An Emerging Threat: A Systematic Review of Endocarditis Caused by Gemella Species

Infective endocarditis caused by Gemella species is increasingly recognized as an emerging clinical entity. Gemella species are fastidious gram-positive cocci that are typically commensal organisms but can become opportunistic pathogens. This systematic review aimed to provide a comprehensive overview of endocarditis due to Gemella species by synthesizing existing evidence. A total of 52 case reports were identified through a rigorous search and selection process. The most prevalent causative species were G. morbillorum (46.3%) and G. haemolysans (25.9%), with a striking male predominance (79.6%). The clinical presentation was largely nonspecific, mirroring typical infective endocarditis. However, the indolent nature of the illness and fastidious growth requirements of Gemella species often led to diagnostic delays. Echocardiography, particularly transesophageal echocardiography, played a crucial role in the diagnosis, enabling the detection of valvular vegetation and the assessment of complications. Management posed significant challenges, including the need for broad-spectrum empirical antibiotic therapy and increasing antimicrobial resistance among Gemella isolates. Surgical intervention was frequently required for severe valvular dysfunction, persistent infection, or embolic complications. Despite advances in diagnosis and treatment, endocarditis due to Gemella species remains associated with significant morbidity and mortality, underscoring the importance of early recognition and multidisciplinary management. This review highlights the emerging clinical significance of Gemella species as causative agents of infective endocarditis and identifies areas for further research.


Introduction And Background
Infective endocarditis (IE) is a serious and potentially life-threatening condition characterized by microbial infection of the endocardium, most commonly affecting the heart valves [1].Historically, IE has been predominantly associated with well-known pathogens such as Streptococcus and Staphylococcus species [2].However, there is growing recognition of the role of fastidious bacteria in the etiology of this condition.Among these fastidious organisms, Gemella species have emerged as noteworthy contributors to infective endocarditis [3][4][5][6][7].Gemella species belong to the genus Gemella, a group of gram-positive cocci that are facultative anaerobes.These organisms are part of the normal flora of humans [8].While they typically exist as commensals, Gemella species possess virulence factors that enable them to cause disease under certain conditions.In recent years, Gemella species, including G. haemolysans, G. morbillorum, and G. sanguinis, have been increasingly implicated in cases of infective endocarditis, highlighting the importance of understanding their role in this clinical context.
Endocarditis due to Gemella species presents several unique challenges compared to endocarditis caused by more commonly recognized pathogens.The clinical presentation of endocarditis due to Gemella species often mirrors that of typical IE, with symptoms such as fever, malaise, new-onset murmurs, and signs of systemic embolization.However, the nonspecific nature of these symptoms can complicate diagnosis, leading to delays in appropriate management [9].Furthermore, Gemella species are known for their fastidious growth requirements, making their isolation and identification challenging in routine microbiological cultures.The diagnosis of endocarditis due to Gemella species relies on a combination of clinical evaluation, echocardiography, and microbiological studies.Echocardiography, including transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE), plays a crucial role in detecting valvular vegetation, assessing valvular function, and identifying complications such as abscess formation or valvular regurgitation.Microbiological confirmation of endocarditis due to Gemella species is often based on peripheral blood culture [9].
The management of endocarditis due to Gemella species poses several therapeutic challenges.Empirical antibiotic therapy must be carefully chosen to cover the spectrum of potential pathogens, including fastidious organisms like Gemella species.However, the increasing prevalence of antimicrobial resistance among Gemella isolates underscores the importance of tailored antibiotic regimens based on susceptibility testing and clinical response [10].Surgical intervention, such as valve repair or replacement, may be necessary in cases of severe valvular dysfunction, persistent infection, or embolic complications.Despite advances in diagnostic techniques and treatment modalities, endocarditis due to Gemella species remains associated with significant morbidity and mortality.Therefore, there is a critical need for enhanced awareness, early recognition, and multidisciplinary management of this condition.This systematic review aims to provide a comprehensive overview of Gemella-associated endocarditis, including its clinical presentation, diagnostic approach, treatment strategies, and outcomes.By synthesizing existing evidence and identifying areas for further research, this review seeks to inform clinical practice, guide therapeutic decision-making, and improve patient outcomes in the management of endocarditis due to Gemella species.

Search Strategy
This systematic review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure transparency and rigor in the review process.A comprehensive search of relevant literature was conducted across prominent databases renowned for their extensive coverage of medical and scientific literature, including PubMed, Embase, Web of Science, and Scopus.These databases were selected for their comprehensive collection of peer-reviewed articles, providing a robust foundation for our systematic review of endocarditis caused by Gemella species.The search strategy employed a meticulously curated set of keywords and phrases aligned with the objectives of the study.These included terms such as "Gemella" and "Endocarditis".Boolean operators "AND" and "OR" were strategically utilized to construct the search algorithm.For instance, the string "Gemella AND Endocarditis" focused specifically on studies addressing endocarditis caused by Gemella species, while the use of "OR" facilitated the inclusion of broader terms associated with the topic.To ensure the inclusion of contemporary and relevant literature, the search was limited to studies published from the inception of each database to January 2024.This timeframe allowed for the incorporation of both historical and current research, offering a comprehensive overview of endocarditis caused by Gemella species.Filters were applied to include studies published in the English language and those involving human subjects, in line with the objectives of our review.Additionally, manual searches of the reference lists of included studies and relevant reviews were conducted to supplement the electronic database search.

Eligibility Criteria
The eligibility criteria for this systematic review were established to ensure precision and relevance in selecting studies for inclusion.Peer-reviewed research articles, observational studies, case reports, and clinical trials were considered eligible for inclusion, reflecting a commitment to evidence-based knowledge.To maintain methodological rigor, only studies published in the English language were included, acknowledging English as the predominant language of scientific communication.The inclusion timeframe spanned from the inception of the respective databases to the present date, allowing for the synthesis of contemporary research on endocarditis caused by Gemella species.Conversely, exclusion criteria were carefully tailored to maintain focus and rigor.Studies not directly addressing endocarditis caused by Gemella species, as well as those lacking relevant outcome measures, were excluded.Non-English language publications, unpublished works, and gray literature such as conference abstracts were also excluded.Furthermore, studies presenting insufficient data on endocarditis caused by Gemella species were excluded to ensure the integrity of the review's findings.

Data Extraction
The data extraction process was conducted in a meticulous and structured manner to ensure the accuracy and completeness of the review findings.This process involved two stages, emphasizing thoroughness and reliability.In the initial stage, articles were screened based on the relevance indicated by titles and abstracts.Two independent reviewers assessed each article's abstract to determine its relevance to the review's focus.Articles deemed relevant or probably relevant underwent a detailed examination in the second stage.In the second stage, full-text articles meeting the inclusion criteria underwent a detailed data extraction process.Two independent reviewers utilized a standardized data extraction template within Microsoft Excel to capture and organize critical information from each study.Any discrepancies between reviewers were resolved through the adjudication of a third independent reviewer.

Study Selection Process
A comprehensive search initially yielded 191 studies, from which duplicates were removed, resulting in a 2024 Gonzalez et al.Cureus 16(4): e58802.DOI 10.7759/cureus.58802refined pool of 163 unique studies.Subsequent screening of titles and abstracts led to the exclusion of 96 records that did not meet predefined relevance criteria.Full-text evaluation of the remaining 67 articles resulted in the exclusion of 15 reports that did not align with stringent inclusion criteria.The culmination of this rigorous selection process identified 52 studies suitable for inclusion in the systematic review, providing a focused and robust source of evidence for the analysis of endocarditis caused by Gemella species.The PRISMA flowchart detailing the study selection process is presented below (Figure 1).

Study Characteristics
This systematic review included a total of 52 case reports on endocarditis caused by Gemella species.Among the reported cases, 43 (79.6%) were male, while 10 (18.5%) were female, indicating a male predominance.Patient ages ranged from 4 to 87 years, with a mean age of 48 years.The most prevalent causative species were G. morbillorum in 25 (46.3%)cases and G. haemolysans in 14 (25.9%)cases, followed by G. sanguinis in 7 (13%) cases and G. bergeri in 4 (74%) cases.There was one case each of infection by both G. haemolysans and G. morbillorum.In terms of valve involvement, isolated mitral and aortic valves were found to have the same incidence of involvement, with 15 (43.4%) cases each.Isolated tricuspid valve was involved in 3 (5.5%)cases.In 10 (18.5%) cases, bivalvular (aortic and mitral) involvement was observed, followed by trivalvular (mitral, pulmonary, and aortic) and panvalvular involvement in 1 case each.In prosthetic valve endocarditis, the prosthetic aortic valve (9.2%) was more commonly involved followed by the prosthetic mitral valve (1.8%).These findings underscore the diversity of Gemella species implicated in endocarditis and the variability in valve involvement among affected individuals (Table 1).The main findings of the included case reports are summarized in Table 2.

Discussion
This systematic review aimed to provide a comprehensive overview of infective endocarditis caused by Gemella species, a group of fastidious gram-positive cocci that are typically commensal organisms but can be opportunistic pathogens.The findings of this review underscore the emerging recognition of Gemella species as causative agents of endocarditis, a condition that has been historically associated with more commonly known pathogens.The review identified 52 case reports of endocarditis due to Gemella species, highlighting the diversity of Gemella species implicated, with G. morbillorum (46.3%) and G. haemolysans (25.9%) being the most prevalent species.The male predominance (79.6%) observed in these cases aligns with the general epidemiological pattern of infective endocarditis, although the underlying reasons for this predilection warrant further investigation [57,58].
The clinical presentation of endocarditis due to Gemella species varies widely, ranging from nonspecific symptoms such as fever, malaise, and fatigue to more specific manifestations like myalgia, dyspnea, and focal neurological deficits [3,5,9,30,45].Additionally, predisposing factors such as dental procedures, congenital heart disease, and immunocompromised states were frequently noted among the patients [5,12,27,42].However, the indolent and insidious nature of the illness, coupled with the fastidious growth requirements of Gemella species, often led to delays in diagnosis and appropriate management [9].This underscores the importance of maintaining a high index of suspicion, particularly in patients with predisposing risk factors or persistent unexplained clinical manifestations.Diagnostic modalities, primarily echocardiography and blood cultures, played crucial roles in confirming the diagnosis of endocarditis and identifying the causative organism.Echocardiography, particularly TEE, enabled the detection of valvular vegetations, assessment of valvular function, and identification of complications.Blood cultures were instrumental in isolating Gemella species, facilitating targeted antibiotic therapy.The review revealed a wide range of valve involvement, with both native and prosthetic valves being affected, further emphasizing the need for thorough evaluation in suspected cases.
The management of endocarditis due to Gemella species posed several challenges.Empirical antibiotic regimens typically included broad-spectrum agents such as penicillin and gentamicin followed by tailored regimens based on susceptibility testing and clinical response [4,45,48,53].The review highlighted the increasing prevalence of antimicrobial resistance among Gemella isolates, underscoring the importance of judicious antibiotic use and the potential need for combination therapy or alternative treatment strategies.Surgical intervention, including valve replacement or repair, was pursued in cases of severe valvular damage, persistent infection, or complications such as abscess formation and embolic events [3,50].Overall outcomes were generally favorable, with most patients showing clinical improvement and resolution of infection following appropriate medical and/or surgical management.However, a small proportion of cases experienced complications or succumbed to the illness, underscoring the importance of timely diagnosis and comprehensive treatment.
This systematic review has several strengths, including the comprehensive search strategy, rigorous study selection process, and detailed data extraction.However, it is essential to acknowledge the limitations inherent in the inclusion of case reports, which may introduce potential selection bias and limit the generalizability of the findings.Additionally, the heterogeneity in reporting and variability in clinical management approaches across the included cases may have influenced the interpretation of the results.

Conclusions
This systematic review highlights the emerging role of Gemella species as causative agents of infective endocarditis, a condition with significant morbidity and mortality.The findings underscore the importance of maintaining a high index of suspicion, particularly in patients with predisposing risk factors or persistent, unexplained clinical manifestations.Prompt diagnosis, tailored antimicrobial therapy, and timely surgical intervention, when indicated, are crucial for optimal patient outcomes.Future research should focus on elucidating the virulence mechanisms of Gemella species, identifying risk factors for infection, and developing evidence-based guidelines for the management of endocarditis due to Gemella species.

4 weeks
of the posterior leaflet of the mitral valve with a small mass IV Benzyl penicillin and gentamicin daily.After 2 weeks, the penicillin was replaced by oral amoxicillin Following cessation of antibiotics, he continued 2024 Gonzalez et al.Cureus 16(4): e58802.DOI 10.7759/cureus.58802Brack et al. [11] 1991 rigors, cultures were positive for G. morbillorum.Altered complete blood count profile He was started on benzylpenicillin 1.2 g IV 4 hourly and gentamicin 80 mg IV 12 hourly.After further cultures were taken, he was given teicoplanin.Then he was given IV hydrocortisone, chlorpheniramine, and salbutamol.Then he was given rifampicin 600 mg orally 12 hourly and erythromycin 500 mg orally 6 hourly due to their sensitivity report and the side effects of previous medications The patient received a total of four weeks of treatment and made a good recovery.He remains well six months later Ukimura et al. fever, loss of weight, and anorexia.Patient 02: intermittent fever, sweating, loss of weight, and basithoracic pain.Patient 03: intermittent fever and a weight loss (01) Altered CBC Report.Blood cultures were positive for G. haemolysans.A transesophageal echocardiogram demonstrated the presence of vegetation on the mitral valve with moderate mitral valve regurgitation.(02) Deranged CBC Report.Blood cultures were positive for Gmella morbillorum.A transesophageal echocardiogram demonstrated aortic valve incompetence but failed to show (01) Treatment with amoxicillin (4 g intravenously at 6-h intervals) and amikacin (5 mg/kg of body weight intravenously at 8-h intervals) was begun.His condition improved rapidly, and after 2 weeks of this regimen, he underwent cardiac surgery to remove the motile vegetation.(02) The patient's treatment began the day after his admission and comprised amoxicillin (4 g (01) One week after surgery antibiotic therapy was discontinued.After 2 years of follow-up, he remains well.(02) Gentamicin was discontinued 1 week later, and amoxicillin was discontinued 3 weeks 2024 Gonzalez et al.Cureus 16(4): e58802.DOI 10.7759/cureus.588026 of 15 of 12 kg over a period of several months any vegetation.(03) Blood cultures were positive for Gemella morbillorum.A transesophageal echocardiogram demonstrated aortic valve vegetation intravenously at 6-hour intervals) and gentamicin (1 mg/kg intravenously at 8-hour intervals).The aortic valve was successfully replaced with a prosthetic device.(03) N/A later.After 1 year of follow-up, he remains well.(03) N/A Mosquera et al. on the aortic valve with moderate valvular insufficiency.G. haemolysans was isolated in the three blood cultures taken on admission The patient was treated with penicillin G (24 MU IV daily, divided into six doses) and tobramycin (100 mg twice a day IV) for 2 weeks The patient showed improvement in his clinical status as well as sterilization of the blood cultures.In a follow-up visit 30 days after discharge, the echocardiogram did not show any vegetation Akiyama et al. [19] 2001 A 55-year-old man with persistent fever and nocturnal dyspnea was referred to hospital.He had a history of noninsulin-dependent diabetes mellitus and type B hepatitis Echocardiography demonstrated massive aortic regurgitation with a vegetation-like high-density echo on the right coronary cusp and moderate mitral regurgitation, but the tricuspid and pulmonary valves did not show any abnormality The patient was treated surgically.Postoperatively, the patient was given IV tobramycin (120 mg/day), cefmetazole sodium (3 g/day), and fosfomycin (3 g/day) for a 6-week period, which resulted in a year-old Western European man visiting Canada, with a known history of asthma, 2024 Gonzalez et al.Cureus 16(4): e58802.DOI 10.7759/cureus.andmitral valves with thickening of the mitral valve, and culture positive for G. morbillorum , and procalcitonin.Increased spleen size at USG and CT abdomen.Left occipital lobe infarction on cerebral MRI.TTE revealed aortic valve vegetation.a Leukocytosis, anemia, elevated CRP, fibrinogen and D-dimer, and hypoalbuminemia were found.TTE showed aortic stenosis and aortic regurgitation with suspected Treatment was started with moxifloxacin and ceftriaxone.Switched after 1 day to vancomycin and gentamicin.Shortly thereafter, was adjusted to He continued to receive IV penicillin treatment for 6 weeks and was discharged with a stable 2024 Gonzalez et al.Cureus 16(4): e58802.DOI 10.7759/cureus.cuspswith vegetations causing severe aortic regurgitation.The anterior leaflet of the mitral valve thickened with multiple vegetations and mild mitral regurgitation.The left atrium and left ventricle dilated.Blood cultures positive for G. bergeri Started empirically on IV ceftriaxone and gentamicin.Later, GCS dropped to 8/15 and CT revealed right frontotemporoparietal intra-axial hematoma for which right-sided decompression craniotomy and insertion of intracerebral pressure monitoring catheter was done.He then received all brain protective measures as per ICU protocol for high ICP.Based on the susceptibility test of the organism, appetite, weakness, fatigue, marked weight loss, arthralgias after the dental procedure TTE and TEE revealed a bicuspid aortic valve with vegetation on the posterior leaflet, moderate to severe aortic regurgitation Empiric IV ceftriaxone, gentamicin, and daptomycin initially, then ceftriaxone for 6 weeks and gentamicin for 2 weeks.Aortic valve replacement after 6 weeks Successful treatment with valve replacement 2024 Gonzalez et al.Cureus 16(4): e58802.DOI 10.7759/cureus.withfatigue, malaise, and acute dyspnea TTE is consistent with aortic valve vegetation.Panorex and TTE revealed no dental abscess.Blood cultures positive for G. haemolysans Vancomycin and cefepime, then penicillin G with gentamycin for