting complaints and associated symptoms are found in Table 2. There were noticeable differences when organized according to age. The predominant symptom was fever, ^{16, 18, 19, 20, 21, 22, 23, 24, 26, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 45, 47, 48, 49, 50, 51, 52, 53, 56, 57, 59, 62, 63, 64, 65, 66, 68, 69, 70, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 87, 90, 91, 92} while fatigue, malaise, lethargy, and weakness were common to all age groups. ^{14, 21, 22, 23, 26, 27, 29, 30, 31, 32, 33, 36, 40, 42, 45, 47, 48, 51, 53, 55, 56, 57, 58, 59, 61, 66, 67, 71, 73, 74, 75, 76, 77, 83, 84, 87, 88} Nausea, vomiting, diarrhea, and weight change were present in the pediatric ^{26, 35, 37, 51, 55, 62, 66, 67} and geriatric populations, ^{25, 29, 30, 31, 34, 38, 40, 42, 43, 45, 46, 48, 52, 54, 56, 58, 61, 64, 68, 70, 71, 72, 74, 75, 76, 78, 81, 83, 84, 86, 87, 88, 91} while shortness of breath, cough, and dyspnea were exclusively found in the adult population. ^{14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 27, 28, 32, 33, 36, 38, 39, 41, 44, 46, 47, 49, 50, 52, 53, 57, 59, 60, 63, 65, 69, 70, 71, 73, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 92}. The pediatric and adult populations exhibited chills and sweating, while rigor, myalgia, back pain and joint pain were observed in the adult and geriatric populations.

20 studies reported a history of congenital heart disease. ^{14, 15, 17, 19, 20, 24, 26, 37, 50, 52, 53, 55, 57, 66, 67, 69, 80, 85, 87, 89} Bicuspid aortic valve was observed in 50.0% of these studies, ^{15, 17, 19, 52, 57, 69, 80, 85, 87, 89} followed by ventricular septal defect (VSD) (20.0%) ^{20, 37, 53, 76} and tetralogy of Fallot (15.0%). ^{24, 55, 66}

A history of some form of infection was found in 21 studies. ^{16, 21, 31, 36, 37, 39, 41, 47, 49, 52, 53, 60, 63, 64, 67, 71, 73, 76, 78, 91} The majority of these patients were found to have had an infection of the mouth (57.14%). ^{16, 21, 37, 41, 49, 60, 63, 64, 71, 73, 76, 78}

A history of invasive procedure was recalled in 37 articles, ^{17, 19, 20, 22, 24, 26, 28, 30, 35, 37, 39, 41, 42, 48, 49, 50, 55, 57, 60, 66, 67, 68, 69, 70, 73, 74, 76, 80, 81, 82, 83, 84, 88, 89, 90} the most being aortic valve replacement or aortic arch repair (45.9%) ^{8, 10, 11, 15, 21, 28, 30, 52, 59, 61, 65, 66, 68, 71, 73, 80} and dental procedure (32.4%). ^{22, 28, 35, 39, 41, 48, 49, 50, 57, 68, 81, 83} Mitral valve replacement, ^{39, 60, 67, 90} pulmonary repair or pulmonary artery repair, ^{24, 37, 55, 66} and VSD repair ^{20, 26, 37, 67} were cited in 4 articles each.

A summary of laboratory tests is found in Table 3. All population groups showed anemia, ^{16, 17, 18, 23, 24, 27, 28, 32, 33, 34, 35, 36, 41, 44, 46, 49, 51, 52, 54, 55, 56, 57, 58, 59, 62, 67, 68, 70, 71, 74, 76, 79, 80, 81, 82, 84, 87, 88, 90} leukocytosis ^{15, 16, 17, 18, 19, 21, 23, 24, 27, 28, 29, 32, 33, 34, 35, 36, 41, 44, 45, 46, 47, 48, 49, 52, 54, 55, 56, 57, 58, 59, 61, 62, 63, 67, 68, 69, 70, 71, 72, 74, 76, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 90, 91} and elevated erythrocyte sedimentation rate. ^{18, 24, 27, 28, 29, 32, 34, 35, 38, 46, 47, 49, 50, 52, 55, 56, 57, 58, 59, 61, 67, 70, 79, 81, 85, 89, 90} C-reactive protein was elevated in the adult and geriatric populations ^{16, 23, 24, 28, 29, 32, 34, 36, 38, 44, 46, 49, 50, 57, 63, 68, 70, 72, 74, 80, 81, 82, 84, 85, 87, 89, 91} but remained normal in the pediatric population. ^{35, 55}

64 patients were evaluated by transthoracic echocardiogram ^{16, 16, 17, 18, 19, 21, 23, 25, 26, 27, 28, 29, 30, 32, 34, 35, 37, 38, 39, 41, 43, 44, 45, 46, 47, 48, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 71, 72, 74, 76, 77, 78, 80, 81, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92} whereas 34 cases used transesophageal echocardiogram. ^{14, 15, 18, 19, 20, 21, 22, 24, 30, 31, 33, 39, 41, 41, 42, 43, 48, 49, 52, 56, 68, 70, 71, 73, 75, 76, 78, 79, 82, 86, 90} The mitral valve was the most common location of vegetation in the pediatric and geriatric populations, whereas the aortic valve vegetation predominated in the adult age group. Gemella haemolysans, Gemella bergeriae, Gemella sanguinis were mainly found on aortic valves ^{15, 16, 17, 19, 20, 21, 22, 29, 30, 33, 34, 38, 39, 43, 44, 49, 52, 54, 56, 57, 59, 60, 61, 63, 68, 69, 71, 72, 73, 74, 75, 76, 77, 80, 81, 82, 84, 85, 87, 89, 91, 92} while Gemella morbillorum and Gemella taiwanensis were discovered predominately on the mitral valve. ^{16, 17, 18, 21, 22, 25, 27, 28, 29, 31, 32, 34, 35, 37, 38, 41, 43, 44, 46, 48, 49, 50, 51, 52, 56, 58, 67, 68, 70, 71, 74, 75, 78, 79, 80, 81, 83, 86, 87, 88, 89, 90, 91}

Management of endocarditis by Gemella spp. was governed by antibiotic susceptibility in 43 studies, ^{17, 18, 19, 23, 24, 30, 32, 35, 37, 39, 41, 42, 44, 46, 47, 48, 50, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 64, 67, 68, 70, 71, 73, 76, 81, 82, 84, 87, 88, 90} most commonly beta-lactam treatment, as shown in Supplementary Table 2. 5 studies, however, demonstrated antibiotic resistance, in particular penicillin, ^{49, 62} aminoglycoside ⁴⁹ and fluoroquinolone. ^{41, 62}

In studies where patients survived the course of treatment, more patients showed clinical improvement after receiving 6 weeks or more of antibiotic therapy ^{16, 19, 21, 25, 30, 31, 32, 33, 34, 38, 39, 41, 47, 48, 49, 50, 51, 55, 57, 62, 66, 67, 71, 72, 76, 80, 82, 87, 89} than patients who received under 6 weeks of antibiotic therapy, ^{15, 23, 24, 27, 35, 36, 37, 46, 52, 53, 58, 59, 61, 63, 65, 69, 81, 84, 85, 90} as demonstrated in Figure 2.

Of the 45 patients who underwent surgical procedure, 43 required valve replacement or repair. ^{14, 15, 16, 17, 18, 21, 27, 28, 29, 32, 33, 38, 39, 40, 41, 49, 50, 52, 53, 56, 59, 60, 62, 63, 65, 66, 68, 69, 70, 71, 72, 75, 76, 78, 79, 81, 82, 83, 87, 88, 89, 92} Furthermore, patients who received longer treatment courses ^{16, 19, 21, 25, 30, 31, 32, 33, 34, 38, 39, 41, 47, 48, 49, 50, 51, 55, 57, 62, 66, 67, 71, 72, 76, 80, 82, 87, 89} underwent less surgical procedures for valve repair than shorter treatment courses. ^{15, 23, 24, 27, 35, 36, 37, 46, 52, 53, 58, 59, 61, 63, 65, 69, 81, 85, 86, 90}

23 studies reported complications following treatment. ^{17, 20, 21, 27, 33, 35, 44, 45, 51, 52, 55, 56, 64, 69, 70, 74, 75, 79, 82, 83, 86, 88, 91} This included implications to the cardiovascular (10.8%), ^{17, 21, 33, 52, 56, 70, 76, 86, 88, 91} neurological (9.6%), ^{20, 27, 44, 45, 74, 75, 79, 82} and renal (6.0%) ^{21, 33, 55, 64, 75} systems. However, there were no reported recurrent infections following successful antibiotic treatment. ^{14, 15, 16, 21, 23, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 43, 46, 47, 48, 49, 50, 51, 52, 53, 55, 57, 58, 59, 60, 61, 62, 63, 65, 66, 67, 68, 69, 71, 72, 73, 75, 76, 80, 81, 82, 84, 85, 87, 89, 90} Death of the patient was reported in 13 articles, ^{17, 20, 44, 45, 54, 56, 70, 74, 79, 83, 86, 88, 91} 46.2% of which occurred post-surgical procedure. ^{17, 56, 70, 79, 83, 88} The clear majority of deaths occurred equal to or greater than 1 week from admission (76.9%) ^{20, 44, 54, 56, 70, 74, 79, 86, 88, 91} in comparison to death occurring under 1 week (23.1%). ^{17, 45, 83}

Due to the nature of descriptive studies, the results being presented are liable to investigator, procedure, and selection bias.

• Statistical analyses were not performed as there were no control/comparison group in the included studies.

4. Discussion

5 species of Gemella were identified in our systematic review, the most common being Gemella morbillorum and haemolysans. Both species have been members of the genus Gemella since 1988. ⁹³ Gemella spp. are opportunistic pathogens, similar to many other commensal bacteria of the human microbiota, causing severe localized and generalized infections. ⁹⁴ Less is known about Gemella bergeri, sanguinis, and taiwanensis. Gemella bergeri and sanguinis were assigned to the Gemella genus in 1998, while Gemella taiwanensis was identified more recently in 2014. ⁹⁵ The misidentification of Gemella spp. can be attributed to the inaccuracy of commercial biochemical tests using phenotypic identification systems. ⁴⁹ Gemella haemolysans and morbillorum have been identified as the causative pathogens in most of the previous cases caused by Gemella spp., yet these findings may be biased by which test are commercially available.

We discovered that predominantly males were more prone to infective endocarditis by Gemella spp. The reduced susceptibility of females could be attributed to the protection from X chromosome and sex hormones, which play an important role in innate and adaptive immunity. ⁹⁶ We also found that the age of the patients was between 31 and 45 years. Infective endocarditis predominantly inflicts young adults in low-income countries, ⁹⁷ while the average age in high-income countries is older than 70 years. ⁹⁸ The majority of studies in this systematic review originated in high income countries such as USA, UK, and Japan.

Two-thirds of infective endocarditis in low-income countries are caused by community-acquired penicillin-sensitive streptococci entering via the oral cavity leading to rheumatic heart disease. ⁹⁷ Infective endocarditis in high-income countries, on the other hand, is due to degenerative valve disease, diabetes, cancer, intravenous drug use, and congenital heart disease. ⁹⁸ This is in large due to improved living standards and availability of antibiotics for streptococcal pharyngitis resulting in substantially reduced incidence of rheumatic heart disease. ⁹⁹ In parallel, the incidence of cases attributable to oral streptococci has decreased due to oral antibiotic prophylaxis. ¹⁰⁰ Interestingly, we showed that 1 in 4 patients reported a history of congenital heart disease, such as bicuspid aortic valve, ventricular septal defect, and tetralogy of Fallot. Furthermore, 1 in 4 patients had a recent history of oral infection, while 1 in 2 patients underwent surgical procedure, such as heart valve replacement or dental repairs. This poses the question whether the incidence and prevalence of infective endocarditis by Gemella spp. is under-reported in low-income countries.

Typically, clinical examination of infective endocarditis shows variable signs of disease, with fever present in 90% of cases and cardiac murmurs in 85% of patients. Splenomegaly or cutaneous manifestations, such as petechiae or splinter haemorrhages, are supportive signs. ^{101, 102} Osler’s nodes, Janeway lesions, and Roth spots are rare, while signs of complications such as heart failure, stroke, or metastatic infection (eg, vertebral osteomyelitis, peripheral abscess) are more prevalent ⁵. Patients with infective endocarditis by Gemella spp. showed fever, tachycardia, and normal blood pressure. The most common clinical manifestations for all patients were fever, fatigue, and chills or sweating. Nausea, vomiting, diarrhea or anorexia were more commonly found in children, while adults displayed chills or sweating. The elderly, on the other hand, exhibited fatigue.

Generally, laboratory tests for infective endocarditis is non-specific, showing raised inflammatory markers and normocytic–normochromic anemia. ¹⁰³ Our systematic review revealed that patients with infective endocarditis by Gemella spp. have anemia, leukocytosis, and elevated erythrocyte sedimentation rate in all age groups, while the adult and geriatric populations have an elevation in C-reactive protein. Diagnostic studies commonly showed mitral valve vegetation in the pediatric and geriatric population, and aortic valve vegetation in the adult age group. Gemella haemolysans, bergeriae, and sanguinis were mainly found on aortic valves, whereas Gemella morbillorum and taiwanensis were discovered predominantly on mitral valves.

We revealed that the most common Gemella-susceptible antibiotics were penicillin, vancomycin, cephalosporin, macrolide, and aminoglycosides. However, antibiotic resistance was observed against penicillin, aminoglycoside, and fluoroquinolone. This management is similar current approach to patients with uncomplicated community-acquired native valve or late prosthetic valve endocarditis by to highly sensitive streptococci, where combination therapy with a beta-lactam antibiotic and aminoglycoside is used. ¹⁰⁴ Finally, we revealed patients that received treatment course for at least 6 weeks or greater showed greater clinical improvement than patients who received antibiotic therapy for less than 6 weeks. This result indicates that special attention should be placed on duration of treatment for future, and we urge more research on that matter.

1 in 2 cases in the systematic review underwent either valve replacement or repair. The primary objectives of surgery are total removal of infected tissues and reconstruction of cardiac morphology. Typically, surgery is undertaken in 40–50% of patients with infective endocarditis. ¹⁰⁵ In mitral valve infective endocarditis, successful valve repair is achieved in up to 80% of patients. ¹⁰⁶

Finally, patients with infective endocarditis by Gemella spp. commonly suffered complication following treatment affected the cardiovascular, neurological, and renal systems. Death occurred in 1 in 8 patients, half of which occurred post-surgical procedure, with the majority occurring equal to or greater than 1 week from admission. This is similar to in-hospital mortality of infective endocarditis, which is estimated at 20% and increases to 25-30% at 6 months. ^{106, 107}

Although the strength of the study is the extensive review of infective endocarditis with Gemella spp, data were limited with regards to recurrent infections

In conclusions, infective endocarditis by Gemella spp. is more likely to infect men ages 31 to 45 years with a history of congenital heart disease, recent oral infection, or surgical procedures, such as heart valve replacement or dental repairs. Laboratory tests will likely indicate anemia, leukocytosis, and elevated erythrocyte sedimentation rate, while diagnostic studies will commonly show mitral or aortic valve vegetation, which is dependent of population or Gemella species. Infective endocarditis by Gemella spp. is managed by empiric treatment with beta-lactam and aminoglycosides combination therapy for at least 6 weeks in duration, or valve replacement or repair, with death occurring in 1 in 8 patients. Therefore, our systematic review highlights the importance of considering rare pathogens, particularly in the presence of predisposing risk factors.

References